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900 | 15,322,675 | 1,615 |
The present invention relates to an anhydrous composition comprising:
from 3% to 15% by weight of at least one lipophilic gelling agent; from 10% to 50% by weight of fillers including at least 5% by weight of a first filler and at least 5% by weight of a second filler different from the first; and from 40% to 85% by weight of at least one fatty phase; the weight amounts being given relative to the total weight of the composition.
The composition in accordance with the invention affords comfortable anhydrous care with a soft-focus effect, i.e. it can render the skin microrelief matt and/or optically smooth, fill wrinkles, hide skin imperfections and better reflect light, while at the same time giving a pleasant feel and a novel sensory effect, that of oily care that is not greasy or tacky, with powdery transformation especially when it is applied, and with a velvety skin finish, and which allows the skin to breathe.
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1. An anhydrous composition comprising: based on a total weight of the composition,
from 3% to 15% by weight of at least one lipophilic gelling agent; from 10% to 50% by weight of fillers including at least 5% by weight of a first filler and at least 5% by weight of a second filler different from the first; and from 40% to 85% by weight of at least one fatty phase; wherein the first filler and the second filler being chosen are selected from the group consisting of spherical cellulose particles, powders of an N-acylamino acid comprising a C8-C22 acyl group, polyamide particles, and spherical porous silica particles. 2. The composition of claim 1, wherein the at least one lipophilic gelling agent is selected from the group consisting of a fatty acid ester of dextrin and a fatty acid of a triester of a C8-C30 fatty acid and of mono- or polyglycerol. 3. The composition of claim 2, wherein the at least one lipophilic gelling agent is the fatty acid ester of dextrin, which is a mono- or polyester of dextrin and of at least one fatty acid of formula (C):
where:
n is an integer ranging from 3 to 150;
R1, R2 and R3 each independently represent a hydrogen atom or an acyl group (R—CO—) in which the radical R is a linear or branched, saturated or unsaturated hydrocarbon-based group containing from 6 to 50 carbon atoms, with the proviso that at least one of R1, R2 and R3 is not a hydrogen atom. 4. The composition of claim 3, wherein the fatty acid ester of dextrin is a compound of formula (C) where:
n ranges from 25 to 35; R—CO— is chosen selected from the group consisting of caprylyl, caproyl, lauroyl, myristyl, palmityl, stearyl, eicosanyl, docosanoyl, isovaleryl, 2-ethylbutyryl, ethylmethylacetyl, isoheptanyl, 2-ethylhexanyl, isononanyl, isodecanyl, isotridecanyl, isomyristyl, isopalmityl, isostearyl, isohexanyl, decenyl, dodecenyl, tetradecenyl, myristyl, hexadecenoyl, palmitolyl, oleyl, elaidyl, eicosenyl, sorbyl, linoleyl, linolenyl, punicyl, arachidonyl, stearolyl, and a mixture thereof. 5. The composition of claim 2, wherein the at least one lipophilic gelling agent is the fatty acid of the triester of a C8-C30 fatty acid and of mono- or polyglycerol, which is a linear or branched, saturated or unsaturated acid comprising from 10 to 24 carbon atoms and
unsubstituted or substituted with one or more hydroxyl groups. 6. The composition of claim 5, in which the triester of a C8-C30 fatty acid and of mono- or polyglycerol is a triester of a C8-C30 fatty acid and of monoglycerol. 7. The composition of claim 1, wherein the first filler and the second filler are selected from the group consisting of spherical cellulose particles, powders of an N-acylamino acid comprising a C8-C22 acyl group, and spherical porous silica particles. 8. The composition of claim 1, wherein the first or the second filler is the powder of an N-acylamino acid comprising a C8-C22 acyl group, which is lauroyl lysine. 9. The composition of claim 1, wherein the first or the second filler is the spherical porous silica particles, which are spherical porous silica microparticles. 10. The composition of claim 1, comprising at least two different fillers selected from the group consisting of spherical cellulose particles and powders of an N-acylamino acid comprising a C8-C22 acyl group. 11. The composition of claim 1, comprising at least two different fillers, one of which is spherical cellulose particles, powders of an N-acylamino acid comprising a C8-C22 acyl group, or polyamide particles, and the other is spherical porous silica particles. 12. The composition of claim 1, comprising at least two different fillers, one of which is spherical cellulose particles and the other is spherical porous silica particles. 13. The composition of claim 1, comprising at least two different fillers, one of which is powders of an N-acylamino acid comprising a C8-C22 acyl group, and the other is spherical porous silica particles. 14. The composition of claim 1, comprising at least three fillers that are different from each other, one of which is spherical porous silica particles, and the other two are selected from the group consisting of spherical cellulose particles, powders of an N-acylamino acid comprising a C8-C22 acyl group, and polyamide particles. 15. The composition of claim 1, comprising at least one filler which is spherical porous silica particles, and a mass ratio R of silica/fillers other than silica is greater than or equal to 0.75. 16. The composition of claim 1, wherein the at least one fatty phase comprises at least one oil. 17. The composition of claim 16, comprising from 15% to 85% by weight of at least one oil selected from the group consisting of a hydrocarbon-based oil of plant origin, a Guerbet alcohol, and an ester of a C8-C30 fatty acid and of a Guerbet alcohol, and optionally from 5% to 25% by weight of at least one oil which is a linear C7-C17 alkane. 18. The composition of claim 1, comprising:
from 3% to 15% by weight of the at least one lipophilic gelling agent, which is a fatty acid ester of dextrin; from 10% to 50% by weight of fillers including at least 5% by weight of spherical porous silica microparticles and at least 5% by weight of powders of an N-acylamino acid comprising a C8-C22 acyl group, a mass ratio R of silica/N-acylamino acid comprising a C8-C22 acyl group being greater than or equal to 0.75; and from 40% to 85% by weight of the at least one fatty phase comprising from 25% to 48% by weight of at least one hydrocarbon-based oil of plant origin. 19. The composition of claim 1, comprising:
from 3% to 15% by weight of the at least one lipophilic gelling agent, which is a fatty acid ester of dextrin; from 10% to 50% by weight of fillers including at least 5% by weight of spherical porous silica microparticles and at least 5% by weight of powders of an N-acylamino acid comprising a C8-C22 acyl group, a mass ratio R of silica/N-acylamino acid comprising a C8-C22 acyl group being greater than or equal to 0.75; and from 40% to 85% by weight of the at least one fatty phase comprising from 25% to 48% by weight of at least one hydrocarbon-based oil of plant origin and from 5% to 25% by weight of at least one linear C7-C17 alkane. 20. The composition of claim 1, comprising:
from 3% to 15% by weight of the at least one lipophilic gelling agent, which is a fatty acid ester of dextrin; from 10% to 50% by weight of fillers including at least 5% by weight of spherical porous silica microparticles and at least 5% by weight of spherical cellulose particles, a mass ratio R of silica/cellulose being greater than or equal to 0.75; and from 40% to 85% by weight of the at least one fatty phase comprising from 25% to 70% by weight of at least one oil selected from the group consisting of a Guerbet alcohol and an ester of a C8-C30 fatty acid and of a Guerbet alcohol. 21. The composition of claim 1, comprising:
from 3% to 15% by weight of the at least one lipophilic gelling agent, which is a triester of a C8-C30 fatty acid and of mono- or polyglycerol; from 10% to 50% by weight of fillers including at least 5% by weight of spherical porous silica microparticles and at least 5% by weight of spherical cellulose particles, a mass ratio R of silica/cellulose being greater than or equal to 0.75; and from 40% to 85% by weight of the at least one fatty phase comprising from 25% to 48% by weight of at least one hydrocarbon-based oil of plant origin and from 5% to 25% by weight of at least one linear C7-C17 alkane. 22. A cosmetic process for treating a keratin material, the process comprising: applying the composition of claim 1 to the keratin material. 23. An aqueous dispersion composition, comprising at least one composition of claim 1 in an aqueous phase.
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The present invention relates to an anhydrous composition comprising:
from 3% to 15% by weight of at least one lipophilic gelling agent; from 10% to 50% by weight of fillers including at least 5% by weight of a first filler and at least 5% by weight of a second filler different from the first; and from 40% to 85% by weight of at least one fatty phase; the weight amounts being given relative to the total weight of the composition.
The composition in accordance with the invention affords comfortable anhydrous care with a soft-focus effect, i.e. it can render the skin microrelief matt and/or optically smooth, fill wrinkles, hide skin imperfections and better reflect light, while at the same time giving a pleasant feel and a novel sensory effect, that of oily care that is not greasy or tacky, with powdery transformation especially when it is applied, and with a velvety skin finish, and which allows the skin to breathe.1. An anhydrous composition comprising: based on a total weight of the composition,
from 3% to 15% by weight of at least one lipophilic gelling agent; from 10% to 50% by weight of fillers including at least 5% by weight of a first filler and at least 5% by weight of a second filler different from the first; and from 40% to 85% by weight of at least one fatty phase; wherein the first filler and the second filler being chosen are selected from the group consisting of spherical cellulose particles, powders of an N-acylamino acid comprising a C8-C22 acyl group, polyamide particles, and spherical porous silica particles. 2. The composition of claim 1, wherein the at least one lipophilic gelling agent is selected from the group consisting of a fatty acid ester of dextrin and a fatty acid of a triester of a C8-C30 fatty acid and of mono- or polyglycerol. 3. The composition of claim 2, wherein the at least one lipophilic gelling agent is the fatty acid ester of dextrin, which is a mono- or polyester of dextrin and of at least one fatty acid of formula (C):
where:
n is an integer ranging from 3 to 150;
R1, R2 and R3 each independently represent a hydrogen atom or an acyl group (R—CO—) in which the radical R is a linear or branched, saturated or unsaturated hydrocarbon-based group containing from 6 to 50 carbon atoms, with the proviso that at least one of R1, R2 and R3 is not a hydrogen atom. 4. The composition of claim 3, wherein the fatty acid ester of dextrin is a compound of formula (C) where:
n ranges from 25 to 35; R—CO— is chosen selected from the group consisting of caprylyl, caproyl, lauroyl, myristyl, palmityl, stearyl, eicosanyl, docosanoyl, isovaleryl, 2-ethylbutyryl, ethylmethylacetyl, isoheptanyl, 2-ethylhexanyl, isononanyl, isodecanyl, isotridecanyl, isomyristyl, isopalmityl, isostearyl, isohexanyl, decenyl, dodecenyl, tetradecenyl, myristyl, hexadecenoyl, palmitolyl, oleyl, elaidyl, eicosenyl, sorbyl, linoleyl, linolenyl, punicyl, arachidonyl, stearolyl, and a mixture thereof. 5. The composition of claim 2, wherein the at least one lipophilic gelling agent is the fatty acid of the triester of a C8-C30 fatty acid and of mono- or polyglycerol, which is a linear or branched, saturated or unsaturated acid comprising from 10 to 24 carbon atoms and
unsubstituted or substituted with one or more hydroxyl groups. 6. The composition of claim 5, in which the triester of a C8-C30 fatty acid and of mono- or polyglycerol is a triester of a C8-C30 fatty acid and of monoglycerol. 7. The composition of claim 1, wherein the first filler and the second filler are selected from the group consisting of spherical cellulose particles, powders of an N-acylamino acid comprising a C8-C22 acyl group, and spherical porous silica particles. 8. The composition of claim 1, wherein the first or the second filler is the powder of an N-acylamino acid comprising a C8-C22 acyl group, which is lauroyl lysine. 9. The composition of claim 1, wherein the first or the second filler is the spherical porous silica particles, which are spherical porous silica microparticles. 10. The composition of claim 1, comprising at least two different fillers selected from the group consisting of spherical cellulose particles and powders of an N-acylamino acid comprising a C8-C22 acyl group. 11. The composition of claim 1, comprising at least two different fillers, one of which is spherical cellulose particles, powders of an N-acylamino acid comprising a C8-C22 acyl group, or polyamide particles, and the other is spherical porous silica particles. 12. The composition of claim 1, comprising at least two different fillers, one of which is spherical cellulose particles and the other is spherical porous silica particles. 13. The composition of claim 1, comprising at least two different fillers, one of which is powders of an N-acylamino acid comprising a C8-C22 acyl group, and the other is spherical porous silica particles. 14. The composition of claim 1, comprising at least three fillers that are different from each other, one of which is spherical porous silica particles, and the other two are selected from the group consisting of spherical cellulose particles, powders of an N-acylamino acid comprising a C8-C22 acyl group, and polyamide particles. 15. The composition of claim 1, comprising at least one filler which is spherical porous silica particles, and a mass ratio R of silica/fillers other than silica is greater than or equal to 0.75. 16. The composition of claim 1, wherein the at least one fatty phase comprises at least one oil. 17. The composition of claim 16, comprising from 15% to 85% by weight of at least one oil selected from the group consisting of a hydrocarbon-based oil of plant origin, a Guerbet alcohol, and an ester of a C8-C30 fatty acid and of a Guerbet alcohol, and optionally from 5% to 25% by weight of at least one oil which is a linear C7-C17 alkane. 18. The composition of claim 1, comprising:
from 3% to 15% by weight of the at least one lipophilic gelling agent, which is a fatty acid ester of dextrin; from 10% to 50% by weight of fillers including at least 5% by weight of spherical porous silica microparticles and at least 5% by weight of powders of an N-acylamino acid comprising a C8-C22 acyl group, a mass ratio R of silica/N-acylamino acid comprising a C8-C22 acyl group being greater than or equal to 0.75; and from 40% to 85% by weight of the at least one fatty phase comprising from 25% to 48% by weight of at least one hydrocarbon-based oil of plant origin. 19. The composition of claim 1, comprising:
from 3% to 15% by weight of the at least one lipophilic gelling agent, which is a fatty acid ester of dextrin; from 10% to 50% by weight of fillers including at least 5% by weight of spherical porous silica microparticles and at least 5% by weight of powders of an N-acylamino acid comprising a C8-C22 acyl group, a mass ratio R of silica/N-acylamino acid comprising a C8-C22 acyl group being greater than or equal to 0.75; and from 40% to 85% by weight of the at least one fatty phase comprising from 25% to 48% by weight of at least one hydrocarbon-based oil of plant origin and from 5% to 25% by weight of at least one linear C7-C17 alkane. 20. The composition of claim 1, comprising:
from 3% to 15% by weight of the at least one lipophilic gelling agent, which is a fatty acid ester of dextrin; from 10% to 50% by weight of fillers including at least 5% by weight of spherical porous silica microparticles and at least 5% by weight of spherical cellulose particles, a mass ratio R of silica/cellulose being greater than or equal to 0.75; and from 40% to 85% by weight of the at least one fatty phase comprising from 25% to 70% by weight of at least one oil selected from the group consisting of a Guerbet alcohol and an ester of a C8-C30 fatty acid and of a Guerbet alcohol. 21. The composition of claim 1, comprising:
from 3% to 15% by weight of the at least one lipophilic gelling agent, which is a triester of a C8-C30 fatty acid and of mono- or polyglycerol; from 10% to 50% by weight of fillers including at least 5% by weight of spherical porous silica microparticles and at least 5% by weight of spherical cellulose particles, a mass ratio R of silica/cellulose being greater than or equal to 0.75; and from 40% to 85% by weight of the at least one fatty phase comprising from 25% to 48% by weight of at least one hydrocarbon-based oil of plant origin and from 5% to 25% by weight of at least one linear C7-C17 alkane. 22. A cosmetic process for treating a keratin material, the process comprising: applying the composition of claim 1 to the keratin material. 23. An aqueous dispersion composition, comprising at least one composition of claim 1 in an aqueous phase.
| 1,600 |
901 | 15,383,211 | 1,627 |
Pharmaceutical compositions for treating, mitigating or preventing kidney stone disease, bladder stone disease or ureter stone disease are described, the compositions comprising a reducing agent capable of undergoing thiol-disulfide exchange with cystine to form a mixed disulfide and a citrate of an alkali metal or alkaline earth metal. Methods for fabricating the compositions and using them are also described.
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1. A pharmaceutical composition for treating, mitigating or preventing kidney stone disease, bladder stone disease or ureter stone disease, the composition comprising:
(a) a therapeutically effective quantity of a first component, wherein the first component comprises at least one pharmaceutically acceptable reducing agent capable of undergoing thiol-disulfide exchange with cystine to form a mixed disulfide; and (b) a therapeutically effective quantity of a second component, wherein the second component comprises a therapeutically effective quantity of at least one urine alkanizing agent selected from the group consisting of alkali metal salts of citric acid, alkaline-earth metal salts of citric acid, and sodium bicarbonate, wherein the first component and the second component form a homogeneous mixture. 2. The composition of claim 1, wherein the reducing agent comprises a thiol moiety and an amino acid moiety. 3. The composition of claim 2, wherein the amino acid is glycine. 4. The composition of claim 1, wherein the reducing agent is selected from the group consisting of tiopronin, penicilamine, and captopril. 5. The composition of claim 4, wherein the reducing agent is tiopronin. 6. The composition of claim 1, wherein the alkali or alkaline-earth metal salts of citric acid are selected from the group consisting of potassium citrate, sodium citrate, and magnesium citrate. 7. The composition of claim 6, wherein the urine alkanizing agent is potassium citrate. 8. The composition of claim 1, wherein the composition is in a form selected from the group consisting of a pill, a tablet, powder, a capsule, and a troche. 9. The composition of claim 1, further comprising a third component, wherein the third component provides the composition with a delayed release feature. 10. The composition of claim 9, wherein the third component is hydroxypropyl methylcellulose. 11. A method for treating, mitigating or preventing kidney stone disease, bladder stone disease or ureter stone disease, comprising administering to a patient in need thereof the pharmaceutical composition of claim 1, thereby treating, mitigating or preventing kidney stone disease, bladder stone disease or ureter stone disease. 12. The method of claim 11, wherein the reducing agent comprises a thiol moiety and an amino acid moiety. 13. The method of claim 12, wherein the amino acid is glycine. 14. The method of claim 11, wherein the reducing agent is selected from the group consisting of tiopronin, penicilamine, and captopril. 15. The method of claim 14, wherein the reducing agent is tiopronin. 16. The method of claim 11, wherein the alkali or alkaline-earth metal salts of citric acid are selected from the group consisting of potassium citrate, sodium citrate, and magnesium citrate. 17. The method of claim 16, wherein the urine alkanizing agent is potassium citrate. 18. The method of claim 11, wherein the composition is in a form selected from the group consisting of a pill, a tablet, powder, a capsule, and a troche. 19. The method of claim 11, wherein the disease is cystinuria. 20. A pharmaceutical article of manufacture, comprising the composition of claim 1, and further comprising:
(a) a first element, comprising the first component; and (b) a second element, comprising the second component, wherein the first element is completely ensconced within the second element, with the further provisos that (1) the first element is a solid structure optionally coated with a pharmaceutically suitable coating or the first element comprises an optionally acid resistant first solid shell defining a first space therein; and (2) the second element is a solid structure optionally coated with a pharmaceutically suitable coating, or the second element comprises an optionally acid resistant second solid shell, and the first element and the second element define the second space therebetween, wherein the second space contains the second component.
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Pharmaceutical compositions for treating, mitigating or preventing kidney stone disease, bladder stone disease or ureter stone disease are described, the compositions comprising a reducing agent capable of undergoing thiol-disulfide exchange with cystine to form a mixed disulfide and a citrate of an alkali metal or alkaline earth metal. Methods for fabricating the compositions and using them are also described.1. A pharmaceutical composition for treating, mitigating or preventing kidney stone disease, bladder stone disease or ureter stone disease, the composition comprising:
(a) a therapeutically effective quantity of a first component, wherein the first component comprises at least one pharmaceutically acceptable reducing agent capable of undergoing thiol-disulfide exchange with cystine to form a mixed disulfide; and (b) a therapeutically effective quantity of a second component, wherein the second component comprises a therapeutically effective quantity of at least one urine alkanizing agent selected from the group consisting of alkali metal salts of citric acid, alkaline-earth metal salts of citric acid, and sodium bicarbonate, wherein the first component and the second component form a homogeneous mixture. 2. The composition of claim 1, wherein the reducing agent comprises a thiol moiety and an amino acid moiety. 3. The composition of claim 2, wherein the amino acid is glycine. 4. The composition of claim 1, wherein the reducing agent is selected from the group consisting of tiopronin, penicilamine, and captopril. 5. The composition of claim 4, wherein the reducing agent is tiopronin. 6. The composition of claim 1, wherein the alkali or alkaline-earth metal salts of citric acid are selected from the group consisting of potassium citrate, sodium citrate, and magnesium citrate. 7. The composition of claim 6, wherein the urine alkanizing agent is potassium citrate. 8. The composition of claim 1, wherein the composition is in a form selected from the group consisting of a pill, a tablet, powder, a capsule, and a troche. 9. The composition of claim 1, further comprising a third component, wherein the third component provides the composition with a delayed release feature. 10. The composition of claim 9, wherein the third component is hydroxypropyl methylcellulose. 11. A method for treating, mitigating or preventing kidney stone disease, bladder stone disease or ureter stone disease, comprising administering to a patient in need thereof the pharmaceutical composition of claim 1, thereby treating, mitigating or preventing kidney stone disease, bladder stone disease or ureter stone disease. 12. The method of claim 11, wherein the reducing agent comprises a thiol moiety and an amino acid moiety. 13. The method of claim 12, wherein the amino acid is glycine. 14. The method of claim 11, wherein the reducing agent is selected from the group consisting of tiopronin, penicilamine, and captopril. 15. The method of claim 14, wherein the reducing agent is tiopronin. 16. The method of claim 11, wherein the alkali or alkaline-earth metal salts of citric acid are selected from the group consisting of potassium citrate, sodium citrate, and magnesium citrate. 17. The method of claim 16, wherein the urine alkanizing agent is potassium citrate. 18. The method of claim 11, wherein the composition is in a form selected from the group consisting of a pill, a tablet, powder, a capsule, and a troche. 19. The method of claim 11, wherein the disease is cystinuria. 20. A pharmaceutical article of manufacture, comprising the composition of claim 1, and further comprising:
(a) a first element, comprising the first component; and (b) a second element, comprising the second component, wherein the first element is completely ensconced within the second element, with the further provisos that (1) the first element is a solid structure optionally coated with a pharmaceutically suitable coating or the first element comprises an optionally acid resistant first solid shell defining a first space therein; and (2) the second element is a solid structure optionally coated with a pharmaceutically suitable coating, or the second element comprises an optionally acid resistant second solid shell, and the first element and the second element define the second space therebetween, wherein the second space contains the second component.
| 1,600 |
902 | 15,900,544 | 1,623 |
A process for preparing a composition (C 1 ) represented by the formula (I): HO—CH 2 —(CHOH) n —CH 2 —O-(G) x -H, in which G represents the remainder of a reducing sugar, n is an integer equal to 2, 3 or 4 and x, which indicates the mean degree of polymerization of the remainder G, represents a decimal number greater than 1 and less than or equal to 5, characterized in that the process includes at least one step a) of reacting a polyol of formula (A 1 ): HO—CH 2 —(CHOH) n —CH 2 —OH, in which n is an integer equal to 2, 3 or 4, with a reducing sugar of formula (II): HO-G-H, in which G represents the remainder of a reducing sugar, in the presence of an acid catalyst (C a ), and in that the acid catalyst (C a ) is chosen from phosphorous acid, phosphoric acid and polyphosphoric acid.
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1. A process for preparing a composition (C2), said composition (C2) comprising, per 100% of its weight:
from 1% to 70% by weight of a polyol of formula (A1):
HO—CH2—(CHOH)n—CH2—OH (A1),
in which n is an integer equal to 2, 3 or 4;
from 25% to 98.9% by weight of a composition (C1) represented by the formula (I):
HO—CH2—(CHOH)n—CH2—O-(G)x-H (I),
in which G represents the residue of a reducing sugar selected from the residues of glucose, xylose and arabinose, n is an integer equal to 2, 3 or 4 and x, which indicates the mean degree of polymerization of said residue G, represents a decimal number of greater than 1 and less than or equal to 5;
from 0.1% to 5% by weight of a compound (B) or of a mixture of compounds (B) chosen from:
the compound of formula (B11):
the compound of formula (B12):
the compound of formula (B13):
and the compound of formula (B14):
said process comprising at least one stage a) of reaction of a polyol of formula (A1):
HO—CH2—(CHOH)n—CH2—OH (A1),
in which n is an integer equal to 2, 3 or 4, with a reducing sugar of formula (II):
HO-G-H (II)
in which G represents the residue of a reducing sugar, in the presence of an acid catalyst (Ca);
wherein said acid catalyst (Ca) is chosen from hypophosphorous acid, phosphoric acid and polyphosphoric acid;
wherein, in stage a), the molar ratio, of a reducing sugar of formula (II) to polyol of formula (A1), is greater than or equal to 1/6 and less than or equal to 4/1; and
wherein, in stage a), the proportion by weight of acid catalyst (Ca) employed is greater than or equal to 0.05% and less than or equal to 2% per 100% of the sum of the weights of a reducing sugar of formula (II) and of polyol of formula (A1). 2. The process according to claim 1, wherein, in the formula (I), x represents a decimal number greater than or equal to 1.05 and less than 3. 3. The process according to claim 1, wherein, in stage a), the acid catalyst (Ca) employed is hypophosphorous acid. 4. The process according to claim 1, wherein, in stage a), the acid catalyst (Ca) employed is phosphoric acid. 5. The process according to claim 1, wherein:
in the formula (A1), n is an integer equal to 2, in the formula (I), n is an integer equal to 2, said residue G of a reducing sugar represents the residue of glucose and x represents a decimal number of between 1.05 and 2.5, and the compound (B) is the compound of formula (B11). 6. The process according to claim 1, wherein:
in the formula (A1), n is an integer equal to 3, in the formula (I), n is an integer equal to 3, said residue G of a reducing sugar represents the residue of glucose and x represents a decimal number of between 1.05 and 2.5, and the compound (B) is the compound of formula (B12). 7. The process according to claim 1, wherein:
in the formula (A1), n is an integer equal to 4, in the formula (I), n is an integer equal to 4, said residue G of a reducing sugar represents the residue of glucose and x represents a decimal number of between 1.05 and 2.5, and the compound (B) is a mixture of the compound of formula (B13) and the compound (B14).
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A process for preparing a composition (C 1 ) represented by the formula (I): HO—CH 2 —(CHOH) n —CH 2 —O-(G) x -H, in which G represents the remainder of a reducing sugar, n is an integer equal to 2, 3 or 4 and x, which indicates the mean degree of polymerization of the remainder G, represents a decimal number greater than 1 and less than or equal to 5, characterized in that the process includes at least one step a) of reacting a polyol of formula (A 1 ): HO—CH 2 —(CHOH) n —CH 2 —OH, in which n is an integer equal to 2, 3 or 4, with a reducing sugar of formula (II): HO-G-H, in which G represents the remainder of a reducing sugar, in the presence of an acid catalyst (C a ), and in that the acid catalyst (C a ) is chosen from phosphorous acid, phosphoric acid and polyphosphoric acid.1. A process for preparing a composition (C2), said composition (C2) comprising, per 100% of its weight:
from 1% to 70% by weight of a polyol of formula (A1):
HO—CH2—(CHOH)n—CH2—OH (A1),
in which n is an integer equal to 2, 3 or 4;
from 25% to 98.9% by weight of a composition (C1) represented by the formula (I):
HO—CH2—(CHOH)n—CH2—O-(G)x-H (I),
in which G represents the residue of a reducing sugar selected from the residues of glucose, xylose and arabinose, n is an integer equal to 2, 3 or 4 and x, which indicates the mean degree of polymerization of said residue G, represents a decimal number of greater than 1 and less than or equal to 5;
from 0.1% to 5% by weight of a compound (B) or of a mixture of compounds (B) chosen from:
the compound of formula (B11):
the compound of formula (B12):
the compound of formula (B13):
and the compound of formula (B14):
said process comprising at least one stage a) of reaction of a polyol of formula (A1):
HO—CH2—(CHOH)n—CH2—OH (A1),
in which n is an integer equal to 2, 3 or 4, with a reducing sugar of formula (II):
HO-G-H (II)
in which G represents the residue of a reducing sugar, in the presence of an acid catalyst (Ca);
wherein said acid catalyst (Ca) is chosen from hypophosphorous acid, phosphoric acid and polyphosphoric acid;
wherein, in stage a), the molar ratio, of a reducing sugar of formula (II) to polyol of formula (A1), is greater than or equal to 1/6 and less than or equal to 4/1; and
wherein, in stage a), the proportion by weight of acid catalyst (Ca) employed is greater than or equal to 0.05% and less than or equal to 2% per 100% of the sum of the weights of a reducing sugar of formula (II) and of polyol of formula (A1). 2. The process according to claim 1, wherein, in the formula (I), x represents a decimal number greater than or equal to 1.05 and less than 3. 3. The process according to claim 1, wherein, in stage a), the acid catalyst (Ca) employed is hypophosphorous acid. 4. The process according to claim 1, wherein, in stage a), the acid catalyst (Ca) employed is phosphoric acid. 5. The process according to claim 1, wherein:
in the formula (A1), n is an integer equal to 2, in the formula (I), n is an integer equal to 2, said residue G of a reducing sugar represents the residue of glucose and x represents a decimal number of between 1.05 and 2.5, and the compound (B) is the compound of formula (B11). 6. The process according to claim 1, wherein:
in the formula (A1), n is an integer equal to 3, in the formula (I), n is an integer equal to 3, said residue G of a reducing sugar represents the residue of glucose and x represents a decimal number of between 1.05 and 2.5, and the compound (B) is the compound of formula (B12). 7. The process according to claim 1, wherein:
in the formula (A1), n is an integer equal to 4, in the formula (I), n is an integer equal to 4, said residue G of a reducing sugar represents the residue of glucose and x represents a decimal number of between 1.05 and 2.5, and the compound (B) is a mixture of the compound of formula (B13) and the compound (B14).
| 1,600 |
903 | 15,677,526 | 1,654 |
Adsorptive media for chromatography, particularly ion-exchange chromatography, derived from a shaped fiber. In certain embodiments, the functionalized shaped fiber presents a fibrillated or ridged structure which greatly increases the surface area of the fibers when compared to ordinary fibers. Also disclosed herein is a method to add surface pendant functional groups that provides cation-exchange or anion-exchange functionality to the high surface area fibers. This pendant functionality is useful for the ion-exchange chromatographic purification of biomolecules, such as monoclonal antibodies (mAbs).
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1. A process for purifying a negatively-charged virus, comprising providing a sample containing negatively-charged virus; contacting said sample containing said negatively-charged virus with an axially compressed bed of cut nylon staple fiber media, wherein said cut fibers have a cross-section comprising a body region defining a substantially longitudinal axis, and have a plurality of projections extending outwardly from said body region, and wherein said fibers have imparted thereon a polymeric functionality, wherein the surfaces of said polymeric functionality are modified with pendant trimethylammonium groups; washing said fibers to remove unbound species; and eluting said negatively-charged virus, thereby to purify the negatively-charged virus. 2. A process for removing a negatively-charged virus from a sample, comprising providing a sample containing negatively-charged virus; contacting said sample containing said negatively-charged virus with an axially compressed bed of cut nylon staple fiber media, wherein said cut fibers have a cross-section comprising a body region defining a substantially longitudinal axis, and have a plurality of projections extending outwardly from said body region, said fibers having imparted thereon a polymeric functionality, wherein the surfaces of said polymeric functionality are modified with pendant trimethylammonium groups, thereby binding said negative-charged virus to said fibers, washing said fibers to remove unbound species; and eluting said negatively-charged virus.
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Adsorptive media for chromatography, particularly ion-exchange chromatography, derived from a shaped fiber. In certain embodiments, the functionalized shaped fiber presents a fibrillated or ridged structure which greatly increases the surface area of the fibers when compared to ordinary fibers. Also disclosed herein is a method to add surface pendant functional groups that provides cation-exchange or anion-exchange functionality to the high surface area fibers. This pendant functionality is useful for the ion-exchange chromatographic purification of biomolecules, such as monoclonal antibodies (mAbs).1. A process for purifying a negatively-charged virus, comprising providing a sample containing negatively-charged virus; contacting said sample containing said negatively-charged virus with an axially compressed bed of cut nylon staple fiber media, wherein said cut fibers have a cross-section comprising a body region defining a substantially longitudinal axis, and have a plurality of projections extending outwardly from said body region, and wherein said fibers have imparted thereon a polymeric functionality, wherein the surfaces of said polymeric functionality are modified with pendant trimethylammonium groups; washing said fibers to remove unbound species; and eluting said negatively-charged virus, thereby to purify the negatively-charged virus. 2. A process for removing a negatively-charged virus from a sample, comprising providing a sample containing negatively-charged virus; contacting said sample containing said negatively-charged virus with an axially compressed bed of cut nylon staple fiber media, wherein said cut fibers have a cross-section comprising a body region defining a substantially longitudinal axis, and have a plurality of projections extending outwardly from said body region, said fibers having imparted thereon a polymeric functionality, wherein the surfaces of said polymeric functionality are modified with pendant trimethylammonium groups, thereby binding said negative-charged virus to said fibers, washing said fibers to remove unbound species; and eluting said negatively-charged virus.
| 1,600 |
904 | 15,411,337 | 1,651 |
According to one embodiment, a microcapsule for selective catalysis of gases, the microcapsule comprising: a polymeric shell permeable to one or more target gases; and at least one biocatalyst disposed in an interior of the polymeric shell. In more embodiments, methods of forming such microcapsules include: emulsifying at least one biocatalyst in a polymer precursor mixture; emulsifying the polymer precursor mixture in an aqueous carrier solution; crosslinking one or more polymer precursors of the polymer precursor mixture to form a plurality of microcapsules each independently comprising: a polymeric shell permeable to one or more target gases; and at least one biocatalyst disposed in an interior of the polymeric shell. In further embodiments, corresponding methods of using the inventive microcapsules for catalyzing one or more target gases using include: exposing a plurality of the biocatalytic microcapsules to the one or more target gases.
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1. A microcapsule for selective catalysis of gases, the microcapsule comprising:
a polymeric shell permeable to one or more target gases; and at least one biocatalyst disposed in an interior of the polymeric shell. 2. The microcapsule as recited in claim 1, comprising a buffer disposed in the interior of the polymeric shell, wherein the at least one biocatalyst is suspended in the buffer. 3. The microcapsule as recited in claim 2, wherein the buffer comprises a reducing agent. 4. The microcapsule as recited in claim 1, the at least one biocatalyst comprising one or more biocatalytic components selected from: one or more enzymes configured to catalyze the one or more target gases; one or more enzyme cofactors; one or more cell membrane fragments; one or more cytosolic cell components; and reconstituted whole cells. 5. The microcapsule as recited in claim 1, the one or more target gases each independently being a C1-C3 compound. 6. The microcapsule as recited in claim 5, the one or more target gases being selected from: methane, carbon monoxide, carbon dioxide, ethane, ethylene; propane; propylene and either or both of hydrogen and oxygen as co-reactants. 7. The microcapsule as recited in claim 1, wherein the polymeric shell comprises one or more crosslinked polymers formed by UV crosslinking one or more polymer precursors selected from: polydimethylsiloxane (PDMS); polyethylene glycol (PEG); polyethylene glycol diacrylate (PEGDA); hexanediol diacrylate (HDDA); polyvinyl alcohol (PVA); poly(lactic acid) (PLA); polyimide; poly(2-methyl-2-oxazoline) (PXMOA); poly(ether ether ketone) (PEEK); cellulose acetate; polypropylene (PP); and silicone acrylate. 8. The microcapsule as recited in claim 1, wherein the polymeric shell is either hydrophobic or amphiphilic. 9. The microcapsule as recited in claim 1, wherein the microcapsule is characterized by an outer diameter in a range from approximately 10 μm to approximately 1000 μm. 10. The microcapsule as recited in claim 1, wherein the polymeric shell is characterized by a thickness in a range from approximately 5 μm to approximately 100 μm. 11. A product, comprising a plurality of the microcapsules as recited in claim 1, wherein the microcapsules are arranged in a configuration selected from: a packed bed; a moving bed; a fluidized bed; a microcapsule-embedded mesh; a packet containing the microcapsules; and a microcapsule-embedded adhesive. 12. A method of forming microcapsules for selective catalysis of gases, the method comprising:
emulsifying at least one biocatalyst in a polymer precursor mixture; emulsifying the polymer precursor mixture in an aqueous carrier solution; crosslinking one or more polymer precursors of the polymer precursor mixture to form a plurality of microcapsules each independently comprising:
a polymeric shell permeable to one or more target gases; and
at least one biocatalyst disposed in an interior of the polymeric shell. 13. The method as recited in claim 12, wherein emulsifying at least one biocatalyst in a polymer precursor mixture and emulsifying the polymer precursor mixture in an aqueous carrier solution forms a double emulsion comprising the biocatalyst, the polymer precursor mixture, and the aqueous carrier solution. 14. The method as recited in claim 12, wherein the biocatalyst is suspended in a buffer. 15. The method as recited in claim 14, wherein the buffer excludes reducing agents. 16. The method as recited in claim 12, the at least one biocatalyst comprising one or more biocatalytic components selected from: one or more enzymes configured to catalyze the one or more target gases; one or more enzyme cofactors; one or more cell membrane fragments; one or more cytosolic cell components; and reconstituted whole cells. 17. The method as recited in claim 12, wherein the aqueous carrier solution comprises:
water present in an amount from about 50 wt % to about 60 wt %; glycerol present in an amount from about 30 wt % to about 40 wt %; and polyvinyl alcohol present in an amount from about 1 wt % to about 5 wt %. 18. The method as recited in claim 12, wherein the polymer precursor mixture comprises one or more polymer precursors selected from a group consisting of: polydimethylsiloxane (PDMS); polyethylene glycol (PEG); polyethylene glycol diacrylate (PEGDA); hexanediol diacrylate (HDDA); polyvinyl alcohol (PVA); poly(lactic acid) (PLA); polyimide; poly(2-methyl-2-oxazoline) (PXMOA); poly(ether ether ketone) (PEEK); cellulose acetate; polypropylene (PP); and silicone acrylate. 19. The method as recited in claim 12, comprising:
isolating the plurality of microcapsules from the aqueous carrier solution; and drying the plurality of microcapsules. 20. A method for catalyzing one or more target gases using biocatalytic microcapsules, the method comprising:
exposing a plurality of the biocatalytic microcapsules to the one or more target gases, wherein the biocatalytic microcapsules each independently comprise: a polymeric shell permeable to the one or more target gases; and at least one biocatalyst disposed in an interior of the polymeric shell. 21. The method as recited in claim 20, wherein the biocatalytic microcapsules are arranged in a configuration selected from: a packed bed; a moving bed; a fluidized bed; immobilized in or on a substrate; a microcapsule-embedded mesh; a packet containing the biocatalyic microcapsules; and a microcapsule-embedded adhesive. 22. The method as recited in claim 20, the one or more target gases each independently being a C1-C3 compound. 23. The method as recited in claim 22, the one or more target gases being selected from: methane, carbon monoxide, carbon dioxide, ethane, ethylene; propane; and propylene, hydrogen and oxygen. 24. The method as recited in claim 20, the at least one biocatalyst comprising one or more biocatalytic components selected from: one or more enzymes configured to catalyze the one or more target gases; one or more enzyme cofactors; one or more cell membrane fragments; one or more cytosolic cell components; and reconstituted whole cells.
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According to one embodiment, a microcapsule for selective catalysis of gases, the microcapsule comprising: a polymeric shell permeable to one or more target gases; and at least one biocatalyst disposed in an interior of the polymeric shell. In more embodiments, methods of forming such microcapsules include: emulsifying at least one biocatalyst in a polymer precursor mixture; emulsifying the polymer precursor mixture in an aqueous carrier solution; crosslinking one or more polymer precursors of the polymer precursor mixture to form a plurality of microcapsules each independently comprising: a polymeric shell permeable to one or more target gases; and at least one biocatalyst disposed in an interior of the polymeric shell. In further embodiments, corresponding methods of using the inventive microcapsules for catalyzing one or more target gases using include: exposing a plurality of the biocatalytic microcapsules to the one or more target gases.1. A microcapsule for selective catalysis of gases, the microcapsule comprising:
a polymeric shell permeable to one or more target gases; and at least one biocatalyst disposed in an interior of the polymeric shell. 2. The microcapsule as recited in claim 1, comprising a buffer disposed in the interior of the polymeric shell, wherein the at least one biocatalyst is suspended in the buffer. 3. The microcapsule as recited in claim 2, wherein the buffer comprises a reducing agent. 4. The microcapsule as recited in claim 1, the at least one biocatalyst comprising one or more biocatalytic components selected from: one or more enzymes configured to catalyze the one or more target gases; one or more enzyme cofactors; one or more cell membrane fragments; one or more cytosolic cell components; and reconstituted whole cells. 5. The microcapsule as recited in claim 1, the one or more target gases each independently being a C1-C3 compound. 6. The microcapsule as recited in claim 5, the one or more target gases being selected from: methane, carbon monoxide, carbon dioxide, ethane, ethylene; propane; propylene and either or both of hydrogen and oxygen as co-reactants. 7. The microcapsule as recited in claim 1, wherein the polymeric shell comprises one or more crosslinked polymers formed by UV crosslinking one or more polymer precursors selected from: polydimethylsiloxane (PDMS); polyethylene glycol (PEG); polyethylene glycol diacrylate (PEGDA); hexanediol diacrylate (HDDA); polyvinyl alcohol (PVA); poly(lactic acid) (PLA); polyimide; poly(2-methyl-2-oxazoline) (PXMOA); poly(ether ether ketone) (PEEK); cellulose acetate; polypropylene (PP); and silicone acrylate. 8. The microcapsule as recited in claim 1, wherein the polymeric shell is either hydrophobic or amphiphilic. 9. The microcapsule as recited in claim 1, wherein the microcapsule is characterized by an outer diameter in a range from approximately 10 μm to approximately 1000 μm. 10. The microcapsule as recited in claim 1, wherein the polymeric shell is characterized by a thickness in a range from approximately 5 μm to approximately 100 μm. 11. A product, comprising a plurality of the microcapsules as recited in claim 1, wherein the microcapsules are arranged in a configuration selected from: a packed bed; a moving bed; a fluidized bed; a microcapsule-embedded mesh; a packet containing the microcapsules; and a microcapsule-embedded adhesive. 12. A method of forming microcapsules for selective catalysis of gases, the method comprising:
emulsifying at least one biocatalyst in a polymer precursor mixture; emulsifying the polymer precursor mixture in an aqueous carrier solution; crosslinking one or more polymer precursors of the polymer precursor mixture to form a plurality of microcapsules each independently comprising:
a polymeric shell permeable to one or more target gases; and
at least one biocatalyst disposed in an interior of the polymeric shell. 13. The method as recited in claim 12, wherein emulsifying at least one biocatalyst in a polymer precursor mixture and emulsifying the polymer precursor mixture in an aqueous carrier solution forms a double emulsion comprising the biocatalyst, the polymer precursor mixture, and the aqueous carrier solution. 14. The method as recited in claim 12, wherein the biocatalyst is suspended in a buffer. 15. The method as recited in claim 14, wherein the buffer excludes reducing agents. 16. The method as recited in claim 12, the at least one biocatalyst comprising one or more biocatalytic components selected from: one or more enzymes configured to catalyze the one or more target gases; one or more enzyme cofactors; one or more cell membrane fragments; one or more cytosolic cell components; and reconstituted whole cells. 17. The method as recited in claim 12, wherein the aqueous carrier solution comprises:
water present in an amount from about 50 wt % to about 60 wt %; glycerol present in an amount from about 30 wt % to about 40 wt %; and polyvinyl alcohol present in an amount from about 1 wt % to about 5 wt %. 18. The method as recited in claim 12, wherein the polymer precursor mixture comprises one or more polymer precursors selected from a group consisting of: polydimethylsiloxane (PDMS); polyethylene glycol (PEG); polyethylene glycol diacrylate (PEGDA); hexanediol diacrylate (HDDA); polyvinyl alcohol (PVA); poly(lactic acid) (PLA); polyimide; poly(2-methyl-2-oxazoline) (PXMOA); poly(ether ether ketone) (PEEK); cellulose acetate; polypropylene (PP); and silicone acrylate. 19. The method as recited in claim 12, comprising:
isolating the plurality of microcapsules from the aqueous carrier solution; and drying the plurality of microcapsules. 20. A method for catalyzing one or more target gases using biocatalytic microcapsules, the method comprising:
exposing a plurality of the biocatalytic microcapsules to the one or more target gases, wherein the biocatalytic microcapsules each independently comprise: a polymeric shell permeable to the one or more target gases; and at least one biocatalyst disposed in an interior of the polymeric shell. 21. The method as recited in claim 20, wherein the biocatalytic microcapsules are arranged in a configuration selected from: a packed bed; a moving bed; a fluidized bed; immobilized in or on a substrate; a microcapsule-embedded mesh; a packet containing the biocatalyic microcapsules; and a microcapsule-embedded adhesive. 22. The method as recited in claim 20, the one or more target gases each independently being a C1-C3 compound. 23. The method as recited in claim 22, the one or more target gases being selected from: methane, carbon monoxide, carbon dioxide, ethane, ethylene; propane; and propylene, hydrogen and oxygen. 24. The method as recited in claim 20, the at least one biocatalyst comprising one or more biocatalytic components selected from: one or more enzymes configured to catalyze the one or more target gases; one or more enzyme cofactors; one or more cell membrane fragments; one or more cytosolic cell components; and reconstituted whole cells.
| 1,600 |
905 | 14,964,297 | 1,627 |
This invention concerns pharmaceutical compositions for administration via intramuscular or subcutaneous injection, comprising micro- or nanoparticles of the NNRTI compound TMC278, suspended in an aqueous pharmaceutically acceptable carrier, and the use of such pharmaceutical compositions in the treatment and prophylaxis of HIV infection.
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1. A method for the long-term treatment of HIV infection, comprising administering to a patient in need thereof by intramuscular or subcutaneous injection a pharmaceutical composition comprising a therapeutically effective amount of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (TMC278), a salt, a stereoisomer or a steriosomeric mixture thereof, in the form of a suspension of micro- or nanoparticles comprising:
(a) TMC278, a salt, a stereoisomer or a stereoisomeric mixture thereof, in micro- or nanoparticle form, having a surface modifier adsorbed to the surface thereof; and (b) a pharmaceutically acceptable aqueous carrier; wherein TMC278 active ingredient is suspended, and wherein the pharmaceutical composition is administered intermittently once every two weeks, once every three weeks, once every month, once every two months, once every three months, once every four months, or in the range of three months to six months. 2. The method of claim 2, wherein the therapeutically effective amount is calculated on a basis of about 5 mg/day to about 50 mg/day of TMC278. 3. The method of claim 3, wherein the therapeutically effective amount is calculated on a basis of about 10 mg/day to about 25 mg/day. 4. The method of claim 2, wherein TMC278 is present in base form or in an acid addition salt form. 5. The method of claim 2, wherein the surface modifier is poloxamer, α-tocopheryl polyethylene glycol succinate, polyoxyethylene sorbitan fatty acid ester or salts of negatively charged phospholipids. 6. The method of claim 5, wherein the surface modifier is poloxamer 338, α-tocopheryl polyethylene glycol 1000 succinate, polysorbate 80 or egg phosphatidyl glycerol sodium. 7. The method of claim 6, wherein the surface modifier is poloxamer 338. 8. The method of claim 6, wherein the average effective particle size of the micro- or nanoparticles is
a. below about 50 μm, about 20 μm, about 10 μm, about 1000 nm, about 500 nm, about 400 nm, about 300 nm, about 200 nm, about 100 nm or about 50 nm; b. from about 50 nm to about 50 μm, from about 50 nm to about 20 μm, from about 50 nm to about 10 μm, from about 50 nm to about 1000 nm, from about 50 nm to about 500 nm, from about 50 nm to about 400 nm, from about 50 nm to about 300 nm, from about 50 nm to about 250 nm, from about 100 nm to about 250 nm, from about 150 nm to about 220 nm, from about 100 nm to about 200 nm, or from about 150 nm to about 200 nm; c. about 50 nm to about 1000 nm; d. about 50 nm to about 400 nm; e. about 150 nm to about 220 nm; f. about 130 nm; or g. about 200 nm. 9. The method of claim 2, wherein the therapeutically effective amount of TMC278 corresponds with a monthly dose of
a. from about 150 mg to about 1500 mg; b. from about 30 mg to about 300 mg; or c. about 300 mg. 10. The method of claim 2, wherein the pharmaceutical composition comprises by weight based on the total volume of the composition:
a. from 3% to 50%, from 10% to 40% or from 10 to 30%, of TMC278 b. from 0.5% to 10% or from 0.5% to 2% of the surface modifier; c. from 0% to 10%, from 0% to 5%, from 0% to 2%, or from 0% to 1% of one of more buffering agents; d. from 0% to 10%, or from 0% to 6% of an isotonizing agent; e. from 0% to 2% preservatives; and f. water for injection q.s. ad 100%. 11. The method of claim 4, wherein TMC278 is present as the E-isomer of the base form. 12. The method of claim 4, wherein TMC278 is present as the E-isomer of the acid addition salt form. 13. The method of claim 10, wherein the buffering agent is tartaric acid, maleic acid, glycine, sodium lactate, lactic acid, ascorbic acid, sodium citrates, citric acid, sodium acetate, acetic acid, sodium bicarbonate, carbonic acid, sodium succinate, succinic acid, sodium benzoate, benzoic acid, sodium phosphates, tris(hydroxymethyl)aminomethane, sodium bicarbonate, sodium carbonate, ammonium hydroxide, benzene sulfonic acid, benzoate sodium, benzoate acid, diethanolamine, glucono delta lactone, hydrochloric acid, hydrogen bromide, lysine, methanesulfonic acid, monoethanolamine, sodium hydroxide, tromethamine, gluconic, glyceric, gluratic, glutamic, ethylene diamine tetraacetic (EDTA), triethanolamine, or a mixture of at least two buffering agents. 14. The method of claim 10, wherein the isotonizing agent is glucose, dextrose, sucrose, fructose, trehalose, lactose, a polyhydric sugar alcohol, a trihydric or higher sugar alcohol, glycerin, erythritol, arabitol, xylitol, sorbitol, mannitol, sodium chloride or sodium sulfate. 15. The method of claim 2, wherein the therapeutically effective amount of TMC278 is calculated on a basis of about 10 mg/day to about 25 mg/day, TMC278 is present as the E-isomer of the base form, and wherein the surface modifier is poloxamer 338. 16. The method of claim 15, wherein TMC278 is present in nanoparticle form. 17. The method of claim 16, wherein the average effective nanoparticle size is from about 150 nm to about 220 nm. 18. The method of claim 2, wherein the pharmaceutical composition comprises TMC278, a salt, a stereoisomer or a steriosomeric mixture thereof, in nanoparticle form. 19. The method of claim 6, wherein the relative amount by weight (w/w) of TMC278 to the surface modifier is in the range of 1:1 to about 20:1. 20. The method of claim 19, wherein the relative amount by weight (w/w) of TMC278 to the surface modifier is about 1:1, about 1:2, about 4:1, about 10:1 or about 20:1.
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This invention concerns pharmaceutical compositions for administration via intramuscular or subcutaneous injection, comprising micro- or nanoparticles of the NNRTI compound TMC278, suspended in an aqueous pharmaceutically acceptable carrier, and the use of such pharmaceutical compositions in the treatment and prophylaxis of HIV infection.1. A method for the long-term treatment of HIV infection, comprising administering to a patient in need thereof by intramuscular or subcutaneous injection a pharmaceutical composition comprising a therapeutically effective amount of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (TMC278), a salt, a stereoisomer or a steriosomeric mixture thereof, in the form of a suspension of micro- or nanoparticles comprising:
(a) TMC278, a salt, a stereoisomer or a stereoisomeric mixture thereof, in micro- or nanoparticle form, having a surface modifier adsorbed to the surface thereof; and (b) a pharmaceutically acceptable aqueous carrier; wherein TMC278 active ingredient is suspended, and wherein the pharmaceutical composition is administered intermittently once every two weeks, once every three weeks, once every month, once every two months, once every three months, once every four months, or in the range of three months to six months. 2. The method of claim 2, wherein the therapeutically effective amount is calculated on a basis of about 5 mg/day to about 50 mg/day of TMC278. 3. The method of claim 3, wherein the therapeutically effective amount is calculated on a basis of about 10 mg/day to about 25 mg/day. 4. The method of claim 2, wherein TMC278 is present in base form or in an acid addition salt form. 5. The method of claim 2, wherein the surface modifier is poloxamer, α-tocopheryl polyethylene glycol succinate, polyoxyethylene sorbitan fatty acid ester or salts of negatively charged phospholipids. 6. The method of claim 5, wherein the surface modifier is poloxamer 338, α-tocopheryl polyethylene glycol 1000 succinate, polysorbate 80 or egg phosphatidyl glycerol sodium. 7. The method of claim 6, wherein the surface modifier is poloxamer 338. 8. The method of claim 6, wherein the average effective particle size of the micro- or nanoparticles is
a. below about 50 μm, about 20 μm, about 10 μm, about 1000 nm, about 500 nm, about 400 nm, about 300 nm, about 200 nm, about 100 nm or about 50 nm; b. from about 50 nm to about 50 μm, from about 50 nm to about 20 μm, from about 50 nm to about 10 μm, from about 50 nm to about 1000 nm, from about 50 nm to about 500 nm, from about 50 nm to about 400 nm, from about 50 nm to about 300 nm, from about 50 nm to about 250 nm, from about 100 nm to about 250 nm, from about 150 nm to about 220 nm, from about 100 nm to about 200 nm, or from about 150 nm to about 200 nm; c. about 50 nm to about 1000 nm; d. about 50 nm to about 400 nm; e. about 150 nm to about 220 nm; f. about 130 nm; or g. about 200 nm. 9. The method of claim 2, wherein the therapeutically effective amount of TMC278 corresponds with a monthly dose of
a. from about 150 mg to about 1500 mg; b. from about 30 mg to about 300 mg; or c. about 300 mg. 10. The method of claim 2, wherein the pharmaceutical composition comprises by weight based on the total volume of the composition:
a. from 3% to 50%, from 10% to 40% or from 10 to 30%, of TMC278 b. from 0.5% to 10% or from 0.5% to 2% of the surface modifier; c. from 0% to 10%, from 0% to 5%, from 0% to 2%, or from 0% to 1% of one of more buffering agents; d. from 0% to 10%, or from 0% to 6% of an isotonizing agent; e. from 0% to 2% preservatives; and f. water for injection q.s. ad 100%. 11. The method of claim 4, wherein TMC278 is present as the E-isomer of the base form. 12. The method of claim 4, wherein TMC278 is present as the E-isomer of the acid addition salt form. 13. The method of claim 10, wherein the buffering agent is tartaric acid, maleic acid, glycine, sodium lactate, lactic acid, ascorbic acid, sodium citrates, citric acid, sodium acetate, acetic acid, sodium bicarbonate, carbonic acid, sodium succinate, succinic acid, sodium benzoate, benzoic acid, sodium phosphates, tris(hydroxymethyl)aminomethane, sodium bicarbonate, sodium carbonate, ammonium hydroxide, benzene sulfonic acid, benzoate sodium, benzoate acid, diethanolamine, glucono delta lactone, hydrochloric acid, hydrogen bromide, lysine, methanesulfonic acid, monoethanolamine, sodium hydroxide, tromethamine, gluconic, glyceric, gluratic, glutamic, ethylene diamine tetraacetic (EDTA), triethanolamine, or a mixture of at least two buffering agents. 14. The method of claim 10, wherein the isotonizing agent is glucose, dextrose, sucrose, fructose, trehalose, lactose, a polyhydric sugar alcohol, a trihydric or higher sugar alcohol, glycerin, erythritol, arabitol, xylitol, sorbitol, mannitol, sodium chloride or sodium sulfate. 15. The method of claim 2, wherein the therapeutically effective amount of TMC278 is calculated on a basis of about 10 mg/day to about 25 mg/day, TMC278 is present as the E-isomer of the base form, and wherein the surface modifier is poloxamer 338. 16. The method of claim 15, wherein TMC278 is present in nanoparticle form. 17. The method of claim 16, wherein the average effective nanoparticle size is from about 150 nm to about 220 nm. 18. The method of claim 2, wherein the pharmaceutical composition comprises TMC278, a salt, a stereoisomer or a steriosomeric mixture thereof, in nanoparticle form. 19. The method of claim 6, wherein the relative amount by weight (w/w) of TMC278 to the surface modifier is in the range of 1:1 to about 20:1. 20. The method of claim 19, wherein the relative amount by weight (w/w) of TMC278 to the surface modifier is about 1:1, about 1:2, about 4:1, about 10:1 or about 20:1.
| 1,600 |
906 | 16,358,798 | 1,627 |
Topical application of Delphinidin twice per day treats rosacea and maintains normal healthy skin in patients with rosacea. Delphinidin applied topically increases and nourishes collagen and promote healthy skin.
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1. A topical cream comprising Delphinidin in an amount effective to ameliorate dermal inflammation due to rosacea or lupus. 2. The topical cream of claim 1, comprising at least about 1% (w/w) Delphinidin. 3. The topical cream of claim 2, comprising at least about 10% (w/w) Delphinidin. 4. The topical cream of claim 1, wherein the Delphinidin comprises at least one glucoside moiety. 5. The topical cream of claim 4, wherein the Delphinidin comprises at least one compound selected from the group consisting of: delphinidin-3-O-sambubioside 5-O-glucoside, delphinidin 3,5-O-diglucoside, delphinidin-3-O-sambubioside and delphinidin-3-O-glucoside. 6. The method of claim 5, wherein the Delphinidin comprises delphinidin-3-O-sambubioside 5-O-glucoside, delphinidin 3,5-O-diglucoside, delphinidin-3-O-sambubioside and delphinidin-3-O-glucoside. 7. A method comprising: applying the topical cream of claim 1 to the skin of a human with a condition selected from the group consisting of rosacea and lupus. 8. A method comprising: applying the topical cream of claim 2 to the skin of a human with a condition selected from the group consisting of rosacea and lupus. 9. A method comprising: applying the topical cream of claim 3 to the skin of a human with a condition selected from the group consisting of rosacea and lupus. 10. The method of claim 7, where the condition comprises rosacea. 11. The method of claim 7, where the condition comprises lupus.
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Topical application of Delphinidin twice per day treats rosacea and maintains normal healthy skin in patients with rosacea. Delphinidin applied topically increases and nourishes collagen and promote healthy skin.1. A topical cream comprising Delphinidin in an amount effective to ameliorate dermal inflammation due to rosacea or lupus. 2. The topical cream of claim 1, comprising at least about 1% (w/w) Delphinidin. 3. The topical cream of claim 2, comprising at least about 10% (w/w) Delphinidin. 4. The topical cream of claim 1, wherein the Delphinidin comprises at least one glucoside moiety. 5. The topical cream of claim 4, wherein the Delphinidin comprises at least one compound selected from the group consisting of: delphinidin-3-O-sambubioside 5-O-glucoside, delphinidin 3,5-O-diglucoside, delphinidin-3-O-sambubioside and delphinidin-3-O-glucoside. 6. The method of claim 5, wherein the Delphinidin comprises delphinidin-3-O-sambubioside 5-O-glucoside, delphinidin 3,5-O-diglucoside, delphinidin-3-O-sambubioside and delphinidin-3-O-glucoside. 7. A method comprising: applying the topical cream of claim 1 to the skin of a human with a condition selected from the group consisting of rosacea and lupus. 8. A method comprising: applying the topical cream of claim 2 to the skin of a human with a condition selected from the group consisting of rosacea and lupus. 9. A method comprising: applying the topical cream of claim 3 to the skin of a human with a condition selected from the group consisting of rosacea and lupus. 10. The method of claim 7, where the condition comprises rosacea. 11. The method of claim 7, where the condition comprises lupus.
| 1,600 |
907 | 15,070,005 | 1,651 |
The present disclosure provides the use of a phosphatidylcholine compound as a component of a media composition. The resulting media composition can be used for the cryopreservation of eukaryotic cells. The cryopreserved eukaryotic cells can be thawed and recovered for inoculation and/or growth in a media to reproduce new cells. Provided herein are compositions and methods for the cryopreservation of eukaryotic cells in a media composition containing a phosphatidylcholine compound.
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1. A media composition, comprising:
(i) an aqueous solution including at least one cryopreservation agent, a cell suspension media, and a phosphatidylcholine; and, (ii) a eukaryotic cell. 2. The media composition of claim 1, wherein the cryopreservation agent is selected from the group consisting of glycerol, DMSO (dimethyl sulfoxide), propylene glycol, ethylene glycol, acetamide, and methanol. 3. The media composition of claim 1, wherein the cryopreservation agent is provided at concentrations from 0.5% to 75% of the total volume of the media composition. 4. The media composition of claim 1, wherein the cell suspension media comprises a monocotyledonous plant cell suspension media. 5. The media composition of claim 1, wherein the cell suspension media comprises a dicotyledonous plant cell suspension media. 6. The media composition of claim 1, wherein the eukaryotic cell comprises a plant cell. 7. The media composition of claim 6, wherein the plant cell is selected from the group consisting of a monocotyledonous plant cell and a dicotyledonous plant cell. 8. The media composition of claim 7, wherein the monocotyledonous plant cell is selected from the group consisting of maize, wheat, rice, black grass, tall fescue, bent grass, and anza wheat. 9. The media composition of claim 7, wherein the dicotyledonous plant cell is selected from the group consisting of soybean, tobacco, Arabidopsis, canola, cotton, rape, sunflower, and carrot. 10. The media composition of claim 6, wherein the plant cell comprises a plant suspension cell line, or a photo-autotrophic suspension cell line. 11. The media composition of claim 6, wherein the plant cell comprises a plant tissue or a plant structure. 12. The media composition of claim 11, wherein the plant tissue or the plant structure is selected from the group consisting of embryos, meristematic tissues, leaves, pollen, roots, root tips, anther, silks, flowers, kernels, bulbs, tubers, rhizomes, calli, and seeds thereof. 13. The media composition of claim 6, wherein the plant cell comprises a transgene. 14. The media composition of claim 1, wherein the phosphatidylcholine is selected from the group consisting of soybean L-α-phosphatidylcholine, rape seed L-α-phosphatidylcholine, cotton seed L-α-phosphatidylcholine, and sunflower seed L-α-phosphatidylcholine. 15. The media composition of claim 1, wherein the phosphatidylcholine is provided at concentrations from 0.05% to 50% of the total volume of the media composition. 16. The media composition of claim 1, wherein the media composition is cooled. 17. The media composition of claim 1, wherein the media composition is frozen. 18. The media composition according to claim 16 or 17, wherein the media composition comprises a temperature of about 4° C. to about −196° C.
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The present disclosure provides the use of a phosphatidylcholine compound as a component of a media composition. The resulting media composition can be used for the cryopreservation of eukaryotic cells. The cryopreserved eukaryotic cells can be thawed and recovered for inoculation and/or growth in a media to reproduce new cells. Provided herein are compositions and methods for the cryopreservation of eukaryotic cells in a media composition containing a phosphatidylcholine compound.1. A media composition, comprising:
(i) an aqueous solution including at least one cryopreservation agent, a cell suspension media, and a phosphatidylcholine; and, (ii) a eukaryotic cell. 2. The media composition of claim 1, wherein the cryopreservation agent is selected from the group consisting of glycerol, DMSO (dimethyl sulfoxide), propylene glycol, ethylene glycol, acetamide, and methanol. 3. The media composition of claim 1, wherein the cryopreservation agent is provided at concentrations from 0.5% to 75% of the total volume of the media composition. 4. The media composition of claim 1, wherein the cell suspension media comprises a monocotyledonous plant cell suspension media. 5. The media composition of claim 1, wherein the cell suspension media comprises a dicotyledonous plant cell suspension media. 6. The media composition of claim 1, wherein the eukaryotic cell comprises a plant cell. 7. The media composition of claim 6, wherein the plant cell is selected from the group consisting of a monocotyledonous plant cell and a dicotyledonous plant cell. 8. The media composition of claim 7, wherein the monocotyledonous plant cell is selected from the group consisting of maize, wheat, rice, black grass, tall fescue, bent grass, and anza wheat. 9. The media composition of claim 7, wherein the dicotyledonous plant cell is selected from the group consisting of soybean, tobacco, Arabidopsis, canola, cotton, rape, sunflower, and carrot. 10. The media composition of claim 6, wherein the plant cell comprises a plant suspension cell line, or a photo-autotrophic suspension cell line. 11. The media composition of claim 6, wherein the plant cell comprises a plant tissue or a plant structure. 12. The media composition of claim 11, wherein the plant tissue or the plant structure is selected from the group consisting of embryos, meristematic tissues, leaves, pollen, roots, root tips, anther, silks, flowers, kernels, bulbs, tubers, rhizomes, calli, and seeds thereof. 13. The media composition of claim 6, wherein the plant cell comprises a transgene. 14. The media composition of claim 1, wherein the phosphatidylcholine is selected from the group consisting of soybean L-α-phosphatidylcholine, rape seed L-α-phosphatidylcholine, cotton seed L-α-phosphatidylcholine, and sunflower seed L-α-phosphatidylcholine. 15. The media composition of claim 1, wherein the phosphatidylcholine is provided at concentrations from 0.05% to 50% of the total volume of the media composition. 16. The media composition of claim 1, wherein the media composition is cooled. 17. The media composition of claim 1, wherein the media composition is frozen. 18. The media composition according to claim 16 or 17, wherein the media composition comprises a temperature of about 4° C. to about −196° C.
| 1,600 |
908 | 14,547,771 | 1,628 |
Methods of suppressing cachexia in a mammal with cancer comprising administering HDAC inhibitors are provided. Aspects include methods of administering an HDAC class 1 and 2b inhibitor in an amount effective to substantially maintain the mammal's weight compared to a mammal that does receive the HDAC class 1 and 2b inhibitor.
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1. A method of suppressing cachexia in a mammal with cancer comprising administering a HDAC class 1 and 2b inhibitor to said mammal in an amount effective to substantially maintain the mammal's weight compared to a mammal that does not receive the HDAC class 1 and 2b inhibitor. 2. The method of claim 1, wherein the HDAC inhibitor is AR-42. 3. The method of claim 2, wherein the mammal's weight is not reduced by more than about 6% after about the first 15 days following treatment with AR-42. 4. The method of claim 1, wherein the cancer is selected from the group consisting of pancreatic, colon, head, neck, gastric, and esophageal. 5. The method of claim 1, wherein the mammal is a human. 6. The method of claim 2, wherein AR-42 is administered in an amount of about 1 mg/kg to about 100 mg/kg of the mammal. 7. The method of claim 6, wherein AR-42 is administered at least once a day. 8. The method of claim 7, wherein AR-42 is administered twice a day in an amount of about 50 mg/kg of the mammal. 9. The method of claim 2, wherein levels of IL-6 are reduced by about 56% compared to a mammal that does not receive AR-42. 10. The method of claim 2, wherein levels of LIF are reduced by about 88% compared to a mammal that does not receive AR-42. 11. The method of claim 2, wherein expression of Atrogin-1 mRNA is restored to basal levels compared to a mammal that does not receive AR-42. 12. The method of claim 2, wherein expression of MuRF1 mRNA is restored to basal levels compared to a mammal that does not receive AR-42. 13. The method of claim 2, wherein a cachexia-induced increase in IL-6Rα mRNA levels is reduced by about 85% compared to a mammal that does not receive AR-42. 14. The method of claim 2, wherein a cachexia-induced loss of adipose tissue is substantially restored compared to a mammal that does not receive AR-42. 15. The method of claim 2, wherein a cachexia-induced reduction in skeletal muscle fiber size is substantially restored by AR-42 compared to a mammal that does not receive AR-42. 16. A method of maintaining skeletal muscle weight in a mammal having cancer comprising administering a HDAC class 1 and 2b inhibitor to said mammal in an amount effective to maintain at least about 90% of said mammal's skeletal muscle weight over a period of time of at least fifteen days compared to a mammal that does not receive the HDAC class 1 and 2b inhibitor. 17. The method of claim 16, wherein the HDAC class 1 and 2b inhibitor is AR-42. 18. A method of prolonging survival of a mammal having cancer comprising administering a HDAC class 1 and 2b inhibitor to the mammal in an amount effective to substantially prolong survival of the mammal compared to a mammal that does not receive the HDAC class 1 and 2b inhibitor. 19. The method of claim 18, wherein the HDAC class 1 and 2b inhibitor is AR-42. 20. The method of claim 18 wherein the mammal survives at least about 21 days after the administering of AR-42 to the mammal.
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Methods of suppressing cachexia in a mammal with cancer comprising administering HDAC inhibitors are provided. Aspects include methods of administering an HDAC class 1 and 2b inhibitor in an amount effective to substantially maintain the mammal's weight compared to a mammal that does receive the HDAC class 1 and 2b inhibitor.1. A method of suppressing cachexia in a mammal with cancer comprising administering a HDAC class 1 and 2b inhibitor to said mammal in an amount effective to substantially maintain the mammal's weight compared to a mammal that does not receive the HDAC class 1 and 2b inhibitor. 2. The method of claim 1, wherein the HDAC inhibitor is AR-42. 3. The method of claim 2, wherein the mammal's weight is not reduced by more than about 6% after about the first 15 days following treatment with AR-42. 4. The method of claim 1, wherein the cancer is selected from the group consisting of pancreatic, colon, head, neck, gastric, and esophageal. 5. The method of claim 1, wherein the mammal is a human. 6. The method of claim 2, wherein AR-42 is administered in an amount of about 1 mg/kg to about 100 mg/kg of the mammal. 7. The method of claim 6, wherein AR-42 is administered at least once a day. 8. The method of claim 7, wherein AR-42 is administered twice a day in an amount of about 50 mg/kg of the mammal. 9. The method of claim 2, wherein levels of IL-6 are reduced by about 56% compared to a mammal that does not receive AR-42. 10. The method of claim 2, wherein levels of LIF are reduced by about 88% compared to a mammal that does not receive AR-42. 11. The method of claim 2, wherein expression of Atrogin-1 mRNA is restored to basal levels compared to a mammal that does not receive AR-42. 12. The method of claim 2, wherein expression of MuRF1 mRNA is restored to basal levels compared to a mammal that does not receive AR-42. 13. The method of claim 2, wherein a cachexia-induced increase in IL-6Rα mRNA levels is reduced by about 85% compared to a mammal that does not receive AR-42. 14. The method of claim 2, wherein a cachexia-induced loss of adipose tissue is substantially restored compared to a mammal that does not receive AR-42. 15. The method of claim 2, wherein a cachexia-induced reduction in skeletal muscle fiber size is substantially restored by AR-42 compared to a mammal that does not receive AR-42. 16. A method of maintaining skeletal muscle weight in a mammal having cancer comprising administering a HDAC class 1 and 2b inhibitor to said mammal in an amount effective to maintain at least about 90% of said mammal's skeletal muscle weight over a period of time of at least fifteen days compared to a mammal that does not receive the HDAC class 1 and 2b inhibitor. 17. The method of claim 16, wherein the HDAC class 1 and 2b inhibitor is AR-42. 18. A method of prolonging survival of a mammal having cancer comprising administering a HDAC class 1 and 2b inhibitor to the mammal in an amount effective to substantially prolong survival of the mammal compared to a mammal that does not receive the HDAC class 1 and 2b inhibitor. 19. The method of claim 18, wherein the HDAC class 1 and 2b inhibitor is AR-42. 20. The method of claim 18 wherein the mammal survives at least about 21 days after the administering of AR-42 to the mammal.
| 1,600 |
909 | 15,313,512 | 1,613 |
The instant disclosure provides embodiments of orally disintegrating tablet compositions that have rapid disintegrability in the oral cavity and comprise solid lipid particles enclosing at least one active ingredient to mask any unpleasant tastes associated with the active ingredient. Also provided is the process of preparing such orally disintegrating tablet pharmaceutical compositions.
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1. A pharmaceutical composition, comprising:
an orally disintegrating tablet comprising a disintegrant, a binder, and a plurality of solid lipid particles, said solid lipid particles comprising an active agent and a lipid matrix, wherein said binder is present in an amount of from 10 weight percent to 60 weight percent of the total weight of the tablet, wherein said solid lipid particles have an average size of 500 micrometers or less, and wherein the solid lipid particles are present in an amount of from 1 weight percent to 75 weight percent of the total tablet weight. 2. The pharmaceutical composition of claim 1, wherein said disintegrant is selected from the group consisting of a cross-linked polymer, cellulose, microcrystalline cellulose, methyl cellulose, low-substituted hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, croscarmellose, hydroxypropyl methyl cellulose, starch, pregelatinized starch, sodium starch glycolate, sodium carboxymethyl starch, and mixtures thereof. 3. The pharmaceutical composition of claim 1, wherein the disintegrant is selected from the group consisting of sodium starch glycolate, crospovidone, polacrilin potassium, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, starch, sodium carboxymethyl starch, alginic acid, sodium alginate, citric acid, malic acid, tartaric acid, sodium bicarbonate, potassium bicarbonate, calcium carbonate, talc, calcium silicate, silicon dioxide, colloidal silicon dioxide, agar, guar gum, pectin, gellan gum, ion exchange resin, and mixtures thereof. 4. The pharmaceutical composition of claim 1, wherein said disintegrant is present in an amount from 0.5 weight percent to 10 weight percent, based on the total weight of the tablet. 5. The pharmaceutical composition of claim 1, wherein said binder is selected from the group consisting of dextrose, fructose, sucrose, lactose, maltose, mannitol, maltodextrin, colloidal silicon dioxide, corn syrup solids, starch, pregelatinized starch, sorbitol, erythritol, lactitol, fructose, maltitol, trehalose, xylitol, microcrystalline cellulose, gelatin, and combinations thereof. 6. (canceled) 7. The pharmaceutical composition of claim 1, wherein the composition further comprises at least one anti-sticking aid. 8. The pharmaceutical composition of claim 7, wherein the at least one anti-sticking aid selected from the group consisting essentially of talc, calcium carbonate, silica, colloidal silicon dioxide, magnesium trisilicate, starch, tribasic calcium phosphate, or a combination thereof. 9. The pharmaceutical composition of claim 1, further comprising at least one of a flavorant, a sweetener, and combinations thereof, wherein said at least one flavorant, sweetener, and combinations thereof are present outside said solid lipid particles. 10. The pharmaceutical composition of claim 1, wherein said solid lipid particles comprise a continuous phase having a melting point of from 35° C. to 85° C. 11. The pharmaceutical composition of claim 1, wherein said active agent has a particle size ranging from 0.1 micrometers to 10 micrometers in average diameter. 12. The pharmaceutical composition of claim 1, wherein the active agent is completely solubilized in, partially solubilized in, or suspended in the lipid matrix. 13. (canceled) 14. The pharmaceutical composition of claim 1, wherein said solid lipid particles have an average particle size of 250 micrometers or less. 15. The pharmaceutical composition of claim 1, wherein said active agent is selected from dextromethorphan, fexofenadine, guaifenesin, loratadine, sildenafil, vardenafil, tadafil, olanzapine, risperdone, famotidine, loperamide, zolmitriptan, ondansetron, cetirizine, desloratadine, rizatriptan, piroxicam, paracetamol, phloro-glucinol, nicergoline, metopimazine, dihydroergotamine, mirtazapine, clozapine, zolmitriptan, prednisolone, levodopa, carbidopa, lamotrigine, ibuprofen, oxycodone, diphenhydramine, ramosetron, tramadol, zolpidem, fluoxetine, hyoscyamine and combinations thereof. 16. (canceled) 17. The pharmaceutical composition of claim 1, wherein said tablet has a physical robustness in a range from 15 N to 100 N. 18. The pharmaceutical composition of claim 1, wherein said tablet has a physical robustness in a range from 20 N to 50 N. 19. The pharmaceutical composition of claim 1, wherein the active agent comprises at least one of fexofenadine and loratadine. 20. A pharmaceutical composition comprising,
a solid lipid particle in spherical form which is substantially insensitive to moisture, comprising a lipid matrix that includes at least one of (i) a mixture of monoglycerides, diglycerides, and triglycerides having carbon number ranging from C6 to C40, (ii) esters of fatty acids having carbon number ranging from C6 to C12 with ethylene glycol or propylene glycol, (iii) a mixture of triglyceridies having medium chain length, or (iv) a mixture of glycerides having carbon number ranging from C18 to C24; an active ingredient having a taste, the active ingredient incorporated into said solid lipid particle; a mixture of excipients comprising at least one disintegrant and at least one binder; wherein said solid lipid particle intrinsically masks taste of said active ingredient.
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The instant disclosure provides embodiments of orally disintegrating tablet compositions that have rapid disintegrability in the oral cavity and comprise solid lipid particles enclosing at least one active ingredient to mask any unpleasant tastes associated with the active ingredient. Also provided is the process of preparing such orally disintegrating tablet pharmaceutical compositions.1. A pharmaceutical composition, comprising:
an orally disintegrating tablet comprising a disintegrant, a binder, and a plurality of solid lipid particles, said solid lipid particles comprising an active agent and a lipid matrix, wherein said binder is present in an amount of from 10 weight percent to 60 weight percent of the total weight of the tablet, wherein said solid lipid particles have an average size of 500 micrometers or less, and wherein the solid lipid particles are present in an amount of from 1 weight percent to 75 weight percent of the total tablet weight. 2. The pharmaceutical composition of claim 1, wherein said disintegrant is selected from the group consisting of a cross-linked polymer, cellulose, microcrystalline cellulose, methyl cellulose, low-substituted hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, croscarmellose, hydroxypropyl methyl cellulose, starch, pregelatinized starch, sodium starch glycolate, sodium carboxymethyl starch, and mixtures thereof. 3. The pharmaceutical composition of claim 1, wherein the disintegrant is selected from the group consisting of sodium starch glycolate, crospovidone, polacrilin potassium, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, starch, sodium carboxymethyl starch, alginic acid, sodium alginate, citric acid, malic acid, tartaric acid, sodium bicarbonate, potassium bicarbonate, calcium carbonate, talc, calcium silicate, silicon dioxide, colloidal silicon dioxide, agar, guar gum, pectin, gellan gum, ion exchange resin, and mixtures thereof. 4. The pharmaceutical composition of claim 1, wherein said disintegrant is present in an amount from 0.5 weight percent to 10 weight percent, based on the total weight of the tablet. 5. The pharmaceutical composition of claim 1, wherein said binder is selected from the group consisting of dextrose, fructose, sucrose, lactose, maltose, mannitol, maltodextrin, colloidal silicon dioxide, corn syrup solids, starch, pregelatinized starch, sorbitol, erythritol, lactitol, fructose, maltitol, trehalose, xylitol, microcrystalline cellulose, gelatin, and combinations thereof. 6. (canceled) 7. The pharmaceutical composition of claim 1, wherein the composition further comprises at least one anti-sticking aid. 8. The pharmaceutical composition of claim 7, wherein the at least one anti-sticking aid selected from the group consisting essentially of talc, calcium carbonate, silica, colloidal silicon dioxide, magnesium trisilicate, starch, tribasic calcium phosphate, or a combination thereof. 9. The pharmaceutical composition of claim 1, further comprising at least one of a flavorant, a sweetener, and combinations thereof, wherein said at least one flavorant, sweetener, and combinations thereof are present outside said solid lipid particles. 10. The pharmaceutical composition of claim 1, wherein said solid lipid particles comprise a continuous phase having a melting point of from 35° C. to 85° C. 11. The pharmaceutical composition of claim 1, wherein said active agent has a particle size ranging from 0.1 micrometers to 10 micrometers in average diameter. 12. The pharmaceutical composition of claim 1, wherein the active agent is completely solubilized in, partially solubilized in, or suspended in the lipid matrix. 13. (canceled) 14. The pharmaceutical composition of claim 1, wherein said solid lipid particles have an average particle size of 250 micrometers or less. 15. The pharmaceutical composition of claim 1, wherein said active agent is selected from dextromethorphan, fexofenadine, guaifenesin, loratadine, sildenafil, vardenafil, tadafil, olanzapine, risperdone, famotidine, loperamide, zolmitriptan, ondansetron, cetirizine, desloratadine, rizatriptan, piroxicam, paracetamol, phloro-glucinol, nicergoline, metopimazine, dihydroergotamine, mirtazapine, clozapine, zolmitriptan, prednisolone, levodopa, carbidopa, lamotrigine, ibuprofen, oxycodone, diphenhydramine, ramosetron, tramadol, zolpidem, fluoxetine, hyoscyamine and combinations thereof. 16. (canceled) 17. The pharmaceutical composition of claim 1, wherein said tablet has a physical robustness in a range from 15 N to 100 N. 18. The pharmaceutical composition of claim 1, wherein said tablet has a physical robustness in a range from 20 N to 50 N. 19. The pharmaceutical composition of claim 1, wherein the active agent comprises at least one of fexofenadine and loratadine. 20. A pharmaceutical composition comprising,
a solid lipid particle in spherical form which is substantially insensitive to moisture, comprising a lipid matrix that includes at least one of (i) a mixture of monoglycerides, diglycerides, and triglycerides having carbon number ranging from C6 to C40, (ii) esters of fatty acids having carbon number ranging from C6 to C12 with ethylene glycol or propylene glycol, (iii) a mixture of triglyceridies having medium chain length, or (iv) a mixture of glycerides having carbon number ranging from C18 to C24; an active ingredient having a taste, the active ingredient incorporated into said solid lipid particle; a mixture of excipients comprising at least one disintegrant and at least one binder; wherein said solid lipid particle intrinsically masks taste of said active ingredient.
| 1,600 |
910 | 15,723,826 | 1,646 |
A method of treating autoimmune diseases and transplant rejection, comprising the step of treating the autoimmune or transplant patient with an effective amount of SU-5416 is disclosed.
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1. A method of treating a patient with an autoimmune disease or inflammatory disorder comprising the step of:
(a) treating the patient with an effective amount of SU5416, wherein at least one symptom of disease is reduced or alleviated. 2. The method of claim 1, wherein the patient is treated when at least one symptom of the disease is diagnosed. 3. The method of claim 2, wherein the symptom is at acute phase. 4. The method of claim 1 further comprising the step of treating the patient with at least one additional therapeutic compound. 5. The method of claim 4, wherein the additional compound enhances T-cell differentiation to regulatory T cells. 6. The method of claim 5, wherein the compound is selected from the group consisting of Thymoglobulin (rATG), Campath, costimulatory blockade, infliximab, etanercept, adalimumab, golimumab, natalizumab, cytokines IL-10, IL-2, TGF-β, NSAIDs, corticosteroids, immune suppressants and TNF-α inhibitors. 7. The method of claim 6, wherein the immune suppressant is selected from the group consisting of calcineurin inhibitors, corticosteroids, anti-proliferatives, and mTOR inhibitors. 8. The method of claim 1, wherein the dose of SU5416 in the composition is 30-150 mg/m2. 9. The method of claim 8, wherein the dose of SU5416 in the composition is 85-145 mg/m2. 10. The method of claim 1, wherein the acute symptoms are treated for a few weeks to months. 11. The method of claim 1, wherein the disease treated is an autoimmune disease or inflammatory disorder selected from the group consisting of rheumatoid arthritis, psoriatic arthritis diabetes, multiple sclerosis, interstitial fibrosis, lupus, glomerulonephritis, Crohn's Disease, inflammatory bowel disease, psoriasis and autoimmune eye diseases (uveitis). 12. A method of treating a transplant patient comprising the step of
(a) treating a patient with an effective amount of SU5416, wherein at least one symptom of transplant rejection is reduced or alleviated. 13. The method of claim 12, wherein the patient is treated when at least one symptoms of the transplant rejection is diagnosed. 14. The method of claim 13, wherein the symptom is at acute phase. 15. The method of claim 12 further comprising the step of treating the patient with at least one additional therapeutic compound. 16. The method of claim 15, wherein the additional compound enhances T-cell differentiation to regulatory T cells. 17. The method of claim 16, wherein the additional compound is selected from the group consisting of Thymoglobulin (rATG), Campath, costimulatory blockade, infliximab, etanercept, adalimumab, golimumab, natalizumab, cytokines IL-10, IL-2, TGF-β, NSAIDs, corticosteroids, immune suppressants and TNF-α inhibitors. 18. The method of claim 17, wherein the immune suppressant is selected from the group consisting of calcineurin inhibitors, corticosteroids, anti-proliferatives, and mTOR inhibitors, 19. The method of claim 12, wherein the disease treated is a solid organ transplant. 20. The method of claim 12, wherein the solid organ transplant is selected from the group consisting of lung transplant, bronchiolitis-obliterans syndrome (BOS), heart transplant, kidney transplant, liver transplant, pancreas transplant, and corneal transplant. 21. The method of claim 12, wherein the patient are treated for a few weeks to months. 22. The method of claim 12, wherein the amount of SU5416 in the treatment is 30-150 mg/m2. 23. The method of claim 22, wherein the amount of SU5416 in the treatment is 85-145 mg/m2. 24. A composition for treating autoimmune disease or transplant rejection comprising
(a) a effective amount of SU5416; and (b) at least one additional therapeutic compound. 25. The composition of claim 24, wherein the additional therapeutic compound enhances T-cell differentiation to regulatory T cells. 26. The composition of claim 25, wherein the additional compound is selected from the group consisting of Thymoglobulin (rATG), Campath, costimulatory blockade, infliximab, etanercept, adalimumab, golimumab, natalizumab, cytokines IL-10, IL-2, TGF-β, NSAIDs, corticosteroids, immune suppressants and TNF-α inhibitors. 27. The composition of claim 24, wherein the composition treats acute autoimmune disease. 28. The composition of claim 24, wherein the composition treats acute transplant rejection. 29. A method of discovering new therapeutic compounds, comprising the steps of:
(a) examining a target chemical for similar structure or function to SU5416, and (b) identifying a chemical with sufficient functional similarity to SU5416, wherein the treatment with the test chemical produces therapeutic results. 30. The method of claim 29 additionally comprising the step of (c) treating an autoimmune or transplant patient with the identified chemical. 31. The method of claim 30, wherein the suitable chemical equivalent of SU5416 would activate AHR. 32. The method of claim 31, wherein the suitable chemical equivalent of SU5416 would inhibit VEGFR.
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A method of treating autoimmune diseases and transplant rejection, comprising the step of treating the autoimmune or transplant patient with an effective amount of SU-5416 is disclosed.1. A method of treating a patient with an autoimmune disease or inflammatory disorder comprising the step of:
(a) treating the patient with an effective amount of SU5416, wherein at least one symptom of disease is reduced or alleviated. 2. The method of claim 1, wherein the patient is treated when at least one symptom of the disease is diagnosed. 3. The method of claim 2, wherein the symptom is at acute phase. 4. The method of claim 1 further comprising the step of treating the patient with at least one additional therapeutic compound. 5. The method of claim 4, wherein the additional compound enhances T-cell differentiation to regulatory T cells. 6. The method of claim 5, wherein the compound is selected from the group consisting of Thymoglobulin (rATG), Campath, costimulatory blockade, infliximab, etanercept, adalimumab, golimumab, natalizumab, cytokines IL-10, IL-2, TGF-β, NSAIDs, corticosteroids, immune suppressants and TNF-α inhibitors. 7. The method of claim 6, wherein the immune suppressant is selected from the group consisting of calcineurin inhibitors, corticosteroids, anti-proliferatives, and mTOR inhibitors. 8. The method of claim 1, wherein the dose of SU5416 in the composition is 30-150 mg/m2. 9. The method of claim 8, wherein the dose of SU5416 in the composition is 85-145 mg/m2. 10. The method of claim 1, wherein the acute symptoms are treated for a few weeks to months. 11. The method of claim 1, wherein the disease treated is an autoimmune disease or inflammatory disorder selected from the group consisting of rheumatoid arthritis, psoriatic arthritis diabetes, multiple sclerosis, interstitial fibrosis, lupus, glomerulonephritis, Crohn's Disease, inflammatory bowel disease, psoriasis and autoimmune eye diseases (uveitis). 12. A method of treating a transplant patient comprising the step of
(a) treating a patient with an effective amount of SU5416, wherein at least one symptom of transplant rejection is reduced or alleviated. 13. The method of claim 12, wherein the patient is treated when at least one symptoms of the transplant rejection is diagnosed. 14. The method of claim 13, wherein the symptom is at acute phase. 15. The method of claim 12 further comprising the step of treating the patient with at least one additional therapeutic compound. 16. The method of claim 15, wherein the additional compound enhances T-cell differentiation to regulatory T cells. 17. The method of claim 16, wherein the additional compound is selected from the group consisting of Thymoglobulin (rATG), Campath, costimulatory blockade, infliximab, etanercept, adalimumab, golimumab, natalizumab, cytokines IL-10, IL-2, TGF-β, NSAIDs, corticosteroids, immune suppressants and TNF-α inhibitors. 18. The method of claim 17, wherein the immune suppressant is selected from the group consisting of calcineurin inhibitors, corticosteroids, anti-proliferatives, and mTOR inhibitors, 19. The method of claim 12, wherein the disease treated is a solid organ transplant. 20. The method of claim 12, wherein the solid organ transplant is selected from the group consisting of lung transplant, bronchiolitis-obliterans syndrome (BOS), heart transplant, kidney transplant, liver transplant, pancreas transplant, and corneal transplant. 21. The method of claim 12, wherein the patient are treated for a few weeks to months. 22. The method of claim 12, wherein the amount of SU5416 in the treatment is 30-150 mg/m2. 23. The method of claim 22, wherein the amount of SU5416 in the treatment is 85-145 mg/m2. 24. A composition for treating autoimmune disease or transplant rejection comprising
(a) a effective amount of SU5416; and (b) at least one additional therapeutic compound. 25. The composition of claim 24, wherein the additional therapeutic compound enhances T-cell differentiation to regulatory T cells. 26. The composition of claim 25, wherein the additional compound is selected from the group consisting of Thymoglobulin (rATG), Campath, costimulatory blockade, infliximab, etanercept, adalimumab, golimumab, natalizumab, cytokines IL-10, IL-2, TGF-β, NSAIDs, corticosteroids, immune suppressants and TNF-α inhibitors. 27. The composition of claim 24, wherein the composition treats acute autoimmune disease. 28. The composition of claim 24, wherein the composition treats acute transplant rejection. 29. A method of discovering new therapeutic compounds, comprising the steps of:
(a) examining a target chemical for similar structure or function to SU5416, and (b) identifying a chemical with sufficient functional similarity to SU5416, wherein the treatment with the test chemical produces therapeutic results. 30. The method of claim 29 additionally comprising the step of (c) treating an autoimmune or transplant patient with the identified chemical. 31. The method of claim 30, wherein the suitable chemical equivalent of SU5416 would activate AHR. 32. The method of claim 31, wherein the suitable chemical equivalent of SU5416 would inhibit VEGFR.
| 1,600 |
911 | 15,107,206 | 1,616 |
The present invention provides a method of preserving cut roses in the absence of a water supply. The method comprises: (a) cutting roses having a flower bud or a bloomed flower; and (b) packaging the cut roses in a container without immersing or inserting the stems in a hydration system. Instead, the cut roses are treated before or during the packaging by applying a preservation composition onto the flower buds or bloomed flowers The preservation composition contains at least 5 ppm of plant hormone selected from cytokinin, gibberellins and combinations thereof. A flower shipment kit is also disclosed.
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1. -16. (canceled) 17. A flower shipment kit, comprising:
(a) a container defining an inner chamber; and (b) one or more cut roses contained within the inner chamber;
wherein flower buds or bloomed flowers of the one or more cut roses contain added plant hormone, selected from the group consisting of cytokinins, gibberellins and combinations thereof; and
wherein stems of the cut roses are not immersed or inserted into a hydration system. 18. The flower shipment kit according to claim 17, wherein the buds or flowers of the one or more cut roses contain at least 0.5 ppm of the plant hormone. 19. The flower shipment kit according to claim 17, wherein the plant hormone is a cytokinin. 20. The flower shipment kit according to claim 19, wherein the cytokinin is an adenine-type cytokinin. 21. The flower shipment kit according to claim 20, wherein the adenine-type cytokinin is 6-benzyladenine. 22. The flower shipment kit according to claim 19, wherein the cytokinin is thidiazuron. 23. The flower shipment kit according to claim 17, wherein the container is a box. 24. The flower shipment kit according to claim 17, wherein the added plant hormone at flower buds or bloomed flowers is at a concentration at least twice that of the concentration of the added plant hormone in the stems of the one or more cut roses. 25. The flower shipment kit according to claim 17, wherein the chamber of the container holds at least 10 cut roses. 26. A method of preserving cut roses during transportation or storage, comprising:
(a) packaging one or more cut roses having a stem and a flower bud or a bloomed flower in a container without immersing or inserting the stems in a hydration system; (b) applying a preservation composition, before or during the packaging, onto the flower buds or bloomed flowers of the cut roses, wherein the preservation composition comprises at least 5 ppm of plant hormone selected from cytokinin, gibberellins and combinations thereof. 27. The method according to claim 26, wherein the roses are in bud stage when the preservation composition is applied. 28. The method according to claim 26, wherein the preservation composition is applied onto the flower buds or bloomed flowers after the roses have been cut. 29. The method according to claim 26, wherein the preservation composition is applied by spraying or by dipping. 30. The method according to claim 26, further comprising keeping the treated roses in the packaging for at least 1 day under refrigeration conditions and without water supply.
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The present invention provides a method of preserving cut roses in the absence of a water supply. The method comprises: (a) cutting roses having a flower bud or a bloomed flower; and (b) packaging the cut roses in a container without immersing or inserting the stems in a hydration system. Instead, the cut roses are treated before or during the packaging by applying a preservation composition onto the flower buds or bloomed flowers The preservation composition contains at least 5 ppm of plant hormone selected from cytokinin, gibberellins and combinations thereof. A flower shipment kit is also disclosed.1. -16. (canceled) 17. A flower shipment kit, comprising:
(a) a container defining an inner chamber; and (b) one or more cut roses contained within the inner chamber;
wherein flower buds or bloomed flowers of the one or more cut roses contain added plant hormone, selected from the group consisting of cytokinins, gibberellins and combinations thereof; and
wherein stems of the cut roses are not immersed or inserted into a hydration system. 18. The flower shipment kit according to claim 17, wherein the buds or flowers of the one or more cut roses contain at least 0.5 ppm of the plant hormone. 19. The flower shipment kit according to claim 17, wherein the plant hormone is a cytokinin. 20. The flower shipment kit according to claim 19, wherein the cytokinin is an adenine-type cytokinin. 21. The flower shipment kit according to claim 20, wherein the adenine-type cytokinin is 6-benzyladenine. 22. The flower shipment kit according to claim 19, wherein the cytokinin is thidiazuron. 23. The flower shipment kit according to claim 17, wherein the container is a box. 24. The flower shipment kit according to claim 17, wherein the added plant hormone at flower buds or bloomed flowers is at a concentration at least twice that of the concentration of the added plant hormone in the stems of the one or more cut roses. 25. The flower shipment kit according to claim 17, wherein the chamber of the container holds at least 10 cut roses. 26. A method of preserving cut roses during transportation or storage, comprising:
(a) packaging one or more cut roses having a stem and a flower bud or a bloomed flower in a container without immersing or inserting the stems in a hydration system; (b) applying a preservation composition, before or during the packaging, onto the flower buds or bloomed flowers of the cut roses, wherein the preservation composition comprises at least 5 ppm of plant hormone selected from cytokinin, gibberellins and combinations thereof. 27. The method according to claim 26, wherein the roses are in bud stage when the preservation composition is applied. 28. The method according to claim 26, wherein the preservation composition is applied onto the flower buds or bloomed flowers after the roses have been cut. 29. The method according to claim 26, wherein the preservation composition is applied by spraying or by dipping. 30. The method according to claim 26, further comprising keeping the treated roses in the packaging for at least 1 day under refrigeration conditions and without water supply.
| 1,600 |
912 | 14,644,608 | 1,628 |
The present invention provides a method of treating depression disease in a patient comprising administering to a mucosal membrane of a patient an effective amount of a pharmaceutically acceptable composition comprising an effective amount of ketamine or dextromethorphan, or both ketamine and dextromethorphan, wherein the mucosal administration of the ketamine or dextromethorphan containing composition allows for the mucosal absorption of the composition eliminating the digestive tract of the patient for effecting a rapid acting antidepressant treatment of the patient. Preferably, this method includes administering the composition to the oral cavity, and more preferably to the buccal cavity, of the patient. A pharmaceutically acceptable composition comprising ketamine or dextromethorphan and a vehicle is disclosed. A biomarker for identifying a depressive disease is set forth. A method of treating depressive illness in a patient using dextromethorphan via the oral route is provided.
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1. A method of treating depression disease in a patient comprising:
administering to a mucosal membrane of a patient an effective amount of a composition comprising an effective amount of ketamine or dextromethorphan, or both, wherein said mucosal administration of said composition allows for the transmucosal absorption of the composition into the patient's blood stream thereby eliminating the digestive tract of said patient for providing a rapid acting antidepressant effect for treating depression in the patient. 2. The method of claim 1 including administering said composition to said mucosal membrane of said patient over a time period from one millisecond to ten minutes. 3. The method of claim 2 including wherein said time period is from one second to three minutes. 4. The method of claim 1 including wherein said composition is contained within a dosage form capable of being administered to the mucosa of said patient or to the mucosal membrane of said patient. 5. The method of claim 4 including wherein said dosage form is a liquid, gel, powder. 6. The method of claim 4 including wherein said dosage form is in the form of a pharmaceutically acceptable troche, film, capsule, tablet, particle, solution, suspension, lollipop, lozenge, emulsion, spray, or aerosol. 7. The method of claim 1 including wherein said effective amount of said ketamine is 0.5 mg per kilogram of a patient's body mass. 8. The method of claim 1 including administering said composition to said mucosal membrane that is in an oral cavity of said patient. 9. The method of claim 8 including administering said composition to a buccal cavity of said oral cavity of said patient. 10. The method of claim 1 wherein said depression is selected from the group of unipolar depression disease, bipolar depression disease, and depression treatment resistant disease. 11. A pharmaceutically acceptable composition comprising:
an effective amount of ketamine or dextromethorphan, or both ketamine and dextromethorphan, wherein said ketamine or said dextromethorphan, or both are distributed within a pharmaceutically acceptable vehicle, wherein said vehicle is capable of being placed in contact with a mucosal membrane of a patient. 12. The pharmaceutically acceptable composition of claim 11 wherein said composition and said vehicle are capable of delivery to an oral cavity of said patient. 13. The pharmaceutically acceptable composition of claim 12 wherein said composition and said vehicle are capable of delivery to a buccal cavity of the oral cavity of said patient. 14. The pharmaceutically acceptable composition of claim 11 including wherein said composition has a dosage form that is a liquid, gel, or powder. 15. The pharmaceutically acceptable composition of claim 11 that is a dosage form of a pharmaceutically acceptable troche, film, capsule, tablet, particle, solution, suspension, lollipop, lozenge, emulsion, spray, or aerosol. 16. The pharmaceutically acceptable composition of claim 14 including wherein said effective amount of said dextromethorphan is 0.5 mg to 2000.0 mg per dosage form, and wherein said effective amount of said ketamine is approximately 0.5 mg per kilogram of a patient's body mass per dosage form. 17. The pharmaceutically acceptable composition of claim 11 wherein said pharmaceutically acceptable vehicle is capable of being placed in contact with a mucosal membrane of a patient, and wherein the pharmaceutically acceptable vehicle is a device having a mucoadhesive layer containing said ketamine buffered to a pH of between about 4.0 and 7.0, and a non-adhesive backing layer buffered to a pH of between 4.0 and 6.0 wherein the pH of the mucoadhesive layer and the pH of the non-adhesive backing layer are different, wherein the mucoadhesive layer and the non-adhesive backing layer comprise different combinations of polymers but each layer comprises at least one water-erodible polymer selected from the group of cellulosic polymers, olefinic polymers, polyethers, and polyalcohols. 18. The pharmaceutically acceptable composition of claim 17 wherein said water-erodible polymer is at least one selected from the group consisting of polyacrylic acid, sodium carboxymethylcellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, polyethylene oxide, and ethylene oxide-propylene oxide co-polymers. 19. The pharmaceutically acceptable composition of claim 17 wherein said device is in the form of a transmucosal buccal tablet or buccal film. 20. The pharmaceutically acceptable composition of claim 17 including at least one buffering agent contained in said mucoadhesive layer for use in buffering the pH of ketamine or dextromethorphan, or both ketamine and dextromethorphan. 21. The pharmaceutically acceptable composition of claim 20 wherein said buffering agent is selected from the group of phosphates, phosphates monobasic, phosphates dibasic, phosphates tribasic, bicarbonates, acetates, and combinations thereof. 22. The pharmaceutically acceptable composition of claim 17 including a hydrophobic polymer for coating said non-adhesive backing layer for controlling the erodibility of the layer 23. A biomarker for identifying depressive disease in a patient comprising predicting responsiveness to treating a patient by administration to said patient of a pharmaceutically acceptable composition of ketamine, or dextromethorphan, or a combination of ketamine and dextromethorphan, and evaluating a change in alterations in acoustic vocal parameters comprising speech rate and voice frequency, and alterations in corticospinal excitability comprising resting motor threshold, in a patient at baseline prior to treatment and after treatment of said patient. 24. A method of treating depression disease in a patient comprising:
administering to a patient an effective amount of a composition comprising an effective amount of dextromethorphan via the oral route of said patient for providing a rapid acting antidepressant effect for treating depression in the patient.
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The present invention provides a method of treating depression disease in a patient comprising administering to a mucosal membrane of a patient an effective amount of a pharmaceutically acceptable composition comprising an effective amount of ketamine or dextromethorphan, or both ketamine and dextromethorphan, wherein the mucosal administration of the ketamine or dextromethorphan containing composition allows for the mucosal absorption of the composition eliminating the digestive tract of the patient for effecting a rapid acting antidepressant treatment of the patient. Preferably, this method includes administering the composition to the oral cavity, and more preferably to the buccal cavity, of the patient. A pharmaceutically acceptable composition comprising ketamine or dextromethorphan and a vehicle is disclosed. A biomarker for identifying a depressive disease is set forth. A method of treating depressive illness in a patient using dextromethorphan via the oral route is provided.1. A method of treating depression disease in a patient comprising:
administering to a mucosal membrane of a patient an effective amount of a composition comprising an effective amount of ketamine or dextromethorphan, or both, wherein said mucosal administration of said composition allows for the transmucosal absorption of the composition into the patient's blood stream thereby eliminating the digestive tract of said patient for providing a rapid acting antidepressant effect for treating depression in the patient. 2. The method of claim 1 including administering said composition to said mucosal membrane of said patient over a time period from one millisecond to ten minutes. 3. The method of claim 2 including wherein said time period is from one second to three minutes. 4. The method of claim 1 including wherein said composition is contained within a dosage form capable of being administered to the mucosa of said patient or to the mucosal membrane of said patient. 5. The method of claim 4 including wherein said dosage form is a liquid, gel, powder. 6. The method of claim 4 including wherein said dosage form is in the form of a pharmaceutically acceptable troche, film, capsule, tablet, particle, solution, suspension, lollipop, lozenge, emulsion, spray, or aerosol. 7. The method of claim 1 including wherein said effective amount of said ketamine is 0.5 mg per kilogram of a patient's body mass. 8. The method of claim 1 including administering said composition to said mucosal membrane that is in an oral cavity of said patient. 9. The method of claim 8 including administering said composition to a buccal cavity of said oral cavity of said patient. 10. The method of claim 1 wherein said depression is selected from the group of unipolar depression disease, bipolar depression disease, and depression treatment resistant disease. 11. A pharmaceutically acceptable composition comprising:
an effective amount of ketamine or dextromethorphan, or both ketamine and dextromethorphan, wherein said ketamine or said dextromethorphan, or both are distributed within a pharmaceutically acceptable vehicle, wherein said vehicle is capable of being placed in contact with a mucosal membrane of a patient. 12. The pharmaceutically acceptable composition of claim 11 wherein said composition and said vehicle are capable of delivery to an oral cavity of said patient. 13. The pharmaceutically acceptable composition of claim 12 wherein said composition and said vehicle are capable of delivery to a buccal cavity of the oral cavity of said patient. 14. The pharmaceutically acceptable composition of claim 11 including wherein said composition has a dosage form that is a liquid, gel, or powder. 15. The pharmaceutically acceptable composition of claim 11 that is a dosage form of a pharmaceutically acceptable troche, film, capsule, tablet, particle, solution, suspension, lollipop, lozenge, emulsion, spray, or aerosol. 16. The pharmaceutically acceptable composition of claim 14 including wherein said effective amount of said dextromethorphan is 0.5 mg to 2000.0 mg per dosage form, and wherein said effective amount of said ketamine is approximately 0.5 mg per kilogram of a patient's body mass per dosage form. 17. The pharmaceutically acceptable composition of claim 11 wherein said pharmaceutically acceptable vehicle is capable of being placed in contact with a mucosal membrane of a patient, and wherein the pharmaceutically acceptable vehicle is a device having a mucoadhesive layer containing said ketamine buffered to a pH of between about 4.0 and 7.0, and a non-adhesive backing layer buffered to a pH of between 4.0 and 6.0 wherein the pH of the mucoadhesive layer and the pH of the non-adhesive backing layer are different, wherein the mucoadhesive layer and the non-adhesive backing layer comprise different combinations of polymers but each layer comprises at least one water-erodible polymer selected from the group of cellulosic polymers, olefinic polymers, polyethers, and polyalcohols. 18. The pharmaceutically acceptable composition of claim 17 wherein said water-erodible polymer is at least one selected from the group consisting of polyacrylic acid, sodium carboxymethylcellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, polyethylene oxide, and ethylene oxide-propylene oxide co-polymers. 19. The pharmaceutically acceptable composition of claim 17 wherein said device is in the form of a transmucosal buccal tablet or buccal film. 20. The pharmaceutically acceptable composition of claim 17 including at least one buffering agent contained in said mucoadhesive layer for use in buffering the pH of ketamine or dextromethorphan, or both ketamine and dextromethorphan. 21. The pharmaceutically acceptable composition of claim 20 wherein said buffering agent is selected from the group of phosphates, phosphates monobasic, phosphates dibasic, phosphates tribasic, bicarbonates, acetates, and combinations thereof. 22. The pharmaceutically acceptable composition of claim 17 including a hydrophobic polymer for coating said non-adhesive backing layer for controlling the erodibility of the layer 23. A biomarker for identifying depressive disease in a patient comprising predicting responsiveness to treating a patient by administration to said patient of a pharmaceutically acceptable composition of ketamine, or dextromethorphan, or a combination of ketamine and dextromethorphan, and evaluating a change in alterations in acoustic vocal parameters comprising speech rate and voice frequency, and alterations in corticospinal excitability comprising resting motor threshold, in a patient at baseline prior to treatment and after treatment of said patient. 24. A method of treating depression disease in a patient comprising:
administering to a patient an effective amount of a composition comprising an effective amount of dextromethorphan via the oral route of said patient for providing a rapid acting antidepressant effect for treating depression in the patient.
| 1,600 |
913 | 14,611,643 | 1,632 |
A recombinant herpes virus showing high antitumor activity is provided. In particular, a recombinant herpes simplex virus that expresses an ICP6 gene under control of a tumor-specific promoter or tissue-specific promoter on the genome of the virus is provided.
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1-4. (canceled) 5. A recombinant herpes simplex virus comprising an endogenous ICP6 gene functionally linked to a tumor-specific promoter or tissue-specific promoter. 6. The recombinant herpes simplex virus according to claim 5, wherein the tumor-specific promoter or tissue-specific promoter is a promoter selected from the group consisting of a human telomerase reverse transcriptase (hTERT) promoter, a PSES promoter, and an osteocalcin (OC) promoter. 7. The recombinant herpes simplex virus according to claim 5, wherein a γ34.5 gene and/or an ICP47 gene is deleted or inactivated. 8. A pharmaceutical composition comprising the recombinant herpes simplex virus as claimed in claim 5 as an active ingredient. 9. The pharmaceutical composition according to claim 8, which is a therapeutic agent for a tumor. 10. The pharmaceutical composition according to claim 9, wherein the tumor is a tumor selected from the group consisting of tumors with a low growth rate, benign tumors, and tumors with low ribonucleotide reductase activity. 11. The pharmaceutical composition according to claim 9, wherein the tumor is a tumor selected from the group consisting of prostate cancer, kidney cancer, breast cancer, chondrosarcoma, and meningioma. 12. A method of treating a tumor in a subject, comprising administering a therapeutically effective amount of the recombinant herpes simplex virus as claimed in claim 5 to the subject.
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A recombinant herpes virus showing high antitumor activity is provided. In particular, a recombinant herpes simplex virus that expresses an ICP6 gene under control of a tumor-specific promoter or tissue-specific promoter on the genome of the virus is provided.1-4. (canceled) 5. A recombinant herpes simplex virus comprising an endogenous ICP6 gene functionally linked to a tumor-specific promoter or tissue-specific promoter. 6. The recombinant herpes simplex virus according to claim 5, wherein the tumor-specific promoter or tissue-specific promoter is a promoter selected from the group consisting of a human telomerase reverse transcriptase (hTERT) promoter, a PSES promoter, and an osteocalcin (OC) promoter. 7. The recombinant herpes simplex virus according to claim 5, wherein a γ34.5 gene and/or an ICP47 gene is deleted or inactivated. 8. A pharmaceutical composition comprising the recombinant herpes simplex virus as claimed in claim 5 as an active ingredient. 9. The pharmaceutical composition according to claim 8, which is a therapeutic agent for a tumor. 10. The pharmaceutical composition according to claim 9, wherein the tumor is a tumor selected from the group consisting of tumors with a low growth rate, benign tumors, and tumors with low ribonucleotide reductase activity. 11. The pharmaceutical composition according to claim 9, wherein the tumor is a tumor selected from the group consisting of prostate cancer, kidney cancer, breast cancer, chondrosarcoma, and meningioma. 12. A method of treating a tumor in a subject, comprising administering a therapeutically effective amount of the recombinant herpes simplex virus as claimed in claim 5 to the subject.
| 1,600 |
914 | 16,278,030 | 1,656 |
The present invention provides a microorganism-derived soluble coenzyme-binding glucose dehydrogenase which catalyzes a reaction for oxidizing glucose in the presence of an electron acceptor, has an activity to maltose as low as 5% or less, and is inhibited by 1,10-phenanthroline. The invention also provides a method for producing the coenzyme-binding glucose dehydrogenase, and a method and a reagent for measuring employing the coenzyme-binding glucose dehydrogenase. According to the invention, the coenzyme-binding glucose dehydrogenase can be applied to an industrial field, and a use becomes possible also in a material production or analysis including a method for measuring or eliminating glucose in a sample using the coenzyme-binding glucose dehydrogenase as well as a method for producing an organic compound. It became also possible to provide a glucose sensor capable of accurately measuring a blood sugar level. Therefore, it became possible to provide an enzyme having a high utility, such as an ability of being used for modifying a material in the fields of pharmaceuticals, clinical studies and food products.
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1-22. (canceled) 23. A biosensor for measuring glucose, comprising:
an electrode system comprising an action electrode and a counter electrode; and an enzymatic reaction layer in contact with the action electrode and/or the counter electrode, the enzymatic reaction layer comprising an electron acceptor and a soluble flavin compound-binding glucose dehydrogenase obtained from Aspergillus wherein the flavin compound-binding glucose dehydrogenase is secreted from an Aspergillus fungal body and has enzymatic activity to glucose comprising catalyzing a reaction for oxidizing glucose in the presence of the electron acceptor, wherein enzymatic activity to maltose is 5% or less relative to the enzymatic activity to glucose, and wherein enzymatic activity to D-fructose is not more than enzymatic activity to D-mannose, and wherein the biosensor can quantify glucose concentrations ranging from 4.5 mM to 30 mM. 24. The biosensor of claim 23, wherein the enzymatic activity to maltose is 3% or less relative to the enzymatic activity to glucose.
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The present invention provides a microorganism-derived soluble coenzyme-binding glucose dehydrogenase which catalyzes a reaction for oxidizing glucose in the presence of an electron acceptor, has an activity to maltose as low as 5% or less, and is inhibited by 1,10-phenanthroline. The invention also provides a method for producing the coenzyme-binding glucose dehydrogenase, and a method and a reagent for measuring employing the coenzyme-binding glucose dehydrogenase. According to the invention, the coenzyme-binding glucose dehydrogenase can be applied to an industrial field, and a use becomes possible also in a material production or analysis including a method for measuring or eliminating glucose in a sample using the coenzyme-binding glucose dehydrogenase as well as a method for producing an organic compound. It became also possible to provide a glucose sensor capable of accurately measuring a blood sugar level. Therefore, it became possible to provide an enzyme having a high utility, such as an ability of being used for modifying a material in the fields of pharmaceuticals, clinical studies and food products.1-22. (canceled) 23. A biosensor for measuring glucose, comprising:
an electrode system comprising an action electrode and a counter electrode; and an enzymatic reaction layer in contact with the action electrode and/or the counter electrode, the enzymatic reaction layer comprising an electron acceptor and a soluble flavin compound-binding glucose dehydrogenase obtained from Aspergillus wherein the flavin compound-binding glucose dehydrogenase is secreted from an Aspergillus fungal body and has enzymatic activity to glucose comprising catalyzing a reaction for oxidizing glucose in the presence of the electron acceptor, wherein enzymatic activity to maltose is 5% or less relative to the enzymatic activity to glucose, and wherein enzymatic activity to D-fructose is not more than enzymatic activity to D-mannose, and wherein the biosensor can quantify glucose concentrations ranging from 4.5 mM to 30 mM. 24. The biosensor of claim 23, wherein the enzymatic activity to maltose is 3% or less relative to the enzymatic activity to glucose.
| 1,600 |
915 | 14,332,865 | 1,616 |
This invention relates to the use of the compound flutriafol for protecting plants and plant propagation material from Sudden Death Syndrome. The use comprises applying a composition comprising flutriafol to the soil from which the plant propagation material, a plant, part of a plant and/or plant organ grow or grows at a later point in time.
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1. Use of flutriafol for controlling the causative agent of Sudden Death Syndrome (SDS) in a plant propagation material, a plant, part of a plant and/or plant organ, which comprises applying a composition comprising flutriafol to the soil from which the plant propagation material, a plant, part of a plant and/or plant organ grow or grows at a later point in time. 2. The use according to claim 1, wherein the causative agent is one of the following fungi Fusarium virguliforme, Fusarium brasiliense, Fusarium cuneirostrum, and Fusarium tucumaniae. 3. The use according to claim 1, wherein the composition is applied as in-furrow application to the soil from which the plant propagation material, a plant, part of a plant and/or plant organ grow or grows at a later point in time. 4. The use according to claim 1, wherein the composition is applied in an amount ranging from about 25 to about 800 grams flutriafol per hectare. 5. The use according to claim 1, wherein the composition further comprises one or more fertilizers. 6. The use according to claim 1, wherein the use further comprises applying one or more fertilizers and/or soil surfactants to the soil. 7. The use according to claim 1, wherein the use further comprises applying one or more additional fungicides, insecticides and/or nematicides to the soil. 8. The use according to claim 1, wherein the composition further comprises one or more additional fungicides, insecticides and/or nematicides. 9. The use according to claim 1, wherein the plant is selected from the families of Amaranthaceae, Brassicas, Leguminosae, and Poaceae. 10. (canceled) 11. A method of controlling or preventing the causative agent of Sudden Death Syndrome (SDS) in a plant propagation material, a plant, part of a plant and/or plant organ which comprises applying a composition comprising flutriafol to the soil from which the plant propagation material, a plant, part of a plant and/or plant organ grow or grows at a later point in time. 12. The method according to claim 11, wherein the causative agent is one of the following fungi Fusarium virguliforme, Fusarium brasiliense, Fusarium cuneirostrum, and Fusarium tucumaniae. 13. The method according to claim 11, wherein the composition is applied as in-furrow application to the soil from which the plant propagation material, a plant, part of a plant and/or plant organ grow or grows at a later point in time. 14. The method according to claim 11, wherein the composition is applied in an amount ranging from about 25 to about 800 grams flutriafol per hectare. 15. The method according to claim 11, wherein the composition further comprises one or more fertilizers. 16. The method according to claim 11, wherein the method further comprises applying one or more fertilizers and/or soil surfactants to the soil. 17. The method according to claim 11, wherein the composition further comprises one or more additional fungicides, insecticides and/or nematicides. 18. The method according to claim 11, wherein the method further comprises applying one or more additional fungicides, insecticides and/or nematicides to the soil. 19. The method according to claim 11, wherein the plant is selected from the families of Amaranthaceae, Brassicas, Leguminosae, and Poaceae. 20. (canceled) 21. (canceled) 22. (canceled)
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This invention relates to the use of the compound flutriafol for protecting plants and plant propagation material from Sudden Death Syndrome. The use comprises applying a composition comprising flutriafol to the soil from which the plant propagation material, a plant, part of a plant and/or plant organ grow or grows at a later point in time.1. Use of flutriafol for controlling the causative agent of Sudden Death Syndrome (SDS) in a plant propagation material, a plant, part of a plant and/or plant organ, which comprises applying a composition comprising flutriafol to the soil from which the plant propagation material, a plant, part of a plant and/or plant organ grow or grows at a later point in time. 2. The use according to claim 1, wherein the causative agent is one of the following fungi Fusarium virguliforme, Fusarium brasiliense, Fusarium cuneirostrum, and Fusarium tucumaniae. 3. The use according to claim 1, wherein the composition is applied as in-furrow application to the soil from which the plant propagation material, a plant, part of a plant and/or plant organ grow or grows at a later point in time. 4. The use according to claim 1, wherein the composition is applied in an amount ranging from about 25 to about 800 grams flutriafol per hectare. 5. The use according to claim 1, wherein the composition further comprises one or more fertilizers. 6. The use according to claim 1, wherein the use further comprises applying one or more fertilizers and/or soil surfactants to the soil. 7. The use according to claim 1, wherein the use further comprises applying one or more additional fungicides, insecticides and/or nematicides to the soil. 8. The use according to claim 1, wherein the composition further comprises one or more additional fungicides, insecticides and/or nematicides. 9. The use according to claim 1, wherein the plant is selected from the families of Amaranthaceae, Brassicas, Leguminosae, and Poaceae. 10. (canceled) 11. A method of controlling or preventing the causative agent of Sudden Death Syndrome (SDS) in a plant propagation material, a plant, part of a plant and/or plant organ which comprises applying a composition comprising flutriafol to the soil from which the plant propagation material, a plant, part of a plant and/or plant organ grow or grows at a later point in time. 12. The method according to claim 11, wherein the causative agent is one of the following fungi Fusarium virguliforme, Fusarium brasiliense, Fusarium cuneirostrum, and Fusarium tucumaniae. 13. The method according to claim 11, wherein the composition is applied as in-furrow application to the soil from which the plant propagation material, a plant, part of a plant and/or plant organ grow or grows at a later point in time. 14. The method according to claim 11, wherein the composition is applied in an amount ranging from about 25 to about 800 grams flutriafol per hectare. 15. The method according to claim 11, wherein the composition further comprises one or more fertilizers. 16. The method according to claim 11, wherein the method further comprises applying one or more fertilizers and/or soil surfactants to the soil. 17. The method according to claim 11, wherein the composition further comprises one or more additional fungicides, insecticides and/or nematicides. 18. The method according to claim 11, wherein the method further comprises applying one or more additional fungicides, insecticides and/or nematicides to the soil. 19. The method according to claim 11, wherein the plant is selected from the families of Amaranthaceae, Brassicas, Leguminosae, and Poaceae. 20. (canceled) 21. (canceled) 22. (canceled)
| 1,600 |
916 | 14,888,380 | 1,618 |
The present invention relates to balloon catheter coated with an active agent and a shellac alkali salt, preferably shellac ammonium salt. Moreover the present invention relates to a method for coating catheter balloons with a pharmacological active agent and an aqueous solution of shellac.
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1. A balloon catheter comprising a coating with an active agent and a water soluble shellac salt. 2. Balloon catheter according to claim 1, wherein the water soluble shellac salt is a shellac ammonium salt. 3. Balloon catheter according to claim 1 or 2, wherein the coating comprises a concentration gradient of the active agent 4. Balloon catheter according to anyone of claim 1-3, wherein the concentration gradient of the active agent is in the layer of water soluble shellac salt as a matrix substance. 5. Balloon catheter according to anyone of claim 1-4, wherein the active agent is an antirestenotic agent, antiproliferative, immunosuppressive, anti-angiogenic, anti-inflammatory, and/or anti-thrombotic agent. 6. Balloon catheter according to anyone of claim 1-5, wherein the active agent is selected from the group consisting of:
abciximab, acemetacin, acetylvismione B, aclarubicin, ademetionine, adriamycin, aescin, afromosone, akagerine, aldesleukin, amidorone, aminoglutethimide, amsacrine, anakinra, anastrozole, anemonin, anopterine, antimycotics antithrombotics, apocymarin, argatroban, aristolactam-AII, aristolochic acid, ascomycin, asparaginase, aspirin, atorvastatin, auranofin, azathioprine, azithromycin, baccatin, bafilomycin, basiliximab, bendamustine, benzocaine, berberine, betulin, betulinic acid, bilobol, bisparthenolidine, bleomycin, combrestatin, Boswellic acids, bruceanol A, B and C, bryophyllin A, busulfan, antithrombin, bivalirudin, cadherins, camptothecin, capecitabine, o-carbamoyl-phenoxyacetic acid, carboplatin, carmustine, celecoxib, cepharanthin, cerivastatin, CETP inhibitors, chlorambucil, chloroquine phosphate, cicutoxin, ciprofloxacin, cisplatin, cladribine, clarithromycin, colchicine, concanamycin, coumadin, C-type natriuretic peptide, cudraisoflavone A, curcumin, cyclophosphamide, ciclosporin A, cytarabine, dacarbazine, daclizumab, dactinomycin, dapsone, daunorubicin, diclofenac, 1,11-dimethoxycanthin-6-one, docetaxel, doxorubicin, daunamycin, epirubicin, erythromycin, estramustine, etoposide, everolimus, filgrastim, fluroblastin, fluvastatin, fludarabine, fludarabine-5′-dihydrogen phosphate, fluorouracil, folimycin, fosfestrol, gemcitabine, ghalakinoside, ginkgol, ginkgolic acid, glycoside 1a, 4-hydroxyoxycyclo phosphamide, idarubicin, ifosfamide, josamycin, lapachol, lomustine, lovastatin, melphalan, midecamycin, mitoxantrone, nimustine, pitavastatin, pravastatin, procarbazine, mitomycin, methotrexate, mercaptopurine, thioguanine, oxaliplatin, irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin, pegaspargase, exemestane, letrozole, formestane, mycophenolate mofetil, β-lapachone, podophyllotoxin, podophyllic acid-2-ethyl hydrazide, rhuGM-CSF, peginterferon α-2b, r-HuG-CSF, macrogol, cytokine antagonist, cytokinin inhibitors, COX-2 inhibitor, angiopeptin, monoclonal antibodies inhibiting muscle cell proliferation, bFGF antagonists, probucol, prostaglandins, 1-hydroxy-11-methoxycanthin-6-one, scopoletin, NO donors, pentaerythrityl tetranitrate and sydnoimines, tamoxifen, staurosporine, β-estradiol, α-estradiol, estriol, estrone, ethinyl estradiol, medroxyprogesterone, estradiol cypionates, estradiol benzoates, tranilast, kamebakaurin and other terpenoids used in cancer therapy, verapamil, tyrosine kinase inhibitors, paclitaxel, 6-α-hydroxy-paclitaxel, taxoteres, paclitaxel bound to albumin, nap-paclitaxel, mofebutazone, lonazolac, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, penicillamine, hydroxychloroquine, sodium aurothiomalate, oxaceprol, β-sitosterol, myrtecaine, polidocanol, nonivamide, levomenthol, ellipticine, colcemid, cytochalasin A-E, indanocine, nocodazole, bacitracin, vitronectin receptor antagonists, azelastine, guanidyl cyclase stimulator, tissue inhibitor of metal proteinase-1 and -2, free nucleic acids, nucleic acids incorporated into virus transmitters, DNA and RNA fragments, plasminogen activator inhibitor 1, plasminogen activator inhibitor 2, antisense oligonucleotides, VEGF inhibitors, IGF-1, active agents from the group of antibiotics, cefadroxil, cefazolin, cefaclor, cefoxitin, tobramycin, gentamicin, penicillins, dicloxacillin, oxacillin, sulfonamides, metronidazole, enoxaparin, heparin, hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators, dipyramidole, trapidil, nitroprussides, PDGF antagonists, triazolopyrimidine, seramin, ACE inhibitors, captopril, cilazapril, lisinopril, enalapril, losartan, thioprotease inhibitors, prostacyclin, vapiprost, interferon α, β and γ, histamine antagonists, serotonin blockers, apoptosis inhibitors, apoptosis regulators, halofuginone, nifedipine, tocopherol, tranilast, molsidomine, tea polyphenols, epicatechin gallate, epigallocatechin gallate, leflunomide, etanercept, sulfasalazine, tetracycline, triamcinolone, mutamycin, procainimide, retinoic acid, quinidine, disopyrimide, flecainide, propafenone, sotalol, natural and synthetically obtained steroids, bryophyllin A, inotodiol, maquiroside A, ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone, dexamethasone, non-steroidal substances, fenoprofen, ibuprofen, indomethacin, naproxen, phenylbutazone, antiviral agents, acyclovir, ganciclovir zidovudine, clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, terbinafine, antiprotozoal agents, chloroquine, mefloquine, quinine, natural terpenoids, hippocaesculin, barringtogenol-C21-angelate, 14-dehydroagrostistachin, agroskerin, agrostistachin, 17-hydroxyagrostistachin, ovatodiolids, 4,7-oxycycloanisomelic acid baccharinoids B1, B2, B3 and B7, tubeimoside, bruceantinoside C, yadanziosides N and P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A, B C and D, ursolic acid, hyptatic acid A, iso-iridogermanal, maytenfoliol, effusantin A, excisanin A and B, longikaurin B, sculponeatin C, kamebaunin, leukamenin A and B, 13,18-dehydro-6-alpha-senecioyloxychaparrin, taxamairin A and B, regenilol, triptolide, cymarin, hydroxyanopterine, protoanemonin, cheliburin chloride, sinococuline A and B, dihydronitidine, nitidine chloride, 12-β-hydroxypregnadien-3,20-dione, helenalin, indicine, indicine-N-oxide, lasiocarpine, inotodiol, podophyllotoxin, justicidin A and B, larreatin, malloterin, mallotochromanol, isobutyrylmallotochromanol, marchantin A, maytansin, lycoridicin, margetine, pancratistatin, liriodenine, oxoushinsunine, periplocoside A, deoxypsorospermin, psychorubin, ricin A, sanguinarine, manwu wheat acid, methylsorbifolin, chromones of spathelia, stizophyllin, dihydrousambaraensine, hydroxyusambarine, strychnopentamine, strychnophylline, usambarine, usambarensine, liriodenine, daphnoretin, lariciresinol, methoxylariciresinol, syringaresinol, sirolimus, biolimus A9, pimecrolimus, everolimus, zotarolimus, tacrolimus, sirolimus bound to albumin, nap-sirolimus, fasudil, epothilones, somatostatin, roxithromycin, troleandomycin, simvastatin, rosuvastatin, vinblastine, vincristine, vindesine, teniposide, vinorelbine, trofosfamide, treosulfan, temozolomide, thiotepa, tretinoin, spiramycin, umbelliferone, desacetylvismione A, vismione A and B, zeorin. 7. Balloon catheter according to claim 6, wherein the active agent is selected from the group consisting of:
paclitaxel, taxanes, docetaxel, paclitaxel bound to albumin, like nap-paclitaxel, sirolimus, biolimus A9, pimecrolimus, everolimus, zotarolimus, tacrolimus, sirolimus bound to albumin, like nap-sirolimus, fasudil and epothilones. 8. Balloon catheter according to claim 7, wherein the active agent is paclitaxel or sirolimus. 9. Balloon catheter according to anyone of claim 1-4, wherein the coating comprises further a water soluble polymer and/or a plasticizer. 10. Balloon catheter according to claim 9, wherein the water soluble polymer is selected from the group comprising cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, starch, hydroxyl ethyl starch, polyacrylic acid, polyethyleneimine, dextran, agar, carrageenan, alginate, copolymers and/or mixtures of these substances. 11. Method for coating a balloon catheter according to claim 1 comprising the following steps:
IA) providing an uncoated balloon catheter;
and
IIA) providing an aqueous solution of an active agent and a water soluble shellac salt;
or
IIB) providing a solution of the active agent and providing an aqueous solution of a water soluble shellac salt;
and
IIIA) coating the surface of the balloon of the balloon catheter with the aqueous solution of the active agent and the water soluble shellac salt;
or
IIIB) coating the surface of the balloon of the balloon catheter with the solution of the active agent and subsequently with the aqueous solution of the water soluble shellac salt or coating the surface of the balloon of the balloon catheter with the aqueous solution of the water soluble shellac salt and subsequently with the solution of active agent;
IV) drying the coated balloon,
wherein the aqueous solution of the water soluble shellac salt or the aqueous solution of the active agent and the water soluble shellac salt are prepared using an alkali salt or an ammonium salt of shellac. 12. Method according to claim 11, wherein the solution of the ammonium salt of shellac is a solution of ammonia, ammonium carbonate, or ammonium bicarbonate and shellac. 13. Method according to claim 11 or 12, wherein the active agent is paclitaxel or sirolimus. 14. Method according to any one of claims 11 to 13, wherein the active agent containing solution is applied by means of spray coating, brush coating, vapour deposition or pipetting. 15. Coated balloon catheter which can be obtained by the method according to any one of claims 11 to 14.
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The present invention relates to balloon catheter coated with an active agent and a shellac alkali salt, preferably shellac ammonium salt. Moreover the present invention relates to a method for coating catheter balloons with a pharmacological active agent and an aqueous solution of shellac.1. A balloon catheter comprising a coating with an active agent and a water soluble shellac salt. 2. Balloon catheter according to claim 1, wherein the water soluble shellac salt is a shellac ammonium salt. 3. Balloon catheter according to claim 1 or 2, wherein the coating comprises a concentration gradient of the active agent 4. Balloon catheter according to anyone of claim 1-3, wherein the concentration gradient of the active agent is in the layer of water soluble shellac salt as a matrix substance. 5. Balloon catheter according to anyone of claim 1-4, wherein the active agent is an antirestenotic agent, antiproliferative, immunosuppressive, anti-angiogenic, anti-inflammatory, and/or anti-thrombotic agent. 6. Balloon catheter according to anyone of claim 1-5, wherein the active agent is selected from the group consisting of:
abciximab, acemetacin, acetylvismione B, aclarubicin, ademetionine, adriamycin, aescin, afromosone, akagerine, aldesleukin, amidorone, aminoglutethimide, amsacrine, anakinra, anastrozole, anemonin, anopterine, antimycotics antithrombotics, apocymarin, argatroban, aristolactam-AII, aristolochic acid, ascomycin, asparaginase, aspirin, atorvastatin, auranofin, azathioprine, azithromycin, baccatin, bafilomycin, basiliximab, bendamustine, benzocaine, berberine, betulin, betulinic acid, bilobol, bisparthenolidine, bleomycin, combrestatin, Boswellic acids, bruceanol A, B and C, bryophyllin A, busulfan, antithrombin, bivalirudin, cadherins, camptothecin, capecitabine, o-carbamoyl-phenoxyacetic acid, carboplatin, carmustine, celecoxib, cepharanthin, cerivastatin, CETP inhibitors, chlorambucil, chloroquine phosphate, cicutoxin, ciprofloxacin, cisplatin, cladribine, clarithromycin, colchicine, concanamycin, coumadin, C-type natriuretic peptide, cudraisoflavone A, curcumin, cyclophosphamide, ciclosporin A, cytarabine, dacarbazine, daclizumab, dactinomycin, dapsone, daunorubicin, diclofenac, 1,11-dimethoxycanthin-6-one, docetaxel, doxorubicin, daunamycin, epirubicin, erythromycin, estramustine, etoposide, everolimus, filgrastim, fluroblastin, fluvastatin, fludarabine, fludarabine-5′-dihydrogen phosphate, fluorouracil, folimycin, fosfestrol, gemcitabine, ghalakinoside, ginkgol, ginkgolic acid, glycoside 1a, 4-hydroxyoxycyclo phosphamide, idarubicin, ifosfamide, josamycin, lapachol, lomustine, lovastatin, melphalan, midecamycin, mitoxantrone, nimustine, pitavastatin, pravastatin, procarbazine, mitomycin, methotrexate, mercaptopurine, thioguanine, oxaliplatin, irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin, pegaspargase, exemestane, letrozole, formestane, mycophenolate mofetil, β-lapachone, podophyllotoxin, podophyllic acid-2-ethyl hydrazide, rhuGM-CSF, peginterferon α-2b, r-HuG-CSF, macrogol, cytokine antagonist, cytokinin inhibitors, COX-2 inhibitor, angiopeptin, monoclonal antibodies inhibiting muscle cell proliferation, bFGF antagonists, probucol, prostaglandins, 1-hydroxy-11-methoxycanthin-6-one, scopoletin, NO donors, pentaerythrityl tetranitrate and sydnoimines, tamoxifen, staurosporine, β-estradiol, α-estradiol, estriol, estrone, ethinyl estradiol, medroxyprogesterone, estradiol cypionates, estradiol benzoates, tranilast, kamebakaurin and other terpenoids used in cancer therapy, verapamil, tyrosine kinase inhibitors, paclitaxel, 6-α-hydroxy-paclitaxel, taxoteres, paclitaxel bound to albumin, nap-paclitaxel, mofebutazone, lonazolac, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, penicillamine, hydroxychloroquine, sodium aurothiomalate, oxaceprol, β-sitosterol, myrtecaine, polidocanol, nonivamide, levomenthol, ellipticine, colcemid, cytochalasin A-E, indanocine, nocodazole, bacitracin, vitronectin receptor antagonists, azelastine, guanidyl cyclase stimulator, tissue inhibitor of metal proteinase-1 and -2, free nucleic acids, nucleic acids incorporated into virus transmitters, DNA and RNA fragments, plasminogen activator inhibitor 1, plasminogen activator inhibitor 2, antisense oligonucleotides, VEGF inhibitors, IGF-1, active agents from the group of antibiotics, cefadroxil, cefazolin, cefaclor, cefoxitin, tobramycin, gentamicin, penicillins, dicloxacillin, oxacillin, sulfonamides, metronidazole, enoxaparin, heparin, hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators, dipyramidole, trapidil, nitroprussides, PDGF antagonists, triazolopyrimidine, seramin, ACE inhibitors, captopril, cilazapril, lisinopril, enalapril, losartan, thioprotease inhibitors, prostacyclin, vapiprost, interferon α, β and γ, histamine antagonists, serotonin blockers, apoptosis inhibitors, apoptosis regulators, halofuginone, nifedipine, tocopherol, tranilast, molsidomine, tea polyphenols, epicatechin gallate, epigallocatechin gallate, leflunomide, etanercept, sulfasalazine, tetracycline, triamcinolone, mutamycin, procainimide, retinoic acid, quinidine, disopyrimide, flecainide, propafenone, sotalol, natural and synthetically obtained steroids, bryophyllin A, inotodiol, maquiroside A, ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone, dexamethasone, non-steroidal substances, fenoprofen, ibuprofen, indomethacin, naproxen, phenylbutazone, antiviral agents, acyclovir, ganciclovir zidovudine, clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, terbinafine, antiprotozoal agents, chloroquine, mefloquine, quinine, natural terpenoids, hippocaesculin, barringtogenol-C21-angelate, 14-dehydroagrostistachin, agroskerin, agrostistachin, 17-hydroxyagrostistachin, ovatodiolids, 4,7-oxycycloanisomelic acid baccharinoids B1, B2, B3 and B7, tubeimoside, bruceantinoside C, yadanziosides N and P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A, B C and D, ursolic acid, hyptatic acid A, iso-iridogermanal, maytenfoliol, effusantin A, excisanin A and B, longikaurin B, sculponeatin C, kamebaunin, leukamenin A and B, 13,18-dehydro-6-alpha-senecioyloxychaparrin, taxamairin A and B, regenilol, triptolide, cymarin, hydroxyanopterine, protoanemonin, cheliburin chloride, sinococuline A and B, dihydronitidine, nitidine chloride, 12-β-hydroxypregnadien-3,20-dione, helenalin, indicine, indicine-N-oxide, lasiocarpine, inotodiol, podophyllotoxin, justicidin A and B, larreatin, malloterin, mallotochromanol, isobutyrylmallotochromanol, marchantin A, maytansin, lycoridicin, margetine, pancratistatin, liriodenine, oxoushinsunine, periplocoside A, deoxypsorospermin, psychorubin, ricin A, sanguinarine, manwu wheat acid, methylsorbifolin, chromones of spathelia, stizophyllin, dihydrousambaraensine, hydroxyusambarine, strychnopentamine, strychnophylline, usambarine, usambarensine, liriodenine, daphnoretin, lariciresinol, methoxylariciresinol, syringaresinol, sirolimus, biolimus A9, pimecrolimus, everolimus, zotarolimus, tacrolimus, sirolimus bound to albumin, nap-sirolimus, fasudil, epothilones, somatostatin, roxithromycin, troleandomycin, simvastatin, rosuvastatin, vinblastine, vincristine, vindesine, teniposide, vinorelbine, trofosfamide, treosulfan, temozolomide, thiotepa, tretinoin, spiramycin, umbelliferone, desacetylvismione A, vismione A and B, zeorin. 7. Balloon catheter according to claim 6, wherein the active agent is selected from the group consisting of:
paclitaxel, taxanes, docetaxel, paclitaxel bound to albumin, like nap-paclitaxel, sirolimus, biolimus A9, pimecrolimus, everolimus, zotarolimus, tacrolimus, sirolimus bound to albumin, like nap-sirolimus, fasudil and epothilones. 8. Balloon catheter according to claim 7, wherein the active agent is paclitaxel or sirolimus. 9. Balloon catheter according to anyone of claim 1-4, wherein the coating comprises further a water soluble polymer and/or a plasticizer. 10. Balloon catheter according to claim 9, wherein the water soluble polymer is selected from the group comprising cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, starch, hydroxyl ethyl starch, polyacrylic acid, polyethyleneimine, dextran, agar, carrageenan, alginate, copolymers and/or mixtures of these substances. 11. Method for coating a balloon catheter according to claim 1 comprising the following steps:
IA) providing an uncoated balloon catheter;
and
IIA) providing an aqueous solution of an active agent and a water soluble shellac salt;
or
IIB) providing a solution of the active agent and providing an aqueous solution of a water soluble shellac salt;
and
IIIA) coating the surface of the balloon of the balloon catheter with the aqueous solution of the active agent and the water soluble shellac salt;
or
IIIB) coating the surface of the balloon of the balloon catheter with the solution of the active agent and subsequently with the aqueous solution of the water soluble shellac salt or coating the surface of the balloon of the balloon catheter with the aqueous solution of the water soluble shellac salt and subsequently with the solution of active agent;
IV) drying the coated balloon,
wherein the aqueous solution of the water soluble shellac salt or the aqueous solution of the active agent and the water soluble shellac salt are prepared using an alkali salt or an ammonium salt of shellac. 12. Method according to claim 11, wherein the solution of the ammonium salt of shellac is a solution of ammonia, ammonium carbonate, or ammonium bicarbonate and shellac. 13. Method according to claim 11 or 12, wherein the active agent is paclitaxel or sirolimus. 14. Method according to any one of claims 11 to 13, wherein the active agent containing solution is applied by means of spray coating, brush coating, vapour deposition or pipetting. 15. Coated balloon catheter which can be obtained by the method according to any one of claims 11 to 14.
| 1,600 |
917 | 15,434,258 | 1,612 |
A method for applying a composition to teeth and a dispenser for dispensing a composition. The method of the present invention is directed to the storage and dispensing of a composition. During storage and subsequent use the composition in the storage chamber must be maintained segregated from the applicator surface. This is accomplished by delivering the composition from the storage chamber through a delivery channel having a length and a cross-sectional diameter sufficient to preclude the migration of moisture and the enzyme catalase from the application surface to the storage chamber. The composition is applied to teeth by means of bristles, a sponge surface or fibrillated surface. This applicator can be used with both aqueous and non-aqueous compositions.
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1. A method of applying a peroxide containing tooth whitening composition comprising:
a. providing said tooth whitening composition in a housing sealed at one end and having an application means at another end, the application means comprising an applicator surface having an aperture therein at an end of a channel, said aperture having a cross-sectional area and said channel a length in combination sufficient to prevent the migration of substances from the application means into the housing between applications; b. dispensing the tooth whitening composition through said channel and said aperture and to the applicator surface; and c. applying the tooth whitening composition from the applicator surface directly onto at least one tooth. 2. The method according to claim 1 wherein the channel has a cross-sectional area of less than about 5 mm2. 3. The method according to claim 1 wherein said tooth whitening composition has a moisture content of less than about 1 percent by weight. 4. The method according to claim 1 wherein the tooth whitening composition has a peroxide content of about 1% to about 35% by weight. 5. The method according to claim 1 wherein said application means further comprises a plurality of bristles surrounding said aperture. 6. The method according to claim 1 wherein said channel has a diameter of less than about 4 mm. 7. The method according to claim 1 wherein the application means comprises a fibrillated surface. 8. A dispenser for a composition comprising:
a housing comprising a reservoir having a channel, a composition stored in the reservoir; an applicator comprising an applicator surface having an aperture therein provided at an end of the channel; and a drive mechanism disposed within the housing, the drive mechanism comprising:
a moveable piston attached to a threaded piston rod;
a stationary unit; and
a rotary unit comprising rotation limiting cams that directly engage and interact with a cooperating cam surface on said stationary unit; and
wherein interaction between the rotation limiting cams of the rotary unit and the cooperating cam surface of the stationary unit limits rotation of the threaded piston rod to only one direction that moves the movable piston towards the applicator to dispense the composition through the channel and the aperture to the applicator surface. 9. The dispenser according to claim 8 wherein the aperture has a cross-sectional area of less than about 2 mm2. 10. The dispenser according to claim 8 wherein the channel has a length of more than about 10 mm. 11. The dispenser according to claim 8 wherein the channel has a diameter of less than about 4 mm. 12. The dispenser according to claim 8 wherein the applicator comprises a plurality of bristles surrounding the aperture. 13. The dispenser according to claim 8 wherein the aperture comprises a plurality of apertures having a combined surface area of less than about 10 mm2. 14. The dispenser according to claim 8 wherein the composition is a peroxide containing tooth whitening composition for application onto at least one tooth. 15. The dispenser according to claim 8 wherein the housing is elongated along a longitudinal axis, and wherein the applicator surface of the applicator is a planar surface that is oriented oblique to the longitudinal axis. 16. The dispenser according to claim 15 further comprising a plurality of protrusions extending from the applicator surface. 17. The dispenser according to claim 16 wherein each of the protrusions extends up to about 3 mm in length. 18. The dispenser according to claim 8 wherein the threaded piston rod extends through the stationary unit and the rotary unit. 19. A dispenser for a composition comprising:
a housing extending along a longitudinal axis and comprising a reservoir that stores a composition; an applicator provided at an end of the housing, the applicator having a planar applicator surface having an aperture therein, the planar applicator surface being oriented oblique to the longitudinal axis of the housing; and a drive mechanism disposed within the housing and comprising a piston that moves in only one direction towards the applicator to dispense the composition from the reservoir to the applicator surface. 20. The dispenser according to claim 19 further comprising a plurality of protrusions extending from the applicator surface a distance less than 3 mm.
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A method for applying a composition to teeth and a dispenser for dispensing a composition. The method of the present invention is directed to the storage and dispensing of a composition. During storage and subsequent use the composition in the storage chamber must be maintained segregated from the applicator surface. This is accomplished by delivering the composition from the storage chamber through a delivery channel having a length and a cross-sectional diameter sufficient to preclude the migration of moisture and the enzyme catalase from the application surface to the storage chamber. The composition is applied to teeth by means of bristles, a sponge surface or fibrillated surface. This applicator can be used with both aqueous and non-aqueous compositions.1. A method of applying a peroxide containing tooth whitening composition comprising:
a. providing said tooth whitening composition in a housing sealed at one end and having an application means at another end, the application means comprising an applicator surface having an aperture therein at an end of a channel, said aperture having a cross-sectional area and said channel a length in combination sufficient to prevent the migration of substances from the application means into the housing between applications; b. dispensing the tooth whitening composition through said channel and said aperture and to the applicator surface; and c. applying the tooth whitening composition from the applicator surface directly onto at least one tooth. 2. The method according to claim 1 wherein the channel has a cross-sectional area of less than about 5 mm2. 3. The method according to claim 1 wherein said tooth whitening composition has a moisture content of less than about 1 percent by weight. 4. The method according to claim 1 wherein the tooth whitening composition has a peroxide content of about 1% to about 35% by weight. 5. The method according to claim 1 wherein said application means further comprises a plurality of bristles surrounding said aperture. 6. The method according to claim 1 wherein said channel has a diameter of less than about 4 mm. 7. The method according to claim 1 wherein the application means comprises a fibrillated surface. 8. A dispenser for a composition comprising:
a housing comprising a reservoir having a channel, a composition stored in the reservoir; an applicator comprising an applicator surface having an aperture therein provided at an end of the channel; and a drive mechanism disposed within the housing, the drive mechanism comprising:
a moveable piston attached to a threaded piston rod;
a stationary unit; and
a rotary unit comprising rotation limiting cams that directly engage and interact with a cooperating cam surface on said stationary unit; and
wherein interaction between the rotation limiting cams of the rotary unit and the cooperating cam surface of the stationary unit limits rotation of the threaded piston rod to only one direction that moves the movable piston towards the applicator to dispense the composition through the channel and the aperture to the applicator surface. 9. The dispenser according to claim 8 wherein the aperture has a cross-sectional area of less than about 2 mm2. 10. The dispenser according to claim 8 wherein the channel has a length of more than about 10 mm. 11. The dispenser according to claim 8 wherein the channel has a diameter of less than about 4 mm. 12. The dispenser according to claim 8 wherein the applicator comprises a plurality of bristles surrounding the aperture. 13. The dispenser according to claim 8 wherein the aperture comprises a plurality of apertures having a combined surface area of less than about 10 mm2. 14. The dispenser according to claim 8 wherein the composition is a peroxide containing tooth whitening composition for application onto at least one tooth. 15. The dispenser according to claim 8 wherein the housing is elongated along a longitudinal axis, and wherein the applicator surface of the applicator is a planar surface that is oriented oblique to the longitudinal axis. 16. The dispenser according to claim 15 further comprising a plurality of protrusions extending from the applicator surface. 17. The dispenser according to claim 16 wherein each of the protrusions extends up to about 3 mm in length. 18. The dispenser according to claim 8 wherein the threaded piston rod extends through the stationary unit and the rotary unit. 19. A dispenser for a composition comprising:
a housing extending along a longitudinal axis and comprising a reservoir that stores a composition; an applicator provided at an end of the housing, the applicator having a planar applicator surface having an aperture therein, the planar applicator surface being oriented oblique to the longitudinal axis of the housing; and a drive mechanism disposed within the housing and comprising a piston that moves in only one direction towards the applicator to dispense the composition from the reservoir to the applicator surface. 20. The dispenser according to claim 19 further comprising a plurality of protrusions extending from the applicator surface a distance less than 3 mm.
| 1,600 |
918 | 15,542,005 | 1,636 |
Methods for generating immune responses using adenovirus vectors that allow multiple vaccinations with the same adenovirus vector and vaccinations in individuals with preexisting immunity to adenovirus are provided.
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1-158. (canceled) 159. A composition comprising:
(a) a viral vector comprising a nucleotide sequence encoding a MUC1 antigen; (b) a viral vector comprising a nucleotide sequence encoding a Brachyury antigen; and (c) a viral vector comprising a nucleotide sequence encoding a CEA antigen. 160. The composition of claim 159, wherein the MUC1 antigen is a MUC1-C antigen and wherein an amino acid sequence of the MUC1-C antigen has at least 90% sequence identity to SEQ ID NO: 9 or a fragment thereof. 161. The composition of claim 159, wherein the nucleotide sequence encoding the Brachyury antigen has at least 90% sequence identity to SEQ ID NO: 8 or a fragment thereof. 162. The composition of claim 159, wherein the nucleotide sequence encoding the CEA antigen has at least 90% sequence identity to SEQ ID NO: 1 or a fragment thereof. 163. The composition of claim 159, wherein the viral vector comprising the nucleotide sequence encoding the MUC1 antigen, the viral vector comprising the nucleotide sequence encoding the Brachyury antigen, and the viral vector comprising the nucleotide sequence encoding the CEA antigen are recombinant replication defective adenovirus 5 vectors. 164. The composition of claim 159, wherein the viral vector comprising the nucleotide sequence encoding the MUC1 antigen, the viral vector comprising the nucleotide sequence encoding the Brachyury antigen, and the viral vector comprising the nucleotide sequence encoding the CEA antigen comprise a deletion in an E2b gene region, an E1 gene region, an E3 gene region, an E4 gene region, or any combination thereof. 165. The composition of claim 159, further comprising a molecular composition comprising an immune pathway checkpoint modulator, siRNAs, antisense, small molecules, mimic, a recombinant form of a ligand, a recombinant form of a receptor, antibodies, or a combination thereof. 166. The composition of claim 165, wherein the immune pathway checkpoint modulator targets an endogenous immune pathway checkpoint protein or fragment thereof selected from the group consisting of: PD1, PDL1, PDL2, CD28, CD80, CD86, CTLA4, B7RP1, ICOS, B7RPI, B7-H3, B7-H4, BTLA, HVEM, KIR, TCR, LAG3, CD137, CD137L, OX40, OX40L, CD27, CD70, CD40, CD40L, TIM3, GAL9, ADORA, CD276, VTCN1, IDO1, KIR3DL1, HAVCR2, VISTA, and CD244. 167. The composition of claim 165, wherein the immune pathway checkpoint modulator targets a PD1 protein. 168. The composition of claim 159, further comprising an immunogenic component, wherein the immunogenic component comprises a cytokine selected from the group of IFN-γ, TNFα, IL-2, IL-8, IL-12, IL-18, IL-7, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13. 169. The composition of claim 159, wherein a viral vector comprises a sequence encoding at least two antigens selected from the group consisting of the MUC1 antigen, the Brachyury antigen, and the CEA antigen. 170. The composition of claim 159, wherein an amino acid sequence of the CEA antigen comprises SEQ ID NO: 10. 171. A method for treating a subject in need thereof, wherein the method comprises:
administering a viral vector comprising a nucleotide sequence encoding a MUC1 antigen, a viral vector comprising a nucleotide sequence encoding a Brachyury antigen; and a viral vector comprising a nucleotide sequence encoding a CEA antigen to the subject in need thereof; and inducing an immune response against the MUC1 antigen, the Brachyury antigen, or the CEA antigen or cells expressing the MUC1 antigen, the Brachyury antigen, or the CEA antigen, wherein the subject in need thereof has cancer. 172. The method of claim 171, wherein the administering comprises 5×1011 virus particles (VPs) of the viral vector comprising the nucleotide sequence encoding the MUC1 antigen, at least 5×1011 virus particles (VPs) of the viral vector comprising the nucleotide sequence encoding the Brachyury antigen, and at least 5×1011 virus particles (VPs) of the viral vector comprising the nucleotide sequence encoding the CEA antigen. 173. The method of claim 171, wherein the immune response is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 25 fold over basal. 174. The method of claim 171, wherein the immune response is measured as antigen specific antibody response, as antigen specific cell-mediated immunity (CMI), as antigen specific IFN-γ secretion, as antigen specific IL-2 secretion, by ELISpot assay, or any combination thereof. 175. The method of claim 171, wherein the administering comprises subcutaneous administration. 176. The method of claim 171, wherein the subject has colorectal adenocarcinoma; metastatic colorectal cancer; advanced MUC1-C, Brachyury, or CEA expressing colorectal cancer; breast cancer; lung cancer; bladder cancer; or pancreas cancer. 177. The method of claim 171, wherein the subject in need thereof is a human. 178. The method of claim 171, wherein the MUC1 antigen is a MUC1-C antigen and wherein an amino acid sequence of the MUC1-C antigen has at least 90% sequence identity to SEQ ID NO: 9 or a fragment thereof, the nucleotide sequence encoding the Brachyury antigen has at least 90% sequence identity to SEQ ID NO: 8 or a fragment thereof, the nucleotide sequence encoding the CEA antigen has at least 90% sequence identity to SEQ ID NO: 1 or a fragment thereof, an amino acid sequence of the CEA antigen comprises SEQ ID NO: 10, or any combination thereof.
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Methods for generating immune responses using adenovirus vectors that allow multiple vaccinations with the same adenovirus vector and vaccinations in individuals with preexisting immunity to adenovirus are provided.1-158. (canceled) 159. A composition comprising:
(a) a viral vector comprising a nucleotide sequence encoding a MUC1 antigen; (b) a viral vector comprising a nucleotide sequence encoding a Brachyury antigen; and (c) a viral vector comprising a nucleotide sequence encoding a CEA antigen. 160. The composition of claim 159, wherein the MUC1 antigen is a MUC1-C antigen and wherein an amino acid sequence of the MUC1-C antigen has at least 90% sequence identity to SEQ ID NO: 9 or a fragment thereof. 161. The composition of claim 159, wherein the nucleotide sequence encoding the Brachyury antigen has at least 90% sequence identity to SEQ ID NO: 8 or a fragment thereof. 162. The composition of claim 159, wherein the nucleotide sequence encoding the CEA antigen has at least 90% sequence identity to SEQ ID NO: 1 or a fragment thereof. 163. The composition of claim 159, wherein the viral vector comprising the nucleotide sequence encoding the MUC1 antigen, the viral vector comprising the nucleotide sequence encoding the Brachyury antigen, and the viral vector comprising the nucleotide sequence encoding the CEA antigen are recombinant replication defective adenovirus 5 vectors. 164. The composition of claim 159, wherein the viral vector comprising the nucleotide sequence encoding the MUC1 antigen, the viral vector comprising the nucleotide sequence encoding the Brachyury antigen, and the viral vector comprising the nucleotide sequence encoding the CEA antigen comprise a deletion in an E2b gene region, an E1 gene region, an E3 gene region, an E4 gene region, or any combination thereof. 165. The composition of claim 159, further comprising a molecular composition comprising an immune pathway checkpoint modulator, siRNAs, antisense, small molecules, mimic, a recombinant form of a ligand, a recombinant form of a receptor, antibodies, or a combination thereof. 166. The composition of claim 165, wherein the immune pathway checkpoint modulator targets an endogenous immune pathway checkpoint protein or fragment thereof selected from the group consisting of: PD1, PDL1, PDL2, CD28, CD80, CD86, CTLA4, B7RP1, ICOS, B7RPI, B7-H3, B7-H4, BTLA, HVEM, KIR, TCR, LAG3, CD137, CD137L, OX40, OX40L, CD27, CD70, CD40, CD40L, TIM3, GAL9, ADORA, CD276, VTCN1, IDO1, KIR3DL1, HAVCR2, VISTA, and CD244. 167. The composition of claim 165, wherein the immune pathway checkpoint modulator targets a PD1 protein. 168. The composition of claim 159, further comprising an immunogenic component, wherein the immunogenic component comprises a cytokine selected from the group of IFN-γ, TNFα, IL-2, IL-8, IL-12, IL-18, IL-7, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13. 169. The composition of claim 159, wherein a viral vector comprises a sequence encoding at least two antigens selected from the group consisting of the MUC1 antigen, the Brachyury antigen, and the CEA antigen. 170. The composition of claim 159, wherein an amino acid sequence of the CEA antigen comprises SEQ ID NO: 10. 171. A method for treating a subject in need thereof, wherein the method comprises:
administering a viral vector comprising a nucleotide sequence encoding a MUC1 antigen, a viral vector comprising a nucleotide sequence encoding a Brachyury antigen; and a viral vector comprising a nucleotide sequence encoding a CEA antigen to the subject in need thereof; and inducing an immune response against the MUC1 antigen, the Brachyury antigen, or the CEA antigen or cells expressing the MUC1 antigen, the Brachyury antigen, or the CEA antigen, wherein the subject in need thereof has cancer. 172. The method of claim 171, wherein the administering comprises 5×1011 virus particles (VPs) of the viral vector comprising the nucleotide sequence encoding the MUC1 antigen, at least 5×1011 virus particles (VPs) of the viral vector comprising the nucleotide sequence encoding the Brachyury antigen, and at least 5×1011 virus particles (VPs) of the viral vector comprising the nucleotide sequence encoding the CEA antigen. 173. The method of claim 171, wherein the immune response is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 25 fold over basal. 174. The method of claim 171, wherein the immune response is measured as antigen specific antibody response, as antigen specific cell-mediated immunity (CMI), as antigen specific IFN-γ secretion, as antigen specific IL-2 secretion, by ELISpot assay, or any combination thereof. 175. The method of claim 171, wherein the administering comprises subcutaneous administration. 176. The method of claim 171, wherein the subject has colorectal adenocarcinoma; metastatic colorectal cancer; advanced MUC1-C, Brachyury, or CEA expressing colorectal cancer; breast cancer; lung cancer; bladder cancer; or pancreas cancer. 177. The method of claim 171, wherein the subject in need thereof is a human. 178. The method of claim 171, wherein the MUC1 antigen is a MUC1-C antigen and wherein an amino acid sequence of the MUC1-C antigen has at least 90% sequence identity to SEQ ID NO: 9 or a fragment thereof, the nucleotide sequence encoding the Brachyury antigen has at least 90% sequence identity to SEQ ID NO: 8 or a fragment thereof, the nucleotide sequence encoding the CEA antigen has at least 90% sequence identity to SEQ ID NO: 1 or a fragment thereof, an amino acid sequence of the CEA antigen comprises SEQ ID NO: 10, or any combination thereof.
| 1,600 |
919 | 15,170,337 | 1,653 |
Compositions for topical administration to a urogenital area and/or in a vagina are disclosed. The compositions includes a therapeutically effective amount of a selective estrogen receptor modulator (SERM), an intracellular carrier for carrying the SERM into a cell, and a therapeutically effective amount of a cellular anti-inflammatory agent. Methods for treating atrophic vaginitis, peri- and post-menopausal dyspareunia, and/or oopherectomized females prior to menopause by topically applying such compositions to the urogenital area and/or into a vagina are also disclosed.
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1. A composition for topical administration in a urogenital area and/or a vagina comprising:
a therapeutically effective amount of a selective estrogen receptor modulator (SERM); an intracellular carrier for carrying the SERM into a cell; and a therapeutically effective amount of a cellular anti-inflammatory agent. 2. The composition of claim 1, wherein the SERM is selected from the group consisting of droloxifene, idoxifene, raloxifene, tamoxifen, toremifene, TAT-59, and combinations thereof. 3. The composition of claim 1, wherein the SERM comprises raloxifene. 4. The composition of claim 1, wherein the SERM comprises about 0.038 mg/ml of the composition to about 1.9 mg/ml of the composition. 5. The composition of claim 1, wherein the intracellular carrier comprises a natural oil selected from the group consisting of almond oil, avocado oil, coconut oil, corn oil, flaxseed oil, mustard oil, olive oil, peanut oil, rice bran oil, soybean oil, walnut oil, and combinations thereof. 6. The composition of claim 1, wherein the intracellular carrier comprises one or more of avocado oil, coconut oil, and olive oil. 7. The composition of claim 1, wherein the intracellular carrier comprises about 15% by volume to about 54% by volume of the liquid ingredients. 8. The composition of claim 1, wherein the cellular anti-inflammatory agent comprises a medicinal grade honey as about 30% by volume to about 62% by volume of the total liquid ingredients. 9. The composition of claim 8, wherein the medicinal grade honey includes Manuka honey. 10. The composition of claim 1, further comprising a solute that dissolved the SERM. 11. The composition of claim 1, further comprising a thickening agent, and one or more tocopherol and tocotrienols that have Vitamin E activity. 12. A method for treating atrophic vaginitis, peri- and post-menopausal dyspareunia, and/or oopherectomized females prior to menopause, the method comprising:
providing a composition according to claim 1; and topically applying about 2 ml to about 8 ml of the composition to the urogenital area and/or into the vagina daily, every other day, or at least once weekly. 13. The method of claim 12, wherein the composition further comprises a solute that dissolved the SERM, and a biologically acceptable thickening agent. 14. The method of claim 13, wherein the composition further comprises one or more tocopherol and/or tocotrienols that have Vitamin E activity. 15. The method of claim 12, wherein the intracellular carrier comprises a natural oil selected from the group consisting of almond oil, avocado oil, coconut oil, corn oil, flaxseed oil, mustard oil, olive oil, peanut oil, rice bran oil, soybean oil, walnut oil, and combinations thereof. 16. The method of claim 12, wherein the intracellular carrier comprises about 15% by volume to about 54% by volume of the liquid ingredients, and the cellular anti-inflammatory agent comprises a medicinal grade honey comprising about 30% by volume to about 62% by volume of the total liquid ingredients. 17. A composition for topical administration in a urogenital area and/or a vagina comprising:
a therapeutically effective amount of a medicinal grade honey; a therapeutically effective amount of a natural oil; and being free of estrogen. 18. The composition of claim 17, wherein the natural oil is selected from the group consisting of almond oil, avocado oil, coconut oil, corn oil, flaxseed oil, mustard oil, olive oil, peanut oil, rice bran oil, soybean oil, walnut oil, and combinations thereof. 19. The composition of claim 18, wherein the natural oil comprises one or more of avocado oil, coconut oil, and olive oil, and the natural oil is about 15% by volume to about 54% by volume of the composition. 20. The composition of claim 17, wherein the medicinal grade honey includes Manuka honey. 21. The composition of claim 17, wherein the medicinal grade honey comprises about 30% by volume to about 62% by volume of the composition. 22. The composition of claim 17, further comprising a thickening agent, and one or more tocopherol and tocotrienols that have Vitamin E activity. 23. The composition of claim 17, wherein the composition is free of a selective estrogen receptor modulator.
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Compositions for topical administration to a urogenital area and/or in a vagina are disclosed. The compositions includes a therapeutically effective amount of a selective estrogen receptor modulator (SERM), an intracellular carrier for carrying the SERM into a cell, and a therapeutically effective amount of a cellular anti-inflammatory agent. Methods for treating atrophic vaginitis, peri- and post-menopausal dyspareunia, and/or oopherectomized females prior to menopause by topically applying such compositions to the urogenital area and/or into a vagina are also disclosed.1. A composition for topical administration in a urogenital area and/or a vagina comprising:
a therapeutically effective amount of a selective estrogen receptor modulator (SERM); an intracellular carrier for carrying the SERM into a cell; and a therapeutically effective amount of a cellular anti-inflammatory agent. 2. The composition of claim 1, wherein the SERM is selected from the group consisting of droloxifene, idoxifene, raloxifene, tamoxifen, toremifene, TAT-59, and combinations thereof. 3. The composition of claim 1, wherein the SERM comprises raloxifene. 4. The composition of claim 1, wherein the SERM comprises about 0.038 mg/ml of the composition to about 1.9 mg/ml of the composition. 5. The composition of claim 1, wherein the intracellular carrier comprises a natural oil selected from the group consisting of almond oil, avocado oil, coconut oil, corn oil, flaxseed oil, mustard oil, olive oil, peanut oil, rice bran oil, soybean oil, walnut oil, and combinations thereof. 6. The composition of claim 1, wherein the intracellular carrier comprises one or more of avocado oil, coconut oil, and olive oil. 7. The composition of claim 1, wherein the intracellular carrier comprises about 15% by volume to about 54% by volume of the liquid ingredients. 8. The composition of claim 1, wherein the cellular anti-inflammatory agent comprises a medicinal grade honey as about 30% by volume to about 62% by volume of the total liquid ingredients. 9. The composition of claim 8, wherein the medicinal grade honey includes Manuka honey. 10. The composition of claim 1, further comprising a solute that dissolved the SERM. 11. The composition of claim 1, further comprising a thickening agent, and one or more tocopherol and tocotrienols that have Vitamin E activity. 12. A method for treating atrophic vaginitis, peri- and post-menopausal dyspareunia, and/or oopherectomized females prior to menopause, the method comprising:
providing a composition according to claim 1; and topically applying about 2 ml to about 8 ml of the composition to the urogenital area and/or into the vagina daily, every other day, or at least once weekly. 13. The method of claim 12, wherein the composition further comprises a solute that dissolved the SERM, and a biologically acceptable thickening agent. 14. The method of claim 13, wherein the composition further comprises one or more tocopherol and/or tocotrienols that have Vitamin E activity. 15. The method of claim 12, wherein the intracellular carrier comprises a natural oil selected from the group consisting of almond oil, avocado oil, coconut oil, corn oil, flaxseed oil, mustard oil, olive oil, peanut oil, rice bran oil, soybean oil, walnut oil, and combinations thereof. 16. The method of claim 12, wherein the intracellular carrier comprises about 15% by volume to about 54% by volume of the liquid ingredients, and the cellular anti-inflammatory agent comprises a medicinal grade honey comprising about 30% by volume to about 62% by volume of the total liquid ingredients. 17. A composition for topical administration in a urogenital area and/or a vagina comprising:
a therapeutically effective amount of a medicinal grade honey; a therapeutically effective amount of a natural oil; and being free of estrogen. 18. The composition of claim 17, wherein the natural oil is selected from the group consisting of almond oil, avocado oil, coconut oil, corn oil, flaxseed oil, mustard oil, olive oil, peanut oil, rice bran oil, soybean oil, walnut oil, and combinations thereof. 19. The composition of claim 18, wherein the natural oil comprises one or more of avocado oil, coconut oil, and olive oil, and the natural oil is about 15% by volume to about 54% by volume of the composition. 20. The composition of claim 17, wherein the medicinal grade honey includes Manuka honey. 21. The composition of claim 17, wherein the medicinal grade honey comprises about 30% by volume to about 62% by volume of the composition. 22. The composition of claim 17, further comprising a thickening agent, and one or more tocopherol and tocotrienols that have Vitamin E activity. 23. The composition of claim 17, wherein the composition is free of a selective estrogen receptor modulator.
| 1,600 |
920 | 16,061,121 | 1,615 |
A synthetic nutritional composition comprising a phospholipid and/or a metabolic precursor and/or metabolite thereof for use to promote, support or optimise de novo myelination, in particular the de novo myelination trajectory, and/or brain structure, and/or brain connectivity, and/or intellectual potential and/or cognitive potential, and/or learning potential and/or cognitive functioning in a subject, in particular a formula fed subject.
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1. A method to promote, support or optimise de novo myelination, and/or brain structure, and/or brain connectivity, and/or intellectual potential, and/or cognitive potential, and/or learning potential and cognitive functioning in a subject, in particular a formula fed subject, wherein, brain structure refers to the amount and/or spatial distribution of myelinated matter throughout the brain, and/or in specific brain regions, and wherein said cognitive function is optimised if said subject's scores in a standardized neurodevelopmental test are less than one standard deviation different from that of an exclusively breastfed subject of a well-nourished mother comprising administering a synthetic nutritional composition comprising a phospholipid and/or a metabolic precursor and/or metabolite thereof to a subject. 2. A method according to claim 1 wherein the subject is a human infant or child. 3. A method according to claim 1 wherein the phospholipid is a compound of formula (I) or a mixture of compounds of formula (I)
wherein,
R1 is 0;
X is NH or 0;
R2 is a C2-C44 saturated or unsaturated, linear or branched acyl group;
R3 is a substituent of formula (II) or formula (III):
Wherein, R5 is a C2-C44 saturated or unsaturated, linear or branched acyl group and
R6 is a C2-C44 saturated alkyl or alkenyl group; and
R4 is selected from; a C5 or C6 substituted or unsubstituted cyclic alkyl or alkenyl group, or,
—(CH2)n—R7, wherein n is an integer ranging from 1 to 4, in particular 1 to 2 and R7 is —N(CH3)3+, NH3+, or a substituent of formula (IV) and, 4. A method according to claim 3 wherein the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylinositole, phosphatidylserine, phosphatidylethanolamine, and sphingomyelin, and any mixture of any of the foregoing. 5. A method according to claim 4 wherein, the composition comprises sphingomyelin in an amount greater than 300 mg/kg dry weight of the composition. 6. A method according to claim 1 wherein the composition further comprises an ingredient selected from the group consisting of a vitamin, a mineral, choline, and a fatty acid derivative wherein, the fatty acid derivative is a compound comprising a fatty acid other than a phospholipid. 7. A method according to claim 6 wherein the vitamin is selected from the group consisting of vitamin B12, folic acid, and combinations thereof; the mineral is selected from the group consisting of iron, zinc, calcium, phosphorus, copper and combinations thereof; and wherein the fatty acid derivative comprises a fatty acid selected from the group consisting of docosahexaenoic acid, arachidonic acid, stearic acid, nervonic acid, and combinations thereof. 8. A method according to claim 6 wherein if iron is present in the composition it is in an amount greater than 5 mg/100 g dry weight of the composition, wherein, if a fatty acid derivative comprising DHA is present in the composition it is in the composition in a an amount of 60 to 350 mg/100 g dry weight of the composition, and wherein if a fatty acid derivative is arachidonic acid in the composition it is in an amount of 60 to 350 mg/100 g dry weight of the composition, wherein if folic acid is in the composition it is present in amount of at least 100 mcg/kg, wherein if vitamin B12 is present in the composition it is present in amount of at least 5 mcg/100 g, wherein all weights are by dry weight of the composition. 9. A method according to claim 1 wherein the composition is in a composition form selected from the group consisting of an infant formula, a growing up milk, a composition for infants that is intended to be added or diluted with human breast milk, and a food stuff intended for consumption by an infant and/or child either alone or in combination with human breast milk. 10-11. (canceled) 12. A method according to claim 1 wherein the phospholipid is administered to a subject separately, sequentially and/or simultaneously with an ingredient selected from the group consisting of: folic acid, and/or vitamin B12, iron, and a fatty acid derivative, other than a phospholipid. 13-14. (canceled) 15. A synthetic nutritional composition comprising a phospholipid metabolic precursor or metabolite thereof wherein, if sphingomyelin is present in the composition it is present in an amount of at least 300 mg/kg, wherein if folic acid is present in the composition it is present in amount of at least 100 mcg/kg, wherein if vitamin B12 is present in the composition it is present in amount of at least 5 mcg/100 g, wherein if iron is present in the composition it is present in an amount of at least 5 mg/100 g, wherein, if the composition comprises a fatty acid derivative comprising docosahexaenoic acid it is present in the composition in an amount of 60 to 350 mg/100 g, wherein if a fatty acid derivative comprising arachidonic acid is present in the composition it is in an amount of 60 to 350 mg/100 g, wherein all weights are by dry weight of the composition and wherein, the composition is a composition selected from the group consisting of an infant formula, a growing up milk, a composition for infants that is intended to be added or diluted with human breast milk, and a food stuff intended for consumption by an infant and/or child either alone or in combination with human breast milk. 16. A synthetic nutritional composition as defined in claim 15 wherein the composition comprises a fatty acid derivative comprising DHA in a concentration of 1023 mg/kg, a fatty acid derivative comprising ARA in a concentration of 1023 mg/kg, vitamin B12 in a concentration of 54 mcg/kg, folic acid in a concentration of 1698 mcg/kg, sphingomyelin in a concentration of 814 mg/kg and iron in a concentration of 67 mg/kg.
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A synthetic nutritional composition comprising a phospholipid and/or a metabolic precursor and/or metabolite thereof for use to promote, support or optimise de novo myelination, in particular the de novo myelination trajectory, and/or brain structure, and/or brain connectivity, and/or intellectual potential and/or cognitive potential, and/or learning potential and/or cognitive functioning in a subject, in particular a formula fed subject.1. A method to promote, support or optimise de novo myelination, and/or brain structure, and/or brain connectivity, and/or intellectual potential, and/or cognitive potential, and/or learning potential and cognitive functioning in a subject, in particular a formula fed subject, wherein, brain structure refers to the amount and/or spatial distribution of myelinated matter throughout the brain, and/or in specific brain regions, and wherein said cognitive function is optimised if said subject's scores in a standardized neurodevelopmental test are less than one standard deviation different from that of an exclusively breastfed subject of a well-nourished mother comprising administering a synthetic nutritional composition comprising a phospholipid and/or a metabolic precursor and/or metabolite thereof to a subject. 2. A method according to claim 1 wherein the subject is a human infant or child. 3. A method according to claim 1 wherein the phospholipid is a compound of formula (I) or a mixture of compounds of formula (I)
wherein,
R1 is 0;
X is NH or 0;
R2 is a C2-C44 saturated or unsaturated, linear or branched acyl group;
R3 is a substituent of formula (II) or formula (III):
Wherein, R5 is a C2-C44 saturated or unsaturated, linear or branched acyl group and
R6 is a C2-C44 saturated alkyl or alkenyl group; and
R4 is selected from; a C5 or C6 substituted or unsubstituted cyclic alkyl or alkenyl group, or,
—(CH2)n—R7, wherein n is an integer ranging from 1 to 4, in particular 1 to 2 and R7 is —N(CH3)3+, NH3+, or a substituent of formula (IV) and, 4. A method according to claim 3 wherein the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylinositole, phosphatidylserine, phosphatidylethanolamine, and sphingomyelin, and any mixture of any of the foregoing. 5. A method according to claim 4 wherein, the composition comprises sphingomyelin in an amount greater than 300 mg/kg dry weight of the composition. 6. A method according to claim 1 wherein the composition further comprises an ingredient selected from the group consisting of a vitamin, a mineral, choline, and a fatty acid derivative wherein, the fatty acid derivative is a compound comprising a fatty acid other than a phospholipid. 7. A method according to claim 6 wherein the vitamin is selected from the group consisting of vitamin B12, folic acid, and combinations thereof; the mineral is selected from the group consisting of iron, zinc, calcium, phosphorus, copper and combinations thereof; and wherein the fatty acid derivative comprises a fatty acid selected from the group consisting of docosahexaenoic acid, arachidonic acid, stearic acid, nervonic acid, and combinations thereof. 8. A method according to claim 6 wherein if iron is present in the composition it is in an amount greater than 5 mg/100 g dry weight of the composition, wherein, if a fatty acid derivative comprising DHA is present in the composition it is in the composition in a an amount of 60 to 350 mg/100 g dry weight of the composition, and wherein if a fatty acid derivative is arachidonic acid in the composition it is in an amount of 60 to 350 mg/100 g dry weight of the composition, wherein if folic acid is in the composition it is present in amount of at least 100 mcg/kg, wherein if vitamin B12 is present in the composition it is present in amount of at least 5 mcg/100 g, wherein all weights are by dry weight of the composition. 9. A method according to claim 1 wherein the composition is in a composition form selected from the group consisting of an infant formula, a growing up milk, a composition for infants that is intended to be added or diluted with human breast milk, and a food stuff intended for consumption by an infant and/or child either alone or in combination with human breast milk. 10-11. (canceled) 12. A method according to claim 1 wherein the phospholipid is administered to a subject separately, sequentially and/or simultaneously with an ingredient selected from the group consisting of: folic acid, and/or vitamin B12, iron, and a fatty acid derivative, other than a phospholipid. 13-14. (canceled) 15. A synthetic nutritional composition comprising a phospholipid metabolic precursor or metabolite thereof wherein, if sphingomyelin is present in the composition it is present in an amount of at least 300 mg/kg, wherein if folic acid is present in the composition it is present in amount of at least 100 mcg/kg, wherein if vitamin B12 is present in the composition it is present in amount of at least 5 mcg/100 g, wherein if iron is present in the composition it is present in an amount of at least 5 mg/100 g, wherein, if the composition comprises a fatty acid derivative comprising docosahexaenoic acid it is present in the composition in an amount of 60 to 350 mg/100 g, wherein if a fatty acid derivative comprising arachidonic acid is present in the composition it is in an amount of 60 to 350 mg/100 g, wherein all weights are by dry weight of the composition and wherein, the composition is a composition selected from the group consisting of an infant formula, a growing up milk, a composition for infants that is intended to be added or diluted with human breast milk, and a food stuff intended for consumption by an infant and/or child either alone or in combination with human breast milk. 16. A synthetic nutritional composition as defined in claim 15 wherein the composition comprises a fatty acid derivative comprising DHA in a concentration of 1023 mg/kg, a fatty acid derivative comprising ARA in a concentration of 1023 mg/kg, vitamin B12 in a concentration of 54 mcg/kg, folic acid in a concentration of 1698 mcg/kg, sphingomyelin in a concentration of 814 mg/kg and iron in a concentration of 67 mg/kg.
| 1,600 |
921 | 15,430,729 | 1,619 |
Compositions and methods are provided for improving canine exercise performance. The compositions are pre-exercise supplements that generally comprise (a) about 35% to about 60% protein or amino acids, comprising one or more structural proteins, one or more bioavailable proteins and one or more branched chain amino acids; (b) about 20% to about 38% fat, comprising at least one source of medium chain triglycerides; and (c) about 5% to about 25% carbohydrate. The methods involve administering the supplement to the animal within about 30-60 minutes before the beginning of the exercise session. The supplements can be administered in conjunction with one or more other exercise performance-enhancing or recovery agents.
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1. A canine pre-exercise supplement comprising:
a. about 35% to about 60% protein or amino acids, comprising one or more structural proteins, one or more bioavailable proteins and one or more branched chain amino acids; b. about 20% to about 38% fat, comprising at least one source of medium chain triglycerides; and c. about 5% to about 25% carbohydrate. 2. The supplement of claim 1, formulated to provide the canine with (a) between about 1.2 g/kg BW and about 2.0 g/kg BW total nutrition. 3. The supplement of claim 1, wherein the structural protein includes animal muscle. 4. The supplement of claim 3, wherein the muscle is heart muscle. 5. The supplement of claim 1, wherein the bioavailable protein is selected from whey, partially hydrolyzed soy and hydrolyzed amino acids, or any combination thereof. 6. The supplement of claim 1, wherein the branched chain amino acids include L-leucine. 7. The supplement of claim 1, wherein the source of medium chain triglycerides is coconut oil. 8. The supplement of claim 1, wherein the carbohydrate comprises complex carbohydrates. 9. The supplement of claim 1, comprising beef heart, soy meal and soy protein. 10. The supplement of claim 9, comprising coconut oil and L-leucine. 11. A method for improving exercise performance in a canine, comprising:
a. identifying a canine that will be performing exercise; and b. administering to the canine a pre-exercise supplement in an effective amount, the pre-exercise supplement comprising (i) about 35% to about 60% protein or amino acids, comprising one or more structural proteins, one or more bioavailable proteins and one or more branched chain amino acids; (ii) about 20% to about 38% fat, comprising at least one source of medium chain triglycerides; and (iii) about 5% to about 25% carbohydrate, wherein the supplement is formulated to provide the canine or with between about 1.2 g/kg BW and about 2.0 g/kg BW total nutrition,
wherein the supplement is administered to the canine between about zero and about 60 minutes prior to exercise. 12. The method of claim 11, wherein the supplement is administered to the canine between about zero and about 30 minutes prior to exercise. 13. The method of claim 11, wherein the structural protein in the supplement includes animal muscle. 14. The method of claim 13, wherein the muscle is heart muscle. 15. The method of claim 11, wherein the bioavailable protein in the supplement is selected from whey, partially hydrolyzed soy and hydrolyzed amino acids, or any combination thereof. 16. The method of claim 11, wherein the branched chain amino acids in the supplement include L-leucine. 17. The method of claim 11, wherein the source of medium chain triglycerides in the supplement is coconut oil. 18. The method of claim 11, wherein the carbohydrate in the supplement comprises complex carbohydrates. 19. The method of claim 11, wherein administration of the supplement does not cause a substantial increase in blood insulin. 20. The method of claim 11, wherein, relative to a control animal not receiving the supplement, the blood level of branched chain amino acids is increased 30 to 60 minutes after the animal ingests the supplement. 21. The method of claim 11, wherein the supplement comprises leucine and, relative to a control animal not receiving the supplement, the blood level of the leucine is increased 30 to 60 minutes after the animal ingests the supplement. 22. The method of claim 11, wherein the effective amount provides at least one of the following: (1) increased BCAA in the blood within 30 minutes following administration, (2) increased leucine in the blood within 30 minutes following administration; (3) increased availability of free fatty acids or glycerol for exercising muscles as measured by an increase of the free fatty acids or the glycerol in blood circulating levels; (4) insulin secretion of no more than 5% increase following administration; (5) reduction of activity-induced protein catabolism; (6) increased protein biosynthesis (7) stable or increased blood oxygenation, (8) reduced production of at least one stress hormone; (9) reduced production of protein oxidation products, (10) increased or reduced-depletion of endogenous pH buffering agents including beta-alanine or carnosine; and (11) reduced fatigue or reduced soreness.
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Compositions and methods are provided for improving canine exercise performance. The compositions are pre-exercise supplements that generally comprise (a) about 35% to about 60% protein or amino acids, comprising one or more structural proteins, one or more bioavailable proteins and one or more branched chain amino acids; (b) about 20% to about 38% fat, comprising at least one source of medium chain triglycerides; and (c) about 5% to about 25% carbohydrate. The methods involve administering the supplement to the animal within about 30-60 minutes before the beginning of the exercise session. The supplements can be administered in conjunction with one or more other exercise performance-enhancing or recovery agents.1. A canine pre-exercise supplement comprising:
a. about 35% to about 60% protein or amino acids, comprising one or more structural proteins, one or more bioavailable proteins and one or more branched chain amino acids; b. about 20% to about 38% fat, comprising at least one source of medium chain triglycerides; and c. about 5% to about 25% carbohydrate. 2. The supplement of claim 1, formulated to provide the canine with (a) between about 1.2 g/kg BW and about 2.0 g/kg BW total nutrition. 3. The supplement of claim 1, wherein the structural protein includes animal muscle. 4. The supplement of claim 3, wherein the muscle is heart muscle. 5. The supplement of claim 1, wherein the bioavailable protein is selected from whey, partially hydrolyzed soy and hydrolyzed amino acids, or any combination thereof. 6. The supplement of claim 1, wherein the branched chain amino acids include L-leucine. 7. The supplement of claim 1, wherein the source of medium chain triglycerides is coconut oil. 8. The supplement of claim 1, wherein the carbohydrate comprises complex carbohydrates. 9. The supplement of claim 1, comprising beef heart, soy meal and soy protein. 10. The supplement of claim 9, comprising coconut oil and L-leucine. 11. A method for improving exercise performance in a canine, comprising:
a. identifying a canine that will be performing exercise; and b. administering to the canine a pre-exercise supplement in an effective amount, the pre-exercise supplement comprising (i) about 35% to about 60% protein or amino acids, comprising one or more structural proteins, one or more bioavailable proteins and one or more branched chain amino acids; (ii) about 20% to about 38% fat, comprising at least one source of medium chain triglycerides; and (iii) about 5% to about 25% carbohydrate, wherein the supplement is formulated to provide the canine or with between about 1.2 g/kg BW and about 2.0 g/kg BW total nutrition,
wherein the supplement is administered to the canine between about zero and about 60 minutes prior to exercise. 12. The method of claim 11, wherein the supplement is administered to the canine between about zero and about 30 minutes prior to exercise. 13. The method of claim 11, wherein the structural protein in the supplement includes animal muscle. 14. The method of claim 13, wherein the muscle is heart muscle. 15. The method of claim 11, wherein the bioavailable protein in the supplement is selected from whey, partially hydrolyzed soy and hydrolyzed amino acids, or any combination thereof. 16. The method of claim 11, wherein the branched chain amino acids in the supplement include L-leucine. 17. The method of claim 11, wherein the source of medium chain triglycerides in the supplement is coconut oil. 18. The method of claim 11, wherein the carbohydrate in the supplement comprises complex carbohydrates. 19. The method of claim 11, wherein administration of the supplement does not cause a substantial increase in blood insulin. 20. The method of claim 11, wherein, relative to a control animal not receiving the supplement, the blood level of branched chain amino acids is increased 30 to 60 minutes after the animal ingests the supplement. 21. The method of claim 11, wherein the supplement comprises leucine and, relative to a control animal not receiving the supplement, the blood level of the leucine is increased 30 to 60 minutes after the animal ingests the supplement. 22. The method of claim 11, wherein the effective amount provides at least one of the following: (1) increased BCAA in the blood within 30 minutes following administration, (2) increased leucine in the blood within 30 minutes following administration; (3) increased availability of free fatty acids or glycerol for exercising muscles as measured by an increase of the free fatty acids or the glycerol in blood circulating levels; (4) insulin secretion of no more than 5% increase following administration; (5) reduction of activity-induced protein catabolism; (6) increased protein biosynthesis (7) stable or increased blood oxygenation, (8) reduced production of at least one stress hormone; (9) reduced production of protein oxidation products, (10) increased or reduced-depletion of endogenous pH buffering agents including beta-alanine or carnosine; and (11) reduced fatigue or reduced soreness.
| 1,600 |
922 | 14,969,798 | 1,644 |
The present invention relates to the general field of treatment and prevention of diseases involving an inflammatory condition, namely sepsis or infectious or viral diseases as well as diseases requiring for the treatment of immunosuppressive activity namely autoimmune diseases and graft rejection. In particular, the invention relates to an inhibitor of the activity or the formation of the PP1/GADD34 complex for the treatment of a condition requiring an immunosuppressive activity or an anti-inflammatory activity.
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1-15. (canceled) 16. A method of treating an inflammatory condition in a patient in need thereof, comprising the step of
administering to said patient a therapeutic amount of an inhibitor of activity or formation of a PP1/GADD34 complex to treat said inflammatory condition. 17. The method of claim 16, wherein said inflammatory condition is inflammatory bowel disease. 18. The method of claim 16, wherein said inhibitor is an inhibitor of GADD34. 19. The method of claim 16, wherein said inhibitor is an inhibitor of PP1 in complex with GADD34. 20. The method of claim 16, wherein said inhibitor inhibits an interaction domain comprising amino acid residues 540 to 600 of GADD34. 21. The method of claim 16, wherein said inhibitor is selected from the groups consisting of salubrinal, tautomycine, calyculin A, a peptide comprising a fragment of GADD34 and a peptide consisting of a fragment of GADD34. 22. The method of claim 16, wherein said inhibitor is a selective inhibitor of said PP1/GADD34 complex. 23. The method of claim 16, wherein said inhibitor is salubrinal.
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The present invention relates to the general field of treatment and prevention of diseases involving an inflammatory condition, namely sepsis or infectious or viral diseases as well as diseases requiring for the treatment of immunosuppressive activity namely autoimmune diseases and graft rejection. In particular, the invention relates to an inhibitor of the activity or the formation of the PP1/GADD34 complex for the treatment of a condition requiring an immunosuppressive activity or an anti-inflammatory activity.1-15. (canceled) 16. A method of treating an inflammatory condition in a patient in need thereof, comprising the step of
administering to said patient a therapeutic amount of an inhibitor of activity or formation of a PP1/GADD34 complex to treat said inflammatory condition. 17. The method of claim 16, wherein said inflammatory condition is inflammatory bowel disease. 18. The method of claim 16, wherein said inhibitor is an inhibitor of GADD34. 19. The method of claim 16, wherein said inhibitor is an inhibitor of PP1 in complex with GADD34. 20. The method of claim 16, wherein said inhibitor inhibits an interaction domain comprising amino acid residues 540 to 600 of GADD34. 21. The method of claim 16, wherein said inhibitor is selected from the groups consisting of salubrinal, tautomycine, calyculin A, a peptide comprising a fragment of GADD34 and a peptide consisting of a fragment of GADD34. 22. The method of claim 16, wherein said inhibitor is a selective inhibitor of said PP1/GADD34 complex. 23. The method of claim 16, wherein said inhibitor is salubrinal.
| 1,600 |
923 | 10,097,106 | 1,644 |
Novel compounds carrying ligands capable of ligating to counter receptors on relevant target cells are disclosed. The compounds possess a number of advantageous features, rendering them very suitable for a wide range of applications, including use as detection systems, detection of relevant target cells as well as in various methods. In particular, novel MHC molecule constructs comprising one or more MHC molecules are disclosed. The affinity and avidity of the MHC molecules of the constructs are surprisingly high. The possibility of presenting to the target cells a plurality of MHC molecules makes the MHC molecule constructs an extremely powerful tool e.g. in the field of diagnosis. The invention relates in general to the field of therapy, including therapeutic methods and therapeutic compositions. Also comprised by the present invention is the sample-mounted use of MHC molecules, MHC molecule multimers, and MHC molecule constructs.
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1. A MHC molecule construct comprising
a carrier molecule having attached thereto one or more MHC molecules, said MHC molecules being attached to the carrier molecule either directly or via one or more binding entities. 2. The MHC molecule construct according to claim 1, wherein the MHC molecule is a vertebrate MHC molecule such as a human, a murine, a rat, a porcine, a bovine or an avian molecule. 3. The MHC molecule construct according to claim 1 or 2, wherein the MHC molecule is a human MHC molecule. 4. The MHC molecule construct according to any one of claims 1-3, wherein the MHC molecule is
a MHC Class I molecule selected from the group consisting of a heavy chain, a heavy chain combined with a β2m, a heavy chain combined with a peptide, and a heavy chain/β2m dimer with a peptide; or a MHC Class II molecule selected from the group consisting of an α/β dimer, an α/β dimer with a peptide, α/β dimer combined through an affinity tag and a α/β dimer combined through an affinity tag with a peptide; or a MHC Class I like molecule or MHC Class II like molecule. 5. The MHC molecule construct according to any one of claims 1-4, wherein the MHC molecule is a peptide free MHC molecule. 6. The MHC molecule construct according to any one of claims 1-5, wherein at least two of the MHC molecules are different. 7. The MHC molecule construct according to any one of claims 1-5, wherein the MHC molecules are the same. 8. The MHC molecule construct according to any one of claims 1-7, wherein at least two of the peptides harboured by the MHC molecules are different. 9. The MHC molecule construct according to any one of claims 1-7, wherein the peptides harboured by the MHC molecules are the same. 10. The MHC molecule construct according to any one of claims 1-9, wherein the MHC molecules are attached to the carrier molecule directly. 11. The MHC molecule construct according to any one of claims 1-9, wherein the MHC molecules are attached to the carrier molecule via one or more binding entities. 12. The MHC molecule construct according to claim 11, wherein each binding entity has attached thereto from 1 to 10 MHC molecules. 13. The MHC molecule construct according to claim 11, wherein each binding entity has attached thereto from 1 to 8 MHC molecules. 14. The MHC molecule construct according to claim 11, wherein each binding entity has attached thereto from 1 to 6 MHC molecules. 15. The MHC molecule construct according to claim 11, wherein each binding entity has attached thereto from 1 to 4 MHC molecules. 16. The MHC molecule construct according to claim 11, wherein each binding entity has attached thereto from 1 to 3 MHC molecules. 17. The MHC molecule construct according to claim 11, wherein each binding entity has attached thereto 1 or 2 MHC molecules. 18. The MHC molecule construct according to any one of claims 1-17, wherein the total number of MHC molecules of the construct is from 1 to 100. 19. The MHC molecule construct according to any one of claims 1-17, wherein the total number of MHC molecules of the construct is from 1 to 50. 20. The MHC molecule construct according to any one of claims 1-17, wherein the total number of MHC molecules of the construct is from 1 to 25. 21. The MHC molecule construct according to claim 1, wherein the binding entity is selected from streptavidin (SA) and avidin and derivatives thereof, biotin, immunoglobulins, antibodies (monoclonal, polyclonal, and recombinant), antibody fragments and derivatives thereof, leucine zipper domain of AP-1 (jun and fos), hexa-his (metal chelate moiety), hexa-hat GST (glutathione S-tranferase) glutathione affinity, Calmodulin-binding peptide (CBP), Strep-tag, Cellulose Binding Domain, Maltose Binding Protein, S-Peptide Tag, Chitin Binding Tag, Immuno-reactive Epitopes, Epitope Tags, E2Tag, HA Epitope Tag, Myc Epitope, FLAG Epitope, AU1 and AU5 Epitopes, Glu-Glu Epitope, KT3 Epitope, IRS Epitope, Btag Epitope, Protein Kinase-C Epitope, VSV Epitope, lectins that mediate binding to a diversity of compounds, including carbohydrates, lipids and proteins, e.g. Con A (Canavalia ensiformis) or WGA (wheat germ agglutinin) and tetranectin or Protein A or G (antibody affinity). 22. The MHC molecule construct according to any one of claims 1-21, further comprising one or more biologically active molecules. 23. The MHC molecule construct according to claim 22, wherein the biologically active molecules is selected from proteins, co-stimulatory molecules, cell modulating molecules, receptors, accessory molecules, adhesion molecules, natural ligands, and toxic molecules, and antibodies and recombinant binding molecules thereto, and combinations thereof. 24. The MHC molecule construct according to claim 22 or 23, wherein the biologically active molecule is attached to the carrier molecule either directly or via one or more of the binding entities. 25. The MHC molecule construct according to any one of claims 22-24, wherein the biologically active molecule is selected from
proteins such as MHC Class I-like proteins like MIC A, MIC B, CD1d, HLA E, HLA F, HLA G, HLA H, ULBP-1, ULBP-2, and ULBP-3, co-stimulatory molecules such as CD2, CD3, CD4, CD5, CD8, CD9, CD27, CD28, CD30, CD69, CD134 (OX40), CD137 (4-1BB), CD147, CDw150 (SLAM), CD152 (CTLA-4), CD153 (CD30L), CD40L (CD154), NKG2D, ICOS, HVEM, HLA Class II, PD-1, Fas (CD95), FasL expressed on T and/or NK cells, CD40, CD48, CD58, CD70, CD72, B7.1 (CD80), B7.2 (CD86), B7RP-1, B7-H3, PD-L1, PD-L2, CD134L, CD137L, ICOSL, LIGHT expressed on APC and/or tumour cells, cell modulating molecules such as CD16, NKp30, NKp44, NKp46, NKp80, 2B4, KIR, LIR, CD94/NKG2A, CD94/NKG2C expressed on NK cells, IFN-alpha, IFN-beta, IFN-gamma, IL-1, IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, IL-10, IL-11, IL-12, IL-15, CSFs (colony-stimulating factors), vitamin D3, IL-2 toxins, cyclosporin, FK-506, rapamycin, TGF-beta, clotrimazole, nitrendipine, and charybdotoxin, accessory molecules such as LFA-1, CD11a/18, CD54 (ICAM-1), CD106 (VCAM), and CD49a,b,c,d,e,f/CD29 (VLA-4), adhesion molecules such as ICAM-1, ICAM-2, GlyCAM-1, CD34, anti-LFA-1, anti-CD44, anti-beta7, chemokines, CXCR4, CCR5, anti-selectin L, anti-selectin E, and anti-selectin P, toxic molecules such as cyclophosphamide, methrotrexate, Azathioprine, mizoribine, 15-deoxuspergualin, neomycin, staurosporine, genestein, herbimycin A, Pseudomonas exotoxin A, saporin, Rituxan, Ricin, gemtuzumab ozogamicin, Shiga toxin, heavy metals like inorganic and organic mercurials, and FN18-CRM9, radioisotopes such as incorporated isotopes of iodide, cobalt, selenium, tritium, and phosphor, and haptens such as DNP, and digoxiginin, and antibodies thereto, or antibody derivatives or fragments thereof, and combinations thereof. 26. The MHC molecule construct according to any of claims 1-25 further comprising one or more labelling compounds. 27. The MHC molecule construct according to claim 26, wherein one or more labelling compounds are attached to the carrier molecule. 28. The MHC molecule construct according to claim 26, wherein one or more labelling compounds are attached to one or more of the binding entities. 29. The MHC molecule construct according to claim 26, wherein one or more labelling compounds are attached to one or more of the MHC molecules. 30. The MHC molecule construct according to claim 26, wherein one or more labelling compounds are attached to the carrier molecule and/or one or more of the binding entities and/or one or more of the MHC molecules. 31. The MHC molecule construct according to any one of claims 26-30, wherein the labelling compound is directly or indirectly detectable. 32. The MHC molecule construct according to any of claims 26-31, wherein the labelling compound is a fluorescent label, an enzyme label, a radioisotope, a chemiluminescent label, a bioluminescent label, a polymer, a metal particle, a hapten, an antibody, or a dye. 33. The MHC molecule construct according to any one of claims 26-32, wherein the labelling compound is selected from fluorescent labels such as 5-(and 6)-carboxyfluorescein, 5- or 6-carboxyfluorescein, 6-(fluorescein)-5-(and 6)-carboxamido hexanoic acid, fluorescein isothiocyanate (F)TC), rhodamine, tetramethylrhodamine, and dyes such as Cyt, Cy3, and Cy5, optionally substituted coumarin including AMCA, PerCP, phycobiliproteins including R-phycoerythrin (RPE) and allophycoerythrin (APC), Texas Red, Princeston Red, Green fluorescent protein (GFP) and analogues thereof, and conjugates of R-phycoerythrin or allophycoerythrin and e.g. Cy5 or Texas Red, and inorganic fluorescent labels based on semiconductor nanocrystals (like quantum dot and Qdot™ nanocrystals), and time-resolved fluorescent labels based on lanthanides like Eu3+ and Sm3+,
from haptens such as DNP, biotin, and digoxiginin, or
is selected from enzymatic labels such as horse radish peroxidase (HRP), alkaline phosphatase (AP), beta-galactosidase (GAL), glucose-6-phosphate dehydrogenase, beta-N-acetylglucosaminidase, β-glucuronidase, invertase, Xanthine Oxidase, firefly luciferase and glucose oxidase (GO), or
is selected from luminiscence labels such as luminol, isoluminol, acridinium esters, 1,2-dioxetanes and pyridopyridazines, or
is selected from radioactivity labels such as incorporated isotopes of iodide, cobalt, selenium, tritium, and phosphor. 34. The MHC molecule construct according to any one of claims 1-33, wherein the carrier molecule is selected from
polysaccharides including dextrans, carboxy methyl dextran, dextran polyaldehyde, carboxymethyl dextran lactone, and cyclodextrins, pullulans, schizophyllan, scleroglucan, xanthan, gellan, O-ethylamino guaran, chitins and chitosans including 6-O-carboxymethyl chitin and N-carboxymethyl chitosan, derivatised cellolosics including carboxymethyl cellulose, carboxymethyl hydroxyethyl cellulose, hydroxyethyl cellulose, 6-amino-6-deoxy cellulose and O-ethylamine cellulose, hydroxylated starch, hydroxypropyl starch, hydroxyethyl starch, carrageenans, alginates, and agarose, synthetic polysaccharides including ficoll and carboxymethylated ficoll, vinyl polymers including poly(acrylic acid), poly(acryl amides), poly(acrylic esters), poly(2-hydroxy ethyl methacrylate), poly(methyl methacrylate), poly(maleic acid), poly(maleic anhydride), poly(acrylamide), poly(ethyl-co-vinyl acetate), poly(methacrylic acid), poly(vinylalcohol), poly(vinyl alcohol-co-vinyl chloroacetate), aminated poly(vinyl alcohol), and co block polymers thereof, poly ethylene glycol (PEG) or polypropylene glycol or poly-(ethylene oxide-co-propylene oxides) containing polymer backbones including linear, comb-shaped or StarBurst™ dendrimers, poly amino acids including polylysines, polyglutamic acid, polyurethanes, poly(ethylene imines), pluriol. proteins including albumins, immunoglobulins, and virus-like proteins (VLP), and polynucleotides, DNA, PNA, LNA, oligonucleotides and oligonucleotide dendrimer constructs. 35. The MHC molecule construct according to any one of claims 1-34, wherein the carrier molecule is a soluble carrier molecule. 36. The MHC molecule construct according to any one of claims 1-35 in soluble form. 37. The MHC molecule construct according to any one of claims 1-36 immobilised onto a solid or semi-solid support. 38. The MHC molecule construct according to claim 37, immobilised directly to the solid or semi-solid support. 39. The MHC molecule construct according to claim 37, immobilised to the solid or semi-solid support via a linker, a spacer, or an antibody, an antibody derivative or a fragment thereof. 40. The MHC molecule construct according to any one of claims 37-39, wherein the support is selected from particles, beads, biodegradable particles, sheets, gels, filters, membranes (e. g. nylon membranes), fibres, capillaries, needles, microtitre strips, tubes, plates or wells, combs, pipette tips, micro arrays, and chips. 41. The MHC molecule construct according to claim 40, wherein the support is selected from beads and particles. 42. The MHC molecule construct according to claim 41, wherein the beads and particles are polymeric beads, polymeric particles, magnetic beads, magnetic particles, supermagnetic beads, or supermagnetic particles. 43. The MHC molecule construct according to any one of claims 1-42 for use in a flow cytometric method. 44. The MHC molecule construct according to any one of claims 1-42 for use in a histological method. 45. The MHC molecule construct according to any one of claims 1-42 for use in a cytological method. 46. A method for detecting the presence of MHC recognising cells in a sample comprising the steps of
(a) providing a sample suspected of comprising MHC recognising cells, (b) contacting the sample with a MHC molecule construct according to claims 1-42, and (c) determining any binding of the MHC molecule construct, which binding indicates the presence of MHC recognising cells. 47. A method for monitoring MHC recognising cells comprising the steps of
(a) providing a sample suspected of comprising MHC recognising cells, (b) contacting the sample with a MHC molecule construct according to claims 1-42, and (c) determining any binding of the MHC molecule construct, thereby monitoring MHC recognising cells. 48. A method for establishing a prognosis of a disease involving MHC recognising cells comprising the steps of
(a) providing a sample suspected of comprising MHC recognising cells, (b) contacting the sample with a MHC molecule construct according to claims 1-42, and (c) determining any binding of the MHC molecule construct, thereby establishing a prognosis of a disease involving MHC recognising cells. 49. A method for determining the status of a disease involving MHC recognising cells comprising the steps of
(a) providing a sample suspected of comprising MHC recognising cells, (b) contacting the sample with a MHC molecule construct according to claims 1-42, and (c) determining any binding of the MHC molecule construct, thereby determining the status of a disease involving MHC recognising cells. 50. A method for diagnosing a disease involving MHC recognising cells comprising the steps of
(a) providing a sample suspected of comprising MHC recognising cells, (b) contacting the sample with a MHC molecule construct according to claims 1-42, and (c) determining any binding of the MHC molecule construct, thereby diagnosing a disease involving MHC recognising cells. 51. A method for determining the effectiveness of a medicament against a disease involving MHC recognising cells comprising the steps of
(a) providing a sample from a subject receiving treatment with a medicament, (b) contacting the sample with a MHC molecule construct according to claims 1-42, and (c) determining any binding of the MHC molecule construct, thereby determining the effectiveness of the medicament. 52. The method according to any one of claims 46-51, wherein the MHC recognising cells are involved in a disease of inflammatory, auto-immune, allergic, viral, cancerous, infectious, allo- or xenogene (graft versus host and host versus graft) origin. 53. The method according to claim 52, wherein the disease is a chronic inflammatory bowel disease such as Crohn's disease or ulcerative colitis, sclerosis, type I diabetes, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, malignant melanoma, renal carcinoma, breast cancer, lung cancer, cancer of the uterus, cervical cancer, prostatic cancer, brain cancer, head and neck cancer, leukaemia, cutaneous lymphoma, hepatic carcinoma, colorectal cancer, bladder cancer, rejection-related disease, Graft-versus-host-related disease, or a viral disease associated with hepatitis, AIDS, measles, pox, chicken pox, rubella or herpes. 54. The method according to any one of claims 46-53, wherein the MHC recognising cells selected from subpopulations of CD3+ T-cells, gamma, delta T-cells, alpha, beta T-cells, CD4+ T-cells, T helper cells, CD8+ T-cells, Suppressor T-cells, CD8+ cytotoxic T-cells, CTLs, NK cells, NKT cells, LAK cells, and MAK. 55. The method according to any one of claims 46-51, wherein the sample is selected from histological material, cytological material, primary tumours, secondary organ metastasis, fine needle aspirates, spleen tissue, bone marrow specimens, cell smears, exfoliative cytological specimens, touch preparations, oral swabs, laryngeal swabs, vaginal swabs, bronchial lavage, gastric lavage, from the umbilical cord, and from body fluids such as blood (e.g. from a peripheral blood mononuclear cell (PBMC) population isolated from blood or from other blood-derived preparations such as leukopheresis products), from sputum samples, expectorates, and bronchial aspirates. 56. The method according to any one of claims 46-55, wherein the determination of the binding is carried out by inspection in a microscope, by light, by fluorescence, by electron transmission, or by flow cytometry. 57. The method according to any one of claims 46-56, wherein the sample is mounted on a support. 58. The method according to claim 57, wherein the support is a solid or semi-solid support. 59. The method according to claim 57 or 58, wherein the support is selected from glass slides, microtiter plates having one or more wells, beads, particles, membranes, filters, filter membranes, polymer slides, polymer membranes, chamber slides, dishes, and petridishes. 60. A composition comprising a MHC molecule construct according to any one of claims 1-42 in a solubilising medium. 61. The composition according to claim 60, wherein the MHC molecule construct comprises peptide filled MHC molecules. 62. The composition according to claim 60, wherein the MHC molecule construct comprises peptide free MHC molecules. 63. The composition according to claim 62, wherein peptides to fill the peptide free MHC molecules, and the MHC molecule construct comprising peptide free molecules are provided separately. 64. A composition comprising a MHC molecule construct according to any one of claims 1-42, wherein the MHC molecule construct is immobilised onto a solid or semi-solid support. 65. The composition according to claim 64, wherein the support is selected from glass slides, microtiter plates having one or more wells, beads, particles, membranes, filters, filter membranes, polymer slides, polymer membranes, chamber slides, dishes, and petridishes. 66. The composition according to claim 64 or 65, wherein the beads and particles are polymeric beads, polymeric particles, magnetic beads, magnetic particles, supermagnetic beads, or supermagnetic particles. 67. The composition according to claim 64, wherein the MHC molecule construct comprises peptide filled MHC molecules. 68. The composition according to claim 64, wherein the MHC molecule construct comprises peptide free MHC molecules. 69. The composition according to claim 68, wherein peptides to fill the peptide free MHC molecules, and the MHC molecule construct comprising peptide free molecules are provided separately. 70. Use of a MHC molecule construct according to any one of claims 1-42 as a detection system. 71. Use of a MHC molecule construct according to any one of claims 1-42 for diagnosing a disease involving MHC recognising cells. 72. Use of a MHC molecule construct according to any one of claims 1-42 for monitoring a disease involving MHC recognising cells. 73. Use of a MHC molecule construct according to any one of claims 1-42 for establishing a prognosis for a disease involving MHC recognising cells. 74. Use of a MHC molecule construct according to any one of claims 1-42 for determining the status of a disease involving MHC recognising cells. 75. Use of a MHC molecule construct according to any one of claims 1-42 for determining the effectiveness of a medicament against a disease involving MHC recognising cells. 76. Use according to any one of claim 71, wherein the MHC recognising cells are involved in a disease of inflammatory, auto-immune, allergic, viral, cancerous, infectious, allo- or xenogene (graft-versus-host and host-versus-graft) origin. 77. Use according to claim 76, wherein the disease is a chronic inflammatory bowel disease such as Crohn's disease or ulcerative colitis, sclerosis, type I diabetes, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, malignant melanoma, renal carcinoma, breast cancer, lung cancer, cancer of the uterus, cervical cancer, prostatic cancer, brain cancer, head and neck cancer, leukaemia, cutaneous lymphoma, hepatic carcinoma, colorectal cancer, bladder cancer, rejection-related disease, Graft-versus-host-related disease, or a viral disease associated with hepatitis, AIDS, measles, pox, chicken pox, rubella or herpes. 78. Use according to any one of claims 70-77, wherein the MHC recognising cells are selected from subpopulations of CD3+ T-cells, gamma, delta T-cells, alpha, beta T-cells, CD4+ T-cells, T helper cells, CD8+ T-cells, Suppressor T-cells, CD8+ cytotoxic T-cells, CTLs, NK cells, NKT cells, LAK cells, and MAK. 79. The MHC molecule construct according to any one of claims 1-42 for use as a therapeutic composition. 80. The MHC molecule construct according to any one of claims 1-42 for use in in vivo therapy. 81. The MHC molecule construct according to any one of claims 1-42 for use in ex vivo therapy. 82. A therapeutic composition comprising as active ingredient a MHC molecule construct as defined in any one of claims 1-42. 83. The therapeutic composition according to claim 82, wherein the MHC molecule construct is immobilised to a biodegradable solid or semi-solid support. 84. The therapeutic composition according to claim 82 or 83, wherein the MHC molecule construct comprises
a carrier molecule having attached thereto one or more MHC molecules, said MHC molecules being attached to the carrier molecule either directly or via one or more binding entities. 85. The therapeutic composition according to claim 82 or 83, wherein the MHC molecule is a vertebrate MHC molecule such as a human, a murine, a rat, a porcine, a bovine or an avian molecule. 86. The therapeutic composition according to any one of claims 82-85, wherein the MHC molecule is a human MHC molecule. 87. The therapeutic composition according to any one of claims 82-86, wherein the MHC molecule is
a MHC Class I molecule selected from the group consisting of a heavy chain, a heavy chain combined with a β2m, a heavy chain combined with a peptide, and a heavy chain/β2m dimer with a peptide; or a MHC Class II molecule selected from the group consisting of an α/β dimer, an α/β dimer with a peptide, α/β dimer combined through an affinity tag and a α/β dimer combined through an affinity tag with a peptide or a MHC Class I like molecule or a MHC Class II like molecule. 88. The therapeutic composition according to any one of claims 82-87, wherein the MHC molecule is a peptide free MHC molecule. 89. The therapeutic composition according to any one of claims 82-88, wherein at least two of the MHC molecules are different. 90. The therapeutic composition according to any one of claims 82-88, wherein the MHC molecules are the same. 91. The therapeutic composition according to any one of claims 82-88, wherein at least two of the peptides harboured by the MHC molecules are different. 92. The therapeutic composition according to any one of claims 82-88, wherein the peptides harboured by the MHC molecules are the same. 93. The therapeutic composition according to any one of claims 82-92, wherein the MHC molecules are attached to the carrier molecule directly. 94. The therapeutic composition according to any one of claims 82-92, wherein the MHC molecules are attached to the carrier molecule via one or more binding entities. 95. The therapeutic composition according to claim 94, wherein each binding entity has attached thereto from 1 to 10 MHC molecules. 96. The therapeutic composition according to claim 94, wherein each binding entity has attached thereto from 1 to 8 MHC molecules. 97. The therapeutic composition according to claim 94, wherein each binding entity has attached thereto from 1 to 6 MHC molecules. 98. The therapeutic composition according to claim 94, wherein each binding entity has attached thereto from 1 to 4 MHC molecules. 99. The therapeutic composition according to claim 94, wherein each binding entity has attached thereto from 1 to 3 MHC molecules. 100. The therapeutic composition according to claim 94, wherein each binding entity has attached thereto 1 or 2 MHC molecules. 101. The therapeutic composition according to any one of claims 82-100, wherein the total number of MHC molecules of the construct is from 1 to 100. 102. The therapeutic composition according to any one of claims 82-100, wherein the total number of MHC molecules of the construct is from 1 to 50. 103. The therapeutic composition according to any one of claims 82-100, wherein the total number of MHC molecules of the construct is from 1 to 25. 104. The therapeutic composition according to claim 94, wherein the binding entity is selected from streptavidin (SA) and avidin and derivatives thereof, biotin, immunoglobulins, antibodies (monoclonal, polyclonal, and recombinant), antibody fragments and derivatives thereof, leucine zipper domain of AP-1 (jun and fos), hexa-his (metal chelate moiety), hexa-hat GST (glutathione S-tranferase) glutathione affinity, Calmodulin-binding peptide (CBP), Strep-tag, Cellulose Binding Domain, Maltose Binding Protein, S-Peptide Tag, Chitin Binding Tag, Immuno-reactive Epitopes, Epitope Tags, E2Tag, HA Epitope Tag, Myc Epitope, FLAG Epitope, AU1 and AU5 Epitopes, Glu-Glu Epitope, KT3 Epitope, IRS Epitope, Btag Epitope, Protein Kinase-C Epitope, VSV Epitope, lectins that mediate binding to a diversity of compounds, including carbohydrates, lipids and proteins, e.g. Con A (Canavalia ensiformis) or WGA (wheat germ agglutinin) and tetranectin or Protein A or G (antibody affinity). 105. The therapeutic composition according to any one of claims 82-104 further comprising one or more biologically active molecules. 106. The therapeutic composition according to claim 105, wherein the biologically active molecules is selected from proteins, co-stimulatory molecules, cell modulating molecules, receptors, accessory molecules, adhesion molecules, natural ligands, and toxic molecules, and antibodies and recombinant binding molecules thereto, and combinations thereof. 107. The therapeutic composition according to claim 105 or 106, wherein the biologically active molecule is attached to the carrier molecule either directly or via one or more of the binding entities. 108. The therapeutic composition according to any one of claims 105-107, wherein the biologically active molecule is selected from
proteins such as MHC Class I-like proteins like MIC A, MIC B, CD1d, HLA E, HLA F, HLA G, HLA H, ULBP-1, ULBP-2, and ULBP-3, co-stimulatory molecules such as CD2, CD3, CD4, CD5, CD8, CD9, CD27, CD28, CD30, CD69, CD134 (OX40), CD137 (4-1BB), CD147, CDw150 (SLAM), CD152 (CTLA-4), CD153 (CD30L), CD40L (CD154), NKG2D, ICOS, HVEM, HLA Class II, PD-1, Fas (CD95), FasL expressed on T and/or NK cells, CD40, CD48, CD58, CD70, CD72, B7.1 (CD80), B7.2 (CD86), B7RP-1, B7-H3, PD-L1, PD-L2, CD134L, CD137L, ICOSL, LIGHT expressed on APC and/or tumour cells, cell modulating molecules such as CD16, NKp30, NKp44, NKp46, NKp80, 2B4, KIR, LIR, CD94/NKG2A, CD94/NKG2C expressed on NK cells, IFN-alpha, IFN-beta, IFN-gamma, IL-1, IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, IL-10, IL-11, IL-12, IL-15, CSFs (colony-stimulating factors), vitamin D3, IL-2 toxins, cyclosporin, FK-506, rapamycin, TGF-beta, clotrimazole, nitrendipine, and charybdotoxin, accessory molecules such as LFA-1, CD11a/18, CD54 (ICAM-1), CD106 (VCAM), and CD49a,b,c,d,e,f/CD29 (VLA-4), adhesion molecules such as ICAM-1, ICAM-2, GlyCAM-1, CD34, anti-LFA-1, anti-CD44, anti-beta7, chemokines, CXCR4, CCR5, anti-selectin L, anti-selectin E, and anti-selectin P, toxic molecules such as cyclophosphamide, methrotrexate, Azathioprine, mizoribine, 15-deoxuspergualin, neomycin, staurosporine, genestein, herbimycin A, Pseudomonas exotoxin A, saporin, Rituxan, Ricin, gemtuzumab ozogamicin, Shiga toxin, heavy metals like inorganic and organic mercurials, and FN18-CRM9, radioisotopes such as incorporated isotopes of iodide, cobalt, selenium, tritium, and phosphor, and haptens such as DNP, and digoxiginin, and antibodies thereto, or antibody derivatives or fragments thereof, and combinations thereof. 109. The therapeutic composition according to any one of claims 82-108, wherein the carrier molecule is selected from
polysaccharides including dextrans, carboxy methyl dextran, dextran polyaldehyde, carboxymethyl dextran lactone, and cyclodextrins, pullulans, schizophyllan, scleroglucan, xanthan, gellan, O-ethylamino guaran, chitins and chitosans including 6-O-carboxymethyl chitin and N-carboxymethyl chitosan, derivatised cellolosics including carboxymethyl cellulose, carboxymethyl hydroxyethyl cellulose, hydroxyethyl cellulose, 6-amino-6-deoxy cellulose and O-ethylamine cellulose, hydroxylated starch, hydroxypropyl starch, hydroxyethyl starch, carrageenans, alginates, and agarose, synthetic polysaccharides including ficoll and carboxymethylated ficoll, vinyl polymers including poly(acrylic acid), poly(acryl amides), poly(acrylic esters), poly(2-hydroxy ethyl methacrylate), poly(methyl methacrylate), poly(maleic acid), poly(maleic anhydride), poly(acrylamide), poly(ethyl-co-vinyl acetate), poly(methacrylic acid), poly(vinylalcohol), poly(vinyl alcohol-co-vinyl chloroacetate), aminated poly(vinyl alcohol), and co block polymers thereof, poly ethylene glycol (PEG) or polypropylene glycol or poly-(ethylene oxide-co-propylene oxides) containing polymer backbones including linear, comb-shaped or StarBurst™ dendrimers, poly amino acids including polylysines, polyglutamic acid, polyurethanes, poly(ethylene imines), pluriol. proteins including albumins, immunoglobulins, and virus-like proteins (VLP), and polynucleotides, DNA, PNA, LNA, oligonucleotides and oligonucleotide dendrimer constructs. 110. The therapeutic composition according to any one of claims 82-109, wherein the carrier molecule is a soluble carrier molecule. 111. The therapeutic composition according to any one of claims 82-110 further comprising one or more adjuvants and/or excipients. 112. The therapeutic composition according to claim 111, wherein the adjuvant is selected from saponins such as Quil A and Qs-21, oil in water emulsions such as MF59, MPL, PLG, PLGA, aluminium salts, calcium phosphate, water in oil emulsions such as IFA (Freund's incomplete adjuvant) and CFA (Freund's complete adjuvant), interleukins such as IL-1β, IL-2, IL-7, IL-12, and INFγ, Adju-Phos®, glucan, antigen formulation, biodegradable microparticles, Cholera Holotoxin, liposomes, DDE, DHEA, DMPC, DMPG, DOC/Alum Complex, ISCOMs®, muramyl dipeptide, monophosphoryl lipid A, muramyl tripeptide, and phospatidylethanolamine In a preferred embodiment, the adjuvant is selected from saponins such as Quil A and Qs-21, MF59, MPL, PLG, PLGA, calcium phosphate, and aluminium salts. 113. The therapeutic composition according to claim 113, wherein the excipient is selected from diluents, buffers, suspending agents, wetting agents, solubilising agents, pH-adjusting agents, dispersing agents, preserving agents, and/or colorants. 114. The therapeutic composition according to any one of claims 82-113 for the treatment, prevention, stabilisation, or alleviation of disease involving MHC recognising cells. 115. The therapeutic composition according to claim 114, wherein the MHC recognising cells are involved in a disease of inflammatory, auto-immune, allergic, viral, cancerous, infectious, allo- or xenogene (graft versus host and host versus graft) origin. 116. The therapeutic composition according to claim 115, wherein the disease is a chronic inflammatory bowel disease such as Crohn's disease or ulcerative colitis, sclerosis, type I diabetes, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, malignant melanoma, renal carcinoma, breast cancer, lung cancer, cancer of the uterus, prostatic cancer, brain cancer, head and neck cancer, leukaemia, cutaneous lymphoma, hepatic carcinoma, colorectal cancer, bladder cancer, rejection-related disease, Graft-versus-host-related disease, or a viral disease associated with hepatitis, AIDS, measles, pox, chicken pox, rubella or herpes. 117. The therapeutic composition according to any one of claims 82-116 formulated for parenteral administration, including intravenous, intramuscular, intraarticular, subcutaneous, intradermal, epicutantous/transdermal, and intraperitoneal administration, for infusion, for oral administration, for nasal administration, for rectal administration, or for topic administration. 118. A therapeutic composition comprising as active ingredient an effective amount of MHC recognising cells, the MHC recognising cells being obtained by
bringing a sample from a subject comprising MHC recognising cells into contact with a MHC molecule construct according to any one of claims 1-42, whereby the MHC recognising cells become bound to the MHC molecule construct, isolating the bound MHC molecule construct and the MHC recognising cells, and expanding such MHC recognising cells to a clinically relevant number. 119. The therapeutic composition according to claim 118, wherein the isolated MHC recognising cells are liberated from the MHC molecule construct prior to expansion. 120. The therapeutic composition according to claim 118 or 119, wherein the MHC molecule construct is immobilised onto a solid or semi-solid support. 121. The therapeutic composition according to claim 120, wherein the MHC molecule construct is immobilised onto the solid or semi-solid support prior to contact with the sample. 122. The therapeutic composition according to claim 120, wherein the MHC molecule construct is immobilised onto the solid or semi-solid support following contact with the sample. 123. The therapeutic composition according to any one of claims 118-122, wherein the expansion is carried out in the presence of one or more MHC molecule constructs, optionally one or more biologically active molecules and optionally feeder cells such as dendritic cells or feeder cells. 124. The therapeutic composition according to any one of claims 120-123, wherein the MHC molecule construct is immobilised onto the solid or semi-solid support directly. 125. The therapeutic composition according to any one of claims 120-124, wherein the MHC molecule construct is immobilised to the solid or semi-solid support via a linker, a spacer, or an antibody, an antibody derivative or a fragment thereof. 126. The therapeutic composition according to any one of claims 120-125, wherein the solid or semi-solid support is selected from particles, beads, biodegradable particles, sheets, gels, filters, membranes, fibres, capillaries, needles, microtitre strips, tubes, plates or wells, combs, pipette tips, micro arrays, chips, and microtiter plates having one or more wells. 127. The therapeutic composition according to any one of claims 120-126, wherein the solid support is selected from particles and beads. 128. The therapeutic composition according to claim 127, wherein the particles and beads are polymeric, magnetic or superparamagnetic. 129. The therapeutic composition according to any one of claims 118-128, wherein the isolation is performed by applying a magnetic field or by flow cytometry. 130. The therapeutic composition according to any one of claims 118-128, wherein the MHC molecule construct comprises
a carrier molecule having attached thereto one or more MHC molecules, said MHC molecules being attached to the carrier molecule either directly or via one or more binding entities. 131. The therapeutic composition according to any one of claims 118-130, wherein the MHC molecule is a vertebrate MHC molecule such as a human, a murine, a rat, a porcine, a bovine or an avian molecule. 132. The therapeutic composition according to any one of claims 118-131, wherein the MHC molecule is a human MHC molecule. 133. The therapeutic composition according to any one of claims 118-132, wherein the MHC molecule is
a MHC Class I molecule selected from the group consisting of a heavy chain, a heavy chain combined with a β2m, a heavy chain combined with a peptide, and a heavy chain/β2m dimer with a peptide; or a MHC Class II molecule selected from the group consisting of an α/β dimer, an α/β dimer with a peptide, α/β dimer combined through an affinity tag and a α/β dimer combined through an affinity tag with a peptide; or a MHC Class I like molecule or a MHC Class II molecule. 134. The therapeutic composition according to any one of claims 118-133, wherein the MHC molecule is a peptide free MHC molecule. 135. The therapeutic composition according to any one of claims 118-134, wherein at least two of the MHC molecules are different. 136. The therapeutic composition according to any one of claims 118-135, wherein the MHC molecules are the same. 137. The therapeutic composition according to any one of claims 118-136, wherein at least two of the peptides harboured by the MHC molecules are different. 138. The therapeutic composition according to any one of claims 118-137, wherein the peptides harboured by the MHC molecules are the same. 139. The therapeutic composition according to any one of claims 118-138, wherein the MHC molecules are attached to the carrier molecule directly. 140. The therapeutic composition according to any one of claims 118-138, wherein the MHC molecules are attached to the carrier molecule via one or more binding entities. 141. The therapeutic composition according to claim 140, wherein each binding entity has attached thereto from 1 to 10 MHC molecules. 142. The therapeutic composition according to claim 140, wherein each binding entity has attached thereto from 1 to 8 MHC molecules. 143. The therapeutic composition according to claim 140, wherein each binding entity has attached thereto from 1 to 6 MHC molecules. 144. The therapeutic composition according to claim 140, wherein each binding entity has attached thereto from 1 to 4 MHC molecules. 145. The therapeutic composition according to claim 140, wherein each binding entity has attached thereto from 1 to 3 MHC molecules. 146. The therapeutic composition according to claim 140, wherein each binding entity has attached thereto 1 or 2 MHC molecules. 147. The therapeutic composition according to any one of claims 118-146, wherein the total number of MHC molecules of the construct is from 1 to 100. 148. The therapeutic composition according to any one of claims 118-146, wherein the total number of MHC molecules of the construct is from 1 to 50. 149. The therapeutic composition according to any one of claims 118-146, wherein the total number of MHC molecules of the construct is from 1 to 25. 150. The therapeutic composition according to claim 140, wherein the binding entity is selected from streptavidin streptavidin (SA) and avidin and derivatives thereof, biotin, immunoglobulins, antibodies (monoclonal, polyclonal, and recombinant), antibody fragments and derivatives thereof, leucine zipper domain of AP-1 (jun and fos), hexa-his (metal chelate moiety), hexa-hat GST (glutathione S-tranferase) glutathione affinity, Calmodulin-binding peptide (CBP), Strep-tag, Cellulose Binding Domain, Maltose Binding Protein, S-Peptide Tag, Chitin Binding Tag, Immuno-reactive Epitopes, Epitope Tags, E2Tag, HA Epitope Tag, Myc Epitope, FLAG Epitope, AU1 and AU5 Epitopes, Glu-Glu Epitope, KT3 Epitope, IRS Epitope, Btag Epitope, Protein Kinase-C Epitope, VSV Epitope, lectins that mediate binding to a diversity of compounds, including carbohydrates, lipids and proteins, e.g. Con A (Canavalia ensiformis) or WGA (wheat germ agglutinin) and tetranectin or Protein A or G (antibody affinity). 151. The therapeutic composition according to any one of claims 118-150 further comprising one or more biologically active molecules. 152. The therapeutic composition according to claim 151, wherein the biologically active molecules is selected from proteins, co-stimulatory molecules, cell modulating molecules, receptors, accessory molecules, adhesion molecules, natural ligands, and toxic molecules, and antibodies and recombinant binding molecules thereto, and combinations thereof. 153. The therapeutic composition according to claim 150 or 151, wherein the biologically active molecule is attached to the carrier molecule either directly or via one or more of the binding entities. 154. The therapeutic composition according to any one of claims 151-153, wherein the biologically active molecule is selected from
proteins such as MHC Class I-like proteins like MIC A, MIC B, CD1d, HLA E, HLA F, HLA G, HLA H, ULBP-1, ULBP-2, and ULBP-3, co-stimulatory molecules such as CD2, CD3, CD4, CD5, CD8, CD9, CD27, CD28, CD30, CD69, CD134 (OX40), CD137 (4-1BB), CD147, CDw150 (SLAM), CD152 (CTLA-4), CD153 (CD30L), CD40L (CD154), NKG2D, ICOS, HVEM, HLA Class II, PD-1, Fas (CD95), FasL expressed on T and/or NK cells, CD40, CD48, CD58, CD70, CD72, B7.1 (CD80), B7.2 (CD86), B7RP-1, B7-H3, PD-L1, PD-L2, CD134L, CD137L, ICOSL, LIGHT expressed on APC and/or tumour cells, cell modulating molecules such as CD16, NKp30, NKp44, NKp46, NKp80, 2B4, KIR, LIR, CD94/NKG2A, CD94/NKG2C expressed on NK cells, IFN-alpha, IFN-beta, IFN-gamma, IL-1, IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, IL-10, IL-11, IL-12, IL-15, CSFs (colony-stimulating factors), vitamin D3, IL-2 toxins, cyclosporin, FK-506, rapamycin, TGF-beta, clotrimazole, nitrendipine, and charybdotoxin, accessory molecules such as LFA-1, CD11a/18, CD54 (ICAM-1), CD106 (VCAM), and CD49a,b,c,d,e,f/CD29 (VLA-4), adhesion molecules such as ICAM-1, ICAM-2, GlyCAM-1, CD34, anti-LFA-1, anti-CD44, anti-beta7, chemokines, CXCR4, CCR5, anti-selectin L, anti-selectin E, and anti-selectin P, toxic molecules such as cyclophosphamide, methrotrexate, Azathioprine, mizoribine, 15-deoxuspergualin, neomycin, staurosporine, genestein, herbimycin A, Pseudomonas exotoxin A, saporin, Rituxan, Ricin, gemtuzumab ozogamicin, Shiga toxin, heavy metals like inorganic and organic mercurials, and FN18-CRM9, radioisotopes such as incorporated isotopes of iodide, cobalt, selenium, tritium, and phosphor, and haptens such as DNP, and digoxiginin, and antibodies thereto, or antibody derivatives or fragments thereof, and combinations thereof. 155. The therapeutic composition according to any one of claims 118-154, wherein the carrier molecule is selected from
polysaccharides including dextrans, carboxy methyl dextran, dextran polyaldehyde, carboxymethyl dextran lactone, and cyclodextrins, pullulans, schizophyllan, scleroglucan, xanthan, gellan, O-ethylamino guaran, chitins and chitosans including 6-O-carboxymethyl chitin and N-carboxymethyl chitosan, derivatised cellolosics including carboxymethyl cellulose, carboxymethyl hydroxyethyl cellulose, hydroxyethyl cellulose, 6-amino-6-deoxy cellulose and O-ethylamine cellulose, hydroxylated starch, hydroxypropyl starch, hydroxyethyl starch, carrageenans, alginates, and agarose, synthetic polysaccharides including ficoll and carboxymethylated ficoll, vinyl polymers including poly(acrylic acid), poly(acryl amides), poly(acrylic esters), poly(2-hydroxy ethyl methacrylate), poly(methyl methacrylate), poly(maleic acid), poly(maleic anhydride), poly(acrylamide), poly(ethyl-co-vinyl acetate), poly(methacrylic acid), poly(vinylalcohol), poly(vinyl alcohol-co-vinyl chloroacetate), aminated poly(vinyl alcohol), and co block polymers thereof, poly ethylene glycol (PEG) or polypropylene glycol or poly-(ethylene oxide-co-propylene oxides) containing polymer backbones including linear, comb-shaped or StarBurst™ dendrimers, poly amino acids including polylysines, polyglutamic acid, polyurethanes, poly(ethylene imines), pluriol. proteins including albumins, immunoglobulins, and virus-like proteins (VLP), and polynucleotides, DNA, PNA, LNA, oligonucleotides and oligonucleotide dendrimer constructs. 156. The therapeutic composition according to any one of claims 118-155 further comprising one or more labelling compounds. 157. The therapeutic composition according to claim 156, wherein one or more labelling compounds are attached to the carrier molecule. 158. The therapeutic composition according to claim 156, wherein one or more labelling compounds are attached to one or more of the binding entities. 159. The therapeutic composition according to claim 156, wherein one or more labelling compounds are attached to one or more of the MHC molecules. 160. The therapeutic composition according to claim 156, wherein one or more labelling compounds are attached to the carrier molecule and/or one or more of the binding entities and/or one or more of the MHC molecules. 161. The therapeutic composition according to any one of claims 156-160, wherein the labelling compound is directly or indirectly detectable. 162. The therapeutic composition according to any one of claims 156-161, wherein the labelling compound is a fluorescent label, an enzyme label, a radioisotope, a chemiluminescent label, a bioluminescent label, a polymer, a metal particle, a hapten, an antibody, or a dye. 163. The therapeutic composition according to any one of claims 156-162, wherein the labelling compound
is selected from fluorescent labels such as 5-(and 6)-carboxyfluorescein, 5- or 6-carboxyfluorescein, 6-(fluorescein)-5-(and 6)-carboxamido hexanoic acid, fluorescein isothiocyanate (FITC), rhodamine, tetramethylrhodamine, and dyes such as Cy2, Cy3, and Cy5, optionally substituted coumarin including AMCA, PerCP, phycobiliproteins including R-phycoerythrin (RPE) and allophycoerythrin (APC), Texas Red, Princeston Red, Green fluorescent protein (GFP) and analogues thereof, and conjugates of R-phycoerythrin or allophycoerythrin and e.g. Cy5 or Texas Red, and inorganic fluorescent labels based on semiconductor nanocrystals (like quantum dot and Qdot™ nanocrystals), and time-resolved fluorescent labels based on lanthanides like Eu3+ and Sm3+, from haptens such as DNP, biotin, and digoxiginin, or is selected from haptens such as DNP, fluorescein isothiocyanate (FITC), biotin, and digoxiginin, or is selected from enzymatic labels such as horse radish peroxidase (HRP), alkaline phosphatase (AP), beta-galactosidase (GAL), glucose-6-phosphate dehydrogenase, beta-N-acetylglucosaminidase, β-glucuronidase, invertase, Xanthine Oxidase, firefly luciferase and glucose oxidase (GO), or is selected from luminiscence labels such as luminol, isoluminol, acridinium esters, 1,2-dioxetanes and pyridopyridazines, or is selected from radioactivity labels such as incorporated isotopes of iodide, cobalt, selenium, tritium, and phosphor. 164. The therapeutic composition according any one of claims 118-163, wherein the carrier molecule is a soluble carrier molecule. 165. The therapeutic composition according to any one of claims 118-164 further comprising one or more excipients. 166. The therapeutic composition according to claim 165, wherein the excipient is selected from diluents, buffers, suspending agents, wetting agents, solubilising agents, pH-adjusting agents, dispersing agents, preserving agents, and/or colorants. 167. The therapeutic composition according to any one of claims 118-166 for the treatment, prevention, stabilisation, or alleviation of a disease involving MHC recognising cells. 168. The therapeutic composition according to claim 167, wherein MHC recognising cells are involved in a disease of inflammatory, auto-immune, allergic, viral, cancerous, infectious, allo- or xenogene (graft versus host and host versus graft) origin. 169. The therapeutic composition according to claim 167 or 168, wherein the disease is a chronic inflammatory bowel disease such as Crohn's disease or ulcerative colitis, sclerosis, type I diabetes, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, malignant melanoma, renal carcinoma, breast cancer, lung cancer, cancer of the uterus, prostatic cancer, brain cancer, head and neck cancer, leukaemia, cutaneous lymphoma, hepatic carcinoma, colorectal cancer, bladder cancer, rejection-related disease, Graft-versus-host-related-disease, or a viral disease associated with hepatitis, AIDS, measles, pox, chicken pox, rubella or herpes. 170. The therapeutic composition according to any one of claims 118-169 formulated for parenteral administration, including intravenous, intramuscular, intraarticular, subcutaneous, intradermal, epicutantous/transdermal, and intraperitoneal administration, for infusion, for oral administration, for nasal administration, for rectal administration, or for topic administration. 171. The therapeutic composition according to any one of claims 82-170 for use in in vivo therapy. 172. A method of treating an animal, including a human being, comprising administering a therapeutic composition according to any one of claims 82-170 in an effective amount. 173. A method of up-regulating, down-regulating, modulate an immune response in an animal, including a human being, comprising administering a therapeutic composition according to any one of claims 82-170 in an effective amount. 174. A method of inducing anergy of a cell in an animal, including a human being, comprising administering a therapeutic composition according to any one of claims 82-170 in an effective amount. 175. An adoptive cellular immunotherapeutic method comprising administrating to an animal, including a human being, a therapeutic composition according to any one of claims 82-170. 176. A method of obtaining MHC recognising cells comprising
bringing into contact a MHC molecule construct according to any one of claims 1-42 and a sample suspected of comprising MHC recognising cells under conditions whereby the MHC recognising cells bind to the MHC molecule construct, and isolating the bound MHC molecule construct and MHC recognising cells. 177. The method according to claim 176, wherein the isolation is carried out by applying a magnetic field or by flow cytometry. 178. A method for producing a therapeutic composition according to any one of claims 82-170, comprising
providing a MHC molecule construct as defined in claims 1-42, solubilising or dispersing the MHC molecule construct in a medium suitable for therapeutic substances, and optionally adding other adjuvants and/or excipients. 179. A method for producing a therapeutic composition according to any one of claims 118-170, comprising
obtaining MHC recognising cells using a MHC molecule construct according to any one of claims 1-42, expanding such MHC recognising cells to a clinically relevant number, formulating the obtained cells in a medium suitable for administration, and optionally adding adjuvants and/or excipients. 180. Use of a MHC molecule construct according to any one of claims 1-42 for ex vivo expansion of MHC recognising cells. 181. Use according to claim 180, wherein the MHC molecule construct is in soluble form. 182. Use according to claim 180, wherein the MHC molecule construct is immobilised onto a solid or semi-solid support. 183. Use according to claim 182, wherein the solid or semi-solid support is selected from particles, beads, biodegradable particles, sheets, gels, filters, membranes (e.g. nylon membranes), fibres, capillaries, needles, microtitre strips, tubes, plates or wells, combs, pipette tips, micro arrays, chips, and slides. 184. Use according to claim 182 or 183, wherein the solid or semi-solid support is selected from beads and particles. 185. Use according to claim 184, wherein the solid or semi-solid support is selected from polymeric, magnetic or superparamagnetic particles and beads. 186. Use according to any one of claims 180-185, wherein the MHC molecule construct further comprises one or more biologically active molecules. 187. Use according to any one of claims 180-186, wherein wherein the biologically active molecule is selected from
proteins such as MHC Class I-like proteins like MIC A, MIC B, CD1d, HLA E, HLA F, HLA G, HLA H, ULBP-1, ULBP-2, and ULBP-3, co-stimulatory molecules such as CD2, CD3, CD4, CD5, CD8, CD9, CD27, CD28, CD30, CD69, CD134 (OX40), CD137 (4-1BB), CD147, CDw150 (SLAM), CD152 (CTLA-4), CD153 (CD30L), CD40L (CD154), NKG2D, ICOS, HVEM, HLA Class II, PD-1, Fas (CD95), FasL expressed on T and/or NK cells, CD40, CD48, CD58, CD70, CD72, B7.1 (CD80), B7.2 (CD86), B7RP-1, B7-H3, PD-L1, PD-L2, CD134L, CD137L, ICOSL, LIGHT expressed on APC and/or tumour cells, cell modulating molecules such as CD16, NKp30, NKp44, NKp46, NKp80, 2B4, KIR, LIR, CD94/NKG2A, CD94/NKG2C expressed on NK cells, IFN-alpha, IFN-beta, IFN-gamma, IL-1, IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, IL-10, IL-11, IL-12, IL-15, CSFs (colony-stimulating factors), vitamin D3, IL-2 toxins, cyclosporin, FK-506, rapamycin, TGF-beta, clotrimazole, nitrendipine, and charybdotoxin, accessory molecules such as LFA-1, CD11a/18, CD54 (ICAM-1), CD106 (VCAM), and CD49a,b,c,d,e,f/CD29 (VLA-4), adhesion molecules such as ICAM-1, ICAM-2, GlyCAM-1, CD34, anti-LFA-1, anti-CD44, anti-beta7, chemokines, CXCR4, CCR5, anti-selectin L, anti-selectin E, and anti-selectin P, toxic molecules such as cyclophosphamide, methrotrexate, Azathioprine, mizoribine, 15-deoxuspergualin, neomycin, staurosporine, genestein, herbimycin A, Pseudomonas exotoxin A, saporin, Rituxan, Ricin, gemtuzumab ozogamicin, Shiga toxin, heavy metals like inorganic and organic mercurials, and FN18-CRM9, radioisotopes such as incorporated isotopes of iodide, cobalt, selenium, tritium, and phosphor, and haptens such as DNP, and digoxiginin, and antibodies thereto, or antibody derivatives or fragments thereof, and combinations thereof. 187. Use of a MHC molecule in a histological method. 188. Use of a MHC molecule in a cytological method. 189. Use of a MHC molecule according to claim 187 or 188 in a method for determining the presence of MHC recognising cells in a sample, in which method the MHC recognising cells of the sample are mounted on a support. 190. Use of a MHC molecule according to claim 187 or 188, in a method for monitoring the presence of MHC recognising cells in a sample, in which method the MHC recognising cells of the sample are mounted on a support. 191. Use of a MHC molecule according to claim 187 or 188 in a method for determining the status of a disease involving MHC recognising cells, in which method the MHC recognising cells of the sample are mounted on a support. 192. Use of a MHC molecule according to claim 187 or 188 in a method for establishing a prognosis of a disease involving MHC recognising cells, in which method the MHC recognising cells of the sample are mounted on a support. 193. Use of a MHC molecule according to any one of claims 187-192, wherein the support is a solid or semi-solid support. 194. Use of a MHC molecule according to any one of claims 187-193, wherein the support is selected from glass slides, membranes, filters, polymer slides, chamber slides, dishes, and petridishes. 195. Use according to any one of claims 187-194, wherein the sample is selected from histological material, cytological material, primary tumours, secondary organ metastasis, fine needle aspirates, spleen tissue, bone marrow specimens, cell smears, exfoliative cytological specimens, touch preparations, oral swabs, laryngeal swabs, vaginal swabs, bronchial lavage, gastric lavage, from the umbilical cord, and from body fluids such as blood (e.g. from a peripheral blood mononuclear cell (PBMC) population isolated from blood or from other blood-derived preparations such as leukopheresis products), from sputum samples, expectorates, and bronchial aspirates. 196. The use according to any one of claims 187-195, wherein the MHC molecule is
a MHC Class I molecule selected from the group consisting of a heavy chain, a heavy chain combined with a β2m, a heavy chain combined with a peptide, and a heavy chain/β2m dimer with a peptide; or a MHC Class II molecule selected from the group consisting of an α/β dimer, an α/β dimer with a peptide, α/β dimer combined through an affinity tag and a α/β dimer combined through an affinity tag with a peptide; or a MHC Class I like molecule or a MHC Class II like molecule. 197. The use according to any one of claims 187-196, wherein the MHC molecule is a vertebrate MHC molecule such as a human, a murine, a rat, a porcine, a bovine or an avian molecule. 198. The use according to any one of claims 187-197, wherein the MHC molecule is a human MHC molecule. 199. The use according to any one of claims 187-198, wherein the MHC molecule is a peptide free MHC molecule. 200. The use according to any one of claims 187-199, wherein the MHC molecule is attached to a binding entity. 201. Use according to claim 200, wherein the binding entity has attached thereto from 1 to 10 MHC molecules, such as from 1 to 9, from 1 to 8, from 1 to 7, from 1 to 6, from 1 to 5, from 1 to 4, from 1 to 3, or 1 or 2 MHC molecules. 202. Use according to claim 200, wherein the binding entity is selected from streptavidin streptavidin (SA) and avidin and derivatives thereof, biotin, immunoglobulins, antibodies (monoclonal, polyclonal, and recombinant), antibody fragments and derivatives thereof, leucine zipper domain of AP-1 (jun and fos), hexa-his (metal chelate moiety), hexa-hat GST (glutathione S-tranferase) glutathione affinity, Calmodulin-binding peptide (CBP), Strep-tag, Cellulose Binding Domain, Maltose Binding Protein, S-Peptide Tag, Chitin Binding Tag, Immuno-reactive Epitopes, Epitope Tags, E2Tag, HA Epitope Tag, Myc Epitope, FLAG Epitope, AU1 and AU5 Epitopes, Glu-Glu Epitope, KT3 Epitope, IRS Epitope, Btag Epitope, Protein Kinase-C Epitope, VSV Epitope, lectins that mediate binding to a diversity of compounds, including carbohydrates, lipids and proteins, e.g. Con A (Canavalia ensiformis) or WGA (wheat germ agglutinin) and tetranectin or Protein A or G (antibody affinity). 203. Use according to any one of claims 187-202, wherein the MHC molecule further comprises a labelling compound. 204. Use according to claim 203, wherein the labelling compound can be detected directly or indirectly. 205. Use according to claim 203 or 204, wherein the labelling compound is a fluorescent label, an enzyme label, a radioisotope, a chemiluminescent label, a bioluminescent label, a polymer, a metal particle, a hapten, an antibody, or a dye. 206. Use according to any one of claims 203-205, wherein the labelling compound is selected from
5-(and 6)-carboxyfluorescein, 5- or 6-carboxyfluorescein, 6-(fluorescein)-5-(and 6)-carboxamido hexanoic acid, fluorescein isothiocyanate (FITC), rhodamine, tetramethylrhodamine, and dyes such as Cy2, Cy3, and Cy5, optionally substituted coumarin including AMCA, PerCP, phycobiliproteins including R-phycoerythrin (RPE) and allophycoerythrin (APC), Texas Red, Princeston Red, Green fluorescent protein (GFP) and analogues thereof, and conjugates of R-phycoerythrin or allophycoerythrin and e.g. Cy5 or Texas Red, and inorganic fluorescent labels based on semiconductor nanocrystals (like quantum dot and Qdot™ nanocrystals), and time-resolved fluorescent labels based on lanthanides like Eu3+ and Sm3+, from haptens such as DNP, biotin, and digoxiginin or is selected from enzymatic labels such as horse radish peroxidase (HRP), alkaline phosphatase (AP), beta-galactosidase (GAL), glucose-6-phosphate dehydrogenase, beta-N-acetylglucosaminidase, β-glucuronidase, invertase, Xanthine Oxidase, firefly luciferase and glucose oxidase (GO), or is selected from luminiscence labels such as luminol, isoluminol, acridinium esters, 1,2-dioxetanes and pyridopyridazines, or is selected from radioactivity labels such as incorporated isotopes of iodide, cobalt, selenium, tritium, and phosphor. 207. The use according to any one of claims 203-206, wherein the labelling compound is attached to the MHC molecule and/or the binding entity. 208. A method for detecting the presence of MHC recognising cells in a sample comprising the steps of
(a) providing a sample suspected of comprising MHC recognising cells mounted on a support, (b) contacting the sample with a MHC molecule as defined in claims 187-207, and (c) determining any binding of the MHC molecule, which binding indicates the presence of MHC recognising cells. 209. A method for monitoring MHC recognising cells comprising the steps of
(a) providing a sample suspected comprising MHC recognising cells mounted on a support, (b) contacting the sample with a MHC molecule as defined in claims 187-207, and (c) determining any binding of the MHC molecule, thereby monitoring MHC recognising cells. 210. A method for the prognosis of a disease involving MHC recognising cells comprising the steps of
(a) providing a sample suspected comprising MHC recognising cells mounted on a support, (b) contacting the sample with a MHC molecule as defined in claims 187-207, and (c) determining any binding of the MHC molecule, thereby establishing a prognosis of a disease involving MHC recognising cells. 211. A method for determining the status of a disease involving MHC recognising cells comprising the steps of
(a) providing a sample suspected comprising MHC recognising cells mounted on a support, (b) contacting the sample with a MHC molecule as defined in claims 187-207, and (c) determining any binding of the MHC molecule, thereby determining the status of a disease involving MHC recognising cells. 212. A method for the diagnosis of a disease involving MHC recognising cells comprising the steps of
(a) providing a sample suspected comprising MHC recognising cells mounted on a support, (b) contacting the sample with a MHC molecule as defined in claims 187-207, and (c) determining any binding of the MHC molecule, thereby diagnosing a disease involving MHC recognising cells. 213. A method for the effectiveness of a medicament against a disease involving MHC recognising cells comprising the steps of
(a) providing a sample from a subject receiving treatment with a medicament mounted on a support, (b) contacting the sample with a MHC molecule as defined in claims 187-207, and (c) determining any binding of the MHC molecule, thereby determining the effectiveness of the medicament. 214. The method according to any one of claims 208-213, wherein the MHC recognising cells are involved in a disease of inflammatory, auto-immune, allergic, viral, cancerous, infectious, allo- or xenogene (graft-versus-host and host-versus-graft) origin. 215. The method according to claim 214, wherein the disease is a chronic inflammatory bowel disease such as Crohn's disease or ulcerative colitis, sclerosis, type I diabetes, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, malignant melanoma, renal carcinoma, breast cancer, lung cancer, cancer of the uterus, cervical cancer, prostatic cancer, brain cancer, head and neck cancer, leukaemia, cutaneous lymphoma, hepatic carcinoma, colorectal cancer, bladder cancer, rejection-related disease, Graft-versus-host-related disease, or a viral disease associated with hepatitis, AIDS, measles, pox, chicken pox, rubella or herpes. 216. The method according to any one of claims 208-214, wherein the MHC recognising cells are selected from subpopulations of CD3+ T-cells, gamma, delta T-cells, alpha, beta T-cells, CD4+ T-cells, T helper cells, CD8+ T-cells, Suppressor T-cells, CD8+ cytotoxic T-cells, CTLs, NK cells, NKT cells, LAK cells, and MAK. 210. The method according to any one of claims 201-209, wherein the sample is selected from histological material, cytological material, primary tumours, secondary organ metastasis, fine needle aspirates, spleen tissue, bone marrow specimens, cell smears, exfoliative cytological specimens, touch preparations, oral swabs, laryngeal swabs, vaginal swabs, bronchial lavage, gastric lavage, from the umbilical cord, and from body fluids such as blood (e.g. from a peripheral blood mononuclear cell (PBMC) population isolated from blood or from other blood-derived preparations such as leukopheresis products), from sputum samples, expectorates, and bronchial aspirates.
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Novel compounds carrying ligands capable of ligating to counter receptors on relevant target cells are disclosed. The compounds possess a number of advantageous features, rendering them very suitable for a wide range of applications, including use as detection systems, detection of relevant target cells as well as in various methods. In particular, novel MHC molecule constructs comprising one or more MHC molecules are disclosed. The affinity and avidity of the MHC molecules of the constructs are surprisingly high. The possibility of presenting to the target cells a plurality of MHC molecules makes the MHC molecule constructs an extremely powerful tool e.g. in the field of diagnosis. The invention relates in general to the field of therapy, including therapeutic methods and therapeutic compositions. Also comprised by the present invention is the sample-mounted use of MHC molecules, MHC molecule multimers, and MHC molecule constructs.1. A MHC molecule construct comprising
a carrier molecule having attached thereto one or more MHC molecules, said MHC molecules being attached to the carrier molecule either directly or via one or more binding entities. 2. The MHC molecule construct according to claim 1, wherein the MHC molecule is a vertebrate MHC molecule such as a human, a murine, a rat, a porcine, a bovine or an avian molecule. 3. The MHC molecule construct according to claim 1 or 2, wherein the MHC molecule is a human MHC molecule. 4. The MHC molecule construct according to any one of claims 1-3, wherein the MHC molecule is
a MHC Class I molecule selected from the group consisting of a heavy chain, a heavy chain combined with a β2m, a heavy chain combined with a peptide, and a heavy chain/β2m dimer with a peptide; or a MHC Class II molecule selected from the group consisting of an α/β dimer, an α/β dimer with a peptide, α/β dimer combined through an affinity tag and a α/β dimer combined through an affinity tag with a peptide; or a MHC Class I like molecule or MHC Class II like molecule. 5. The MHC molecule construct according to any one of claims 1-4, wherein the MHC molecule is a peptide free MHC molecule. 6. The MHC molecule construct according to any one of claims 1-5, wherein at least two of the MHC molecules are different. 7. The MHC molecule construct according to any one of claims 1-5, wherein the MHC molecules are the same. 8. The MHC molecule construct according to any one of claims 1-7, wherein at least two of the peptides harboured by the MHC molecules are different. 9. The MHC molecule construct according to any one of claims 1-7, wherein the peptides harboured by the MHC molecules are the same. 10. The MHC molecule construct according to any one of claims 1-9, wherein the MHC molecules are attached to the carrier molecule directly. 11. The MHC molecule construct according to any one of claims 1-9, wherein the MHC molecules are attached to the carrier molecule via one or more binding entities. 12. The MHC molecule construct according to claim 11, wherein each binding entity has attached thereto from 1 to 10 MHC molecules. 13. The MHC molecule construct according to claim 11, wherein each binding entity has attached thereto from 1 to 8 MHC molecules. 14. The MHC molecule construct according to claim 11, wherein each binding entity has attached thereto from 1 to 6 MHC molecules. 15. The MHC molecule construct according to claim 11, wherein each binding entity has attached thereto from 1 to 4 MHC molecules. 16. The MHC molecule construct according to claim 11, wherein each binding entity has attached thereto from 1 to 3 MHC molecules. 17. The MHC molecule construct according to claim 11, wherein each binding entity has attached thereto 1 or 2 MHC molecules. 18. The MHC molecule construct according to any one of claims 1-17, wherein the total number of MHC molecules of the construct is from 1 to 100. 19. The MHC molecule construct according to any one of claims 1-17, wherein the total number of MHC molecules of the construct is from 1 to 50. 20. The MHC molecule construct according to any one of claims 1-17, wherein the total number of MHC molecules of the construct is from 1 to 25. 21. The MHC molecule construct according to claim 1, wherein the binding entity is selected from streptavidin (SA) and avidin and derivatives thereof, biotin, immunoglobulins, antibodies (monoclonal, polyclonal, and recombinant), antibody fragments and derivatives thereof, leucine zipper domain of AP-1 (jun and fos), hexa-his (metal chelate moiety), hexa-hat GST (glutathione S-tranferase) glutathione affinity, Calmodulin-binding peptide (CBP), Strep-tag, Cellulose Binding Domain, Maltose Binding Protein, S-Peptide Tag, Chitin Binding Tag, Immuno-reactive Epitopes, Epitope Tags, E2Tag, HA Epitope Tag, Myc Epitope, FLAG Epitope, AU1 and AU5 Epitopes, Glu-Glu Epitope, KT3 Epitope, IRS Epitope, Btag Epitope, Protein Kinase-C Epitope, VSV Epitope, lectins that mediate binding to a diversity of compounds, including carbohydrates, lipids and proteins, e.g. Con A (Canavalia ensiformis) or WGA (wheat germ agglutinin) and tetranectin or Protein A or G (antibody affinity). 22. The MHC molecule construct according to any one of claims 1-21, further comprising one or more biologically active molecules. 23. The MHC molecule construct according to claim 22, wherein the biologically active molecules is selected from proteins, co-stimulatory molecules, cell modulating molecules, receptors, accessory molecules, adhesion molecules, natural ligands, and toxic molecules, and antibodies and recombinant binding molecules thereto, and combinations thereof. 24. The MHC molecule construct according to claim 22 or 23, wherein the biologically active molecule is attached to the carrier molecule either directly or via one or more of the binding entities. 25. The MHC molecule construct according to any one of claims 22-24, wherein the biologically active molecule is selected from
proteins such as MHC Class I-like proteins like MIC A, MIC B, CD1d, HLA E, HLA F, HLA G, HLA H, ULBP-1, ULBP-2, and ULBP-3, co-stimulatory molecules such as CD2, CD3, CD4, CD5, CD8, CD9, CD27, CD28, CD30, CD69, CD134 (OX40), CD137 (4-1BB), CD147, CDw150 (SLAM), CD152 (CTLA-4), CD153 (CD30L), CD40L (CD154), NKG2D, ICOS, HVEM, HLA Class II, PD-1, Fas (CD95), FasL expressed on T and/or NK cells, CD40, CD48, CD58, CD70, CD72, B7.1 (CD80), B7.2 (CD86), B7RP-1, B7-H3, PD-L1, PD-L2, CD134L, CD137L, ICOSL, LIGHT expressed on APC and/or tumour cells, cell modulating molecules such as CD16, NKp30, NKp44, NKp46, NKp80, 2B4, KIR, LIR, CD94/NKG2A, CD94/NKG2C expressed on NK cells, IFN-alpha, IFN-beta, IFN-gamma, IL-1, IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, IL-10, IL-11, IL-12, IL-15, CSFs (colony-stimulating factors), vitamin D3, IL-2 toxins, cyclosporin, FK-506, rapamycin, TGF-beta, clotrimazole, nitrendipine, and charybdotoxin, accessory molecules such as LFA-1, CD11a/18, CD54 (ICAM-1), CD106 (VCAM), and CD49a,b,c,d,e,f/CD29 (VLA-4), adhesion molecules such as ICAM-1, ICAM-2, GlyCAM-1, CD34, anti-LFA-1, anti-CD44, anti-beta7, chemokines, CXCR4, CCR5, anti-selectin L, anti-selectin E, and anti-selectin P, toxic molecules such as cyclophosphamide, methrotrexate, Azathioprine, mizoribine, 15-deoxuspergualin, neomycin, staurosporine, genestein, herbimycin A, Pseudomonas exotoxin A, saporin, Rituxan, Ricin, gemtuzumab ozogamicin, Shiga toxin, heavy metals like inorganic and organic mercurials, and FN18-CRM9, radioisotopes such as incorporated isotopes of iodide, cobalt, selenium, tritium, and phosphor, and haptens such as DNP, and digoxiginin, and antibodies thereto, or antibody derivatives or fragments thereof, and combinations thereof. 26. The MHC molecule construct according to any of claims 1-25 further comprising one or more labelling compounds. 27. The MHC molecule construct according to claim 26, wherein one or more labelling compounds are attached to the carrier molecule. 28. The MHC molecule construct according to claim 26, wherein one or more labelling compounds are attached to one or more of the binding entities. 29. The MHC molecule construct according to claim 26, wherein one or more labelling compounds are attached to one or more of the MHC molecules. 30. The MHC molecule construct according to claim 26, wherein one or more labelling compounds are attached to the carrier molecule and/or one or more of the binding entities and/or one or more of the MHC molecules. 31. The MHC molecule construct according to any one of claims 26-30, wherein the labelling compound is directly or indirectly detectable. 32. The MHC molecule construct according to any of claims 26-31, wherein the labelling compound is a fluorescent label, an enzyme label, a radioisotope, a chemiluminescent label, a bioluminescent label, a polymer, a metal particle, a hapten, an antibody, or a dye. 33. The MHC molecule construct according to any one of claims 26-32, wherein the labelling compound is selected from fluorescent labels such as 5-(and 6)-carboxyfluorescein, 5- or 6-carboxyfluorescein, 6-(fluorescein)-5-(and 6)-carboxamido hexanoic acid, fluorescein isothiocyanate (F)TC), rhodamine, tetramethylrhodamine, and dyes such as Cyt, Cy3, and Cy5, optionally substituted coumarin including AMCA, PerCP, phycobiliproteins including R-phycoerythrin (RPE) and allophycoerythrin (APC), Texas Red, Princeston Red, Green fluorescent protein (GFP) and analogues thereof, and conjugates of R-phycoerythrin or allophycoerythrin and e.g. Cy5 or Texas Red, and inorganic fluorescent labels based on semiconductor nanocrystals (like quantum dot and Qdot™ nanocrystals), and time-resolved fluorescent labels based on lanthanides like Eu3+ and Sm3+,
from haptens such as DNP, biotin, and digoxiginin, or
is selected from enzymatic labels such as horse radish peroxidase (HRP), alkaline phosphatase (AP), beta-galactosidase (GAL), glucose-6-phosphate dehydrogenase, beta-N-acetylglucosaminidase, β-glucuronidase, invertase, Xanthine Oxidase, firefly luciferase and glucose oxidase (GO), or
is selected from luminiscence labels such as luminol, isoluminol, acridinium esters, 1,2-dioxetanes and pyridopyridazines, or
is selected from radioactivity labels such as incorporated isotopes of iodide, cobalt, selenium, tritium, and phosphor. 34. The MHC molecule construct according to any one of claims 1-33, wherein the carrier molecule is selected from
polysaccharides including dextrans, carboxy methyl dextran, dextran polyaldehyde, carboxymethyl dextran lactone, and cyclodextrins, pullulans, schizophyllan, scleroglucan, xanthan, gellan, O-ethylamino guaran, chitins and chitosans including 6-O-carboxymethyl chitin and N-carboxymethyl chitosan, derivatised cellolosics including carboxymethyl cellulose, carboxymethyl hydroxyethyl cellulose, hydroxyethyl cellulose, 6-amino-6-deoxy cellulose and O-ethylamine cellulose, hydroxylated starch, hydroxypropyl starch, hydroxyethyl starch, carrageenans, alginates, and agarose, synthetic polysaccharides including ficoll and carboxymethylated ficoll, vinyl polymers including poly(acrylic acid), poly(acryl amides), poly(acrylic esters), poly(2-hydroxy ethyl methacrylate), poly(methyl methacrylate), poly(maleic acid), poly(maleic anhydride), poly(acrylamide), poly(ethyl-co-vinyl acetate), poly(methacrylic acid), poly(vinylalcohol), poly(vinyl alcohol-co-vinyl chloroacetate), aminated poly(vinyl alcohol), and co block polymers thereof, poly ethylene glycol (PEG) or polypropylene glycol or poly-(ethylene oxide-co-propylene oxides) containing polymer backbones including linear, comb-shaped or StarBurst™ dendrimers, poly amino acids including polylysines, polyglutamic acid, polyurethanes, poly(ethylene imines), pluriol. proteins including albumins, immunoglobulins, and virus-like proteins (VLP), and polynucleotides, DNA, PNA, LNA, oligonucleotides and oligonucleotide dendrimer constructs. 35. The MHC molecule construct according to any one of claims 1-34, wherein the carrier molecule is a soluble carrier molecule. 36. The MHC molecule construct according to any one of claims 1-35 in soluble form. 37. The MHC molecule construct according to any one of claims 1-36 immobilised onto a solid or semi-solid support. 38. The MHC molecule construct according to claim 37, immobilised directly to the solid or semi-solid support. 39. The MHC molecule construct according to claim 37, immobilised to the solid or semi-solid support via a linker, a spacer, or an antibody, an antibody derivative or a fragment thereof. 40. The MHC molecule construct according to any one of claims 37-39, wherein the support is selected from particles, beads, biodegradable particles, sheets, gels, filters, membranes (e. g. nylon membranes), fibres, capillaries, needles, microtitre strips, tubes, plates or wells, combs, pipette tips, micro arrays, and chips. 41. The MHC molecule construct according to claim 40, wherein the support is selected from beads and particles. 42. The MHC molecule construct according to claim 41, wherein the beads and particles are polymeric beads, polymeric particles, magnetic beads, magnetic particles, supermagnetic beads, or supermagnetic particles. 43. The MHC molecule construct according to any one of claims 1-42 for use in a flow cytometric method. 44. The MHC molecule construct according to any one of claims 1-42 for use in a histological method. 45. The MHC molecule construct according to any one of claims 1-42 for use in a cytological method. 46. A method for detecting the presence of MHC recognising cells in a sample comprising the steps of
(a) providing a sample suspected of comprising MHC recognising cells, (b) contacting the sample with a MHC molecule construct according to claims 1-42, and (c) determining any binding of the MHC molecule construct, which binding indicates the presence of MHC recognising cells. 47. A method for monitoring MHC recognising cells comprising the steps of
(a) providing a sample suspected of comprising MHC recognising cells, (b) contacting the sample with a MHC molecule construct according to claims 1-42, and (c) determining any binding of the MHC molecule construct, thereby monitoring MHC recognising cells. 48. A method for establishing a prognosis of a disease involving MHC recognising cells comprising the steps of
(a) providing a sample suspected of comprising MHC recognising cells, (b) contacting the sample with a MHC molecule construct according to claims 1-42, and (c) determining any binding of the MHC molecule construct, thereby establishing a prognosis of a disease involving MHC recognising cells. 49. A method for determining the status of a disease involving MHC recognising cells comprising the steps of
(a) providing a sample suspected of comprising MHC recognising cells, (b) contacting the sample with a MHC molecule construct according to claims 1-42, and (c) determining any binding of the MHC molecule construct, thereby determining the status of a disease involving MHC recognising cells. 50. A method for diagnosing a disease involving MHC recognising cells comprising the steps of
(a) providing a sample suspected of comprising MHC recognising cells, (b) contacting the sample with a MHC molecule construct according to claims 1-42, and (c) determining any binding of the MHC molecule construct, thereby diagnosing a disease involving MHC recognising cells. 51. A method for determining the effectiveness of a medicament against a disease involving MHC recognising cells comprising the steps of
(a) providing a sample from a subject receiving treatment with a medicament, (b) contacting the sample with a MHC molecule construct according to claims 1-42, and (c) determining any binding of the MHC molecule construct, thereby determining the effectiveness of the medicament. 52. The method according to any one of claims 46-51, wherein the MHC recognising cells are involved in a disease of inflammatory, auto-immune, allergic, viral, cancerous, infectious, allo- or xenogene (graft versus host and host versus graft) origin. 53. The method according to claim 52, wherein the disease is a chronic inflammatory bowel disease such as Crohn's disease or ulcerative colitis, sclerosis, type I diabetes, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, malignant melanoma, renal carcinoma, breast cancer, lung cancer, cancer of the uterus, cervical cancer, prostatic cancer, brain cancer, head and neck cancer, leukaemia, cutaneous lymphoma, hepatic carcinoma, colorectal cancer, bladder cancer, rejection-related disease, Graft-versus-host-related disease, or a viral disease associated with hepatitis, AIDS, measles, pox, chicken pox, rubella or herpes. 54. The method according to any one of claims 46-53, wherein the MHC recognising cells selected from subpopulations of CD3+ T-cells, gamma, delta T-cells, alpha, beta T-cells, CD4+ T-cells, T helper cells, CD8+ T-cells, Suppressor T-cells, CD8+ cytotoxic T-cells, CTLs, NK cells, NKT cells, LAK cells, and MAK. 55. The method according to any one of claims 46-51, wherein the sample is selected from histological material, cytological material, primary tumours, secondary organ metastasis, fine needle aspirates, spleen tissue, bone marrow specimens, cell smears, exfoliative cytological specimens, touch preparations, oral swabs, laryngeal swabs, vaginal swabs, bronchial lavage, gastric lavage, from the umbilical cord, and from body fluids such as blood (e.g. from a peripheral blood mononuclear cell (PBMC) population isolated from blood or from other blood-derived preparations such as leukopheresis products), from sputum samples, expectorates, and bronchial aspirates. 56. The method according to any one of claims 46-55, wherein the determination of the binding is carried out by inspection in a microscope, by light, by fluorescence, by electron transmission, or by flow cytometry. 57. The method according to any one of claims 46-56, wherein the sample is mounted on a support. 58. The method according to claim 57, wherein the support is a solid or semi-solid support. 59. The method according to claim 57 or 58, wherein the support is selected from glass slides, microtiter plates having one or more wells, beads, particles, membranes, filters, filter membranes, polymer slides, polymer membranes, chamber slides, dishes, and petridishes. 60. A composition comprising a MHC molecule construct according to any one of claims 1-42 in a solubilising medium. 61. The composition according to claim 60, wherein the MHC molecule construct comprises peptide filled MHC molecules. 62. The composition according to claim 60, wherein the MHC molecule construct comprises peptide free MHC molecules. 63. The composition according to claim 62, wherein peptides to fill the peptide free MHC molecules, and the MHC molecule construct comprising peptide free molecules are provided separately. 64. A composition comprising a MHC molecule construct according to any one of claims 1-42, wherein the MHC molecule construct is immobilised onto a solid or semi-solid support. 65. The composition according to claim 64, wherein the support is selected from glass slides, microtiter plates having one or more wells, beads, particles, membranes, filters, filter membranes, polymer slides, polymer membranes, chamber slides, dishes, and petridishes. 66. The composition according to claim 64 or 65, wherein the beads and particles are polymeric beads, polymeric particles, magnetic beads, magnetic particles, supermagnetic beads, or supermagnetic particles. 67. The composition according to claim 64, wherein the MHC molecule construct comprises peptide filled MHC molecules. 68. The composition according to claim 64, wherein the MHC molecule construct comprises peptide free MHC molecules. 69. The composition according to claim 68, wherein peptides to fill the peptide free MHC molecules, and the MHC molecule construct comprising peptide free molecules are provided separately. 70. Use of a MHC molecule construct according to any one of claims 1-42 as a detection system. 71. Use of a MHC molecule construct according to any one of claims 1-42 for diagnosing a disease involving MHC recognising cells. 72. Use of a MHC molecule construct according to any one of claims 1-42 for monitoring a disease involving MHC recognising cells. 73. Use of a MHC molecule construct according to any one of claims 1-42 for establishing a prognosis for a disease involving MHC recognising cells. 74. Use of a MHC molecule construct according to any one of claims 1-42 for determining the status of a disease involving MHC recognising cells. 75. Use of a MHC molecule construct according to any one of claims 1-42 for determining the effectiveness of a medicament against a disease involving MHC recognising cells. 76. Use according to any one of claim 71, wherein the MHC recognising cells are involved in a disease of inflammatory, auto-immune, allergic, viral, cancerous, infectious, allo- or xenogene (graft-versus-host and host-versus-graft) origin. 77. Use according to claim 76, wherein the disease is a chronic inflammatory bowel disease such as Crohn's disease or ulcerative colitis, sclerosis, type I diabetes, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, malignant melanoma, renal carcinoma, breast cancer, lung cancer, cancer of the uterus, cervical cancer, prostatic cancer, brain cancer, head and neck cancer, leukaemia, cutaneous lymphoma, hepatic carcinoma, colorectal cancer, bladder cancer, rejection-related disease, Graft-versus-host-related disease, or a viral disease associated with hepatitis, AIDS, measles, pox, chicken pox, rubella or herpes. 78. Use according to any one of claims 70-77, wherein the MHC recognising cells are selected from subpopulations of CD3+ T-cells, gamma, delta T-cells, alpha, beta T-cells, CD4+ T-cells, T helper cells, CD8+ T-cells, Suppressor T-cells, CD8+ cytotoxic T-cells, CTLs, NK cells, NKT cells, LAK cells, and MAK. 79. The MHC molecule construct according to any one of claims 1-42 for use as a therapeutic composition. 80. The MHC molecule construct according to any one of claims 1-42 for use in in vivo therapy. 81. The MHC molecule construct according to any one of claims 1-42 for use in ex vivo therapy. 82. A therapeutic composition comprising as active ingredient a MHC molecule construct as defined in any one of claims 1-42. 83. The therapeutic composition according to claim 82, wherein the MHC molecule construct is immobilised to a biodegradable solid or semi-solid support. 84. The therapeutic composition according to claim 82 or 83, wherein the MHC molecule construct comprises
a carrier molecule having attached thereto one or more MHC molecules, said MHC molecules being attached to the carrier molecule either directly or via one or more binding entities. 85. The therapeutic composition according to claim 82 or 83, wherein the MHC molecule is a vertebrate MHC molecule such as a human, a murine, a rat, a porcine, a bovine or an avian molecule. 86. The therapeutic composition according to any one of claims 82-85, wherein the MHC molecule is a human MHC molecule. 87. The therapeutic composition according to any one of claims 82-86, wherein the MHC molecule is
a MHC Class I molecule selected from the group consisting of a heavy chain, a heavy chain combined with a β2m, a heavy chain combined with a peptide, and a heavy chain/β2m dimer with a peptide; or a MHC Class II molecule selected from the group consisting of an α/β dimer, an α/β dimer with a peptide, α/β dimer combined through an affinity tag and a α/β dimer combined through an affinity tag with a peptide or a MHC Class I like molecule or a MHC Class II like molecule. 88. The therapeutic composition according to any one of claims 82-87, wherein the MHC molecule is a peptide free MHC molecule. 89. The therapeutic composition according to any one of claims 82-88, wherein at least two of the MHC molecules are different. 90. The therapeutic composition according to any one of claims 82-88, wherein the MHC molecules are the same. 91. The therapeutic composition according to any one of claims 82-88, wherein at least two of the peptides harboured by the MHC molecules are different. 92. The therapeutic composition according to any one of claims 82-88, wherein the peptides harboured by the MHC molecules are the same. 93. The therapeutic composition according to any one of claims 82-92, wherein the MHC molecules are attached to the carrier molecule directly. 94. The therapeutic composition according to any one of claims 82-92, wherein the MHC molecules are attached to the carrier molecule via one or more binding entities. 95. The therapeutic composition according to claim 94, wherein each binding entity has attached thereto from 1 to 10 MHC molecules. 96. The therapeutic composition according to claim 94, wherein each binding entity has attached thereto from 1 to 8 MHC molecules. 97. The therapeutic composition according to claim 94, wherein each binding entity has attached thereto from 1 to 6 MHC molecules. 98. The therapeutic composition according to claim 94, wherein each binding entity has attached thereto from 1 to 4 MHC molecules. 99. The therapeutic composition according to claim 94, wherein each binding entity has attached thereto from 1 to 3 MHC molecules. 100. The therapeutic composition according to claim 94, wherein each binding entity has attached thereto 1 or 2 MHC molecules. 101. The therapeutic composition according to any one of claims 82-100, wherein the total number of MHC molecules of the construct is from 1 to 100. 102. The therapeutic composition according to any one of claims 82-100, wherein the total number of MHC molecules of the construct is from 1 to 50. 103. The therapeutic composition according to any one of claims 82-100, wherein the total number of MHC molecules of the construct is from 1 to 25. 104. The therapeutic composition according to claim 94, wherein the binding entity is selected from streptavidin (SA) and avidin and derivatives thereof, biotin, immunoglobulins, antibodies (monoclonal, polyclonal, and recombinant), antibody fragments and derivatives thereof, leucine zipper domain of AP-1 (jun and fos), hexa-his (metal chelate moiety), hexa-hat GST (glutathione S-tranferase) glutathione affinity, Calmodulin-binding peptide (CBP), Strep-tag, Cellulose Binding Domain, Maltose Binding Protein, S-Peptide Tag, Chitin Binding Tag, Immuno-reactive Epitopes, Epitope Tags, E2Tag, HA Epitope Tag, Myc Epitope, FLAG Epitope, AU1 and AU5 Epitopes, Glu-Glu Epitope, KT3 Epitope, IRS Epitope, Btag Epitope, Protein Kinase-C Epitope, VSV Epitope, lectins that mediate binding to a diversity of compounds, including carbohydrates, lipids and proteins, e.g. Con A (Canavalia ensiformis) or WGA (wheat germ agglutinin) and tetranectin or Protein A or G (antibody affinity). 105. The therapeutic composition according to any one of claims 82-104 further comprising one or more biologically active molecules. 106. The therapeutic composition according to claim 105, wherein the biologically active molecules is selected from proteins, co-stimulatory molecules, cell modulating molecules, receptors, accessory molecules, adhesion molecules, natural ligands, and toxic molecules, and antibodies and recombinant binding molecules thereto, and combinations thereof. 107. The therapeutic composition according to claim 105 or 106, wherein the biologically active molecule is attached to the carrier molecule either directly or via one or more of the binding entities. 108. The therapeutic composition according to any one of claims 105-107, wherein the biologically active molecule is selected from
proteins such as MHC Class I-like proteins like MIC A, MIC B, CD1d, HLA E, HLA F, HLA G, HLA H, ULBP-1, ULBP-2, and ULBP-3, co-stimulatory molecules such as CD2, CD3, CD4, CD5, CD8, CD9, CD27, CD28, CD30, CD69, CD134 (OX40), CD137 (4-1BB), CD147, CDw150 (SLAM), CD152 (CTLA-4), CD153 (CD30L), CD40L (CD154), NKG2D, ICOS, HVEM, HLA Class II, PD-1, Fas (CD95), FasL expressed on T and/or NK cells, CD40, CD48, CD58, CD70, CD72, B7.1 (CD80), B7.2 (CD86), B7RP-1, B7-H3, PD-L1, PD-L2, CD134L, CD137L, ICOSL, LIGHT expressed on APC and/or tumour cells, cell modulating molecules such as CD16, NKp30, NKp44, NKp46, NKp80, 2B4, KIR, LIR, CD94/NKG2A, CD94/NKG2C expressed on NK cells, IFN-alpha, IFN-beta, IFN-gamma, IL-1, IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, IL-10, IL-11, IL-12, IL-15, CSFs (colony-stimulating factors), vitamin D3, IL-2 toxins, cyclosporin, FK-506, rapamycin, TGF-beta, clotrimazole, nitrendipine, and charybdotoxin, accessory molecules such as LFA-1, CD11a/18, CD54 (ICAM-1), CD106 (VCAM), and CD49a,b,c,d,e,f/CD29 (VLA-4), adhesion molecules such as ICAM-1, ICAM-2, GlyCAM-1, CD34, anti-LFA-1, anti-CD44, anti-beta7, chemokines, CXCR4, CCR5, anti-selectin L, anti-selectin E, and anti-selectin P, toxic molecules such as cyclophosphamide, methrotrexate, Azathioprine, mizoribine, 15-deoxuspergualin, neomycin, staurosporine, genestein, herbimycin A, Pseudomonas exotoxin A, saporin, Rituxan, Ricin, gemtuzumab ozogamicin, Shiga toxin, heavy metals like inorganic and organic mercurials, and FN18-CRM9, radioisotopes such as incorporated isotopes of iodide, cobalt, selenium, tritium, and phosphor, and haptens such as DNP, and digoxiginin, and antibodies thereto, or antibody derivatives or fragments thereof, and combinations thereof. 109. The therapeutic composition according to any one of claims 82-108, wherein the carrier molecule is selected from
polysaccharides including dextrans, carboxy methyl dextran, dextran polyaldehyde, carboxymethyl dextran lactone, and cyclodextrins, pullulans, schizophyllan, scleroglucan, xanthan, gellan, O-ethylamino guaran, chitins and chitosans including 6-O-carboxymethyl chitin and N-carboxymethyl chitosan, derivatised cellolosics including carboxymethyl cellulose, carboxymethyl hydroxyethyl cellulose, hydroxyethyl cellulose, 6-amino-6-deoxy cellulose and O-ethylamine cellulose, hydroxylated starch, hydroxypropyl starch, hydroxyethyl starch, carrageenans, alginates, and agarose, synthetic polysaccharides including ficoll and carboxymethylated ficoll, vinyl polymers including poly(acrylic acid), poly(acryl amides), poly(acrylic esters), poly(2-hydroxy ethyl methacrylate), poly(methyl methacrylate), poly(maleic acid), poly(maleic anhydride), poly(acrylamide), poly(ethyl-co-vinyl acetate), poly(methacrylic acid), poly(vinylalcohol), poly(vinyl alcohol-co-vinyl chloroacetate), aminated poly(vinyl alcohol), and co block polymers thereof, poly ethylene glycol (PEG) or polypropylene glycol or poly-(ethylene oxide-co-propylene oxides) containing polymer backbones including linear, comb-shaped or StarBurst™ dendrimers, poly amino acids including polylysines, polyglutamic acid, polyurethanes, poly(ethylene imines), pluriol. proteins including albumins, immunoglobulins, and virus-like proteins (VLP), and polynucleotides, DNA, PNA, LNA, oligonucleotides and oligonucleotide dendrimer constructs. 110. The therapeutic composition according to any one of claims 82-109, wherein the carrier molecule is a soluble carrier molecule. 111. The therapeutic composition according to any one of claims 82-110 further comprising one or more adjuvants and/or excipients. 112. The therapeutic composition according to claim 111, wherein the adjuvant is selected from saponins such as Quil A and Qs-21, oil in water emulsions such as MF59, MPL, PLG, PLGA, aluminium salts, calcium phosphate, water in oil emulsions such as IFA (Freund's incomplete adjuvant) and CFA (Freund's complete adjuvant), interleukins such as IL-1β, IL-2, IL-7, IL-12, and INFγ, Adju-Phos®, glucan, antigen formulation, biodegradable microparticles, Cholera Holotoxin, liposomes, DDE, DHEA, DMPC, DMPG, DOC/Alum Complex, ISCOMs®, muramyl dipeptide, monophosphoryl lipid A, muramyl tripeptide, and phospatidylethanolamine In a preferred embodiment, the adjuvant is selected from saponins such as Quil A and Qs-21, MF59, MPL, PLG, PLGA, calcium phosphate, and aluminium salts. 113. The therapeutic composition according to claim 113, wherein the excipient is selected from diluents, buffers, suspending agents, wetting agents, solubilising agents, pH-adjusting agents, dispersing agents, preserving agents, and/or colorants. 114. The therapeutic composition according to any one of claims 82-113 for the treatment, prevention, stabilisation, or alleviation of disease involving MHC recognising cells. 115. The therapeutic composition according to claim 114, wherein the MHC recognising cells are involved in a disease of inflammatory, auto-immune, allergic, viral, cancerous, infectious, allo- or xenogene (graft versus host and host versus graft) origin. 116. The therapeutic composition according to claim 115, wherein the disease is a chronic inflammatory bowel disease such as Crohn's disease or ulcerative colitis, sclerosis, type I diabetes, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, malignant melanoma, renal carcinoma, breast cancer, lung cancer, cancer of the uterus, prostatic cancer, brain cancer, head and neck cancer, leukaemia, cutaneous lymphoma, hepatic carcinoma, colorectal cancer, bladder cancer, rejection-related disease, Graft-versus-host-related disease, or a viral disease associated with hepatitis, AIDS, measles, pox, chicken pox, rubella or herpes. 117. The therapeutic composition according to any one of claims 82-116 formulated for parenteral administration, including intravenous, intramuscular, intraarticular, subcutaneous, intradermal, epicutantous/transdermal, and intraperitoneal administration, for infusion, for oral administration, for nasal administration, for rectal administration, or for topic administration. 118. A therapeutic composition comprising as active ingredient an effective amount of MHC recognising cells, the MHC recognising cells being obtained by
bringing a sample from a subject comprising MHC recognising cells into contact with a MHC molecule construct according to any one of claims 1-42, whereby the MHC recognising cells become bound to the MHC molecule construct, isolating the bound MHC molecule construct and the MHC recognising cells, and expanding such MHC recognising cells to a clinically relevant number. 119. The therapeutic composition according to claim 118, wherein the isolated MHC recognising cells are liberated from the MHC molecule construct prior to expansion. 120. The therapeutic composition according to claim 118 or 119, wherein the MHC molecule construct is immobilised onto a solid or semi-solid support. 121. The therapeutic composition according to claim 120, wherein the MHC molecule construct is immobilised onto the solid or semi-solid support prior to contact with the sample. 122. The therapeutic composition according to claim 120, wherein the MHC molecule construct is immobilised onto the solid or semi-solid support following contact with the sample. 123. The therapeutic composition according to any one of claims 118-122, wherein the expansion is carried out in the presence of one or more MHC molecule constructs, optionally one or more biologically active molecules and optionally feeder cells such as dendritic cells or feeder cells. 124. The therapeutic composition according to any one of claims 120-123, wherein the MHC molecule construct is immobilised onto the solid or semi-solid support directly. 125. The therapeutic composition according to any one of claims 120-124, wherein the MHC molecule construct is immobilised to the solid or semi-solid support via a linker, a spacer, or an antibody, an antibody derivative or a fragment thereof. 126. The therapeutic composition according to any one of claims 120-125, wherein the solid or semi-solid support is selected from particles, beads, biodegradable particles, sheets, gels, filters, membranes, fibres, capillaries, needles, microtitre strips, tubes, plates or wells, combs, pipette tips, micro arrays, chips, and microtiter plates having one or more wells. 127. The therapeutic composition according to any one of claims 120-126, wherein the solid support is selected from particles and beads. 128. The therapeutic composition according to claim 127, wherein the particles and beads are polymeric, magnetic or superparamagnetic. 129. The therapeutic composition according to any one of claims 118-128, wherein the isolation is performed by applying a magnetic field or by flow cytometry. 130. The therapeutic composition according to any one of claims 118-128, wherein the MHC molecule construct comprises
a carrier molecule having attached thereto one or more MHC molecules, said MHC molecules being attached to the carrier molecule either directly or via one or more binding entities. 131. The therapeutic composition according to any one of claims 118-130, wherein the MHC molecule is a vertebrate MHC molecule such as a human, a murine, a rat, a porcine, a bovine or an avian molecule. 132. The therapeutic composition according to any one of claims 118-131, wherein the MHC molecule is a human MHC molecule. 133. The therapeutic composition according to any one of claims 118-132, wherein the MHC molecule is
a MHC Class I molecule selected from the group consisting of a heavy chain, a heavy chain combined with a β2m, a heavy chain combined with a peptide, and a heavy chain/β2m dimer with a peptide; or a MHC Class II molecule selected from the group consisting of an α/β dimer, an α/β dimer with a peptide, α/β dimer combined through an affinity tag and a α/β dimer combined through an affinity tag with a peptide; or a MHC Class I like molecule or a MHC Class II molecule. 134. The therapeutic composition according to any one of claims 118-133, wherein the MHC molecule is a peptide free MHC molecule. 135. The therapeutic composition according to any one of claims 118-134, wherein at least two of the MHC molecules are different. 136. The therapeutic composition according to any one of claims 118-135, wherein the MHC molecules are the same. 137. The therapeutic composition according to any one of claims 118-136, wherein at least two of the peptides harboured by the MHC molecules are different. 138. The therapeutic composition according to any one of claims 118-137, wherein the peptides harboured by the MHC molecules are the same. 139. The therapeutic composition according to any one of claims 118-138, wherein the MHC molecules are attached to the carrier molecule directly. 140. The therapeutic composition according to any one of claims 118-138, wherein the MHC molecules are attached to the carrier molecule via one or more binding entities. 141. The therapeutic composition according to claim 140, wherein each binding entity has attached thereto from 1 to 10 MHC molecules. 142. The therapeutic composition according to claim 140, wherein each binding entity has attached thereto from 1 to 8 MHC molecules. 143. The therapeutic composition according to claim 140, wherein each binding entity has attached thereto from 1 to 6 MHC molecules. 144. The therapeutic composition according to claim 140, wherein each binding entity has attached thereto from 1 to 4 MHC molecules. 145. The therapeutic composition according to claim 140, wherein each binding entity has attached thereto from 1 to 3 MHC molecules. 146. The therapeutic composition according to claim 140, wherein each binding entity has attached thereto 1 or 2 MHC molecules. 147. The therapeutic composition according to any one of claims 118-146, wherein the total number of MHC molecules of the construct is from 1 to 100. 148. The therapeutic composition according to any one of claims 118-146, wherein the total number of MHC molecules of the construct is from 1 to 50. 149. The therapeutic composition according to any one of claims 118-146, wherein the total number of MHC molecules of the construct is from 1 to 25. 150. The therapeutic composition according to claim 140, wherein the binding entity is selected from streptavidin streptavidin (SA) and avidin and derivatives thereof, biotin, immunoglobulins, antibodies (monoclonal, polyclonal, and recombinant), antibody fragments and derivatives thereof, leucine zipper domain of AP-1 (jun and fos), hexa-his (metal chelate moiety), hexa-hat GST (glutathione S-tranferase) glutathione affinity, Calmodulin-binding peptide (CBP), Strep-tag, Cellulose Binding Domain, Maltose Binding Protein, S-Peptide Tag, Chitin Binding Tag, Immuno-reactive Epitopes, Epitope Tags, E2Tag, HA Epitope Tag, Myc Epitope, FLAG Epitope, AU1 and AU5 Epitopes, Glu-Glu Epitope, KT3 Epitope, IRS Epitope, Btag Epitope, Protein Kinase-C Epitope, VSV Epitope, lectins that mediate binding to a diversity of compounds, including carbohydrates, lipids and proteins, e.g. Con A (Canavalia ensiformis) or WGA (wheat germ agglutinin) and tetranectin or Protein A or G (antibody affinity). 151. The therapeutic composition according to any one of claims 118-150 further comprising one or more biologically active molecules. 152. The therapeutic composition according to claim 151, wherein the biologically active molecules is selected from proteins, co-stimulatory molecules, cell modulating molecules, receptors, accessory molecules, adhesion molecules, natural ligands, and toxic molecules, and antibodies and recombinant binding molecules thereto, and combinations thereof. 153. The therapeutic composition according to claim 150 or 151, wherein the biologically active molecule is attached to the carrier molecule either directly or via one or more of the binding entities. 154. The therapeutic composition according to any one of claims 151-153, wherein the biologically active molecule is selected from
proteins such as MHC Class I-like proteins like MIC A, MIC B, CD1d, HLA E, HLA F, HLA G, HLA H, ULBP-1, ULBP-2, and ULBP-3, co-stimulatory molecules such as CD2, CD3, CD4, CD5, CD8, CD9, CD27, CD28, CD30, CD69, CD134 (OX40), CD137 (4-1BB), CD147, CDw150 (SLAM), CD152 (CTLA-4), CD153 (CD30L), CD40L (CD154), NKG2D, ICOS, HVEM, HLA Class II, PD-1, Fas (CD95), FasL expressed on T and/or NK cells, CD40, CD48, CD58, CD70, CD72, B7.1 (CD80), B7.2 (CD86), B7RP-1, B7-H3, PD-L1, PD-L2, CD134L, CD137L, ICOSL, LIGHT expressed on APC and/or tumour cells, cell modulating molecules such as CD16, NKp30, NKp44, NKp46, NKp80, 2B4, KIR, LIR, CD94/NKG2A, CD94/NKG2C expressed on NK cells, IFN-alpha, IFN-beta, IFN-gamma, IL-1, IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, IL-10, IL-11, IL-12, IL-15, CSFs (colony-stimulating factors), vitamin D3, IL-2 toxins, cyclosporin, FK-506, rapamycin, TGF-beta, clotrimazole, nitrendipine, and charybdotoxin, accessory molecules such as LFA-1, CD11a/18, CD54 (ICAM-1), CD106 (VCAM), and CD49a,b,c,d,e,f/CD29 (VLA-4), adhesion molecules such as ICAM-1, ICAM-2, GlyCAM-1, CD34, anti-LFA-1, anti-CD44, anti-beta7, chemokines, CXCR4, CCR5, anti-selectin L, anti-selectin E, and anti-selectin P, toxic molecules such as cyclophosphamide, methrotrexate, Azathioprine, mizoribine, 15-deoxuspergualin, neomycin, staurosporine, genestein, herbimycin A, Pseudomonas exotoxin A, saporin, Rituxan, Ricin, gemtuzumab ozogamicin, Shiga toxin, heavy metals like inorganic and organic mercurials, and FN18-CRM9, radioisotopes such as incorporated isotopes of iodide, cobalt, selenium, tritium, and phosphor, and haptens such as DNP, and digoxiginin, and antibodies thereto, or antibody derivatives or fragments thereof, and combinations thereof. 155. The therapeutic composition according to any one of claims 118-154, wherein the carrier molecule is selected from
polysaccharides including dextrans, carboxy methyl dextran, dextran polyaldehyde, carboxymethyl dextran lactone, and cyclodextrins, pullulans, schizophyllan, scleroglucan, xanthan, gellan, O-ethylamino guaran, chitins and chitosans including 6-O-carboxymethyl chitin and N-carboxymethyl chitosan, derivatised cellolosics including carboxymethyl cellulose, carboxymethyl hydroxyethyl cellulose, hydroxyethyl cellulose, 6-amino-6-deoxy cellulose and O-ethylamine cellulose, hydroxylated starch, hydroxypropyl starch, hydroxyethyl starch, carrageenans, alginates, and agarose, synthetic polysaccharides including ficoll and carboxymethylated ficoll, vinyl polymers including poly(acrylic acid), poly(acryl amides), poly(acrylic esters), poly(2-hydroxy ethyl methacrylate), poly(methyl methacrylate), poly(maleic acid), poly(maleic anhydride), poly(acrylamide), poly(ethyl-co-vinyl acetate), poly(methacrylic acid), poly(vinylalcohol), poly(vinyl alcohol-co-vinyl chloroacetate), aminated poly(vinyl alcohol), and co block polymers thereof, poly ethylene glycol (PEG) or polypropylene glycol or poly-(ethylene oxide-co-propylene oxides) containing polymer backbones including linear, comb-shaped or StarBurst™ dendrimers, poly amino acids including polylysines, polyglutamic acid, polyurethanes, poly(ethylene imines), pluriol. proteins including albumins, immunoglobulins, and virus-like proteins (VLP), and polynucleotides, DNA, PNA, LNA, oligonucleotides and oligonucleotide dendrimer constructs. 156. The therapeutic composition according to any one of claims 118-155 further comprising one or more labelling compounds. 157. The therapeutic composition according to claim 156, wherein one or more labelling compounds are attached to the carrier molecule. 158. The therapeutic composition according to claim 156, wherein one or more labelling compounds are attached to one or more of the binding entities. 159. The therapeutic composition according to claim 156, wherein one or more labelling compounds are attached to one or more of the MHC molecules. 160. The therapeutic composition according to claim 156, wherein one or more labelling compounds are attached to the carrier molecule and/or one or more of the binding entities and/or one or more of the MHC molecules. 161. The therapeutic composition according to any one of claims 156-160, wherein the labelling compound is directly or indirectly detectable. 162. The therapeutic composition according to any one of claims 156-161, wherein the labelling compound is a fluorescent label, an enzyme label, a radioisotope, a chemiluminescent label, a bioluminescent label, a polymer, a metal particle, a hapten, an antibody, or a dye. 163. The therapeutic composition according to any one of claims 156-162, wherein the labelling compound
is selected from fluorescent labels such as 5-(and 6)-carboxyfluorescein, 5- or 6-carboxyfluorescein, 6-(fluorescein)-5-(and 6)-carboxamido hexanoic acid, fluorescein isothiocyanate (FITC), rhodamine, tetramethylrhodamine, and dyes such as Cy2, Cy3, and Cy5, optionally substituted coumarin including AMCA, PerCP, phycobiliproteins including R-phycoerythrin (RPE) and allophycoerythrin (APC), Texas Red, Princeston Red, Green fluorescent protein (GFP) and analogues thereof, and conjugates of R-phycoerythrin or allophycoerythrin and e.g. Cy5 or Texas Red, and inorganic fluorescent labels based on semiconductor nanocrystals (like quantum dot and Qdot™ nanocrystals), and time-resolved fluorescent labels based on lanthanides like Eu3+ and Sm3+, from haptens such as DNP, biotin, and digoxiginin, or is selected from haptens such as DNP, fluorescein isothiocyanate (FITC), biotin, and digoxiginin, or is selected from enzymatic labels such as horse radish peroxidase (HRP), alkaline phosphatase (AP), beta-galactosidase (GAL), glucose-6-phosphate dehydrogenase, beta-N-acetylglucosaminidase, β-glucuronidase, invertase, Xanthine Oxidase, firefly luciferase and glucose oxidase (GO), or is selected from luminiscence labels such as luminol, isoluminol, acridinium esters, 1,2-dioxetanes and pyridopyridazines, or is selected from radioactivity labels such as incorporated isotopes of iodide, cobalt, selenium, tritium, and phosphor. 164. The therapeutic composition according any one of claims 118-163, wherein the carrier molecule is a soluble carrier molecule. 165. The therapeutic composition according to any one of claims 118-164 further comprising one or more excipients. 166. The therapeutic composition according to claim 165, wherein the excipient is selected from diluents, buffers, suspending agents, wetting agents, solubilising agents, pH-adjusting agents, dispersing agents, preserving agents, and/or colorants. 167. The therapeutic composition according to any one of claims 118-166 for the treatment, prevention, stabilisation, or alleviation of a disease involving MHC recognising cells. 168. The therapeutic composition according to claim 167, wherein MHC recognising cells are involved in a disease of inflammatory, auto-immune, allergic, viral, cancerous, infectious, allo- or xenogene (graft versus host and host versus graft) origin. 169. The therapeutic composition according to claim 167 or 168, wherein the disease is a chronic inflammatory bowel disease such as Crohn's disease or ulcerative colitis, sclerosis, type I diabetes, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, malignant melanoma, renal carcinoma, breast cancer, lung cancer, cancer of the uterus, prostatic cancer, brain cancer, head and neck cancer, leukaemia, cutaneous lymphoma, hepatic carcinoma, colorectal cancer, bladder cancer, rejection-related disease, Graft-versus-host-related-disease, or a viral disease associated with hepatitis, AIDS, measles, pox, chicken pox, rubella or herpes. 170. The therapeutic composition according to any one of claims 118-169 formulated for parenteral administration, including intravenous, intramuscular, intraarticular, subcutaneous, intradermal, epicutantous/transdermal, and intraperitoneal administration, for infusion, for oral administration, for nasal administration, for rectal administration, or for topic administration. 171. The therapeutic composition according to any one of claims 82-170 for use in in vivo therapy. 172. A method of treating an animal, including a human being, comprising administering a therapeutic composition according to any one of claims 82-170 in an effective amount. 173. A method of up-regulating, down-regulating, modulate an immune response in an animal, including a human being, comprising administering a therapeutic composition according to any one of claims 82-170 in an effective amount. 174. A method of inducing anergy of a cell in an animal, including a human being, comprising administering a therapeutic composition according to any one of claims 82-170 in an effective amount. 175. An adoptive cellular immunotherapeutic method comprising administrating to an animal, including a human being, a therapeutic composition according to any one of claims 82-170. 176. A method of obtaining MHC recognising cells comprising
bringing into contact a MHC molecule construct according to any one of claims 1-42 and a sample suspected of comprising MHC recognising cells under conditions whereby the MHC recognising cells bind to the MHC molecule construct, and isolating the bound MHC molecule construct and MHC recognising cells. 177. The method according to claim 176, wherein the isolation is carried out by applying a magnetic field or by flow cytometry. 178. A method for producing a therapeutic composition according to any one of claims 82-170, comprising
providing a MHC molecule construct as defined in claims 1-42, solubilising or dispersing the MHC molecule construct in a medium suitable for therapeutic substances, and optionally adding other adjuvants and/or excipients. 179. A method for producing a therapeutic composition according to any one of claims 118-170, comprising
obtaining MHC recognising cells using a MHC molecule construct according to any one of claims 1-42, expanding such MHC recognising cells to a clinically relevant number, formulating the obtained cells in a medium suitable for administration, and optionally adding adjuvants and/or excipients. 180. Use of a MHC molecule construct according to any one of claims 1-42 for ex vivo expansion of MHC recognising cells. 181. Use according to claim 180, wherein the MHC molecule construct is in soluble form. 182. Use according to claim 180, wherein the MHC molecule construct is immobilised onto a solid or semi-solid support. 183. Use according to claim 182, wherein the solid or semi-solid support is selected from particles, beads, biodegradable particles, sheets, gels, filters, membranes (e.g. nylon membranes), fibres, capillaries, needles, microtitre strips, tubes, plates or wells, combs, pipette tips, micro arrays, chips, and slides. 184. Use according to claim 182 or 183, wherein the solid or semi-solid support is selected from beads and particles. 185. Use according to claim 184, wherein the solid or semi-solid support is selected from polymeric, magnetic or superparamagnetic particles and beads. 186. Use according to any one of claims 180-185, wherein the MHC molecule construct further comprises one or more biologically active molecules. 187. Use according to any one of claims 180-186, wherein wherein the biologically active molecule is selected from
proteins such as MHC Class I-like proteins like MIC A, MIC B, CD1d, HLA E, HLA F, HLA G, HLA H, ULBP-1, ULBP-2, and ULBP-3, co-stimulatory molecules such as CD2, CD3, CD4, CD5, CD8, CD9, CD27, CD28, CD30, CD69, CD134 (OX40), CD137 (4-1BB), CD147, CDw150 (SLAM), CD152 (CTLA-4), CD153 (CD30L), CD40L (CD154), NKG2D, ICOS, HVEM, HLA Class II, PD-1, Fas (CD95), FasL expressed on T and/or NK cells, CD40, CD48, CD58, CD70, CD72, B7.1 (CD80), B7.2 (CD86), B7RP-1, B7-H3, PD-L1, PD-L2, CD134L, CD137L, ICOSL, LIGHT expressed on APC and/or tumour cells, cell modulating molecules such as CD16, NKp30, NKp44, NKp46, NKp80, 2B4, KIR, LIR, CD94/NKG2A, CD94/NKG2C expressed on NK cells, IFN-alpha, IFN-beta, IFN-gamma, IL-1, IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, IL-10, IL-11, IL-12, IL-15, CSFs (colony-stimulating factors), vitamin D3, IL-2 toxins, cyclosporin, FK-506, rapamycin, TGF-beta, clotrimazole, nitrendipine, and charybdotoxin, accessory molecules such as LFA-1, CD11a/18, CD54 (ICAM-1), CD106 (VCAM), and CD49a,b,c,d,e,f/CD29 (VLA-4), adhesion molecules such as ICAM-1, ICAM-2, GlyCAM-1, CD34, anti-LFA-1, anti-CD44, anti-beta7, chemokines, CXCR4, CCR5, anti-selectin L, anti-selectin E, and anti-selectin P, toxic molecules such as cyclophosphamide, methrotrexate, Azathioprine, mizoribine, 15-deoxuspergualin, neomycin, staurosporine, genestein, herbimycin A, Pseudomonas exotoxin A, saporin, Rituxan, Ricin, gemtuzumab ozogamicin, Shiga toxin, heavy metals like inorganic and organic mercurials, and FN18-CRM9, radioisotopes such as incorporated isotopes of iodide, cobalt, selenium, tritium, and phosphor, and haptens such as DNP, and digoxiginin, and antibodies thereto, or antibody derivatives or fragments thereof, and combinations thereof. 187. Use of a MHC molecule in a histological method. 188. Use of a MHC molecule in a cytological method. 189. Use of a MHC molecule according to claim 187 or 188 in a method for determining the presence of MHC recognising cells in a sample, in which method the MHC recognising cells of the sample are mounted on a support. 190. Use of a MHC molecule according to claim 187 or 188, in a method for monitoring the presence of MHC recognising cells in a sample, in which method the MHC recognising cells of the sample are mounted on a support. 191. Use of a MHC molecule according to claim 187 or 188 in a method for determining the status of a disease involving MHC recognising cells, in which method the MHC recognising cells of the sample are mounted on a support. 192. Use of a MHC molecule according to claim 187 or 188 in a method for establishing a prognosis of a disease involving MHC recognising cells, in which method the MHC recognising cells of the sample are mounted on a support. 193. Use of a MHC molecule according to any one of claims 187-192, wherein the support is a solid or semi-solid support. 194. Use of a MHC molecule according to any one of claims 187-193, wherein the support is selected from glass slides, membranes, filters, polymer slides, chamber slides, dishes, and petridishes. 195. Use according to any one of claims 187-194, wherein the sample is selected from histological material, cytological material, primary tumours, secondary organ metastasis, fine needle aspirates, spleen tissue, bone marrow specimens, cell smears, exfoliative cytological specimens, touch preparations, oral swabs, laryngeal swabs, vaginal swabs, bronchial lavage, gastric lavage, from the umbilical cord, and from body fluids such as blood (e.g. from a peripheral blood mononuclear cell (PBMC) population isolated from blood or from other blood-derived preparations such as leukopheresis products), from sputum samples, expectorates, and bronchial aspirates. 196. The use according to any one of claims 187-195, wherein the MHC molecule is
a MHC Class I molecule selected from the group consisting of a heavy chain, a heavy chain combined with a β2m, a heavy chain combined with a peptide, and a heavy chain/β2m dimer with a peptide; or a MHC Class II molecule selected from the group consisting of an α/β dimer, an α/β dimer with a peptide, α/β dimer combined through an affinity tag and a α/β dimer combined through an affinity tag with a peptide; or a MHC Class I like molecule or a MHC Class II like molecule. 197. The use according to any one of claims 187-196, wherein the MHC molecule is a vertebrate MHC molecule such as a human, a murine, a rat, a porcine, a bovine or an avian molecule. 198. The use according to any one of claims 187-197, wherein the MHC molecule is a human MHC molecule. 199. The use according to any one of claims 187-198, wherein the MHC molecule is a peptide free MHC molecule. 200. The use according to any one of claims 187-199, wherein the MHC molecule is attached to a binding entity. 201. Use according to claim 200, wherein the binding entity has attached thereto from 1 to 10 MHC molecules, such as from 1 to 9, from 1 to 8, from 1 to 7, from 1 to 6, from 1 to 5, from 1 to 4, from 1 to 3, or 1 or 2 MHC molecules. 202. Use according to claim 200, wherein the binding entity is selected from streptavidin streptavidin (SA) and avidin and derivatives thereof, biotin, immunoglobulins, antibodies (monoclonal, polyclonal, and recombinant), antibody fragments and derivatives thereof, leucine zipper domain of AP-1 (jun and fos), hexa-his (metal chelate moiety), hexa-hat GST (glutathione S-tranferase) glutathione affinity, Calmodulin-binding peptide (CBP), Strep-tag, Cellulose Binding Domain, Maltose Binding Protein, S-Peptide Tag, Chitin Binding Tag, Immuno-reactive Epitopes, Epitope Tags, E2Tag, HA Epitope Tag, Myc Epitope, FLAG Epitope, AU1 and AU5 Epitopes, Glu-Glu Epitope, KT3 Epitope, IRS Epitope, Btag Epitope, Protein Kinase-C Epitope, VSV Epitope, lectins that mediate binding to a diversity of compounds, including carbohydrates, lipids and proteins, e.g. Con A (Canavalia ensiformis) or WGA (wheat germ agglutinin) and tetranectin or Protein A or G (antibody affinity). 203. Use according to any one of claims 187-202, wherein the MHC molecule further comprises a labelling compound. 204. Use according to claim 203, wherein the labelling compound can be detected directly or indirectly. 205. Use according to claim 203 or 204, wherein the labelling compound is a fluorescent label, an enzyme label, a radioisotope, a chemiluminescent label, a bioluminescent label, a polymer, a metal particle, a hapten, an antibody, or a dye. 206. Use according to any one of claims 203-205, wherein the labelling compound is selected from
5-(and 6)-carboxyfluorescein, 5- or 6-carboxyfluorescein, 6-(fluorescein)-5-(and 6)-carboxamido hexanoic acid, fluorescein isothiocyanate (FITC), rhodamine, tetramethylrhodamine, and dyes such as Cy2, Cy3, and Cy5, optionally substituted coumarin including AMCA, PerCP, phycobiliproteins including R-phycoerythrin (RPE) and allophycoerythrin (APC), Texas Red, Princeston Red, Green fluorescent protein (GFP) and analogues thereof, and conjugates of R-phycoerythrin or allophycoerythrin and e.g. Cy5 or Texas Red, and inorganic fluorescent labels based on semiconductor nanocrystals (like quantum dot and Qdot™ nanocrystals), and time-resolved fluorescent labels based on lanthanides like Eu3+ and Sm3+, from haptens such as DNP, biotin, and digoxiginin or is selected from enzymatic labels such as horse radish peroxidase (HRP), alkaline phosphatase (AP), beta-galactosidase (GAL), glucose-6-phosphate dehydrogenase, beta-N-acetylglucosaminidase, β-glucuronidase, invertase, Xanthine Oxidase, firefly luciferase and glucose oxidase (GO), or is selected from luminiscence labels such as luminol, isoluminol, acridinium esters, 1,2-dioxetanes and pyridopyridazines, or is selected from radioactivity labels such as incorporated isotopes of iodide, cobalt, selenium, tritium, and phosphor. 207. The use according to any one of claims 203-206, wherein the labelling compound is attached to the MHC molecule and/or the binding entity. 208. A method for detecting the presence of MHC recognising cells in a sample comprising the steps of
(a) providing a sample suspected of comprising MHC recognising cells mounted on a support, (b) contacting the sample with a MHC molecule as defined in claims 187-207, and (c) determining any binding of the MHC molecule, which binding indicates the presence of MHC recognising cells. 209. A method for monitoring MHC recognising cells comprising the steps of
(a) providing a sample suspected comprising MHC recognising cells mounted on a support, (b) contacting the sample with a MHC molecule as defined in claims 187-207, and (c) determining any binding of the MHC molecule, thereby monitoring MHC recognising cells. 210. A method for the prognosis of a disease involving MHC recognising cells comprising the steps of
(a) providing a sample suspected comprising MHC recognising cells mounted on a support, (b) contacting the sample with a MHC molecule as defined in claims 187-207, and (c) determining any binding of the MHC molecule, thereby establishing a prognosis of a disease involving MHC recognising cells. 211. A method for determining the status of a disease involving MHC recognising cells comprising the steps of
(a) providing a sample suspected comprising MHC recognising cells mounted on a support, (b) contacting the sample with a MHC molecule as defined in claims 187-207, and (c) determining any binding of the MHC molecule, thereby determining the status of a disease involving MHC recognising cells. 212. A method for the diagnosis of a disease involving MHC recognising cells comprising the steps of
(a) providing a sample suspected comprising MHC recognising cells mounted on a support, (b) contacting the sample with a MHC molecule as defined in claims 187-207, and (c) determining any binding of the MHC molecule, thereby diagnosing a disease involving MHC recognising cells. 213. A method for the effectiveness of a medicament against a disease involving MHC recognising cells comprising the steps of
(a) providing a sample from a subject receiving treatment with a medicament mounted on a support, (b) contacting the sample with a MHC molecule as defined in claims 187-207, and (c) determining any binding of the MHC molecule, thereby determining the effectiveness of the medicament. 214. The method according to any one of claims 208-213, wherein the MHC recognising cells are involved in a disease of inflammatory, auto-immune, allergic, viral, cancerous, infectious, allo- or xenogene (graft-versus-host and host-versus-graft) origin. 215. The method according to claim 214, wherein the disease is a chronic inflammatory bowel disease such as Crohn's disease or ulcerative colitis, sclerosis, type I diabetes, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, malignant melanoma, renal carcinoma, breast cancer, lung cancer, cancer of the uterus, cervical cancer, prostatic cancer, brain cancer, head and neck cancer, leukaemia, cutaneous lymphoma, hepatic carcinoma, colorectal cancer, bladder cancer, rejection-related disease, Graft-versus-host-related disease, or a viral disease associated with hepatitis, AIDS, measles, pox, chicken pox, rubella or herpes. 216. The method according to any one of claims 208-214, wherein the MHC recognising cells are selected from subpopulations of CD3+ T-cells, gamma, delta T-cells, alpha, beta T-cells, CD4+ T-cells, T helper cells, CD8+ T-cells, Suppressor T-cells, CD8+ cytotoxic T-cells, CTLs, NK cells, NKT cells, LAK cells, and MAK. 210. The method according to any one of claims 201-209, wherein the sample is selected from histological material, cytological material, primary tumours, secondary organ metastasis, fine needle aspirates, spleen tissue, bone marrow specimens, cell smears, exfoliative cytological specimens, touch preparations, oral swabs, laryngeal swabs, vaginal swabs, bronchial lavage, gastric lavage, from the umbilical cord, and from body fluids such as blood (e.g. from a peripheral blood mononuclear cell (PBMC) population isolated from blood or from other blood-derived preparations such as leukopheresis products), from sputum samples, expectorates, and bronchial aspirates.
| 1,600 |
924 | 14,994,521 | 1,619 |
Aerosol compositions propelled by compressed gas providing enhanced intensity of one or more active components (e.g., fragrance, malodor counteractant, insecticide, disinfectant, or antimicrobial) over an extended period of time in the environment of use consistently over the life of the product. This is provided by a selected combination of spray rate and average particle size of the composition. The increased intensity over time can be further enhanced by further selection of the initial and terminal pressure under which the composition is maintained, and the pressure drop ratio, with respect to the composition product and a suitable dispensing container.
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1. Article of manufacture for aerosol treatment of air and surfaces comprising
(a) a dispensing device comprising a plastic container adapted to hold a treating composition and a compressed gas propellant, wherein said plastic container is made of polyethyleneterephthalate (PET); (b) the treating composition comprising
(1) about 0.1 to about 2 wt. % of at least one nonionic surfactant comprising polyalkoxylated hydrogenated castor oil;
(2) about 0.1 to about 10 wt. % of at least one non-water solvent comprising at least one alkylene glycol;
(3) about 0.1 to about 2 wt. % of a fragrance component;
(4) about 0.2 to about 2 wt. % of the compressed gas propellant;
(5) optionally, about 0.01 to about 1 wt. % of a preservative; and
(6) a balance of water to 100 wt. %. 2. Article of manufacture for aerosol treatment of air and surfaces comprising
(a) a dispensing device comprising a plastic container adapted to hold a treating composition and a compressed gas propellant, wherein said plastic container is made of one of polyethyleneterephthalate (PET), polycarbonate, polyethylene, polyethylenenapthalate (PEN); (b) the treating composition comprising
(1) about 0.1 to about 2 wt. % of at least one nonionic surfactant comprising polyalkoxylated hydrogenated castor oil;
(2) about 0.1 to about 10 wt. % of at least one non-water solvent comprising at least one alkylene glycol;
(3) about 0.1 to about 2 wt. % of a fragrance component;
(4) about 0.2 to about 2 wt. % of the compressed gas propellant;
(5) optionally, about 0.01 to about 1 wt. % of a preservative; and
(6) a balance of water to 100 wt. %. 3. The article of claim 1, wherein
(1) said at least one nonionic surfactant is present in an amount of about 0.5 to about 1.5 wt. %, (2) said at least one non-water solvent is present in an amount of about 0.1 wt. % to about 6 wt. %, (3) said fragrance component is present in an amount of about 0.3 wt. % to about 1 wt. %, (4) said compressed gas is present in an amount of about 0.5 wt. % to about 1 wt. %, (5) optionally, said preservative is present in an amount of about 0.05 wt. % to about 0.2 wt. %, and (6) a balance of water to 100 wt. %. 4. The article of claim 2, wherein
(1) said at least one nonionic surfactant is present in an amount of about 0.5 to about 1.5 wt. %, (2) said at least one non-water solvent is present in an amount of about 0.1 wt. % to about 6 wt. %, (3) said fragrance component is present in an amount of about 0.3 wt. % to about 1 wt. %, (4) said compressed gas is present in an amount of about 0.5 wt. % to about 1 wt. %, (5) optionally, said preservative is present in an amount of about 0.05 wt. % to about 0.2 wt. %, and (6) a balance of water to 100 wt. %. 5. The article of claim 1, wherein the at least one nonionic surfactant further comprises one or more of secondary alcohol ethoxylate, ethoxylated linear alcohol, sorbitan monooleate, polyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, alkyl polyglycoside, polyethyleneoxide/polypropyleneoxide, and alkyl phenol ethoxylated carboxylated alcohol. 6. The article of claim 2, wherein the at least one nonionic surfactant further comprises one or more of secondary alcohol ethoxylate, ethoxylated linear alcohol, sorbitan monooleate, polyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, alkyl polyglycoside, polyethyleneoxide/polypropyleneoxide, and alkyl phenol ethoxylated carboxylated alcohol. 7. The article of claim 1, wherein said at least one nonionic surfactant is a polyalkoxylated hydrogenated castor oil and a secondary alcohol ethoxylate. 8. The article of claim 2, wherein said at least one nonionic surfactant is a polyalkoxylated hydrogenated castor oil and a secondary alcohol ethoxylate. 9. The article of claim 1, wherein said alkylene glycol is one or more of ethylene glycol and propylene glycol. 10. The article of claim 2, wherein said alkylene glycol is one or more of ethylene glycol and propylene glycol. 11. The article of claim 1, wherein said compressed gas is one or more of nitrogen, an inert gas, air, nitrous oxide, and carbon dioxide. 12. The article of claim 2, wherein said compressed gas is one or more of nitrogen, an inert gas, air, nitrous oxide, and carbon dioxide. 13. The article of claim 1, wherein said preservative is present and is about 0.05 to about 0.2 wt. % of an isothiazolinone compound. 14. The article of claim 2, wherein said preservative is present and is about 0.05 to about 0.2 wt. % of an isothiazolinone compound. 15. The article of claim 1, wherein said dispensing device is under an initial pressure in a range of about 100 to about 180 psig at 70° F. (21° C.) and has a pressure drop ratio of about less than 4:1 for a headspace of 25% by volume. 16. The article of claim 2, wherein said dispensing device is under an initial pressure in a range of about 100 to about 180 psig at 70° F. (21° C.) and has a pressure drop ratio of about less than 4:1 for a headspace of 25% by volume. 17. The article of claim 1, wherein said treating composition has a ratio of compressed gas to remaining composition components of about 50:50 to about 25:75 by volume of the plastic container. 18. The article of claim 2, wherein said treating composition has a ratio of compressed gas to remaining composition components of about 50:50 to about 25:75 by volume of the plastic container. 19. Article of manufacture for aerosol treatment of air and surfaces comprising
(a) a dispensing device comprising a plastic container adapted to hold a treating composition and a compressed gas propellant, wherein said plastic container is made of polyethyleneterephthalate (PET); (b) the treating composition comprising
(1) about 0.5 to about 1.5 wt. % of a polyalkoxylated hydrogenated castor oil and a secondary alcohol ethoxylate;
(2) about 0.5 to about 1.5 wt. % of at least one alkylene glycol;
(3) about 0.3 to about 1 wt. % of a fragrance component;
(4) about 0.5 to about 1 wt. % of a compressed gas propellant including at least nitrogen;
(5) about 0.05 to about 0.2 wt. % of a preservative; and
(6) a balance of water to 100 wt. %. 20. The article of claim 19, wherein said polyalkoxylated hydrogenated castor oil is an ethoxylated hydrogenated castor oil; said at least one alkylene glycol is propylene glycol; said compressed gas propellant is nitrogen; and said preservative is an isothiazolinone compound.
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Aerosol compositions propelled by compressed gas providing enhanced intensity of one or more active components (e.g., fragrance, malodor counteractant, insecticide, disinfectant, or antimicrobial) over an extended period of time in the environment of use consistently over the life of the product. This is provided by a selected combination of spray rate and average particle size of the composition. The increased intensity over time can be further enhanced by further selection of the initial and terminal pressure under which the composition is maintained, and the pressure drop ratio, with respect to the composition product and a suitable dispensing container.1. Article of manufacture for aerosol treatment of air and surfaces comprising
(a) a dispensing device comprising a plastic container adapted to hold a treating composition and a compressed gas propellant, wherein said plastic container is made of polyethyleneterephthalate (PET); (b) the treating composition comprising
(1) about 0.1 to about 2 wt. % of at least one nonionic surfactant comprising polyalkoxylated hydrogenated castor oil;
(2) about 0.1 to about 10 wt. % of at least one non-water solvent comprising at least one alkylene glycol;
(3) about 0.1 to about 2 wt. % of a fragrance component;
(4) about 0.2 to about 2 wt. % of the compressed gas propellant;
(5) optionally, about 0.01 to about 1 wt. % of a preservative; and
(6) a balance of water to 100 wt. %. 2. Article of manufacture for aerosol treatment of air and surfaces comprising
(a) a dispensing device comprising a plastic container adapted to hold a treating composition and a compressed gas propellant, wherein said plastic container is made of one of polyethyleneterephthalate (PET), polycarbonate, polyethylene, polyethylenenapthalate (PEN); (b) the treating composition comprising
(1) about 0.1 to about 2 wt. % of at least one nonionic surfactant comprising polyalkoxylated hydrogenated castor oil;
(2) about 0.1 to about 10 wt. % of at least one non-water solvent comprising at least one alkylene glycol;
(3) about 0.1 to about 2 wt. % of a fragrance component;
(4) about 0.2 to about 2 wt. % of the compressed gas propellant;
(5) optionally, about 0.01 to about 1 wt. % of a preservative; and
(6) a balance of water to 100 wt. %. 3. The article of claim 1, wherein
(1) said at least one nonionic surfactant is present in an amount of about 0.5 to about 1.5 wt. %, (2) said at least one non-water solvent is present in an amount of about 0.1 wt. % to about 6 wt. %, (3) said fragrance component is present in an amount of about 0.3 wt. % to about 1 wt. %, (4) said compressed gas is present in an amount of about 0.5 wt. % to about 1 wt. %, (5) optionally, said preservative is present in an amount of about 0.05 wt. % to about 0.2 wt. %, and (6) a balance of water to 100 wt. %. 4. The article of claim 2, wherein
(1) said at least one nonionic surfactant is present in an amount of about 0.5 to about 1.5 wt. %, (2) said at least one non-water solvent is present in an amount of about 0.1 wt. % to about 6 wt. %, (3) said fragrance component is present in an amount of about 0.3 wt. % to about 1 wt. %, (4) said compressed gas is present in an amount of about 0.5 wt. % to about 1 wt. %, (5) optionally, said preservative is present in an amount of about 0.05 wt. % to about 0.2 wt. %, and (6) a balance of water to 100 wt. %. 5. The article of claim 1, wherein the at least one nonionic surfactant further comprises one or more of secondary alcohol ethoxylate, ethoxylated linear alcohol, sorbitan monooleate, polyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, alkyl polyglycoside, polyethyleneoxide/polypropyleneoxide, and alkyl phenol ethoxylated carboxylated alcohol. 6. The article of claim 2, wherein the at least one nonionic surfactant further comprises one or more of secondary alcohol ethoxylate, ethoxylated linear alcohol, sorbitan monooleate, polyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, alkyl polyglycoside, polyethyleneoxide/polypropyleneoxide, and alkyl phenol ethoxylated carboxylated alcohol. 7. The article of claim 1, wherein said at least one nonionic surfactant is a polyalkoxylated hydrogenated castor oil and a secondary alcohol ethoxylate. 8. The article of claim 2, wherein said at least one nonionic surfactant is a polyalkoxylated hydrogenated castor oil and a secondary alcohol ethoxylate. 9. The article of claim 1, wherein said alkylene glycol is one or more of ethylene glycol and propylene glycol. 10. The article of claim 2, wherein said alkylene glycol is one or more of ethylene glycol and propylene glycol. 11. The article of claim 1, wherein said compressed gas is one or more of nitrogen, an inert gas, air, nitrous oxide, and carbon dioxide. 12. The article of claim 2, wherein said compressed gas is one or more of nitrogen, an inert gas, air, nitrous oxide, and carbon dioxide. 13. The article of claim 1, wherein said preservative is present and is about 0.05 to about 0.2 wt. % of an isothiazolinone compound. 14. The article of claim 2, wherein said preservative is present and is about 0.05 to about 0.2 wt. % of an isothiazolinone compound. 15. The article of claim 1, wherein said dispensing device is under an initial pressure in a range of about 100 to about 180 psig at 70° F. (21° C.) and has a pressure drop ratio of about less than 4:1 for a headspace of 25% by volume. 16. The article of claim 2, wherein said dispensing device is under an initial pressure in a range of about 100 to about 180 psig at 70° F. (21° C.) and has a pressure drop ratio of about less than 4:1 for a headspace of 25% by volume. 17. The article of claim 1, wherein said treating composition has a ratio of compressed gas to remaining composition components of about 50:50 to about 25:75 by volume of the plastic container. 18. The article of claim 2, wherein said treating composition has a ratio of compressed gas to remaining composition components of about 50:50 to about 25:75 by volume of the plastic container. 19. Article of manufacture for aerosol treatment of air and surfaces comprising
(a) a dispensing device comprising a plastic container adapted to hold a treating composition and a compressed gas propellant, wherein said plastic container is made of polyethyleneterephthalate (PET); (b) the treating composition comprising
(1) about 0.5 to about 1.5 wt. % of a polyalkoxylated hydrogenated castor oil and a secondary alcohol ethoxylate;
(2) about 0.5 to about 1.5 wt. % of at least one alkylene glycol;
(3) about 0.3 to about 1 wt. % of a fragrance component;
(4) about 0.5 to about 1 wt. % of a compressed gas propellant including at least nitrogen;
(5) about 0.05 to about 0.2 wt. % of a preservative; and
(6) a balance of water to 100 wt. %. 20. The article of claim 19, wherein said polyalkoxylated hydrogenated castor oil is an ethoxylated hydrogenated castor oil; said at least one alkylene glycol is propylene glycol; said compressed gas propellant is nitrogen; and said preservative is an isothiazolinone compound.
| 1,600 |
925 | 14,848,990 | 1,641 |
Disclosed is a method for preparing a composition enriched for receptors (typically molecular impringet polymers, MIPs) that bind an agent, where said receptors each specifically bind at least two discrete sites on said agent, by subjecting a sample of receptors to a first step of affinity purification with the agent where one binding site on the agent is non-accessible for binding to the receptors and subsequently subjecting the purified receptors to at least one further step of affinity purification with the agent where a second binding site on the agent is non-accessible.
Also disclosed is a method for treatment, amelioration or prophylaxis of a disease selected from the group consisting of phenylketonuria (PKU, Følling's disease), hyperphenylalaninemia (HPA), alcaptonuria (black urine disease), tyrosinemia, hypertyrosinemia, myasthenia gravis, histidinemia, urocanic aciduria, maple syrup urine disease (MSUD), isovaleric acidemia (isovaleryl-CoA dehydrogenase deficiency), homocystinuria, propionic acidemia, methylmalonic acidemia, and glutaric aciduria Type 1 (GA-1), galactosemia, comprising administering to the gastrointestinal tract of a patient in need thereof an effective amount of a composition of molecular imprinted polymers (MIPs), said composition being capable of binding a symptom provoking agent of said disease.
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1. (canceled) 2. (canceled) 3. A method for treatment, amelioration or prophylaxis of a disease selected from the group consisting of hyperphenylalaninemia (HPA), alcaptonuria (black urine disease), tyrosinemia, hypertyrosinemia, myasthenia gravis, histidinemia, urocanic aciduria, maple syrup urine disease (MSUD), isovaleric acidemia (isovaleryl-CoA dehydrogenase deficiency), homocystinuria, propionic acidemia, methylmalonic acidemia, glutaric aciduria Type 1 (GA-1), and galactosemia, comprising administering to the gastrointestinal tract of a patient in need thereof an effective amount of a composition of molecular imprinted polymers (MIPs), said composition being capable of binding a symptom provoking agent of said disease. 4. A method for treatment, amelioration or prophylaxis of a disease selected from the group consisting of phenylketonuria, hyperphenylalaninemia (HPA), alcaptonuria (black urine disease), tyrosinemia, hypertyrosinemia, myasthenia gravis, histidinemia, urocanic aciduria, maple syrup urine disease (MSUD), isovaleric acidemia (isovaleryl-CoA dehydrogenase deficiency), homocystinuria, propionic acidemia, methylmalonic acidemia, glutaric aciduria Type 1 (GA-1), and galactosemia, comprising administering to the gastrointestinal tract of a patient in need thereof an effective amount of a composition of molecular imprinted polymers (MIPs), said composition being capable of binding a symptom provoking agent of said disease, wherein the composition of MIPs is prepared by:
i-a. obtaining a suspension of insoluble molecular imprinted polymers, which bind the symptom provoking agent, and which have been prepared using the symptom provoking agent or a mimic thereof as template molecule, i-b. subjecting the suspended molecular imprinted polymers to an affinity purification procedure, wherein the template molecule or a fragment thereof or a mimic thereof is used as capture agent, i-c. recovering the molecular imprinted polymers that bind the capture agent in the affinity purification procedure while substantially excluding the capture agent and molecular imprinted polymers that do not bind the capture agent from the recovered product; or, prepared by a method comprising, ii-a. providing a sample comprising MIPs that bind said symptom provoking agent, ii-b. subjecting said sample to a first step of affinity chromatography, where said symptom provoking agent is used as affinity purification agent, and wherein said agent is immobilised to a solid or semi-solid phase via binding to one single of said at least two discrete sites, ii-c. recovering MIPs binding to the symptom provoking agent, ii-d. subjecting MIPs recovered in the previous step to at least one further step of affinity chromatography, where said symptom provoking agent is used as affinity purification agent, and wherein said agent is immobilised to a solid or semi-solid phase via binding to another of said at least two discrete sites, and recovering MIPs binding to the agent, wherein, in each said at least one further step of affinity chromatography, said another of said at least two discrete sites is different from any one of said at least two discrete sites, which has been used previously in steps b and d for immobilization of the agent to a solid of semi-solid phase. 5. The method according to claim 3, wherein the composition of MIPs is essentially free from MIPs which do not bind said symptom provoking agent. 6. The method according to claim 4, wherein the composition of MIPs is essentially free from MIPs which do not bind said symptom provoking agent. 7. The method of claim 3, wherein
a) said symptom provoking agent is L-phenylalanine and said disease is hyperphenylalaninemia, alcaptonuria, tyrosinemia, or hypertyrosinemia; or b) said symptom provoking agent is L-tyrosine and said disease is tyrosinemia or hypertyrosinemia; or c) said symptom provoking agent is L-histidine and said disease is myasthenia gravis, histininemia, or urocanic aciduria; or d) said symptom provoking agent is L-leucine and said disease is maple syrup urine disease or isovaleric acidemia, or e) said symptom provoking agent is L-methionine and said disease is homocystinuria, or f) said symptom provoking agent is L-isoleucine or L-valine or L-methionine or L-threonine and said disease is proprionic academia or methylmalonic academia, or g) said symptom provoking agent is L-tryptophan or L-lysine and said disease is glutaric aciduria h) said symptom provoking agent is D-galactose or lactose and said disease is galactosemia. 8. The method of claim 4, wherein
a) said symptom provoking agent is L-phenylalanine and said disease is hyperphenylalaninemia, alcaptonuria, tyrosinemia, or hypertyrosinemia, or b) said symptom provoking agent is L-tyrosine and said disease is tyrosinemia or hypertyrosinemia, or c) said symptom provoking agent is L-histidine and said disease is myasthenia gravis, histininemia, or urocanic aciduria, or d) said symptom provoking agent is L-leucine and said disease is maple syrup urine disease or isovaleric acidemia, or e) said symptom provoking agent is L-methionine and said disease is homocystinuria, or f) said symptom provoking agent is L-isoleucine or L-valine or L-methionine or L-threonine and said disease is proprionic academia or methylmalonic academia, or g) said symptom provoking agent is L-tryptophan or L-lysine and said disease is glutaric aciduria Type 1, or h) said symptom provoking agent is D-galactose or lactose and said disease is galactosemia. 9. The method of claim 5, wherein
a) said symptom provoking agent is L-phenylalanine and said disease is hyperphenylalaninemia, alcaptonuria, tyrosinemia, or hypertyrosinemia, or b) said symptom provoking agent is L-tyrosine and said disease is tyrosinemia or hypertyrosinemia, or c) said symptom provoking agent is L-histidine and said disease is myasthenia gravis, histininemia, or urocanic aciduria, or d) said symptom provoking agent is L-leucine and said disease is maple syrup urine disease or isovaleric acidemia, or e) said symptom provoking agent is L-methionine and said disease is homocystinuria, or f) said symptom provoking agent is L-isoleucine or L-valine or L-methionine or L-threonine and said disease is proprionic academia or methylmalonic academia, or g) said symptom provoking agent is L-tryptophan or L-lysine and said disease is glutaric aciduria Type 1, or h) said symptom provoking agent is D-galactose or lactose and said disease is galactosemia. 10. The method of claim 3, wherein said symptom provoking agent is L-phenylalanine and said disease is hyperphenylalaninemia, alcaptonuria, tyrosinemia, or hypertyrosinemia. 11. The method of claim 4, wherein said symptom provoking agent is L-phenylalanine and said disease is hyperphenylalaninemia, alcaptonuria, tyrosinemia, or hypertyrosinemia. 12. The method of claim 4, wherein said symptom provoking agent is L-phenylalanine and said disease is hyperphenylalaninemia, alcaptonuria, tyrosinemia, or hypertyrosinemia.
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Disclosed is a method for preparing a composition enriched for receptors (typically molecular impringet polymers, MIPs) that bind an agent, where said receptors each specifically bind at least two discrete sites on said agent, by subjecting a sample of receptors to a first step of affinity purification with the agent where one binding site on the agent is non-accessible for binding to the receptors and subsequently subjecting the purified receptors to at least one further step of affinity purification with the agent where a second binding site on the agent is non-accessible.
Also disclosed is a method for treatment, amelioration or prophylaxis of a disease selected from the group consisting of phenylketonuria (PKU, Følling's disease), hyperphenylalaninemia (HPA), alcaptonuria (black urine disease), tyrosinemia, hypertyrosinemia, myasthenia gravis, histidinemia, urocanic aciduria, maple syrup urine disease (MSUD), isovaleric acidemia (isovaleryl-CoA dehydrogenase deficiency), homocystinuria, propionic acidemia, methylmalonic acidemia, and glutaric aciduria Type 1 (GA-1), galactosemia, comprising administering to the gastrointestinal tract of a patient in need thereof an effective amount of a composition of molecular imprinted polymers (MIPs), said composition being capable of binding a symptom provoking agent of said disease.1. (canceled) 2. (canceled) 3. A method for treatment, amelioration or prophylaxis of a disease selected from the group consisting of hyperphenylalaninemia (HPA), alcaptonuria (black urine disease), tyrosinemia, hypertyrosinemia, myasthenia gravis, histidinemia, urocanic aciduria, maple syrup urine disease (MSUD), isovaleric acidemia (isovaleryl-CoA dehydrogenase deficiency), homocystinuria, propionic acidemia, methylmalonic acidemia, glutaric aciduria Type 1 (GA-1), and galactosemia, comprising administering to the gastrointestinal tract of a patient in need thereof an effective amount of a composition of molecular imprinted polymers (MIPs), said composition being capable of binding a symptom provoking agent of said disease. 4. A method for treatment, amelioration or prophylaxis of a disease selected from the group consisting of phenylketonuria, hyperphenylalaninemia (HPA), alcaptonuria (black urine disease), tyrosinemia, hypertyrosinemia, myasthenia gravis, histidinemia, urocanic aciduria, maple syrup urine disease (MSUD), isovaleric acidemia (isovaleryl-CoA dehydrogenase deficiency), homocystinuria, propionic acidemia, methylmalonic acidemia, glutaric aciduria Type 1 (GA-1), and galactosemia, comprising administering to the gastrointestinal tract of a patient in need thereof an effective amount of a composition of molecular imprinted polymers (MIPs), said composition being capable of binding a symptom provoking agent of said disease, wherein the composition of MIPs is prepared by:
i-a. obtaining a suspension of insoluble molecular imprinted polymers, which bind the symptom provoking agent, and which have been prepared using the symptom provoking agent or a mimic thereof as template molecule, i-b. subjecting the suspended molecular imprinted polymers to an affinity purification procedure, wherein the template molecule or a fragment thereof or a mimic thereof is used as capture agent, i-c. recovering the molecular imprinted polymers that bind the capture agent in the affinity purification procedure while substantially excluding the capture agent and molecular imprinted polymers that do not bind the capture agent from the recovered product; or, prepared by a method comprising, ii-a. providing a sample comprising MIPs that bind said symptom provoking agent, ii-b. subjecting said sample to a first step of affinity chromatography, where said symptom provoking agent is used as affinity purification agent, and wherein said agent is immobilised to a solid or semi-solid phase via binding to one single of said at least two discrete sites, ii-c. recovering MIPs binding to the symptom provoking agent, ii-d. subjecting MIPs recovered in the previous step to at least one further step of affinity chromatography, where said symptom provoking agent is used as affinity purification agent, and wherein said agent is immobilised to a solid or semi-solid phase via binding to another of said at least two discrete sites, and recovering MIPs binding to the agent, wherein, in each said at least one further step of affinity chromatography, said another of said at least two discrete sites is different from any one of said at least two discrete sites, which has been used previously in steps b and d for immobilization of the agent to a solid of semi-solid phase. 5. The method according to claim 3, wherein the composition of MIPs is essentially free from MIPs which do not bind said symptom provoking agent. 6. The method according to claim 4, wherein the composition of MIPs is essentially free from MIPs which do not bind said symptom provoking agent. 7. The method of claim 3, wherein
a) said symptom provoking agent is L-phenylalanine and said disease is hyperphenylalaninemia, alcaptonuria, tyrosinemia, or hypertyrosinemia; or b) said symptom provoking agent is L-tyrosine and said disease is tyrosinemia or hypertyrosinemia; or c) said symptom provoking agent is L-histidine and said disease is myasthenia gravis, histininemia, or urocanic aciduria; or d) said symptom provoking agent is L-leucine and said disease is maple syrup urine disease or isovaleric acidemia, or e) said symptom provoking agent is L-methionine and said disease is homocystinuria, or f) said symptom provoking agent is L-isoleucine or L-valine or L-methionine or L-threonine and said disease is proprionic academia or methylmalonic academia, or g) said symptom provoking agent is L-tryptophan or L-lysine and said disease is glutaric aciduria h) said symptom provoking agent is D-galactose or lactose and said disease is galactosemia. 8. The method of claim 4, wherein
a) said symptom provoking agent is L-phenylalanine and said disease is hyperphenylalaninemia, alcaptonuria, tyrosinemia, or hypertyrosinemia, or b) said symptom provoking agent is L-tyrosine and said disease is tyrosinemia or hypertyrosinemia, or c) said symptom provoking agent is L-histidine and said disease is myasthenia gravis, histininemia, or urocanic aciduria, or d) said symptom provoking agent is L-leucine and said disease is maple syrup urine disease or isovaleric acidemia, or e) said symptom provoking agent is L-methionine and said disease is homocystinuria, or f) said symptom provoking agent is L-isoleucine or L-valine or L-methionine or L-threonine and said disease is proprionic academia or methylmalonic academia, or g) said symptom provoking agent is L-tryptophan or L-lysine and said disease is glutaric aciduria Type 1, or h) said symptom provoking agent is D-galactose or lactose and said disease is galactosemia. 9. The method of claim 5, wherein
a) said symptom provoking agent is L-phenylalanine and said disease is hyperphenylalaninemia, alcaptonuria, tyrosinemia, or hypertyrosinemia, or b) said symptom provoking agent is L-tyrosine and said disease is tyrosinemia or hypertyrosinemia, or c) said symptom provoking agent is L-histidine and said disease is myasthenia gravis, histininemia, or urocanic aciduria, or d) said symptom provoking agent is L-leucine and said disease is maple syrup urine disease or isovaleric acidemia, or e) said symptom provoking agent is L-methionine and said disease is homocystinuria, or f) said symptom provoking agent is L-isoleucine or L-valine or L-methionine or L-threonine and said disease is proprionic academia or methylmalonic academia, or g) said symptom provoking agent is L-tryptophan or L-lysine and said disease is glutaric aciduria Type 1, or h) said symptom provoking agent is D-galactose or lactose and said disease is galactosemia. 10. The method of claim 3, wherein said symptom provoking agent is L-phenylalanine and said disease is hyperphenylalaninemia, alcaptonuria, tyrosinemia, or hypertyrosinemia. 11. The method of claim 4, wherein said symptom provoking agent is L-phenylalanine and said disease is hyperphenylalaninemia, alcaptonuria, tyrosinemia, or hypertyrosinemia. 12. The method of claim 4, wherein said symptom provoking agent is L-phenylalanine and said disease is hyperphenylalaninemia, alcaptonuria, tyrosinemia, or hypertyrosinemia.
| 1,600 |
926 | 14,701,002 | 1,642 |
A method for the in vitro diagnosis of colorectal cancer by determining the presence of the Ezrin tumor marker in a biological sample taken from a patient suspected of having colorectal cancer using at least one anti-Ezrin monoclonal antibody directed against an Ezrin epitope chosen from the epitopes of sequence SEQ ID No.1, SEQ ID No.2, SEQ ID No.3, SEQ ID No.4+SEQ ID No.5, SEQ ID No.6+SEQ ID No.7 and SEQ ID No.8. Said method can be used for early diagnosis, screening, therapeutic follow-up and prognosis, and also for relapse diagnosis in relation to colorectal cancer.
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1. A monoclonal antibody directed against an epitope selected from the group consisting of SEQ ID No.1, SEQ ID No.2, SEQ ID No.3, SEQ ID No.4+SEQ ID No.5, SEQ ID No.6+SEQ ID No.7, and SEQ ID No.8. 2. The monoclonal antibody of claim 1 directed against the epitope of SEQ ID No.1. 3. The monoclonal antibody of claim 1 directed against the epitope of SEQ ID No.2. 4. The monoclonal antibody of claim 1 directed against the epitope of SEQ ID No.3. 5. The monoclonal antibody of claim 1 directed against the epitope of SEQ ID No.4+SEQ ID No.5. 6. The monoclonal antibody of claim 1 directed against the epitope of SEQ ID No.6+SEQ ID No.7. 7. The monoclonal antibody of claim 1 directed against the epitope of SEQ ID No.8. 8. The monoclonal antibody of claim 1 attached to a label capable of producing a detectable signal. 9. The monoclonal antibody of claim 1 attached to an imaging tracer capable of producing a detectable signal. 10. The monoclonal antibody of claim 1 attached to a solid support. 11. An assay comprising:
the monoclonal antibody of claim 2 as a first monoclonal antibody; and a second monoclonal antibody directed against an epitope selected from the group consisting of SEQ ID No.2, SEQ ID No.4+SEQ ID No.5, and SEQ ID No.6+SEQ ID No.7. 12. The assay of claim 11, wherein the second monoclonal antibody is directed against the epitope of SEQ ID No.4+SEQ ID No.5. 13. A kit comprising:
the monoclonal antibody of claim 2 as a first monoclonal antibody; and a second monoclonal antibody directed against an epitope selected from the group consisting of SEQ ID No.2, SEQ ID No.4+SEQ ID No.5, and SEQ ID No.6+SEQ ID No.7. 14. The kit of claim 13, wherein the second monoclonal antibody is directed against the epitope of SEQ ID No.4+SEQ ID No.5. 15. A hybridoma capable of producing the monoclonal antibody of claim 1. 16. A method of obtaining the monoclonal antibody of claim 1, comprising:
culturing a hybridoma capable of producing the monoclonal antibody so as to produce the monoclonal antibody; and obtaining the monoclonal antibody produced by the cultured hybridoma. 17. The method of claim 16, further comprising:
immunizing an animal with an antigen comprising at least one epitope selected from the group consisting of SEQ ID No.1, SEQ ID No.2, SEQ ID No.3, SEQ ID No.4+SEQ ID No.5, SEQ ID No.6+SEQ ID No.7, and SEQ ID No.8; obtaining an antibody-producing lymphocyte from the immunized animal; and fusing the antibody-producing lymphocyte with a myeloma cell to produce the hybridoma.
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A method for the in vitro diagnosis of colorectal cancer by determining the presence of the Ezrin tumor marker in a biological sample taken from a patient suspected of having colorectal cancer using at least one anti-Ezrin monoclonal antibody directed against an Ezrin epitope chosen from the epitopes of sequence SEQ ID No.1, SEQ ID No.2, SEQ ID No.3, SEQ ID No.4+SEQ ID No.5, SEQ ID No.6+SEQ ID No.7 and SEQ ID No.8. Said method can be used for early diagnosis, screening, therapeutic follow-up and prognosis, and also for relapse diagnosis in relation to colorectal cancer.1. A monoclonal antibody directed against an epitope selected from the group consisting of SEQ ID No.1, SEQ ID No.2, SEQ ID No.3, SEQ ID No.4+SEQ ID No.5, SEQ ID No.6+SEQ ID No.7, and SEQ ID No.8. 2. The monoclonal antibody of claim 1 directed against the epitope of SEQ ID No.1. 3. The monoclonal antibody of claim 1 directed against the epitope of SEQ ID No.2. 4. The monoclonal antibody of claim 1 directed against the epitope of SEQ ID No.3. 5. The monoclonal antibody of claim 1 directed against the epitope of SEQ ID No.4+SEQ ID No.5. 6. The monoclonal antibody of claim 1 directed against the epitope of SEQ ID No.6+SEQ ID No.7. 7. The monoclonal antibody of claim 1 directed against the epitope of SEQ ID No.8. 8. The monoclonal antibody of claim 1 attached to a label capable of producing a detectable signal. 9. The monoclonal antibody of claim 1 attached to an imaging tracer capable of producing a detectable signal. 10. The monoclonal antibody of claim 1 attached to a solid support. 11. An assay comprising:
the monoclonal antibody of claim 2 as a first monoclonal antibody; and a second monoclonal antibody directed against an epitope selected from the group consisting of SEQ ID No.2, SEQ ID No.4+SEQ ID No.5, and SEQ ID No.6+SEQ ID No.7. 12. The assay of claim 11, wherein the second monoclonal antibody is directed against the epitope of SEQ ID No.4+SEQ ID No.5. 13. A kit comprising:
the monoclonal antibody of claim 2 as a first monoclonal antibody; and a second monoclonal antibody directed against an epitope selected from the group consisting of SEQ ID No.2, SEQ ID No.4+SEQ ID No.5, and SEQ ID No.6+SEQ ID No.7. 14. The kit of claim 13, wherein the second monoclonal antibody is directed against the epitope of SEQ ID No.4+SEQ ID No.5. 15. A hybridoma capable of producing the monoclonal antibody of claim 1. 16. A method of obtaining the monoclonal antibody of claim 1, comprising:
culturing a hybridoma capable of producing the monoclonal antibody so as to produce the monoclonal antibody; and obtaining the monoclonal antibody produced by the cultured hybridoma. 17. The method of claim 16, further comprising:
immunizing an animal with an antigen comprising at least one epitope selected from the group consisting of SEQ ID No.1, SEQ ID No.2, SEQ ID No.3, SEQ ID No.4+SEQ ID No.5, SEQ ID No.6+SEQ ID No.7, and SEQ ID No.8; obtaining an antibody-producing lymphocyte from the immunized animal; and fusing the antibody-producing lymphocyte with a myeloma cell to produce the hybridoma.
| 1,600 |
927 | 13,981,706 | 1,619 |
The present invention relates to microparticles comprising a gel body, wherein the gel body comprises a synthetic polymer and a drug, wherein the microparticles have an average diameter in the range 40 to 1500 μm, wherein the polymer is cross-linked by groups comprising disulfide linkages and is in the form of a hydrogel.
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1. Microparticles comprising a gel body, wherein the gel body comprises a synthetic polymer and a drug, wherein the microparticles have an average diameter in the range 40 to 1500 μm, wherein the polymer is cross-linked by groups comprising disulfide linkages and is in the form of a hydrogel. 2. Microparticles according to claim 1 for use in a method of treatment by embolisation, wherein in the treatment drug is released. 3. Microparticles according to claim 2, wherein in the method of treatment of embolisation, the microparticles are exposed to a hypoxic environment, in which the disulfide linkages are cleaved, facilitating release of the drug. 4. Microparticles according to claim 2, wherein the method of treatment by embolisation is treatment of a tumour. 5. Microparticles according to claim 1, wherein the drug is selected from the group consisting of anti-tumour drugs, anti-angiogenesis drugs, anti-fungal drugs, antiviral drugs, anti-inflammatory drugs, anti-bacterial drugs, anti-histamine drugs, antineoplastic drugs, enzymes and anti-allergenic drugs, and is preferably an anthracycline or camptothecin compound. 6. Microparticles according to claim 1, wherein the microparticles are microspheres. 7. Microparticles according to claim 1, wherein the polymer is an acrylic-based polymer. 8. Microparticles according to claim 1, wherein the polymer is a vinyl alcohol polymer. 9. Microparticles according to claim 1 which have an average diameter in the range 40-300 μm. 10. Microparticles according to claim 1, wherein the polymer is anionic, and the drug is cationic, and electrostatically associated with the polymer. 11. Microparticles according to claim 10, wherein the groups which cross-link the polymer contribute to the anionic charge on the polymer. 12. Microparticles according to claim 1, wherein the polymer has been cross-linked using a reagent comprising a disulfide linkage which comprises two cationically or anionically charged groups at physiological pH, symmetrically arranged either side of the disulfide linkage. 13. Microparticles according to claim 12, wherein the two cationically or anionically charged groups are electrostatically associated with the drug. 14. Microparticles according to claim 1, wherein the polymer is formed from a PVA macromer. 15. Microparticles according to claim 1, wherein the microparticles are biodegradable. 16. A pharmaceutical composition comprising microparticles according to claim 1. 17. A composition according to claim 16 further comprising a pharmaceutically acceptable liquid vehicle, preferably comprising physiological saline and/or a contrast agent visible by imaging devices, for instance x-ray. 18. Use of microparticles as defined in claim 1 in the manufacture of an embolic composition for use in a method of treatment by embolisation wherein the drug is released from the microparticle. 19. Use according to claim 18, wherein the method of treatment is of a tumour, preferably wherein the drug is released from the microparticle in a hypoxic environment.
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The present invention relates to microparticles comprising a gel body, wherein the gel body comprises a synthetic polymer and a drug, wherein the microparticles have an average diameter in the range 40 to 1500 μm, wherein the polymer is cross-linked by groups comprising disulfide linkages and is in the form of a hydrogel.1. Microparticles comprising a gel body, wherein the gel body comprises a synthetic polymer and a drug, wherein the microparticles have an average diameter in the range 40 to 1500 μm, wherein the polymer is cross-linked by groups comprising disulfide linkages and is in the form of a hydrogel. 2. Microparticles according to claim 1 for use in a method of treatment by embolisation, wherein in the treatment drug is released. 3. Microparticles according to claim 2, wherein in the method of treatment of embolisation, the microparticles are exposed to a hypoxic environment, in which the disulfide linkages are cleaved, facilitating release of the drug. 4. Microparticles according to claim 2, wherein the method of treatment by embolisation is treatment of a tumour. 5. Microparticles according to claim 1, wherein the drug is selected from the group consisting of anti-tumour drugs, anti-angiogenesis drugs, anti-fungal drugs, antiviral drugs, anti-inflammatory drugs, anti-bacterial drugs, anti-histamine drugs, antineoplastic drugs, enzymes and anti-allergenic drugs, and is preferably an anthracycline or camptothecin compound. 6. Microparticles according to claim 1, wherein the microparticles are microspheres. 7. Microparticles according to claim 1, wherein the polymer is an acrylic-based polymer. 8. Microparticles according to claim 1, wherein the polymer is a vinyl alcohol polymer. 9. Microparticles according to claim 1 which have an average diameter in the range 40-300 μm. 10. Microparticles according to claim 1, wherein the polymer is anionic, and the drug is cationic, and electrostatically associated with the polymer. 11. Microparticles according to claim 10, wherein the groups which cross-link the polymer contribute to the anionic charge on the polymer. 12. Microparticles according to claim 1, wherein the polymer has been cross-linked using a reagent comprising a disulfide linkage which comprises two cationically or anionically charged groups at physiological pH, symmetrically arranged either side of the disulfide linkage. 13. Microparticles according to claim 12, wherein the two cationically or anionically charged groups are electrostatically associated with the drug. 14. Microparticles according to claim 1, wherein the polymer is formed from a PVA macromer. 15. Microparticles according to claim 1, wherein the microparticles are biodegradable. 16. A pharmaceutical composition comprising microparticles according to claim 1. 17. A composition according to claim 16 further comprising a pharmaceutically acceptable liquid vehicle, preferably comprising physiological saline and/or a contrast agent visible by imaging devices, for instance x-ray. 18. Use of microparticles as defined in claim 1 in the manufacture of an embolic composition for use in a method of treatment by embolisation wherein the drug is released from the microparticle. 19. Use according to claim 18, wherein the method of treatment is of a tumour, preferably wherein the drug is released from the microparticle in a hypoxic environment.
| 1,600 |
928 | 15,756,146 | 1,612 |
Anhydrous oral care compositions and methods for preventing phase separation in the anhydrous oral care composition are disclosed. The oral care composition may include an orally acceptable vehicle, a thickening system, and a whitening agent. The orally acceptable vehicle may include propylene glycol, and the thickening system may include a polymeric thickener. The polymeric thickener may be or include a copolymer of 2-acrylamidomethylpropanesulphonic acid or a salt thereof.
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1. An anhydrous oral care composition, comprising:
an orally acceptable vehicle, the orally acceptable vehicle comprising propylene glycol; a thickening system, the thickening system comprising a polymeric thickener, wherein the polymeric thickener is a copolymer of 2-acrylamidomethylpropanesulphonic acid or a salt thereof; and a whitening agent. 2. The anhydrous oral care composition of claim 1, wherein the polymeric thickener is a block copolymer. 3. The anhydrous oral care composition of claim 1, wherein the polymeric thickener comprises a block copolymer of a first monomer and a second monomer,
wherein the first monomer comprises the 2-acrylamidomethylpropanesulphonic acid or a salt thereof, and wherein the second monomer comprises a vinyl monomer having a nitrogenous side chain. 4. The anhydrous oral care composition of claim 3, wherein the vinyl monomer is at least one of a methacrylic acid, a methacrylate, a methacrylamide, a methacrylate salt, and a vinyl pyrrolidone. 5. The anhydrous oral care composition of claim 4, wherein the first monomer is an ammonium salt of 2-acrylamidomethylpropanesulphonic acid. 6. The anhydrous oral care composition of claim 3, wherein the second monomer comprises a vinyl monomer having an amide functional group. 7. The anhydrous oral care composition of claim 6, wherein the second monomer is N-vinylpyrrolidone. 8. The anhydrous oral care composition of claim 1, wherein the polymeric thickener comprises a copolymer of an ammonium salt of 2-acrylamidomethylpropanesulphonic acid and a N-vinylpyrrolidone. 9. The anhydrous oral care composition of claim 1, wherein the thickening system consists of a copolymer of an ammonium salt of 2-acrylamidomethylpropanesulphonic acid and a N-vinylpyrrolidone. 10. The anhydrous oral care composition of claim 1, wherein the polymeric thickener is present in an amount of from about 0.1 wt. % to about 1 wt. %, of the anhydrous oral care composition. 11. The anhydrous oral care composition of claim 1, wherein the polymeric thickener is present in an amount of from about 0.25 wt. % to about 0.75 wt. %, optionally 0.4 wt. % or 0.55 wt. %, of the anhydrous oral care composition. 12. The anhydrous oral care composition of claim 1, wherein the anhydrous oral care composition is substantially free of fluoride, and optionally fluoride free. 13. The anhydrous oral care composition of claim 1, wherein the anhydrous oral care composition does not comprise fumed silica and/or cross-linked polyvinylpyrrolidone. 14. The anhydrous oral care composition of claim 1, wherein the oral care composition comprises less than 5.0 weight % water, preferably less than 1.0 weight % water, and more preferably less than 0.1 weight % water. 15. The anhydrous oral care composition of claim 1, wherein the whitening agent comprises a cross-linked polyvinylpyrrolidone (PVP) hydrogen peroxide complex. 16. A method for preventing phase separation in an anhydrous oral care composition, comprising:
contacting an orally acceptable vehicle comprising propylene glycol and a whitening agent with one another to form the oral care composition; and contacting the anhydrous oral care composition with a polymeric thickener. 17. A method for whitening a tooth of a subject need thereof, comprising: contacting an oral cavity surface of said subject with an anhydrous oral care composition according to claim 1.
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Anhydrous oral care compositions and methods for preventing phase separation in the anhydrous oral care composition are disclosed. The oral care composition may include an orally acceptable vehicle, a thickening system, and a whitening agent. The orally acceptable vehicle may include propylene glycol, and the thickening system may include a polymeric thickener. The polymeric thickener may be or include a copolymer of 2-acrylamidomethylpropanesulphonic acid or a salt thereof.1. An anhydrous oral care composition, comprising:
an orally acceptable vehicle, the orally acceptable vehicle comprising propylene glycol; a thickening system, the thickening system comprising a polymeric thickener, wherein the polymeric thickener is a copolymer of 2-acrylamidomethylpropanesulphonic acid or a salt thereof; and a whitening agent. 2. The anhydrous oral care composition of claim 1, wherein the polymeric thickener is a block copolymer. 3. The anhydrous oral care composition of claim 1, wherein the polymeric thickener comprises a block copolymer of a first monomer and a second monomer,
wherein the first monomer comprises the 2-acrylamidomethylpropanesulphonic acid or a salt thereof, and wherein the second monomer comprises a vinyl monomer having a nitrogenous side chain. 4. The anhydrous oral care composition of claim 3, wherein the vinyl monomer is at least one of a methacrylic acid, a methacrylate, a methacrylamide, a methacrylate salt, and a vinyl pyrrolidone. 5. The anhydrous oral care composition of claim 4, wherein the first monomer is an ammonium salt of 2-acrylamidomethylpropanesulphonic acid. 6. The anhydrous oral care composition of claim 3, wherein the second monomer comprises a vinyl monomer having an amide functional group. 7. The anhydrous oral care composition of claim 6, wherein the second monomer is N-vinylpyrrolidone. 8. The anhydrous oral care composition of claim 1, wherein the polymeric thickener comprises a copolymer of an ammonium salt of 2-acrylamidomethylpropanesulphonic acid and a N-vinylpyrrolidone. 9. The anhydrous oral care composition of claim 1, wherein the thickening system consists of a copolymer of an ammonium salt of 2-acrylamidomethylpropanesulphonic acid and a N-vinylpyrrolidone. 10. The anhydrous oral care composition of claim 1, wherein the polymeric thickener is present in an amount of from about 0.1 wt. % to about 1 wt. %, of the anhydrous oral care composition. 11. The anhydrous oral care composition of claim 1, wherein the polymeric thickener is present in an amount of from about 0.25 wt. % to about 0.75 wt. %, optionally 0.4 wt. % or 0.55 wt. %, of the anhydrous oral care composition. 12. The anhydrous oral care composition of claim 1, wherein the anhydrous oral care composition is substantially free of fluoride, and optionally fluoride free. 13. The anhydrous oral care composition of claim 1, wherein the anhydrous oral care composition does not comprise fumed silica and/or cross-linked polyvinylpyrrolidone. 14. The anhydrous oral care composition of claim 1, wherein the oral care composition comprises less than 5.0 weight % water, preferably less than 1.0 weight % water, and more preferably less than 0.1 weight % water. 15. The anhydrous oral care composition of claim 1, wherein the whitening agent comprises a cross-linked polyvinylpyrrolidone (PVP) hydrogen peroxide complex. 16. A method for preventing phase separation in an anhydrous oral care composition, comprising:
contacting an orally acceptable vehicle comprising propylene glycol and a whitening agent with one another to form the oral care composition; and contacting the anhydrous oral care composition with a polymeric thickener. 17. A method for whitening a tooth of a subject need thereof, comprising: contacting an oral cavity surface of said subject with an anhydrous oral care composition according to claim 1.
| 1,600 |
929 | 15,257,079 | 1,618 |
The present invention relates to a process for the production of abuse-proofed, thermoformed dosage forms containing, apart from one or more active ingredients with potential for abuse and optionally physiologically acceptable auxiliary substances, at least one synthetic or natural polymer with a breaking strength of at least 500 N.
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1. A process for the production of a solid pharmaceutic dosage forms with at least reduced potential for abuse, comprising:
a) a formulation mixture containing at least one active ingredient with potential for abuse, at least one synthetic or natural polymer (C), which exhibits a breaking strength of at least 500 N, and optionally auxiliary substances (B) is shaped into formed articles by application of force, b) the formed articles are optionally singulated and optionally in each case graded by size and, c) after or during heating at least to the softening point of the polymer (C), the formed articles are exposed to force until they have a breaking hardness of at least 500 N, and optionally provided with a cover and all the formed articles are optionally mixed back together again. 2. A process according to claim 1, which is performed continuously or discontinuously. 3. A process according to claim 1, wherein the formulation mixture consists to an extent of at least 30 wt. % of component (C). 4. A process according to claim 1, wherein the formulation mixture consists to an extent of at least 50 wt. % of component (C). 5. A process according to claim 1, wherein a) shaping of the formulation mixture proceeds with application of a force of at least 0.5 kN and optionally with heating to less than 60° C. 6. A process according to claim 1, wherein, according to c), the formed articles are heated to at least 60° C before or during application of force of at least 0.1 kN. 7. A process according to claim 1, wherein the application of force according to a) or c) is performed with the assistance of a press, shaping rollers or with shaping belts equipped with rollers. 8. A process according to claim wherein shaping according to a) gives rise to tablets. 9. A process according to claim 1, wherein shaping according to a) gives rise to a multiparticulate dosage form with a minimum size of 0.5 mm. 10. A process according to claim 1, wherein opioid active ingredients are used as active ingredients.
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The present invention relates to a process for the production of abuse-proofed, thermoformed dosage forms containing, apart from one or more active ingredients with potential for abuse and optionally physiologically acceptable auxiliary substances, at least one synthetic or natural polymer with a breaking strength of at least 500 N.1. A process for the production of a solid pharmaceutic dosage forms with at least reduced potential for abuse, comprising:
a) a formulation mixture containing at least one active ingredient with potential for abuse, at least one synthetic or natural polymer (C), which exhibits a breaking strength of at least 500 N, and optionally auxiliary substances (B) is shaped into formed articles by application of force, b) the formed articles are optionally singulated and optionally in each case graded by size and, c) after or during heating at least to the softening point of the polymer (C), the formed articles are exposed to force until they have a breaking hardness of at least 500 N, and optionally provided with a cover and all the formed articles are optionally mixed back together again. 2. A process according to claim 1, which is performed continuously or discontinuously. 3. A process according to claim 1, wherein the formulation mixture consists to an extent of at least 30 wt. % of component (C). 4. A process according to claim 1, wherein the formulation mixture consists to an extent of at least 50 wt. % of component (C). 5. A process according to claim 1, wherein a) shaping of the formulation mixture proceeds with application of a force of at least 0.5 kN and optionally with heating to less than 60° C. 6. A process according to claim 1, wherein, according to c), the formed articles are heated to at least 60° C before or during application of force of at least 0.1 kN. 7. A process according to claim 1, wherein the application of force according to a) or c) is performed with the assistance of a press, shaping rollers or with shaping belts equipped with rollers. 8. A process according to claim wherein shaping according to a) gives rise to tablets. 9. A process according to claim 1, wherein shaping according to a) gives rise to a multiparticulate dosage form with a minimum size of 0.5 mm. 10. A process according to claim 1, wherein opioid active ingredients are used as active ingredients.
| 1,600 |
930 | 14,438,962 | 1,631 |
Provided is a brain activity training apparatus for training to cause a change in correlation of connectivity among brain regions, utilizing measured correlations of connections among brains regions as feedback information. From measured data of resting-state functional connectivity MRI of a healthy group and a patient group (S 102 ), correlation matrix of degree of brain activities among prescribed brain regions is derived for each subject. Feature extraction is executed (S 104 ) by regularized canonical correlation analysis on the correlation matrix and attributes of the subject including a disease/healthy label of the subject. Based on the result of regularized canonical correlation analysis, by discriminant analysis through sparse logistic regression, a discriminator is generated (S 108 ). The brain activity training apparatus feeds back a reward value to the subject based on the result of discriminator on the data of functional connectivity MRI of the subject.
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1. A brain activity training apparatus, comprising:
a brain activity detecting device for time-sequentially detecting signals indicative of brain activities at a plurality of prescribed regions in a brain of a first subject; and a storage device for storing information that specifies a discriminator generated from signals measured in advance by time-sequentially measuring signals indicative of the brain activities at said plurality of prescribed regions in a brain of each of a plurality of second subjects different from said first subject, said discriminator executing a discrimination of a target attribute among attributes of said second subjects by contraction expression extracted, from correlations of brain activities among said plurality of prescribed regions, commonly with respect to at least attributes of said plurality of second subjects; said brain activity training apparatus further comprising: a presenting device; and a processing device; wherein said processing device is configured to i) calculate correlations of brain activities from among said plurality of prescribed regions, based on signals detected by said brain activity detecting device, ii) based on said calculated correlations, by said discriminator specified by the information stored in said storage device, calculate a reward value in accordance with degree of similarity of said calculated correlations to target correlations corresponding to said target attribute, and iii) present information indicative of magnitude of said reward value to said subject by said presenting device. 2. The brain activity training apparatus according to claim 1, wherein
said signals measured in advance from said plurality of second subjects are measured by a plurality of brain activity measuring devices; and said contraction expression used by said discriminator is a contraction expression extracted, by variable selection from correlations of brain activities among said plurality of prescribed regions, commonly with respect to measuring conditions of said plurality of brain activity measuring devices, and attributes of said plurality of subjects. 3. The brain activity training apparatus according to claim 1, wherein said discriminator is generated by regression of performing further variable selection on said extracted contraction expression. 4. The brain activity training apparatus according to claim 1, wherein
said discriminator is generated by sparse logistic regression on sparse non-diagonal elements and a target attribute of said second subjects, said sparse non-diagonal elements being made sparse based on a result obtained by regularized canonical correlation analysis with respect to non-diagonal elements of correlation matrix of brain activities at said plurality of prescribed regions of said second subjects and said attributes of said second subjects; and an input to said discriminator is a linear weighted sum of said non-diagonal elements of said first subject corresponding to the result of said regularized canonical correlation analysis. 5. The brain activity training apparatus according to claim 2, wherein
said discriminator is generated by sparse logistic regression on sparse non-diagonal elements and a target attribute of said second subjects, said sparse non-diagonal elements being made sparse based on a result obtained by regularized canonical correlation analysis with respect to non-diagonal elements of correlation matrix of brain activities at said plurality of prescribed regions of said second subjects and said attributes of said second subjects; and an input to said discriminator is a non-diagonal element selected as related to said target attribute, from said non-diagonal elements based on a result of said regularized canonical correlation analysis. 6. The brain activity training apparatus according to claim 1, wherein said brain activity detecting device includes a brain activity detecting device for picking-up a resting-state functional connectivity magnetic resonance image. 7. The brain activity training apparatus according to claim 4, wherein said regularized canonical correlation analysis is canonical correlation analysis with L1 regularization. 8. A brain activity training system, comprising:
a brain activity detecting device for time-sequentially detecting signals indicative of brain activities at a plurality of prescribed regions in a brain of a first subject; and discriminator generating means for generating a discriminator from signals measured in advance by said brain activity detecting device by time-sequentially measuring signals indicative of the brain activities at said plurality of prescribed regions in a brain of each of a plurality of second subjects different from said first subject, said discriminator generating means extracting contraction expression common to at least attributes of said plurality of second subjects from correlations of brain activities among said plurality of prescribed regions and generates a discriminator for the extracted contraction expression with respect to a target attribute among said attributes of said second subjects; said brain activity training system further comprising: a storage device for storing information that specifies said discriminator; a presenting device; and a processing device; wherein said processing device is configured to i) calculate correlations of brain activities from among said plurality of prescribed regions, based on signals detected by said brain activity detecting device, ii) based on said calculated correlations, by a discriminant process by said discriminator specified by the information stored in said storage device, calculate a reward value in accordance with degree of similarity of said calculated correlations to target correlations corresponding to said target attribute, and iii) present information indicative of magnitude of said reward value to said subject by said presenting device. 9. The brain activity training system according to claim 8, wherein
said brain activity detecting device includes a plurality of brain activity measuring devices; and said discriminator generating means includes extracting means for extracting, by variable selection from correlations of brain activities among said plurality of prescribed regions, a contraction expression common to measuring conditions of said plurality of brain activity measuring devices, and attributes of said plurality of subjects. 10. The brain activity training system according to claim 8, wherein
said discriminator generating means includes regression means for generating said discriminator by regression of performing further variable selection on said extracted contraction expression. 11. The brain activity training system according to claim 9, wherein said extracting means includes correlation analyzing means for calculating a correlation matrix of activities at said plurality of prescribed regions from the signals detected by said brain activity detecting device, executing regularized canonical correlation analysis between attributes of said subjects and non-diagonal elements of said correlation matrix and thereby for extracting said contracted expression. 12. The brain activity training system according to claim 10, wherein said regression means includes regression analysis means for generating a discriminator by sparse logistic regression on a result of said regularized canonical correlation analysis and the attributes of said subjects. 13. The brain activity training system according to claim 9, wherein said plurality of brain activity measuring devices are devices for time-sequentially measuring brain activities by functional brain imaging installed at a plurality of different locations, respectively. 14. The brain activity training system according to claim 8, wherein said discriminant process is discrimination of a disease label indicating whether said first subject is healthy or a patient of a neurological/mental disorder. 15. The brain activity training system according to claim 9, wherein
the attributes of said subjects include a disease label indicating whether said subject is healthy or a patient of a neurological/mental disorder, a label indicating individual nature of said subject, and information characterizing measurement by said brain activity detecting device; and said discriminant process is discrimination of a disease label indicating whether said first subject is healthy or a patient of a neurological/mental disorder. 16. The brain activity training system according to claim 11, wherein said regularized canonical correlation analysis is canonical correlation analysis with L1 regularization. 17. The brain activity training system according to claim 9, wherein said brain activity measuring device picks up a resting-state functional connectivity magnetic. 18. The brain activity training apparatus according to claim 2, wherein said discriminator is generated by regression of performing further variable selection on said extracted contraction expression. 19. The brain activity training apparatus according to claim 5, wherein said regularized canonical correlation analysis is canonical correlation analysis with L1 regularization. 20. The brain activity training system according to claim 9, wherein
said discriminator generating means includes regression means for generating said discriminator by regression of performing further variable selection on said extracted contraction expression.
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Provided is a brain activity training apparatus for training to cause a change in correlation of connectivity among brain regions, utilizing measured correlations of connections among brains regions as feedback information. From measured data of resting-state functional connectivity MRI of a healthy group and a patient group (S 102 ), correlation matrix of degree of brain activities among prescribed brain regions is derived for each subject. Feature extraction is executed (S 104 ) by regularized canonical correlation analysis on the correlation matrix and attributes of the subject including a disease/healthy label of the subject. Based on the result of regularized canonical correlation analysis, by discriminant analysis through sparse logistic regression, a discriminator is generated (S 108 ). The brain activity training apparatus feeds back a reward value to the subject based on the result of discriminator on the data of functional connectivity MRI of the subject.1. A brain activity training apparatus, comprising:
a brain activity detecting device for time-sequentially detecting signals indicative of brain activities at a plurality of prescribed regions in a brain of a first subject; and a storage device for storing information that specifies a discriminator generated from signals measured in advance by time-sequentially measuring signals indicative of the brain activities at said plurality of prescribed regions in a brain of each of a plurality of second subjects different from said first subject, said discriminator executing a discrimination of a target attribute among attributes of said second subjects by contraction expression extracted, from correlations of brain activities among said plurality of prescribed regions, commonly with respect to at least attributes of said plurality of second subjects; said brain activity training apparatus further comprising: a presenting device; and a processing device; wherein said processing device is configured to i) calculate correlations of brain activities from among said plurality of prescribed regions, based on signals detected by said brain activity detecting device, ii) based on said calculated correlations, by said discriminator specified by the information stored in said storage device, calculate a reward value in accordance with degree of similarity of said calculated correlations to target correlations corresponding to said target attribute, and iii) present information indicative of magnitude of said reward value to said subject by said presenting device. 2. The brain activity training apparatus according to claim 1, wherein
said signals measured in advance from said plurality of second subjects are measured by a plurality of brain activity measuring devices; and said contraction expression used by said discriminator is a contraction expression extracted, by variable selection from correlations of brain activities among said plurality of prescribed regions, commonly with respect to measuring conditions of said plurality of brain activity measuring devices, and attributes of said plurality of subjects. 3. The brain activity training apparatus according to claim 1, wherein said discriminator is generated by regression of performing further variable selection on said extracted contraction expression. 4. The brain activity training apparatus according to claim 1, wherein
said discriminator is generated by sparse logistic regression on sparse non-diagonal elements and a target attribute of said second subjects, said sparse non-diagonal elements being made sparse based on a result obtained by regularized canonical correlation analysis with respect to non-diagonal elements of correlation matrix of brain activities at said plurality of prescribed regions of said second subjects and said attributes of said second subjects; and an input to said discriminator is a linear weighted sum of said non-diagonal elements of said first subject corresponding to the result of said regularized canonical correlation analysis. 5. The brain activity training apparatus according to claim 2, wherein
said discriminator is generated by sparse logistic regression on sparse non-diagonal elements and a target attribute of said second subjects, said sparse non-diagonal elements being made sparse based on a result obtained by regularized canonical correlation analysis with respect to non-diagonal elements of correlation matrix of brain activities at said plurality of prescribed regions of said second subjects and said attributes of said second subjects; and an input to said discriminator is a non-diagonal element selected as related to said target attribute, from said non-diagonal elements based on a result of said regularized canonical correlation analysis. 6. The brain activity training apparatus according to claim 1, wherein said brain activity detecting device includes a brain activity detecting device for picking-up a resting-state functional connectivity magnetic resonance image. 7. The brain activity training apparatus according to claim 4, wherein said regularized canonical correlation analysis is canonical correlation analysis with L1 regularization. 8. A brain activity training system, comprising:
a brain activity detecting device for time-sequentially detecting signals indicative of brain activities at a plurality of prescribed regions in a brain of a first subject; and discriminator generating means for generating a discriminator from signals measured in advance by said brain activity detecting device by time-sequentially measuring signals indicative of the brain activities at said plurality of prescribed regions in a brain of each of a plurality of second subjects different from said first subject, said discriminator generating means extracting contraction expression common to at least attributes of said plurality of second subjects from correlations of brain activities among said plurality of prescribed regions and generates a discriminator for the extracted contraction expression with respect to a target attribute among said attributes of said second subjects; said brain activity training system further comprising: a storage device for storing information that specifies said discriminator; a presenting device; and a processing device; wherein said processing device is configured to i) calculate correlations of brain activities from among said plurality of prescribed regions, based on signals detected by said brain activity detecting device, ii) based on said calculated correlations, by a discriminant process by said discriminator specified by the information stored in said storage device, calculate a reward value in accordance with degree of similarity of said calculated correlations to target correlations corresponding to said target attribute, and iii) present information indicative of magnitude of said reward value to said subject by said presenting device. 9. The brain activity training system according to claim 8, wherein
said brain activity detecting device includes a plurality of brain activity measuring devices; and said discriminator generating means includes extracting means for extracting, by variable selection from correlations of brain activities among said plurality of prescribed regions, a contraction expression common to measuring conditions of said plurality of brain activity measuring devices, and attributes of said plurality of subjects. 10. The brain activity training system according to claim 8, wherein
said discriminator generating means includes regression means for generating said discriminator by regression of performing further variable selection on said extracted contraction expression. 11. The brain activity training system according to claim 9, wherein said extracting means includes correlation analyzing means for calculating a correlation matrix of activities at said plurality of prescribed regions from the signals detected by said brain activity detecting device, executing regularized canonical correlation analysis between attributes of said subjects and non-diagonal elements of said correlation matrix and thereby for extracting said contracted expression. 12. The brain activity training system according to claim 10, wherein said regression means includes regression analysis means for generating a discriminator by sparse logistic regression on a result of said regularized canonical correlation analysis and the attributes of said subjects. 13. The brain activity training system according to claim 9, wherein said plurality of brain activity measuring devices are devices for time-sequentially measuring brain activities by functional brain imaging installed at a plurality of different locations, respectively. 14. The brain activity training system according to claim 8, wherein said discriminant process is discrimination of a disease label indicating whether said first subject is healthy or a patient of a neurological/mental disorder. 15. The brain activity training system according to claim 9, wherein
the attributes of said subjects include a disease label indicating whether said subject is healthy or a patient of a neurological/mental disorder, a label indicating individual nature of said subject, and information characterizing measurement by said brain activity detecting device; and said discriminant process is discrimination of a disease label indicating whether said first subject is healthy or a patient of a neurological/mental disorder. 16. The brain activity training system according to claim 11, wherein said regularized canonical correlation analysis is canonical correlation analysis with L1 regularization. 17. The brain activity training system according to claim 9, wherein said brain activity measuring device picks up a resting-state functional connectivity magnetic. 18. The brain activity training apparatus according to claim 2, wherein said discriminator is generated by regression of performing further variable selection on said extracted contraction expression. 19. The brain activity training apparatus according to claim 5, wherein said regularized canonical correlation analysis is canonical correlation analysis with L1 regularization. 20. The brain activity training system according to claim 9, wherein
said discriminator generating means includes regression means for generating said discriminator by regression of performing further variable selection on said extracted contraction expression.
| 1,600 |
931 | 15,309,566 | 1,651 |
A method of treating a wound including applying a wound care treatment to the wound, the wound care treatment including a preparation composed of morselized amnion tissue and amniotic fluid cells adsorbed to a porous collagen matrix and optionally, glycosaminoglycan. The morselized amnion tissue includes organized amniotic extracellular matrix (ECM), amniotic tissue cells and growth factors contained within the ECM and amniotic tissue cells. The porous collagen matrix is provided as a solid sheet, a meshed or perforated sheet or a flowable material.
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1. A method of treating a wound comprising:
providing a first preparation including amnion tissue and amniotic fluid cells, wherein the amnion tissue is morselized amnion tissue and includes organized amniotic extracellular matrix (ECM), amniotic tissue cells and growth factors contained within the ECM and amniotic tissue cells, providing a porous matrix including a mammalian collagen and optionally, glycosaminoglycan (GAG), combining the first preparation with the porous matrix to form a second preparation, the second preparation including a portion of the first preparation adsorbed to the porous matrix, and applying the second preparation to a mammal. 2. The method according to claim 1 wherein the first preparation is combined with the porous matrix to form the second preparation no more than about ten minutes prior to applying the second preparation to the wound. 3. The method according to claim 1 wherein the ECM includes amnion-derived collagen, fibronectin, laminin, proteoglycans and glycosaminoglycans. 4. The method according to claim 3 wherein the amnion-derived collagen is derived from an epithelium layer, a basement membrane layer, a compact layer, a fibroblast layer, an intermediate layer and a spongy layer of the amnion tissue. 5. The method according to claim 1 wherein the mammalian collagen is selected from the group consisting of Type I collagen, Type III collagen, a granulated cross-linked tendon collagen and combinations thereof. 6. The method according to claim 5 wherein the collagen is provided as a sheet, a meshed sheet or a flowable matrix. 7. The method according to claim 6 wherein, when the porous matrix is provided as the sheet, the first preparation adsorbs to the sheet in an amount of about 800 μl per square inch of the sheet. 8. The method according to claim 6 wherein, when the porous matrix is provided as the sheet including the GAG, the first preparation adsorbs to the sheet in an amount of about 300 μl to about 999 μl per square inch of the sheet. 9. The method according to claim 1 wherein the ground amnion tissue has an average particle size in a range of about 10 micrometers to about 1000 micrometers. 10. The method according to claim 1 further comprising removing a chorion layer from the amnion tissue. 11. The method according to claim 1 wherein the second preparation is applied to a skin wound of the mammal thereby promoting healing of the wound. 12. The method according to claim 11 comprising applying an effective amount of the second preparation to the wound, the effective amount including about 0.05 mg to about 5 mg of amnion tissue per square centimeter of the wound. 13. The method according to claim 1 wherein an effective amount of the second preparation is applied to a wound surface area, the wound surface area being at least ten times larger than a sum of the surface areas of an amnion side of each piece of the morselized amnion tissue. 14. A method of treating a wound comprising:
providing a first preparation including amnion tissue and amniotic fluid cells, wherein the amnion tissue is ground amnion tissue and includes amniotic extracellular matrix (ECM), amniotic tissue cells and growth factors and wherein the ECM includes fibronectin, laminin, proteoglycans, glycosaminoglycans and amnion-derived collagen that is derived from an epithelium layer, a basement membrane layer, a compact layer, a fibroblast layer, an intermediate layer and a spongy layer of the amnion tissue, providing a porous matrix including a processed collagen, wherein the processed collagen is selected from the group consisting of Type I collagen, Type III collagen, a granulated cross-linked tendon collagen and combinations thereof, combining the first preparation with the porous matrix to form a second preparation, the second preparation including a portion of the first preparation adsorbed to the porous matrix, and applying the second preparation to the wound no later than 180 minutes after forming the second preparation, whereby the second preparation improves a healing rate of the wound. 15. The method according to claim 14 comprising providing the porous matrix as a sheet and adsorbing to the sheet between about 300 μl to about 999 μl of the first preparation per square inch of the sheet. 16. The method according to claim 14 comprising applying an effective amount of the second preparation to the wound, the effective amount including about 0.05 mg to about 5 mg of amnion tissue per square centimeter of the wound 17. The method according to claim 14 wherein the ground amnion tissue has an average particle size of about 250 micrometers. 18. A wound treatment comprising:
a porous collagen matrix, and a preparation adsorbed to the porous collagen matrix, the preparation including amnion tissue and amniotic fluid cells, wherein the amnion tissue is ground amnion tissue and includes amniotic extracellular matrix (ECM), amniotic tissue cells and growth factors and wherein the ECM includes fibronectin, laminin, proteoglycans, glycosaminoglycans and amnion-derived collagen that is derived from an epithelium layer, a basement membrane layer, a compact layer, a fibroblast layer, an intermediate and a spongy layer of the amnion tissue. 19. The wound treatment according to claim 18 wherein, when the porous collagen matrix is in the form of a sheet, the preparation adsorbs to the sheet in an amount equal to about 300 μl to about 999 μl per square inch of the sheet. 20. The wound treatment according to claim 18 wherein the ground amnion tissue has an average particle size in a range of 10 micrometers to 1000 micrometers. 21. The wound treatment according to claim 18 wherein the amnion tissue excludes a chorion layer. 22. A method of treating a mammal comprising applying the wound treatment of claim 18 to a wound of a mammal thereby promoting healing of the wound.
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A method of treating a wound including applying a wound care treatment to the wound, the wound care treatment including a preparation composed of morselized amnion tissue and amniotic fluid cells adsorbed to a porous collagen matrix and optionally, glycosaminoglycan. The morselized amnion tissue includes organized amniotic extracellular matrix (ECM), amniotic tissue cells and growth factors contained within the ECM and amniotic tissue cells. The porous collagen matrix is provided as a solid sheet, a meshed or perforated sheet or a flowable material.1. A method of treating a wound comprising:
providing a first preparation including amnion tissue and amniotic fluid cells, wherein the amnion tissue is morselized amnion tissue and includes organized amniotic extracellular matrix (ECM), amniotic tissue cells and growth factors contained within the ECM and amniotic tissue cells, providing a porous matrix including a mammalian collagen and optionally, glycosaminoglycan (GAG), combining the first preparation with the porous matrix to form a second preparation, the second preparation including a portion of the first preparation adsorbed to the porous matrix, and applying the second preparation to a mammal. 2. The method according to claim 1 wherein the first preparation is combined with the porous matrix to form the second preparation no more than about ten minutes prior to applying the second preparation to the wound. 3. The method according to claim 1 wherein the ECM includes amnion-derived collagen, fibronectin, laminin, proteoglycans and glycosaminoglycans. 4. The method according to claim 3 wherein the amnion-derived collagen is derived from an epithelium layer, a basement membrane layer, a compact layer, a fibroblast layer, an intermediate layer and a spongy layer of the amnion tissue. 5. The method according to claim 1 wherein the mammalian collagen is selected from the group consisting of Type I collagen, Type III collagen, a granulated cross-linked tendon collagen and combinations thereof. 6. The method according to claim 5 wherein the collagen is provided as a sheet, a meshed sheet or a flowable matrix. 7. The method according to claim 6 wherein, when the porous matrix is provided as the sheet, the first preparation adsorbs to the sheet in an amount of about 800 μl per square inch of the sheet. 8. The method according to claim 6 wherein, when the porous matrix is provided as the sheet including the GAG, the first preparation adsorbs to the sheet in an amount of about 300 μl to about 999 μl per square inch of the sheet. 9. The method according to claim 1 wherein the ground amnion tissue has an average particle size in a range of about 10 micrometers to about 1000 micrometers. 10. The method according to claim 1 further comprising removing a chorion layer from the amnion tissue. 11. The method according to claim 1 wherein the second preparation is applied to a skin wound of the mammal thereby promoting healing of the wound. 12. The method according to claim 11 comprising applying an effective amount of the second preparation to the wound, the effective amount including about 0.05 mg to about 5 mg of amnion tissue per square centimeter of the wound. 13. The method according to claim 1 wherein an effective amount of the second preparation is applied to a wound surface area, the wound surface area being at least ten times larger than a sum of the surface areas of an amnion side of each piece of the morselized amnion tissue. 14. A method of treating a wound comprising:
providing a first preparation including amnion tissue and amniotic fluid cells, wherein the amnion tissue is ground amnion tissue and includes amniotic extracellular matrix (ECM), amniotic tissue cells and growth factors and wherein the ECM includes fibronectin, laminin, proteoglycans, glycosaminoglycans and amnion-derived collagen that is derived from an epithelium layer, a basement membrane layer, a compact layer, a fibroblast layer, an intermediate layer and a spongy layer of the amnion tissue, providing a porous matrix including a processed collagen, wherein the processed collagen is selected from the group consisting of Type I collagen, Type III collagen, a granulated cross-linked tendon collagen and combinations thereof, combining the first preparation with the porous matrix to form a second preparation, the second preparation including a portion of the first preparation adsorbed to the porous matrix, and applying the second preparation to the wound no later than 180 minutes after forming the second preparation, whereby the second preparation improves a healing rate of the wound. 15. The method according to claim 14 comprising providing the porous matrix as a sheet and adsorbing to the sheet between about 300 μl to about 999 μl of the first preparation per square inch of the sheet. 16. The method according to claim 14 comprising applying an effective amount of the second preparation to the wound, the effective amount including about 0.05 mg to about 5 mg of amnion tissue per square centimeter of the wound 17. The method according to claim 14 wherein the ground amnion tissue has an average particle size of about 250 micrometers. 18. A wound treatment comprising:
a porous collagen matrix, and a preparation adsorbed to the porous collagen matrix, the preparation including amnion tissue and amniotic fluid cells, wherein the amnion tissue is ground amnion tissue and includes amniotic extracellular matrix (ECM), amniotic tissue cells and growth factors and wherein the ECM includes fibronectin, laminin, proteoglycans, glycosaminoglycans and amnion-derived collagen that is derived from an epithelium layer, a basement membrane layer, a compact layer, a fibroblast layer, an intermediate and a spongy layer of the amnion tissue. 19. The wound treatment according to claim 18 wherein, when the porous collagen matrix is in the form of a sheet, the preparation adsorbs to the sheet in an amount equal to about 300 μl to about 999 μl per square inch of the sheet. 20. The wound treatment according to claim 18 wherein the ground amnion tissue has an average particle size in a range of 10 micrometers to 1000 micrometers. 21. The wound treatment according to claim 18 wherein the amnion tissue excludes a chorion layer. 22. A method of treating a mammal comprising applying the wound treatment of claim 18 to a wound of a mammal thereby promoting healing of the wound.
| 1,600 |
932 | 15,307,143 | 1,617 |
The present invention relates to a process for producing microcapsules which contain a shell and a core of a liquid water-insoluble material, where
(a) a premix (I) is prepared from water and a protective colloid; (b) a further premix (II) is prepared from the water-insoluble material and at least bifunctional isocyanate (A) or a mixture of two or more different isocyanates containing (A); (c) the two premixes (I) and (II) are mixed together until an emulsion is formed; (d) at least a bifunctional amine is then poured into the emulsion from step (c); and (e) the emulsion is then heated until the microcapsules are formed, and
where the liquid water-insoluble material comprises a pesticide, where the protective colloid is a polyvinyl alcohol copolymer having hydrolysis degrees from 60 to 99.9%, and where the polyvinyl alcohol copolymer contains comonomers with anionic groups. Further subject matter are microcapsules obtainable by said process. The present invention also relates to a method of controlling phytopathogenic fungi and/or undesired plant growth and/or undesired insect or mite attack and/or for regulating the growth of plants, wherein the microcapsules are allowed to act on the respective pests, their environment or the crop plants to be protected from the respective pest, on the soil and/or on undesired plants and/or on the crop plants and/or on their environment.
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1-15. (canceled) 16: A process for producing microcapsules which contain a shell and a core of a liquid water-insoluble material, where
(a) a premix (I) is prepared from water and a protective colloid; (b) a further premix (II) is prepared from the water-insoluble material and at least bifunctional isocyanate (A) or a mixture of two or more different isocyanates containing (A); (c) the two premixes (I) and (II) are mixed together until an emulsion is formed; (d) at least a bifunctional amine is then poured into the emulsion from step (c); and (e) the emulsion is then heated until the microcapsules are formed; and where the liquid water-insoluble material comprises a pesticide, where the protective colloid is a polyvinyl alcohol copolymer having hydrolysis degrees from 60 to 99.9%, where the polyvinyl alcohol copolymer contains comonomers with anionic groups, and wherein the isocyanate (A) is selected from alicyclic or aliphatic isocyanates. 17: The process as claimed in claim 16, wherein the polyvinyl alcohol copolymer contains comonomers with anionic groups selected from carboxyl- and/or sulfonic acid groups. 18: The process as claimed in claim 16, wherein the polyvinyl alcohol copolymer contains 0.1 to 30 mol % of the comonomers with anionic groups. 19: The process as claimed in claim 16, wherein the polyvinyl alcohol copolymer is used with amounts from 0.1 to 20% by weight, based on the weight of the microcapsules. 20: The process as claimed in claim 16, wherein the water-insoluble material comprises a pesticide blended with an oily solvent. 21: The process as claimed in claim 16, wherein the isocyanate (A) is selected from hexamethylene diisocyanate or derivatives thereof, or dicyclohexylmethane diisocyanates. 22: The process as claimed in claim 16, wherein a mixture of isocyanate (A) and an anionically modified isocyanate (B) is used, wherein the anionically modified diisocyanates (B) are selected from the group which contain at least one sulfonic acid group in the molecule. 23: The process as claimed in claim 22, wherein the weight ratio between the isocyanates (A) and (B) is in the range from 10:1 to 1:10. 24: The process as claimed in claim 16, wherein the at least bifunctional amine used is a polyethyleneimine. 25: The process as claimed in claim 16, where the pesticide has a water-solubility up to 10 g/l at 20° C. 26: The process as claimed in claim 16, wherein the core-shell ratio (w/w) of the microcapsules is 20:1 to 1:10. 27: The process as claimed in claim 16, wherein microcapsules have a diameter from 1 to 30 μm. 28: The process as claimed in claim 16, wherein the emulsion is then heated to at least 50° C. 29: A method of controlling phytopathogenic fungi and/or undesired plant growth and/or undesired insect or mite attack and/or for regulating the growth of plants, wherein the microcapsules obtainable by a process as defined in claim 16 are allowed to act on the respective pests, their environment or the crop plants to be protected from the respective pest, on the soil and/or on undesired plants and/or on the crop plants and/or on their environment. 30: The method of claim 29, wherein the polyvinyl alcohol copolymer contains comonomers with anionic groups selected from carboxyl- and/or sulfonic acid groups. 31: The method of claim 29, wherein the polyvinyl alcohol copolymer contains 0.1 to 30 mol % of the comonomers with anionic groups. 32: The method of claim 29, wherein the polyvinyl alcohol copolymer is used with amounts from 0.1 to 20% by weight, based on the weight of the microcapsules. 33: The process as claimed in claim 16, wherein the water-insoluble material comprises a pesticide blended with an oily solvent. 34: The method of claim 29, wherein the isocyanate (A) is selected from hexamethylene diisocyanate or derivatives thereof, or dicyclohexylmethane diisocyanates. 35: The method of claim 29, wherein a mixture of isocyanate (A) and an anionically modified isocyanate (B) is used, wherein the anionically modified diisocyanates (B) are selected from the group which contain at least one sulfonic acid group in the molecule.
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The present invention relates to a process for producing microcapsules which contain a shell and a core of a liquid water-insoluble material, where
(a) a premix (I) is prepared from water and a protective colloid; (b) a further premix (II) is prepared from the water-insoluble material and at least bifunctional isocyanate (A) or a mixture of two or more different isocyanates containing (A); (c) the two premixes (I) and (II) are mixed together until an emulsion is formed; (d) at least a bifunctional amine is then poured into the emulsion from step (c); and (e) the emulsion is then heated until the microcapsules are formed, and
where the liquid water-insoluble material comprises a pesticide, where the protective colloid is a polyvinyl alcohol copolymer having hydrolysis degrees from 60 to 99.9%, and where the polyvinyl alcohol copolymer contains comonomers with anionic groups. Further subject matter are microcapsules obtainable by said process. The present invention also relates to a method of controlling phytopathogenic fungi and/or undesired plant growth and/or undesired insect or mite attack and/or for regulating the growth of plants, wherein the microcapsules are allowed to act on the respective pests, their environment or the crop plants to be protected from the respective pest, on the soil and/or on undesired plants and/or on the crop plants and/or on their environment.1-15. (canceled) 16: A process for producing microcapsules which contain a shell and a core of a liquid water-insoluble material, where
(a) a premix (I) is prepared from water and a protective colloid; (b) a further premix (II) is prepared from the water-insoluble material and at least bifunctional isocyanate (A) or a mixture of two or more different isocyanates containing (A); (c) the two premixes (I) and (II) are mixed together until an emulsion is formed; (d) at least a bifunctional amine is then poured into the emulsion from step (c); and (e) the emulsion is then heated until the microcapsules are formed; and where the liquid water-insoluble material comprises a pesticide, where the protective colloid is a polyvinyl alcohol copolymer having hydrolysis degrees from 60 to 99.9%, where the polyvinyl alcohol copolymer contains comonomers with anionic groups, and wherein the isocyanate (A) is selected from alicyclic or aliphatic isocyanates. 17: The process as claimed in claim 16, wherein the polyvinyl alcohol copolymer contains comonomers with anionic groups selected from carboxyl- and/or sulfonic acid groups. 18: The process as claimed in claim 16, wherein the polyvinyl alcohol copolymer contains 0.1 to 30 mol % of the comonomers with anionic groups. 19: The process as claimed in claim 16, wherein the polyvinyl alcohol copolymer is used with amounts from 0.1 to 20% by weight, based on the weight of the microcapsules. 20: The process as claimed in claim 16, wherein the water-insoluble material comprises a pesticide blended with an oily solvent. 21: The process as claimed in claim 16, wherein the isocyanate (A) is selected from hexamethylene diisocyanate or derivatives thereof, or dicyclohexylmethane diisocyanates. 22: The process as claimed in claim 16, wherein a mixture of isocyanate (A) and an anionically modified isocyanate (B) is used, wherein the anionically modified diisocyanates (B) are selected from the group which contain at least one sulfonic acid group in the molecule. 23: The process as claimed in claim 22, wherein the weight ratio between the isocyanates (A) and (B) is in the range from 10:1 to 1:10. 24: The process as claimed in claim 16, wherein the at least bifunctional amine used is a polyethyleneimine. 25: The process as claimed in claim 16, where the pesticide has a water-solubility up to 10 g/l at 20° C. 26: The process as claimed in claim 16, wherein the core-shell ratio (w/w) of the microcapsules is 20:1 to 1:10. 27: The process as claimed in claim 16, wherein microcapsules have a diameter from 1 to 30 μm. 28: The process as claimed in claim 16, wherein the emulsion is then heated to at least 50° C. 29: A method of controlling phytopathogenic fungi and/or undesired plant growth and/or undesired insect or mite attack and/or for regulating the growth of plants, wherein the microcapsules obtainable by a process as defined in claim 16 are allowed to act on the respective pests, their environment or the crop plants to be protected from the respective pest, on the soil and/or on undesired plants and/or on the crop plants and/or on their environment. 30: The method of claim 29, wherein the polyvinyl alcohol copolymer contains comonomers with anionic groups selected from carboxyl- and/or sulfonic acid groups. 31: The method of claim 29, wherein the polyvinyl alcohol copolymer contains 0.1 to 30 mol % of the comonomers with anionic groups. 32: The method of claim 29, wherein the polyvinyl alcohol copolymer is used with amounts from 0.1 to 20% by weight, based on the weight of the microcapsules. 33: The process as claimed in claim 16, wherein the water-insoluble material comprises a pesticide blended with an oily solvent. 34: The method of claim 29, wherein the isocyanate (A) is selected from hexamethylene diisocyanate or derivatives thereof, or dicyclohexylmethane diisocyanates. 35: The method of claim 29, wherein a mixture of isocyanate (A) and an anionically modified isocyanate (B) is used, wherein the anionically modified diisocyanates (B) are selected from the group which contain at least one sulfonic acid group in the molecule.
| 1,600 |
933 | 11,585,607 | 1,633 |
Methods of producing a protein in cell culture comprising an anti-senescence compound, such as the antioxidant carnosine, are provided. According to teachings of the present invention, cells grown in a cell culture medium comprising an anti-senescence compound exhibit increased viability and productivity. Furthermore, cell cultures grown in the presence of an anti-senescence compound exhibit decreased levels of high molecular weight aggregates in the cell culture medium.
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1. A method of producing a protein in cell culture comprising steps of:
culturing mammalian cells that contain a gene encoding a protein of interest, which gene is expressed under conditions of cell culture, in a cell culture medium comprising an anti-senescence compound; and maintaining the culture under conditions and for a time sufficient to permit expression of the protein; wherein the cell culture exhibits an improved cell culture characteristic that differs from a corresponding cell culture characteristic that would be observed under otherwise identical conditions in an otherwise identical medium that lacks the anti-senescence compound; wherein the improved culture characteristic is selected from the group consisting of: increased titer, increased cell specific productivity, increased cell viability, increased integrated viable cell density, decreased accumulation of high molecular weight aggregates, decreased accumulation of acidic species, and combinations thereof. 2. The method of claim 1, wherein the anti-senescence compound is selected from the group consisting of carnosine, acetyl-carnosine, homo-carnosine, anserine, and ∃-alanine and combinations thereof. 3. The method of claim 1, wherein the anti-senescence compound comprises carnosine. 4. The method of claim 1, wherein the anti-senescence compound is present in the cell culture medium at a concentration of between about 5 mM and about 100 mM. 5. The method of claim 1, wherein the cell culture is further provided with supplementary components. 6. The method of claim 5, wherein the supplementary components are provided in a feed medium. 7. The method of claim 5, wherein the supplementary components are selected from the group consisting of hormones and/or other growth factors, particular ions (such as sodium, chloride, calcium, magnesium, and phosphate), buffers, vitamins, nucleosides or nucleotides, trace elements (inorganic compounds usually present at very low final concentrations), amino acids, lipids, glucose or other energy source, and combinations thereof. 8. The method of claim 5, wherein the supplementary components include an anti-senescence compound. 9. A method for producing a protein comprising steps of:
culturing mammalian cells that contain a gene encoding a protein of interest in a cell culture medium, which gene is expressed under conditions of cell culture, at a first temperature or temperature range conducive for cell growth during a growth phase; shifting the temperature or temperature range of the cell culture medium to a second temperature or temperature range conducive for protein production; culturing the host cells in the cell culture medium at the second temperature or temperature range through a transition phase and into a production phase; wherein an anti-senescence compound is added to the cell culture and such that the cell culture exhibits an improved cell culture characteristic that differs from a corresponding cell culture characteristic that would be observed under otherwise identical conditions in an otherwise identical medium that lacks the anti-senescence compound; wherein the improved cell culture characteristic is selected from the group consisting of: increased titer, increased cell specific productivity, increased cell viability, increased integrated viable cell density, decreased accumulation of high molecular weight aggregates, decreased accumulation of acidic species, and combinations thereof. 10. The method of claim 9, wherein the anti-senescence compound is added to the cell culture medium at the beginning of the cell culture process. 11. The method of claim 9, wherein the anti-senescence compound is added to the cell culture medium during the growth phase. 12. The method of claim 9, wherein the anti-senescence compound is added to the cell culture medium during the transition phase. 13. The method of claim 9, wherein the anti-senescence compound is added to the cell culture medium during the production phase. 14. The method of claim 9, wherein the anti-senescence compound is selected from the group consisting of carnosine, acetyl-carnosine, homo-carnosine, anserine, and ∃-alanine and combinations thereof. 15. The method of claim 9, wherein the anti-senescence compound comprises carnosine. 16. The method of claim 9, wherein the anti-senescence compound is present in the cell culture medium at a concentration of between about 5 mM and about 100 mM. 17. The method of claim 9, wherein the cell culture is further provided with supplementary components. 18. The method of claim 17, wherein the supplementary components are provided in a feed medium. 19. The method of claim 17, wherein the supplementary components are selected from the group consisting of hormones and/or other growth factors, particular ions (such as sodium, chloride, calcium, magnesium, and phosphate), buffers, vitamins, nucleosides or nucleotides, trace elements (inorganic compounds usually present at very low final concentrations), amino acids, lipids, glucose or other energy source, and combinations thereof. 20. The method of claim 17, wherein the supplementary components include an anti-senescence compound. 21. The method of claim 1 or 9, wherein the produced protein is heterologous to the mammalian cells. 22. The method of claim 1 or 9, wherein the mammalian cells are CHO cells. 23. A protein produced according to the method of claim 1 or 9. 24. The protein of claim 23, wherein the protein is an antibody. 25. The protein of claim 24, wherein the antibody is an anti-GDF-8 antibody selected from the group consisting of: Myo29, Myo28, Myo22, and combinations thereof. 26. A method for preparing a protein according to claim 1 or 9, further comprising the step of isolating the protein from the cell culture medium. 27. A method according to claim 26, wherein the protein is further purified or processed for formulation. 28. A method according to claim 27, wherein the protein is formulated into a pharmaceutical composition.
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Methods of producing a protein in cell culture comprising an anti-senescence compound, such as the antioxidant carnosine, are provided. According to teachings of the present invention, cells grown in a cell culture medium comprising an anti-senescence compound exhibit increased viability and productivity. Furthermore, cell cultures grown in the presence of an anti-senescence compound exhibit decreased levels of high molecular weight aggregates in the cell culture medium.1. A method of producing a protein in cell culture comprising steps of:
culturing mammalian cells that contain a gene encoding a protein of interest, which gene is expressed under conditions of cell culture, in a cell culture medium comprising an anti-senescence compound; and maintaining the culture under conditions and for a time sufficient to permit expression of the protein; wherein the cell culture exhibits an improved cell culture characteristic that differs from a corresponding cell culture characteristic that would be observed under otherwise identical conditions in an otherwise identical medium that lacks the anti-senescence compound; wherein the improved culture characteristic is selected from the group consisting of: increased titer, increased cell specific productivity, increased cell viability, increased integrated viable cell density, decreased accumulation of high molecular weight aggregates, decreased accumulation of acidic species, and combinations thereof. 2. The method of claim 1, wherein the anti-senescence compound is selected from the group consisting of carnosine, acetyl-carnosine, homo-carnosine, anserine, and ∃-alanine and combinations thereof. 3. The method of claim 1, wherein the anti-senescence compound comprises carnosine. 4. The method of claim 1, wherein the anti-senescence compound is present in the cell culture medium at a concentration of between about 5 mM and about 100 mM. 5. The method of claim 1, wherein the cell culture is further provided with supplementary components. 6. The method of claim 5, wherein the supplementary components are provided in a feed medium. 7. The method of claim 5, wherein the supplementary components are selected from the group consisting of hormones and/or other growth factors, particular ions (such as sodium, chloride, calcium, magnesium, and phosphate), buffers, vitamins, nucleosides or nucleotides, trace elements (inorganic compounds usually present at very low final concentrations), amino acids, lipids, glucose or other energy source, and combinations thereof. 8. The method of claim 5, wherein the supplementary components include an anti-senescence compound. 9. A method for producing a protein comprising steps of:
culturing mammalian cells that contain a gene encoding a protein of interest in a cell culture medium, which gene is expressed under conditions of cell culture, at a first temperature or temperature range conducive for cell growth during a growth phase; shifting the temperature or temperature range of the cell culture medium to a second temperature or temperature range conducive for protein production; culturing the host cells in the cell culture medium at the second temperature or temperature range through a transition phase and into a production phase; wherein an anti-senescence compound is added to the cell culture and such that the cell culture exhibits an improved cell culture characteristic that differs from a corresponding cell culture characteristic that would be observed under otherwise identical conditions in an otherwise identical medium that lacks the anti-senescence compound; wherein the improved cell culture characteristic is selected from the group consisting of: increased titer, increased cell specific productivity, increased cell viability, increased integrated viable cell density, decreased accumulation of high molecular weight aggregates, decreased accumulation of acidic species, and combinations thereof. 10. The method of claim 9, wherein the anti-senescence compound is added to the cell culture medium at the beginning of the cell culture process. 11. The method of claim 9, wherein the anti-senescence compound is added to the cell culture medium during the growth phase. 12. The method of claim 9, wherein the anti-senescence compound is added to the cell culture medium during the transition phase. 13. The method of claim 9, wherein the anti-senescence compound is added to the cell culture medium during the production phase. 14. The method of claim 9, wherein the anti-senescence compound is selected from the group consisting of carnosine, acetyl-carnosine, homo-carnosine, anserine, and ∃-alanine and combinations thereof. 15. The method of claim 9, wherein the anti-senescence compound comprises carnosine. 16. The method of claim 9, wherein the anti-senescence compound is present in the cell culture medium at a concentration of between about 5 mM and about 100 mM. 17. The method of claim 9, wherein the cell culture is further provided with supplementary components. 18. The method of claim 17, wherein the supplementary components are provided in a feed medium. 19. The method of claim 17, wherein the supplementary components are selected from the group consisting of hormones and/or other growth factors, particular ions (such as sodium, chloride, calcium, magnesium, and phosphate), buffers, vitamins, nucleosides or nucleotides, trace elements (inorganic compounds usually present at very low final concentrations), amino acids, lipids, glucose or other energy source, and combinations thereof. 20. The method of claim 17, wherein the supplementary components include an anti-senescence compound. 21. The method of claim 1 or 9, wherein the produced protein is heterologous to the mammalian cells. 22. The method of claim 1 or 9, wherein the mammalian cells are CHO cells. 23. A protein produced according to the method of claim 1 or 9. 24. The protein of claim 23, wherein the protein is an antibody. 25. The protein of claim 24, wherein the antibody is an anti-GDF-8 antibody selected from the group consisting of: Myo29, Myo28, Myo22, and combinations thereof. 26. A method for preparing a protein according to claim 1 or 9, further comprising the step of isolating the protein from the cell culture medium. 27. A method according to claim 26, wherein the protein is further purified or processed for formulation. 28. A method according to claim 27, wherein the protein is formulated into a pharmaceutical composition.
| 1,600 |
934 | 14,443,118 | 1,631 |
The present invention aims to provide a data analysis apparatus capable of clustering appropriately even when there is an exceptional datum resulted from an experimental error and the like. In the data analysis apparatus according to the invention, a cluster range parameter for stretching a cluster boundary is determined in advance according to the range of an experimental error which an experimental error datum describes. In the process of clustering, an exceptional datum which does not belong to any cluster is determined to belong to a cluster when an area at a distance determined by the cluster range parameter from the exceptional datum is contained in the cluster, and the exceptional datum is determined to form an independent cluster when even the area at the distance is not contained in any cluster (see FIG. 7 ).
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1. A data analysis apparatus for clustering and analyzing sample data, having:
a sample data input unit receiving sample data, an experimental error data input unit receiving an experimental error datum which describes information about an experimental error of the sample data, a computing unit clustering the sample data in a clustering space, and an output unit outputting a result of the clustering: characterized in that the computing unit obtains in advance a cluster range parameter for stretching a cluster boundary during the clustering, according to the range of the experimental error which the experimental error datum describes, clusters the sample data according to a temporarily set total cluster number, and determines that an exceptional datum among the sample data which does not belong to any cluster belongs to a cluster when an area at a distance determined by the cluster range parameter from the exceptional datum in the clustering space is contained in the cluster, and determines that the exceptional datum forms an independent cluster when the area is not contained in any cluster. 2. The data analysis apparatus described in claim 1, characterized in that the computing unit
determines an optimal total cluster number by repeating a process of calculating first log-likelihood which indicates the likelihood that the sample data belong to respective clusters obtained by the clustering and second log-likelihood which indicates the likelihood that the sample data do not belong to the respective clusters obtained by the clustering until likelihood of the clustering result calculated using the first log-likelihood and the second log-likelihood reaches a preset threshold, and decides a final clustering result of the sample data according to the obtained optimal total cluster number. 3. The data analysis apparatus described in claim 2, characterized in that the computing unit
calculates the first log-likelihood and the second log-likelihood on the supposition that the sample data belong to temporarily set clusters in the process of clustering the sample data according to the temporarily set total cluster number, estimates the probability that a sample datum which is supposed to belong to the temporarily set cluster belongs to the temporarily set cluster to be lower, as the distance from the center of the temporarily set cluster is larger in the clustering space, and estimates the probability that a sample datum which is not supposed to belong to the temporarily set cluster does not belong to the temporarily set cluster to be higher, as the distance from the center of the temporarily set cluster is larger in the clustering space. 4. The data analysis apparatus described in claim 1, characterized in that the computing unit determines whether the sample data are the exceptional data according to whether the number of the sample data belonging to a cluster is a preset number or larger or not. 5. The data analysis apparatus described in claim 4, characterized in that the computing unit determines the preset number at random. 6. The data analysis apparatus described in claim 4, characterized in that the computing unit determines the preset number at random based on a preset probability distribution. 7. The data analysis apparatus described in claim 2, characterized in that the computing unit
sweeps the cluster range parameter to obtain total cluster numbers obtained by the clustering using respective values of the cluster range parameter, and uses a total cluster number at which the likelihood of the clustering result calculated based on the first log-likelihood and the second log-likelihood takes an extremum as the optimal total cluster number. 8. The data analysis apparatus described in claim 1, characterized in that
the computing unit calculates a reliability index of the clustering result using information obtained in the process of clustering, and the output unit outputs the reliability index with the clustering result. 9. The data analysis apparatus described in claim 8, characterized in that the computing unit calculates the value of the likelihood of the clustering result calculated based on the first log-likelihood and the second log-likelihood as the reliability index of the clustering result. 10. The data analysis apparatus described in claim 1, characterized in that
the sample data input unit and the experimental error data input unit receive data regarding an analysis result of cells as the sample data and the experimental error datum, respectively, and the computing unit groups the cells by the clustering. 11. A data analysis method for clustering and analyzing sample data, containing:
a sample data input step receiving sample data, an experimental error data input step receiving an experimental error datum which describes information about an experimental error of the sample data, a computing step clustering the sample data in a clustering space, and an output step outputting a result of the clustering: characterized in that, in the computing step a cluster range parameter for stretching a cluster boundary during the clustering is obtained in advance according to the range of the experimental error which the experimental error datum describes, the sample data are clustered according to a temporarily set total cluster number, and an exceptional datum among the sample data which does not belong to any cluster is determined to belong to a cluster when an area at a distance determined by the cluster range parameter from the exceptional datum in the clustering space is contained in the cluster, and the exceptional datum is determined to form an independent cluster when the area is not contained in any cluster.
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The present invention aims to provide a data analysis apparatus capable of clustering appropriately even when there is an exceptional datum resulted from an experimental error and the like. In the data analysis apparatus according to the invention, a cluster range parameter for stretching a cluster boundary is determined in advance according to the range of an experimental error which an experimental error datum describes. In the process of clustering, an exceptional datum which does not belong to any cluster is determined to belong to a cluster when an area at a distance determined by the cluster range parameter from the exceptional datum is contained in the cluster, and the exceptional datum is determined to form an independent cluster when even the area at the distance is not contained in any cluster (see FIG. 7 ).1. A data analysis apparatus for clustering and analyzing sample data, having:
a sample data input unit receiving sample data, an experimental error data input unit receiving an experimental error datum which describes information about an experimental error of the sample data, a computing unit clustering the sample data in a clustering space, and an output unit outputting a result of the clustering: characterized in that the computing unit obtains in advance a cluster range parameter for stretching a cluster boundary during the clustering, according to the range of the experimental error which the experimental error datum describes, clusters the sample data according to a temporarily set total cluster number, and determines that an exceptional datum among the sample data which does not belong to any cluster belongs to a cluster when an area at a distance determined by the cluster range parameter from the exceptional datum in the clustering space is contained in the cluster, and determines that the exceptional datum forms an independent cluster when the area is not contained in any cluster. 2. The data analysis apparatus described in claim 1, characterized in that the computing unit
determines an optimal total cluster number by repeating a process of calculating first log-likelihood which indicates the likelihood that the sample data belong to respective clusters obtained by the clustering and second log-likelihood which indicates the likelihood that the sample data do not belong to the respective clusters obtained by the clustering until likelihood of the clustering result calculated using the first log-likelihood and the second log-likelihood reaches a preset threshold, and decides a final clustering result of the sample data according to the obtained optimal total cluster number. 3. The data analysis apparatus described in claim 2, characterized in that the computing unit
calculates the first log-likelihood and the second log-likelihood on the supposition that the sample data belong to temporarily set clusters in the process of clustering the sample data according to the temporarily set total cluster number, estimates the probability that a sample datum which is supposed to belong to the temporarily set cluster belongs to the temporarily set cluster to be lower, as the distance from the center of the temporarily set cluster is larger in the clustering space, and estimates the probability that a sample datum which is not supposed to belong to the temporarily set cluster does not belong to the temporarily set cluster to be higher, as the distance from the center of the temporarily set cluster is larger in the clustering space. 4. The data analysis apparatus described in claim 1, characterized in that the computing unit determines whether the sample data are the exceptional data according to whether the number of the sample data belonging to a cluster is a preset number or larger or not. 5. The data analysis apparatus described in claim 4, characterized in that the computing unit determines the preset number at random. 6. The data analysis apparatus described in claim 4, characterized in that the computing unit determines the preset number at random based on a preset probability distribution. 7. The data analysis apparatus described in claim 2, characterized in that the computing unit
sweeps the cluster range parameter to obtain total cluster numbers obtained by the clustering using respective values of the cluster range parameter, and uses a total cluster number at which the likelihood of the clustering result calculated based on the first log-likelihood and the second log-likelihood takes an extremum as the optimal total cluster number. 8. The data analysis apparatus described in claim 1, characterized in that
the computing unit calculates a reliability index of the clustering result using information obtained in the process of clustering, and the output unit outputs the reliability index with the clustering result. 9. The data analysis apparatus described in claim 8, characterized in that the computing unit calculates the value of the likelihood of the clustering result calculated based on the first log-likelihood and the second log-likelihood as the reliability index of the clustering result. 10. The data analysis apparatus described in claim 1, characterized in that
the sample data input unit and the experimental error data input unit receive data regarding an analysis result of cells as the sample data and the experimental error datum, respectively, and the computing unit groups the cells by the clustering. 11. A data analysis method for clustering and analyzing sample data, containing:
a sample data input step receiving sample data, an experimental error data input step receiving an experimental error datum which describes information about an experimental error of the sample data, a computing step clustering the sample data in a clustering space, and an output step outputting a result of the clustering: characterized in that, in the computing step a cluster range parameter for stretching a cluster boundary during the clustering is obtained in advance according to the range of the experimental error which the experimental error datum describes, the sample data are clustered according to a temporarily set total cluster number, and an exceptional datum among the sample data which does not belong to any cluster is determined to belong to a cluster when an area at a distance determined by the cluster range parameter from the exceptional datum in the clustering space is contained in the cluster, and the exceptional datum is determined to form an independent cluster when the area is not contained in any cluster.
| 1,600 |
935 | 15,834,953 | 1,654 |
The present disclosure relates to pharmaceutical compositions for mammalian consumption containing essential fatty acids, protein, vitamins and choline, or combinations thereof, so constituted to optimize absorption and/or transport and/or efficiency of the co-ingredients of the composition. The pharmaceutical compositions are useful as supplements to provide nutrients to nutritionally deficient patients. The composition can contain essential fatty acids, such as EPA, DHA and/or ALA, cobalamin binding protein, such as Intrinsic Factor, vitamin B12 or a synthetic form thereof, choline, such as choline bitartrate, or combinations thereof.
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1. A composition comprising:
about 10 to about 1500 mg of an essential fatty acid selected from the group consisting of EPA, DHA and ALA; and about 10 to about 33,000 μg of a cobalamin binding protein. 2. The composition of claim 1, wherein the essential fatty acid is DHA. 3. The composition of claim 2, wherein the source of DHA is animal, fish, plant, algae or microorganism produced. 4. The composition of claim 2, wherein the source of DHA is a phosphatidylcholine containing DHA, a lysophosphatidylcholine containing DHA, or combination thereof. 5. The composition of claim 1, wherein the cobalamin binding protein is Intrinsic Factor. 6. The composition of claim 1, wherein the cobalamin binding protein is recombinant human Intrinsic Factor. 7. The composition of claim 1, wherein the molar ratio of essential fatty acid to cobalamin binding protein is about 1:0.025 to about 1:0.00000005. 8. The composition of claim 1, further comprising about 0.25 to about 9,000 μg of vitamin B12 or a synthetic form of vitamin B12. 9. The composition of claim 8, wherein the vitamin B12 or synthetic form of vitamin B12 is selected from the group consisting of cyanocobalamin, methylcobalamin, hydroxocobalamin and adenosylcobalamin. 10. The composition of claim 8, wherein the molar ratio of the cobalamin binding protein to the vitamin B12 or a synthetic form of vitamin B12 is about 1:25,000 to about 1:0.00025. 11. The composition of claim 8, further comprising about 10 to about 3500 mg of choline, a biologically compatible salt thereof, or a phospholipid bound form and intermediates or derivatives thereof. 12. The composition of claim 11, wherein the molar ratio of choline to the essential fatty acid is about 1:0.0005 to about 1:50. 13. The composition of claim 11, wherein the molar ratio of the vitamin B12 or a synthetic form of vitamin B12 to choline is about 1:14 to about 1:200,000,000. 14. The composition of claim 11, wherein the choline is in the form of a salt. 15. The composition of claim 11, wherein the choline is in the form of choline chloride, choline bitartrate, choline hydroxide, choline citrate and choline carbonate or combinations thereof. 16. The composition of claim 11,
wherein the molar ratio of essential fatty acid to cobalamin binding protein is about 1:0.025 to about 1:0.00000005, wherein the molar ratio of the cobalamin binding protein to the vitamin B12 or a synthetic form of vitamin B12 is about 1:25,000 to about 1:0.00025, wherein the molar ratio of the vitamin B12 or a synthetic form of vitamin B12 to choline is about 1:14 to about 1:200,000,000, and wherein the molar ratio of choline to the essential fatty acid is about 1:0.0005 to about 1:50. 17. A method of providing supplemental nutrition to a mammal comprising administering to the mammal the composition of claim 1. 18. The method of claim 17, wherein the nutrition reduces the occurrence of a neural tube defect, low birth weight, premature birth, an allergic disease, a neurodevelopmental defect, a neurodegenerative defect, a neuropsychiatric defect, pervasive development disorder, autism, ADD, ADHD, schizophrenia, bipolar depression, Alzheimer's disease, Parkinson's disease, Huntington's disease, Non-Alcoholic Fatty Liver Disease, Non-Alcoholic Steatohepatitis (NASH), Metabolic Syndrome, cardiovascular disease or combinations thereof. 19. The method of claim 17, wherein the nutrition improves cognitive ability, a neurodevelopmental condition, neurodegenerative condition, a neuropsychiatric condition, brain development and ocular health.
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The present disclosure relates to pharmaceutical compositions for mammalian consumption containing essential fatty acids, protein, vitamins and choline, or combinations thereof, so constituted to optimize absorption and/or transport and/or efficiency of the co-ingredients of the composition. The pharmaceutical compositions are useful as supplements to provide nutrients to nutritionally deficient patients. The composition can contain essential fatty acids, such as EPA, DHA and/or ALA, cobalamin binding protein, such as Intrinsic Factor, vitamin B12 or a synthetic form thereof, choline, such as choline bitartrate, or combinations thereof.1. A composition comprising:
about 10 to about 1500 mg of an essential fatty acid selected from the group consisting of EPA, DHA and ALA; and about 10 to about 33,000 μg of a cobalamin binding protein. 2. The composition of claim 1, wherein the essential fatty acid is DHA. 3. The composition of claim 2, wherein the source of DHA is animal, fish, plant, algae or microorganism produced. 4. The composition of claim 2, wherein the source of DHA is a phosphatidylcholine containing DHA, a lysophosphatidylcholine containing DHA, or combination thereof. 5. The composition of claim 1, wherein the cobalamin binding protein is Intrinsic Factor. 6. The composition of claim 1, wherein the cobalamin binding protein is recombinant human Intrinsic Factor. 7. The composition of claim 1, wherein the molar ratio of essential fatty acid to cobalamin binding protein is about 1:0.025 to about 1:0.00000005. 8. The composition of claim 1, further comprising about 0.25 to about 9,000 μg of vitamin B12 or a synthetic form of vitamin B12. 9. The composition of claim 8, wherein the vitamin B12 or synthetic form of vitamin B12 is selected from the group consisting of cyanocobalamin, methylcobalamin, hydroxocobalamin and adenosylcobalamin. 10. The composition of claim 8, wherein the molar ratio of the cobalamin binding protein to the vitamin B12 or a synthetic form of vitamin B12 is about 1:25,000 to about 1:0.00025. 11. The composition of claim 8, further comprising about 10 to about 3500 mg of choline, a biologically compatible salt thereof, or a phospholipid bound form and intermediates or derivatives thereof. 12. The composition of claim 11, wherein the molar ratio of choline to the essential fatty acid is about 1:0.0005 to about 1:50. 13. The composition of claim 11, wherein the molar ratio of the vitamin B12 or a synthetic form of vitamin B12 to choline is about 1:14 to about 1:200,000,000. 14. The composition of claim 11, wherein the choline is in the form of a salt. 15. The composition of claim 11, wherein the choline is in the form of choline chloride, choline bitartrate, choline hydroxide, choline citrate and choline carbonate or combinations thereof. 16. The composition of claim 11,
wherein the molar ratio of essential fatty acid to cobalamin binding protein is about 1:0.025 to about 1:0.00000005, wherein the molar ratio of the cobalamin binding protein to the vitamin B12 or a synthetic form of vitamin B12 is about 1:25,000 to about 1:0.00025, wherein the molar ratio of the vitamin B12 or a synthetic form of vitamin B12 to choline is about 1:14 to about 1:200,000,000, and wherein the molar ratio of choline to the essential fatty acid is about 1:0.0005 to about 1:50. 17. A method of providing supplemental nutrition to a mammal comprising administering to the mammal the composition of claim 1. 18. The method of claim 17, wherein the nutrition reduces the occurrence of a neural tube defect, low birth weight, premature birth, an allergic disease, a neurodevelopmental defect, a neurodegenerative defect, a neuropsychiatric defect, pervasive development disorder, autism, ADD, ADHD, schizophrenia, bipolar depression, Alzheimer's disease, Parkinson's disease, Huntington's disease, Non-Alcoholic Fatty Liver Disease, Non-Alcoholic Steatohepatitis (NASH), Metabolic Syndrome, cardiovascular disease or combinations thereof. 19. The method of claim 17, wherein the nutrition improves cognitive ability, a neurodevelopmental condition, neurodegenerative condition, a neuropsychiatric condition, brain development and ocular health.
| 1,600 |
936 | 14,360,503 | 1,617 |
A delivery device for a active agent comprises nanoparticles based on a biopolymer such as starch. The delivery device may also be in the form of an aptamer-biopolymer-active agent conjugate wherein the aptamer targets the device for the treatment of specific disorders, such as cancer. The delivery device survives for a period of time in the body sufficient to allow for transport and uptake of the delivery device into targeted cells. The degree of crosslinking can provide a desired release profile of the active agent at, near or inside the target cells. The nanoparticles may be made by applying a high shear force in the presence of a cross linker. The particles may be predominantly in the range of 50-150 nm and form a colloidal dispersion of crosslinked hydrogel particles in water.
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1. A delivery system comprising,
nanoparticles comprising a mass of crosslinked biopolymers, wherein the degree of crosslinking of the biopolymers provides a release profile of an active agent from the nanoparticle within a predetermined range of release profiles. 2. A delivery system comprising, nanoparticles comprising a mass of complexed biopolymers having a swell ration between about 2 and 20, and an active agent. 3. The delivery system of claim 1 wherein the nanoparticles have number average in a size range of 50 to 150 nm when measured by any of SEM, NTA or DLS. 4. The delivery system of claim 1, further comprising targeting molecules that are attached to the nanoparticles. 5. The delivery system of claim 3, wherein the targeting molecules are selected from the group of antibodies, ligands and aptamers. 6. A delivery system of claim 3 having a ratio of glucose repeating units to the targeting molecule, wherein the ratio is within a range between about 100:1 to less than 1000:1. 7. The delivery system of claim 1, wherein the active agent comprises a drug. 8. The delivery system of claim 7, wherein the drug is a chemotherapeutic drug. 9. The delivery system of claim 8 wherein the drug is selected from the group consisting of doxorubicin ((7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione), cyclophosphamide ((RS)—N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide) and carmustine (N,N′-bis(2-chloroethyl)-N-nitroso-urea). 10. A process for making a delivery system comprising:
producing a plurality of batches of crosslinked biopolymer nanoparticles, wherein each batch has a different degree of crosslinking; loading an amount of an active agent into the crosslinked biopolymer nanoparticles of the plurality of batches; defining a release profile, wherein about half of the amount is released from the biopolymer nanoparticles in a first time period; and selecting the batch that matches the defined release profile. 11. A delivery system comprising,
particles comprising a mass of biopolymers, the biopolymers comprising glucose repeating units, and targeting molecules, wherein a ratio of the glucose repeating units to the attached targeting molecules is within a range between about 100:1 to less than 1000:1 or between about 100:1 to 750:1. 12. The process of claim 10, further comprising modifying the crosslinked biopolymer nanoparticles of the selected batch with a modifying agent so the crosslinked biopolymer nanoparticles have a negative zeta potential. 13. The process of claim 12, wherein the modifying agent is a water soluble oxidation catalyst. 14. The process of claim 12, wherein the modifying agent is an immobilized oxidation catalyst. 15. The process of claim 12, wherein the modifying agent is 2,2,6,6-tetramethylpiperidin-1-oxyl radicals. 16. The process of claim 10, including the step of attaching a targeting molecule to the crosslinked biopolymer nanoparticles in the selected batch. 17. The process of claim 16, wherein the targeting molecule is selected from an antibody, a ligand and an aptamer. 18. The process of claim 16, wherein the targeting molecule is an aptamer that is adapted to target cells requiring treatment by the active agent. 19. The process of claim 10, wherein the amount of active agent is greater than an effective amount to kill a cancer cell. 20. The process of claim 19, wherein the amount of active agent is at least twice as great as an effective amount to kill a cancer cell. 21. (canceled) 22. (canceled) 23. (canceled) 24. (canceled) 25. (canceled) 26. (canceled) 27. (canceled) 28. (canceled) 29. (canceled) 30. (canceled) 31. (canceled) 32. (canceled) 33. (canceled)
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A delivery device for a active agent comprises nanoparticles based on a biopolymer such as starch. The delivery device may also be in the form of an aptamer-biopolymer-active agent conjugate wherein the aptamer targets the device for the treatment of specific disorders, such as cancer. The delivery device survives for a period of time in the body sufficient to allow for transport and uptake of the delivery device into targeted cells. The degree of crosslinking can provide a desired release profile of the active agent at, near or inside the target cells. The nanoparticles may be made by applying a high shear force in the presence of a cross linker. The particles may be predominantly in the range of 50-150 nm and form a colloidal dispersion of crosslinked hydrogel particles in water.1. A delivery system comprising,
nanoparticles comprising a mass of crosslinked biopolymers, wherein the degree of crosslinking of the biopolymers provides a release profile of an active agent from the nanoparticle within a predetermined range of release profiles. 2. A delivery system comprising, nanoparticles comprising a mass of complexed biopolymers having a swell ration between about 2 and 20, and an active agent. 3. The delivery system of claim 1 wherein the nanoparticles have number average in a size range of 50 to 150 nm when measured by any of SEM, NTA or DLS. 4. The delivery system of claim 1, further comprising targeting molecules that are attached to the nanoparticles. 5. The delivery system of claim 3, wherein the targeting molecules are selected from the group of antibodies, ligands and aptamers. 6. A delivery system of claim 3 having a ratio of glucose repeating units to the targeting molecule, wherein the ratio is within a range between about 100:1 to less than 1000:1. 7. The delivery system of claim 1, wherein the active agent comprises a drug. 8. The delivery system of claim 7, wherein the drug is a chemotherapeutic drug. 9. The delivery system of claim 8 wherein the drug is selected from the group consisting of doxorubicin ((7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione), cyclophosphamide ((RS)—N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide) and carmustine (N,N′-bis(2-chloroethyl)-N-nitroso-urea). 10. A process for making a delivery system comprising:
producing a plurality of batches of crosslinked biopolymer nanoparticles, wherein each batch has a different degree of crosslinking; loading an amount of an active agent into the crosslinked biopolymer nanoparticles of the plurality of batches; defining a release profile, wherein about half of the amount is released from the biopolymer nanoparticles in a first time period; and selecting the batch that matches the defined release profile. 11. A delivery system comprising,
particles comprising a mass of biopolymers, the biopolymers comprising glucose repeating units, and targeting molecules, wherein a ratio of the glucose repeating units to the attached targeting molecules is within a range between about 100:1 to less than 1000:1 or between about 100:1 to 750:1. 12. The process of claim 10, further comprising modifying the crosslinked biopolymer nanoparticles of the selected batch with a modifying agent so the crosslinked biopolymer nanoparticles have a negative zeta potential. 13. The process of claim 12, wherein the modifying agent is a water soluble oxidation catalyst. 14. The process of claim 12, wherein the modifying agent is an immobilized oxidation catalyst. 15. The process of claim 12, wherein the modifying agent is 2,2,6,6-tetramethylpiperidin-1-oxyl radicals. 16. The process of claim 10, including the step of attaching a targeting molecule to the crosslinked biopolymer nanoparticles in the selected batch. 17. The process of claim 16, wherein the targeting molecule is selected from an antibody, a ligand and an aptamer. 18. The process of claim 16, wherein the targeting molecule is an aptamer that is adapted to target cells requiring treatment by the active agent. 19. The process of claim 10, wherein the amount of active agent is greater than an effective amount to kill a cancer cell. 20. The process of claim 19, wherein the amount of active agent is at least twice as great as an effective amount to kill a cancer cell. 21. (canceled) 22. (canceled) 23. (canceled) 24. (canceled) 25. (canceled) 26. (canceled) 27. (canceled) 28. (canceled) 29. (canceled) 30. (canceled) 31. (canceled) 32. (canceled) 33. (canceled)
| 1,600 |
937 | 15,527,500 | 1,656 |
Disclosed is a method of producing high-concentration collagen for use as a medical material, including: washing tissue of a mammal; subjecting the washed tissue to crushing and immersion in ethyl alcohol; subjecting the tissue to enzymatic treatment with stirring in purified water containing phosphoric acid and pepsin; adding sodium chloride to the collagen subjected to enzymatic treatment, performing stirring, and aggregating collagen; dissolving the aggregated collagen in purified water to give a collagen solution, which is then filtered using a filter and concentrated by removing the pepsin, low-molecular-weight material, and sodium chloride from the collagen solution using a tangential flow filtration device; subjecting the concentrated collagen to sterile filtration, aggregating the collagen using a pH solution in a neutralization tank, and concentrating the collagen by removing a non-aggregated solution; and concentrating the concentrated collagen using a centrifuge and stirring the concentrated collagen using a mixer.
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1. A method of producing high-concentration collagen for use as a medical material, comprising:
washing tissue of a mammal; subjecting the washed tissue to crushing and immersion in ethyl alcohol; subjecting the tissue to enzymatic treatment with stirring in purified water containing phosphoric acid and pepsin; adding sodium chloride to the collagen subjected to enzymatic treatment, performing stirring, and aggregating collagen; dissolving the aggregated collagen in purified water to give a collagen solution, which is then filtered using a filter and concentrated by removing the pepsin, low-molecular-weight material and sodium chloride from the collagen solution using a tangential flow filtration device; subjecting the collagen concentrated using the tangential flow filtration device to sterile filtration, aggregating the collagen using a pH solution in a neutralization tank, and concentrating the collagen by removing a non-aggregated solution; and concentrating the concentrated collagen using a centrifuge and stirring the concentrated collagen using a mixer. 2. The method of claim 1, wherein the crushed tissue of the mammal is immersed in 70% ethyl alcohol for at least 72 hr and is then reacted with pepsin for at least 72 hr in a solution titrated to a pH of 1.5˜2.5 so that a virus is inactivated and collagen is extracted. 3. The method of claim 1, wherein the collagen subjected to enzymatic treatment is added with sodium chloride at a concentration of 0.5˜0.9 M and stirred to thus aggregate collagen, the non-aggregated solution is removed, and the aggregated collagen is dissolved in purified water and then filtered using a filter having a pore size of 2.0˜0.5 μm. 4. The method of claim 1, wherein the tangential flow filtration device comprises a 50˜150 kDa molecular-weight-cutoff filtration membrane, purified water is added in an amount corresponding to an amount of the solution that is removed so as to maintain flowability, materials smaller than a pore size of the filtration membrane are removed, and collagen is concentrated to 5 mg/mL or less so as to pass through a filter having a pore size of 0.22 μm. 5. The method of claim 1, wherein the collagen concentrated using the tangential flow filtration device is allowed to stand for 4 hr˜24 hr under a condition that the collagen is adjusted to a neutral pH (6.0˜8.0) and is maintained at a temperature of 25˜35° C., whereby the aggregated collagen is recovered and centrifuged using a centrifuge, thereby being concentrated. 6. The method of claim 1, wherein the collagen concentrated through neutralization is centrifuged at a gravitational acceleration of 4,000˜6,000 g, thereby being concentrated, and is stirred using a mixer, thus obtaining high-concentration collagen of 120 mg/mL.
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Disclosed is a method of producing high-concentration collagen for use as a medical material, including: washing tissue of a mammal; subjecting the washed tissue to crushing and immersion in ethyl alcohol; subjecting the tissue to enzymatic treatment with stirring in purified water containing phosphoric acid and pepsin; adding sodium chloride to the collagen subjected to enzymatic treatment, performing stirring, and aggregating collagen; dissolving the aggregated collagen in purified water to give a collagen solution, which is then filtered using a filter and concentrated by removing the pepsin, low-molecular-weight material, and sodium chloride from the collagen solution using a tangential flow filtration device; subjecting the concentrated collagen to sterile filtration, aggregating the collagen using a pH solution in a neutralization tank, and concentrating the collagen by removing a non-aggregated solution; and concentrating the concentrated collagen using a centrifuge and stirring the concentrated collagen using a mixer.1. A method of producing high-concentration collagen for use as a medical material, comprising:
washing tissue of a mammal; subjecting the washed tissue to crushing and immersion in ethyl alcohol; subjecting the tissue to enzymatic treatment with stirring in purified water containing phosphoric acid and pepsin; adding sodium chloride to the collagen subjected to enzymatic treatment, performing stirring, and aggregating collagen; dissolving the aggregated collagen in purified water to give a collagen solution, which is then filtered using a filter and concentrated by removing the pepsin, low-molecular-weight material and sodium chloride from the collagen solution using a tangential flow filtration device; subjecting the collagen concentrated using the tangential flow filtration device to sterile filtration, aggregating the collagen using a pH solution in a neutralization tank, and concentrating the collagen by removing a non-aggregated solution; and concentrating the concentrated collagen using a centrifuge and stirring the concentrated collagen using a mixer. 2. The method of claim 1, wherein the crushed tissue of the mammal is immersed in 70% ethyl alcohol for at least 72 hr and is then reacted with pepsin for at least 72 hr in a solution titrated to a pH of 1.5˜2.5 so that a virus is inactivated and collagen is extracted. 3. The method of claim 1, wherein the collagen subjected to enzymatic treatment is added with sodium chloride at a concentration of 0.5˜0.9 M and stirred to thus aggregate collagen, the non-aggregated solution is removed, and the aggregated collagen is dissolved in purified water and then filtered using a filter having a pore size of 2.0˜0.5 μm. 4. The method of claim 1, wherein the tangential flow filtration device comprises a 50˜150 kDa molecular-weight-cutoff filtration membrane, purified water is added in an amount corresponding to an amount of the solution that is removed so as to maintain flowability, materials smaller than a pore size of the filtration membrane are removed, and collagen is concentrated to 5 mg/mL or less so as to pass through a filter having a pore size of 0.22 μm. 5. The method of claim 1, wherein the collagen concentrated using the tangential flow filtration device is allowed to stand for 4 hr˜24 hr under a condition that the collagen is adjusted to a neutral pH (6.0˜8.0) and is maintained at a temperature of 25˜35° C., whereby the aggregated collagen is recovered and centrifuged using a centrifuge, thereby being concentrated. 6. The method of claim 1, wherein the collagen concentrated through neutralization is centrifuged at a gravitational acceleration of 4,000˜6,000 g, thereby being concentrated, and is stirred using a mixer, thus obtaining high-concentration collagen of 120 mg/mL.
| 1,600 |
938 | 16,278,019 | 1,656 |
The present invention provides a microorganism-derived soluble coenzyme-binding glucose dehydrogenase which catalyzes a reaction for oxidizing glucose in the presence of an electron acceptor, has an activity to maltose as low as 5% or less, and is inhibited by 1,10-phenanthroline. The invention also provides a method for producing the coenzyme-binding glucose dehydrogenase, and a method and a reagent for measuring employing the coenzyme-binding glucose dehydrogenase. According to the invention, the coenzyme-binding glucose dehydrogenase can be applied to an industrial field, and a use becomes possible also in a material production or analysis including a method for measuring or eliminating glucose in a sample using the coenzyme-binding glucose dehydrogenase as well as a method for producing an organic compound. It became also possible to provide a glucose sensor capable of accurately measuring a blood sugar level. Therefore, it became possible to provide an enzyme having a high utility, such as an ability of being used for modifying a material in the fields of pharmaceuticals, clinical studies and food products.
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1-22. (canceled) 23. A biosensor for measuring glucose, comprising:
an electrode system comprising an action electrode and a counter electrode; and an enzymatic reaction layer in contact with the action electrode and/or the counter electrode, the enzymatic reaction layer comprising an electron acceptor and a soluble flavin compound-binding glucose dehydrogenase obtained from Aspergillus wherein the flavin compound-binding glucose dehydrogenase is secreted from an Aspergillus fungal body and has enzymatic activity to glucose comprising catalyzing a reaction for oxidizing glucose in the presence of the electron acceptor, wherein enzymatic activity to maltose is 5% or less relative to the enzymatic activity to glucose, and wherein enzymatic activity to D-fructose is not more than the enzymatic activity to maltose, and wherein the biosensor can quantify glucose concentrations ranging from 4.5 mM to 30 mM. 24. The biosensor of claim 23, wherein the enzymatic activity to maltose is 3% or less relative to the enzymatic activity to glucose.
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The present invention provides a microorganism-derived soluble coenzyme-binding glucose dehydrogenase which catalyzes a reaction for oxidizing glucose in the presence of an electron acceptor, has an activity to maltose as low as 5% or less, and is inhibited by 1,10-phenanthroline. The invention also provides a method for producing the coenzyme-binding glucose dehydrogenase, and a method and a reagent for measuring employing the coenzyme-binding glucose dehydrogenase. According to the invention, the coenzyme-binding glucose dehydrogenase can be applied to an industrial field, and a use becomes possible also in a material production or analysis including a method for measuring or eliminating glucose in a sample using the coenzyme-binding glucose dehydrogenase as well as a method for producing an organic compound. It became also possible to provide a glucose sensor capable of accurately measuring a blood sugar level. Therefore, it became possible to provide an enzyme having a high utility, such as an ability of being used for modifying a material in the fields of pharmaceuticals, clinical studies and food products.1-22. (canceled) 23. A biosensor for measuring glucose, comprising:
an electrode system comprising an action electrode and a counter electrode; and an enzymatic reaction layer in contact with the action electrode and/or the counter electrode, the enzymatic reaction layer comprising an electron acceptor and a soluble flavin compound-binding glucose dehydrogenase obtained from Aspergillus wherein the flavin compound-binding glucose dehydrogenase is secreted from an Aspergillus fungal body and has enzymatic activity to glucose comprising catalyzing a reaction for oxidizing glucose in the presence of the electron acceptor, wherein enzymatic activity to maltose is 5% or less relative to the enzymatic activity to glucose, and wherein enzymatic activity to D-fructose is not more than the enzymatic activity to maltose, and wherein the biosensor can quantify glucose concentrations ranging from 4.5 mM to 30 mM. 24. The biosensor of claim 23, wherein the enzymatic activity to maltose is 3% or less relative to the enzymatic activity to glucose.
| 1,600 |
939 | 15,215,804 | 1,617 |
A chewable pharmaceutical product comprises a matrix comprising: a binder, a bulking agent, a lubricant, a humectant, an emulsifier, and optionally a flavoring, wherein the binder comprises one or more maltitol syrups, which are present in the pharmaceutical product in an amount in the range of 60-70% by weight; and colesevelam hydrochloride.
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1. A chewable pharmaceutical product comprising:
a matrix comprising: a binder, a bulking agent, a lubricant, a humectant, an emulsifier, and optionally one or more of a flavoring, a coloring, and an antioxidant, wherein the binder comprises one or more maltitol syrups that are present in the pharmaceutical product in an amount in the range of 60-70% by weight; and colesevelam hydrochloride. 2. The chewable pharmaceutical product of claim 1, wherein the colesevelam hydrochloride is present in a dosage of 3.75 grams±10%. 3. The chewable pharmaceutical product of claim 2 in the form of a bar having a unit weight of 30 g±10%. 4. The chewable pharmaceutical product of claim 1, wherein the colesevelam hydrochloride is present in a dosage of 625 milligrams±10%. 5. The chewable pharmaceutical product of claim 4 in the form of a chew having a unit weight of 5 g±10%. 6. The chewable pharmaceutical product of claim 1, wherein the maltitol syrup comprises one or more maltitol syrups, which in combination have an effective solids content in the range of 81.5-83.3%. 7. The chewable pharmaceutical product of claim 1, wherein the bulking agent is sugar-free, comprising one or more of: sorbitol, mannitol, xylitol, lactitol, maltitol, isomalt, erythritol, polydextrose, maltodextrin, gelatin, gum acacia, gum Arabic, carrageenan, locust bean gum, and guar gum. 8. The chewable pharmaceutical product of claim 1, wherein the lubricant comprises palm oil, cocoa butter, sunflower oil, or combinations thereof. 9. The chewable pharmaceutical product of claim 1, wherein the emulsifier comprises: lecithin, distilled monoglycerides, mono-diglycerides, distilled propylene glycol monoester, succinylated monoglycerides, glyceryl monostearate, diacetyl tartaric acid esters of mono-diglycerides, glycerol lacto palmitates, polyglycerol esters, stearol lactylates, sorbitan esters of polysorbates, or combinations thereof. 10. The chewable pharmaceutical product of claim 1, wherein the humectant comprises: glycerin, propylene glycol, or combinations thereof. 11. The chewable pharmaceutical product of claim 1, comprising the flavoring that comprises: chocolate flavor, vanilla flavor, strawberry flavor, caramel flavor, or combinations thereof. 12. The chewable pharmaceutical product of claim 1 comprising by weight of the pharmaceutical product:
(i) colesevelam hydrochloride in an amount of 3.75 grams±10%;
(j) maltitol syrup as the binder in an amount in the range of 63-66%;
(k) one or more of: maltodextrin and gum acacia as the bulking agent totaling an amount in the range of 5-15%;
(l) palm oil as the lubricant in an amount in the range of 1.5-6%;
(m) glycerin as the humectant in an amount in the range of 1-3%;
(n) lecithin as the emulsifier in an amount in the range of 1-2%;
(o) a flavoring in an amount in the range of 0.01-6%; and
(p) optionally one or more of a powdered sweetener, a coloring, and an antioxidant. 13. The chewable pharmaceutical product of claim 1 comprising by weight of the pharmaceutical product:
(j) colesevelam hydrochloride in an amount of 12.5%;
(k) maltitol solids in an amount in the range of 52-54%;
(l) one or more of: maltodextrin and gum acacia as the bulking agent totaling an amount in the range of 5-15%;
(m) palm oil as the lubricant in an amount in the range of 1.5-6%;
(n) glycerin as the humectant in an amount in the range of 1-3%;
(o) lecithin as the emulsifier in an amount in the range of 1-2%;
(p) a flavoring in an amount in the range of 0.01-6%;
(q) water in an amount in the range of 11.5-12.5% and
(r) optionally one or more of a powdered sweetener, a coloring, and an antioxidant;
wherein ingredients (a)-(i) total 100%. 14. A method of delivering colesevelam hydrochloride comprising: administering the chewable pharmaceutical product of claim 1 to a patient in need of glycemic control or lipid-lowering. 15. The method of claim 14, wherein the chewable pharmaceutical product is ingested once per day. 16. A method of making a chewable pharmaceutical product for delivery of colesevelam hydrochloride comprising:
(ix) heating an amount of one or more maltitol syrups to a temperature of in the range of 120-160° F.; (x) melting a lubricant; (xi) blending dry ingredients in a mixer, the dry ingredients comprising: at least colesevelam hydrochloride and a bulking agent, (xii) adding the maltitol syrups, the lubricant, a humectant, and an emulsifier to the dry ingredients in the mixer; (xiii) optionally adding one or more of a flavoring, coloring, and an antioxidant to the mixture; (xiv) mixing all of the ingredients until substantially uniform to form an active-ingredient-containing matrix; (xv) extruding the active-ingredient-containing matrix and then cutting to form the chewable pharmaceutical product,
wherein the amount of the one or more maltitol syrups in the chewable pharmaceutical product is in the range of 60-70% by;
(xvi) packaging the chewable pharmaceutical product. 17. The method of claim 16, wherein extruding occurs at a temperature of 40° C.±10° C. 18. The method of claim 16, wherein the pharmaceutical product comprises by weight of the pharmaceutical product:
(a) colesevelam hydrochloride in an amount of 3.75 grams±10%; (b) maltitol syrup as the binder in an amount in the range of 63-66%; (c) one or more of: maltodextrin and gum acacia as the bulking agent totaling an amount in the range of 5-15%; (d) palm oil as the lubricant in an amount in the range of 1.5-6%; (e) glycerin as the humectant in an amount in the range of 1-3%; (f) lecithin as the emulsifier in an amount in the range of 1-2%; (g) a flavoring in an amount in the range of 0.01-6%; and (h) optionally one or more of a powdered sweetener, a coloring, and an antioxidant; wherein ingredients (a)-(h) total 100%. 19. The method of claim 16, wherein the pharmaceutical product comprises by weight of the pharmaceutical product:
(a) colesevelam hydrochloride in an amount of 12.5%; (b) maltitol solids in an amount in the range of 52-54%; (c) one or more of: maltodextrin and gum acacia as the bulking agent totaling an amount in the range of 5-15%; (d) palm oil as the lubricant in an amount in the range of 1.5-6%; (e) glycerin as the humectant in an amount in the range of 1-3%; (f) lecithin as the emulsifier in an amount in the range of 1-2%; (g) a flavoring in an amount in the range of 0.01-6%; (h) water in an amount in the range of 11.5-12.5% and (i) optionally one or more of a powdered sweetener, a coloring, and an antioxidant; wherein ingredients (a)-(i) total 100%.
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A chewable pharmaceutical product comprises a matrix comprising: a binder, a bulking agent, a lubricant, a humectant, an emulsifier, and optionally a flavoring, wherein the binder comprises one or more maltitol syrups, which are present in the pharmaceutical product in an amount in the range of 60-70% by weight; and colesevelam hydrochloride.1. A chewable pharmaceutical product comprising:
a matrix comprising: a binder, a bulking agent, a lubricant, a humectant, an emulsifier, and optionally one or more of a flavoring, a coloring, and an antioxidant, wherein the binder comprises one or more maltitol syrups that are present in the pharmaceutical product in an amount in the range of 60-70% by weight; and colesevelam hydrochloride. 2. The chewable pharmaceutical product of claim 1, wherein the colesevelam hydrochloride is present in a dosage of 3.75 grams±10%. 3. The chewable pharmaceutical product of claim 2 in the form of a bar having a unit weight of 30 g±10%. 4. The chewable pharmaceutical product of claim 1, wherein the colesevelam hydrochloride is present in a dosage of 625 milligrams±10%. 5. The chewable pharmaceutical product of claim 4 in the form of a chew having a unit weight of 5 g±10%. 6. The chewable pharmaceutical product of claim 1, wherein the maltitol syrup comprises one or more maltitol syrups, which in combination have an effective solids content in the range of 81.5-83.3%. 7. The chewable pharmaceutical product of claim 1, wherein the bulking agent is sugar-free, comprising one or more of: sorbitol, mannitol, xylitol, lactitol, maltitol, isomalt, erythritol, polydextrose, maltodextrin, gelatin, gum acacia, gum Arabic, carrageenan, locust bean gum, and guar gum. 8. The chewable pharmaceutical product of claim 1, wherein the lubricant comprises palm oil, cocoa butter, sunflower oil, or combinations thereof. 9. The chewable pharmaceutical product of claim 1, wherein the emulsifier comprises: lecithin, distilled monoglycerides, mono-diglycerides, distilled propylene glycol monoester, succinylated monoglycerides, glyceryl monostearate, diacetyl tartaric acid esters of mono-diglycerides, glycerol lacto palmitates, polyglycerol esters, stearol lactylates, sorbitan esters of polysorbates, or combinations thereof. 10. The chewable pharmaceutical product of claim 1, wherein the humectant comprises: glycerin, propylene glycol, or combinations thereof. 11. The chewable pharmaceutical product of claim 1, comprising the flavoring that comprises: chocolate flavor, vanilla flavor, strawberry flavor, caramel flavor, or combinations thereof. 12. The chewable pharmaceutical product of claim 1 comprising by weight of the pharmaceutical product:
(i) colesevelam hydrochloride in an amount of 3.75 grams±10%;
(j) maltitol syrup as the binder in an amount in the range of 63-66%;
(k) one or more of: maltodextrin and gum acacia as the bulking agent totaling an amount in the range of 5-15%;
(l) palm oil as the lubricant in an amount in the range of 1.5-6%;
(m) glycerin as the humectant in an amount in the range of 1-3%;
(n) lecithin as the emulsifier in an amount in the range of 1-2%;
(o) a flavoring in an amount in the range of 0.01-6%; and
(p) optionally one or more of a powdered sweetener, a coloring, and an antioxidant. 13. The chewable pharmaceutical product of claim 1 comprising by weight of the pharmaceutical product:
(j) colesevelam hydrochloride in an amount of 12.5%;
(k) maltitol solids in an amount in the range of 52-54%;
(l) one or more of: maltodextrin and gum acacia as the bulking agent totaling an amount in the range of 5-15%;
(m) palm oil as the lubricant in an amount in the range of 1.5-6%;
(n) glycerin as the humectant in an amount in the range of 1-3%;
(o) lecithin as the emulsifier in an amount in the range of 1-2%;
(p) a flavoring in an amount in the range of 0.01-6%;
(q) water in an amount in the range of 11.5-12.5% and
(r) optionally one or more of a powdered sweetener, a coloring, and an antioxidant;
wherein ingredients (a)-(i) total 100%. 14. A method of delivering colesevelam hydrochloride comprising: administering the chewable pharmaceutical product of claim 1 to a patient in need of glycemic control or lipid-lowering. 15. The method of claim 14, wherein the chewable pharmaceutical product is ingested once per day. 16. A method of making a chewable pharmaceutical product for delivery of colesevelam hydrochloride comprising:
(ix) heating an amount of one or more maltitol syrups to a temperature of in the range of 120-160° F.; (x) melting a lubricant; (xi) blending dry ingredients in a mixer, the dry ingredients comprising: at least colesevelam hydrochloride and a bulking agent, (xii) adding the maltitol syrups, the lubricant, a humectant, and an emulsifier to the dry ingredients in the mixer; (xiii) optionally adding one or more of a flavoring, coloring, and an antioxidant to the mixture; (xiv) mixing all of the ingredients until substantially uniform to form an active-ingredient-containing matrix; (xv) extruding the active-ingredient-containing matrix and then cutting to form the chewable pharmaceutical product,
wherein the amount of the one or more maltitol syrups in the chewable pharmaceutical product is in the range of 60-70% by;
(xvi) packaging the chewable pharmaceutical product. 17. The method of claim 16, wherein extruding occurs at a temperature of 40° C.±10° C. 18. The method of claim 16, wherein the pharmaceutical product comprises by weight of the pharmaceutical product:
(a) colesevelam hydrochloride in an amount of 3.75 grams±10%; (b) maltitol syrup as the binder in an amount in the range of 63-66%; (c) one or more of: maltodextrin and gum acacia as the bulking agent totaling an amount in the range of 5-15%; (d) palm oil as the lubricant in an amount in the range of 1.5-6%; (e) glycerin as the humectant in an amount in the range of 1-3%; (f) lecithin as the emulsifier in an amount in the range of 1-2%; (g) a flavoring in an amount in the range of 0.01-6%; and (h) optionally one or more of a powdered sweetener, a coloring, and an antioxidant; wherein ingredients (a)-(h) total 100%. 19. The method of claim 16, wherein the pharmaceutical product comprises by weight of the pharmaceutical product:
(a) colesevelam hydrochloride in an amount of 12.5%; (b) maltitol solids in an amount in the range of 52-54%; (c) one or more of: maltodextrin and gum acacia as the bulking agent totaling an amount in the range of 5-15%; (d) palm oil as the lubricant in an amount in the range of 1.5-6%; (e) glycerin as the humectant in an amount in the range of 1-3%; (f) lecithin as the emulsifier in an amount in the range of 1-2%; (g) a flavoring in an amount in the range of 0.01-6%; (h) water in an amount in the range of 11.5-12.5% and (i) optionally one or more of a powdered sweetener, a coloring, and an antioxidant; wherein ingredients (a)-(i) total 100%.
| 1,600 |
940 | 15,095,702 | 1,627 |
A medication comprising tetrahydropyridoethers for use in the treatment of AMD.
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1. A method of removing lipofuscin accumulated in retinal pigment endothelium cells in a treatment of a subject, comprising: administering to the subject in need of such treatment a medication comprising a compound according to the following formula I as active ingredient in suitable amount,
in which
R1 is methyl or hydroxymethyl, one of the substituents R2a and R2b is hydrogen and the other is hydroxy, methoxy, ethoxy, isopropoxy, methoxyethoxy or ethoxypropoxy, one of the substituents R3a and R3b is hydrogen and the other is hydroxy, methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, where R2a or R2b on the one hand and R3a or R3b on the other hand are not simultaneously hydroxy, and its salts. 2. The method of claim 1, wherein R1 is methyl, one of the substituents R2a and R2b is hydrogen and the other is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, one of the substituents R3a and R3b is hydrogen and the other is hydroxy, and its salts. 3. The method according to claim 1, wherein R1 is methyl, one of the substituents R2a and R2b is hydrogen and the other is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, one of the substituents R3a and R3b is hydrogen and the other is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, and its salts. 4. The method according to claim 1, wherein R3b is hydrogen. 5. The method according to claim 1, wherein R2a and R3b are hydrogen. 6. The method according to claim 1, wherein R2a is hydrogen and R2b is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, and its salts. 7. A method of removing lipofuscin accumulated in retinal pigment endothelium cells in a treatment of a subject, comprising: administering to the subject in need of such treatment a medication comprising a compound according to the following formula I* as active ingredient in a suitable amount,
in which R1 is methyl or hydroxymethyl, one of the substituents R2a and R2b is hydrogen and the other is hydroxy, methoxy, ethoxy, isopropoxy, methoxyethoxy or ethoxypropoxy, one of the substituents R3a and R3b is hydrogen and the other is hydroxy, methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, where R2a or R2b on the one hand and R3a or R3b on the other hand are not simultaneously hydroxy, and its salts. 8. The method according to claim 7, wherein R1 is methyl, one of the substituents R2a and R2b is hydrogen and the other is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, one of the substituents R3a and R3b is hydrogen and the other is hydroxy, and its salts. 9. The method according to claim 7, wherein R1 is methyl, one of the substituents R2a and R2b is hydrogen and the other is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, one of the substituents R3a and R3b is hydrogen and the other is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, and its salts. 10. The method according to claim 7, wherein R3b is hydrogen. 11. The method according to claim 7, wherein R2a and R3b are hydrogen. 12. A method of removing lipofuscin accumulated in retinal pigment endothelium cells in a treatment of a subject, comprising: administering to the subject in need of such treatment a medication comprising a compound according to the following formula I** as active ingredient in a suitable amount,
wherein one of the substituents Ra and Rb is hydrogen and the other is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, and its salts. 13. The method according to claim 12, wherein Ra is hydrogen and Rb is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, and its salts. 14. The method according to claim 12, wherein the compounds according to formula I** is selected from (7R, 8R, 9R)-2,3-Dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7, 8, 9, 10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine and its salts or (7R, 8R, 9R)-2,3-Dimethyl-7-ethoxy-8-hydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7] naphthyridine and its pharmacologically acceptable salts. 15. The method of claim 1, wherein the medication is administered to the subject under treatment by way of administration selected from the group consisting of topical, intravitral, subretinal or periocular administration. 16. The method of claim 7, wherein the medication is administered to the subject under treatment by way of administration selected from the group consisting of topical, intravitral, subretinal or periocular administration. 17. The method of claim 12, wherein the medication is administered to the subject under treatment by way of administration selected from the group consisting of topical, intravitral, subretinal or periocular administration.
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A medication comprising tetrahydropyridoethers for use in the treatment of AMD.1. A method of removing lipofuscin accumulated in retinal pigment endothelium cells in a treatment of a subject, comprising: administering to the subject in need of such treatment a medication comprising a compound according to the following formula I as active ingredient in suitable amount,
in which
R1 is methyl or hydroxymethyl, one of the substituents R2a and R2b is hydrogen and the other is hydroxy, methoxy, ethoxy, isopropoxy, methoxyethoxy or ethoxypropoxy, one of the substituents R3a and R3b is hydrogen and the other is hydroxy, methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, where R2a or R2b on the one hand and R3a or R3b on the other hand are not simultaneously hydroxy, and its salts. 2. The method of claim 1, wherein R1 is methyl, one of the substituents R2a and R2b is hydrogen and the other is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, one of the substituents R3a and R3b is hydrogen and the other is hydroxy, and its salts. 3. The method according to claim 1, wherein R1 is methyl, one of the substituents R2a and R2b is hydrogen and the other is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, one of the substituents R3a and R3b is hydrogen and the other is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, and its salts. 4. The method according to claim 1, wherein R3b is hydrogen. 5. The method according to claim 1, wherein R2a and R3b are hydrogen. 6. The method according to claim 1, wherein R2a is hydrogen and R2b is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, and its salts. 7. A method of removing lipofuscin accumulated in retinal pigment endothelium cells in a treatment of a subject, comprising: administering to the subject in need of such treatment a medication comprising a compound according to the following formula I* as active ingredient in a suitable amount,
in which R1 is methyl or hydroxymethyl, one of the substituents R2a and R2b is hydrogen and the other is hydroxy, methoxy, ethoxy, isopropoxy, methoxyethoxy or ethoxypropoxy, one of the substituents R3a and R3b is hydrogen and the other is hydroxy, methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, where R2a or R2b on the one hand and R3a or R3b on the other hand are not simultaneously hydroxy, and its salts. 8. The method according to claim 7, wherein R1 is methyl, one of the substituents R2a and R2b is hydrogen and the other is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, one of the substituents R3a and R3b is hydrogen and the other is hydroxy, and its salts. 9. The method according to claim 7, wherein R1 is methyl, one of the substituents R2a and R2b is hydrogen and the other is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, one of the substituents R3a and R3b is hydrogen and the other is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, and its salts. 10. The method according to claim 7, wherein R3b is hydrogen. 11. The method according to claim 7, wherein R2a and R3b are hydrogen. 12. A method of removing lipofuscin accumulated in retinal pigment endothelium cells in a treatment of a subject, comprising: administering to the subject in need of such treatment a medication comprising a compound according to the following formula I** as active ingredient in a suitable amount,
wherein one of the substituents Ra and Rb is hydrogen and the other is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, and its salts. 13. The method according to claim 12, wherein Ra is hydrogen and Rb is methoxy, ethoxy, isopropoxy, methoxyethoxy or methoxypropoxy, and its salts. 14. The method according to claim 12, wherein the compounds according to formula I** is selected from (7R, 8R, 9R)-2,3-Dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7, 8, 9, 10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine and its salts or (7R, 8R, 9R)-2,3-Dimethyl-7-ethoxy-8-hydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7] naphthyridine and its pharmacologically acceptable salts. 15. The method of claim 1, wherein the medication is administered to the subject under treatment by way of administration selected from the group consisting of topical, intravitral, subretinal or periocular administration. 16. The method of claim 7, wherein the medication is administered to the subject under treatment by way of administration selected from the group consisting of topical, intravitral, subretinal or periocular administration. 17. The method of claim 12, wherein the medication is administered to the subject under treatment by way of administration selected from the group consisting of topical, intravitral, subretinal or periocular administration.
| 1,600 |
941 | 15,087,066 | 1,617 |
The disclosure relates to compositions and methods for improving the appearance of the skin. Compositions comprise comprising (A) (a) at least one vinyl-terminated polysiloxane and at least one hydride-functionalized polysiloxane, and (b) at least one filler; and (B) (a) at least one vinyl-terminated polysiloxane; (b) at least one filler, and (c) at least one metal catalyst. Methods comprise applying the compositions to the skin to tighten the skin or hide skin imperfections by forming a film on the skin. Kits comprising the composition are also disclosed.
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1. A skin tightening composition comprising:
(A) (a) at least one vinyl-terminated polysiloxane and at least one hydride-functionalized polysiloxane;
(b) at least one filler; and
(B) (a) at least one vinyl-terminated polysiloxane;
(c) at least one filler; and
(d) at least one at least one metal catalyst,
wherein the viscosity of the at least one vinyl-terminated polysiloxane ranges from about 50,000 to about 100,000 cSt at 25° C., and wherein the specific surface area of the at least one filler is greater than about 300 m2/g. 2. The skin tightening composition of claim 1, wherein the molar ratio of the at least one vinyl-terminated polysiloxane and at least one hydride-functionalized polysiloxane ranges from about 1:1 to about 1:20. 3. The skin tightening composition of claim 1, wherein the total amount of reactive components according to various embodiments of the disclosure ranges from about 10% to about 65% by weight, relative to the total weight of the composition. 4. The skin tightening composition of claim 1, wherein the at least one vinyl-terminated polysiloxane is chosen from compounds of formula I:
wherein:
each of R1a′, R3a′, R4a′, R5a′, R6a′, R8a′, R9a′, and R10a′ are independently chosen from hydrogen, C1-C20 alkyl, C2-C20 alkenyl, C5-C10 aryl, hydroxyl, or C1-C20 alkoxyl; and
p and q are integers independently ranging from about 10 to about 6000. 5. The skin tightening composition of claim 4, wherein the at least one vinyl-terminated polysiloxane is chosen from vinyl terminated polydimethylsiloxane; vinyl terminated diphenylsiloxane-dimethylsiloxane copolymers; vinyl terminated polyphenylmethylsiloxane, vinylphenylmethyl terminated vinylphenylsiloxane-phenylmethylsiloxane copolymer; vinyl terminated trifluoropropylmethylsiloxane-dimethylsiloxane copolymer; vinyl terminated diethylsiloxane-dimethylsiloxane copolymer: vinylmethylsiloxane-dimethylsiloxane copolymer, trimethylsiloxy terminated; vinylmethylsiloxane-dimethylsiloxane copolymers, silanol terminated; vinylmethylsiloxane-dimethylsiloxane copolymers, vinyl terminated; vinyl gums; vinylmethylsiloxane homopolymers; vinyl T-structure polymers; monovinyl terminated polydimethylsiloxanes; vinylmethylsiloxane terpolymers; vinylmethoxysilane homopolymers, and combinations thereof. 6. The skin tightening film of claim 1, wherein the at least one vinyl-terminated polysiloxane is present in the composition in an amount ranging from about 10% to about 60%, by weight, relative to the total weight of the composition. 7. The skin tightening film of claim 1, wherein the at least one vinyl-terminated polysiloxane is present in each of parts (A) and (B), independently, of the composition in an amount ranging from about 10% to about 30%, by weight, relative to the total weight of the part in which it is present. 8. The skin tightening composition of claim 1, wherein the at least one hydride-functionalized polysiloxane has a viscosity ranging up to about 100 cSt at 25° C. 9. The skin tightening composition of claim 8, wherein the at least one hydride-functionalized polysiloxane is chosen from compounds of formula (II):
wherein:
R1b, R2b, R3b, R4b, R5b, R6b, R7b, R8b, R9b and R10b are each independently chosen from hydrogen, C1-20 alkyl, C2-20 alkenyl, C5-10 aryl, hydroxyl or C1-20 alkoxy, and
m and n are each independently an integer ranging from about 10 to about 6000,
with the proviso that at least one of R1b, R2b, R3b, R4b, R5b, R6b, R7b, R8b, R9b and R10b is hydrogen. 10. The skin tightening composition of claim 9, wherein the at least one hydride-functionalized polysiloxane is chosen from hydride terminated polydimethylsiloxane; polyphenyl-(dimethylhydrosiloxy)siloxane, hydride terminated; methylhydrosiloxane-phenylmethylsiloxane copolymer, hydride terminated; methylhydrosiloxane-dimethylsiloxane copolymers, trimethylsiloxy terminated; polymethylhydrosiloxanes, trimethylsiloxy terminated; polyethylhydrosiloxane, triethylsiloxane, methylhydrosiloxane-phenyloctylmethylsiloxane copolymer; methylhydrosiloxane-phenyloctylmethylsiloxane terpolymer, and combinations thereof. 11. The skin tightening composition of claim 1, wherein the at least one hydride-functionalized polysiloxane is present in the composition in an amount ranging from about 0.01% to about 3% by weight, relative to the weight of the composition. 12. The skin tightening composition of claim 1, wherein the at least one filler is chosen from silica. 13. The skin tightening composition of claim 12, wherein the at least one filler is chosen from hydrophobic silica aerogel particles. 14. The skin tightening composition of claim 12, wherein the at least one filler is present in the composition in a total amount ranging from up to about 8% by weight, relative to the total weight of the composition. 15. The skin tightening composition of claim 1, wherein the at least one metal catalyst is chosen from platinum catalysts. 16. The skin tightening composition of claim 1, further comprising at least one additional components chosen from volatile solvents, emulsifiers, colorants, silicone elastomers, and humectants. 17. The skin tightening composition of claim 16, wherein the at least one solvent is chosen from volatile solvents. 18. The skin tightening composition of claim 17, wherein the at least one solvent is chosen from volatile hydrocarbon-based oils and volatile silicone oils. 19. A skin tightening film formed from the composition of claim 1, wherein the film has a Young Modulus greater than about 500 kPa. 20. The skin tightening film of claim 19, wherein the Young Modulus of the film is greater than about 1000 kPa. 21. The skin tightening film of claim 20, wherein the Young Modulus of the film is greater than about 5000 kPa. 22. A method for improving the appearance of the skin, said method comprising forming a film on the skin by applying to the skin a composition comprising:
(A) (a) at least one vinyl-terminated polysiloxane and at least one hydride-functionalized polysiloxane;
(b) at least one filler; and
(B) (a) at least one vinyl-terminated polysiloxane;
(b) at least one filler; and
(c) at least one at least one metal catalyst,
wherein the viscosity of the at least one vinyl-terminated polysiloxane ranges from about 50,000 to about 100,000 cSt at 25° C., and wherein the specific surface area of the at least one filler is greater than about 300 m2/g. 23. The method of claim 22, wherein the Young Modulus of the film ranges from about 500 kPa to about 2000 kPa. 24. The method of claim 22, wherein the Young Modulus of the film ranges from about 500 kPa to about 50,000 kPa. 25. A kit comprising a composition comprising:
(A) (a) at least one vinyl-terminated polysiloxane and at least one hydride-functionalized polysiloxane;
(b) at least one filler; and
(B) (a) at least one vinyl-terminated polysiloxane;
(b) at least one filler; and
(c) at least one at least one metal catalyst,
wherein the viscosity of the at least one vinyl-terminated polysiloxane ranges from about 50,000 to about 100,000 cSt at 25° C., and wherein the specific surface area of the at least one filler is greater than about 300 m2/g; wherein parts (A) and (B) are packaged in separate compartments.
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The disclosure relates to compositions and methods for improving the appearance of the skin. Compositions comprise comprising (A) (a) at least one vinyl-terminated polysiloxane and at least one hydride-functionalized polysiloxane, and (b) at least one filler; and (B) (a) at least one vinyl-terminated polysiloxane; (b) at least one filler, and (c) at least one metal catalyst. Methods comprise applying the compositions to the skin to tighten the skin or hide skin imperfections by forming a film on the skin. Kits comprising the composition are also disclosed.1. A skin tightening composition comprising:
(A) (a) at least one vinyl-terminated polysiloxane and at least one hydride-functionalized polysiloxane;
(b) at least one filler; and
(B) (a) at least one vinyl-terminated polysiloxane;
(c) at least one filler; and
(d) at least one at least one metal catalyst,
wherein the viscosity of the at least one vinyl-terminated polysiloxane ranges from about 50,000 to about 100,000 cSt at 25° C., and wherein the specific surface area of the at least one filler is greater than about 300 m2/g. 2. The skin tightening composition of claim 1, wherein the molar ratio of the at least one vinyl-terminated polysiloxane and at least one hydride-functionalized polysiloxane ranges from about 1:1 to about 1:20. 3. The skin tightening composition of claim 1, wherein the total amount of reactive components according to various embodiments of the disclosure ranges from about 10% to about 65% by weight, relative to the total weight of the composition. 4. The skin tightening composition of claim 1, wherein the at least one vinyl-terminated polysiloxane is chosen from compounds of formula I:
wherein:
each of R1a′, R3a′, R4a′, R5a′, R6a′, R8a′, R9a′, and R10a′ are independently chosen from hydrogen, C1-C20 alkyl, C2-C20 alkenyl, C5-C10 aryl, hydroxyl, or C1-C20 alkoxyl; and
p and q are integers independently ranging from about 10 to about 6000. 5. The skin tightening composition of claim 4, wherein the at least one vinyl-terminated polysiloxane is chosen from vinyl terminated polydimethylsiloxane; vinyl terminated diphenylsiloxane-dimethylsiloxane copolymers; vinyl terminated polyphenylmethylsiloxane, vinylphenylmethyl terminated vinylphenylsiloxane-phenylmethylsiloxane copolymer; vinyl terminated trifluoropropylmethylsiloxane-dimethylsiloxane copolymer; vinyl terminated diethylsiloxane-dimethylsiloxane copolymer: vinylmethylsiloxane-dimethylsiloxane copolymer, trimethylsiloxy terminated; vinylmethylsiloxane-dimethylsiloxane copolymers, silanol terminated; vinylmethylsiloxane-dimethylsiloxane copolymers, vinyl terminated; vinyl gums; vinylmethylsiloxane homopolymers; vinyl T-structure polymers; monovinyl terminated polydimethylsiloxanes; vinylmethylsiloxane terpolymers; vinylmethoxysilane homopolymers, and combinations thereof. 6. The skin tightening film of claim 1, wherein the at least one vinyl-terminated polysiloxane is present in the composition in an amount ranging from about 10% to about 60%, by weight, relative to the total weight of the composition. 7. The skin tightening film of claim 1, wherein the at least one vinyl-terminated polysiloxane is present in each of parts (A) and (B), independently, of the composition in an amount ranging from about 10% to about 30%, by weight, relative to the total weight of the part in which it is present. 8. The skin tightening composition of claim 1, wherein the at least one hydride-functionalized polysiloxane has a viscosity ranging up to about 100 cSt at 25° C. 9. The skin tightening composition of claim 8, wherein the at least one hydride-functionalized polysiloxane is chosen from compounds of formula (II):
wherein:
R1b, R2b, R3b, R4b, R5b, R6b, R7b, R8b, R9b and R10b are each independently chosen from hydrogen, C1-20 alkyl, C2-20 alkenyl, C5-10 aryl, hydroxyl or C1-20 alkoxy, and
m and n are each independently an integer ranging from about 10 to about 6000,
with the proviso that at least one of R1b, R2b, R3b, R4b, R5b, R6b, R7b, R8b, R9b and R10b is hydrogen. 10. The skin tightening composition of claim 9, wherein the at least one hydride-functionalized polysiloxane is chosen from hydride terminated polydimethylsiloxane; polyphenyl-(dimethylhydrosiloxy)siloxane, hydride terminated; methylhydrosiloxane-phenylmethylsiloxane copolymer, hydride terminated; methylhydrosiloxane-dimethylsiloxane copolymers, trimethylsiloxy terminated; polymethylhydrosiloxanes, trimethylsiloxy terminated; polyethylhydrosiloxane, triethylsiloxane, methylhydrosiloxane-phenyloctylmethylsiloxane copolymer; methylhydrosiloxane-phenyloctylmethylsiloxane terpolymer, and combinations thereof. 11. The skin tightening composition of claim 1, wherein the at least one hydride-functionalized polysiloxane is present in the composition in an amount ranging from about 0.01% to about 3% by weight, relative to the weight of the composition. 12. The skin tightening composition of claim 1, wherein the at least one filler is chosen from silica. 13. The skin tightening composition of claim 12, wherein the at least one filler is chosen from hydrophobic silica aerogel particles. 14. The skin tightening composition of claim 12, wherein the at least one filler is present in the composition in a total amount ranging from up to about 8% by weight, relative to the total weight of the composition. 15. The skin tightening composition of claim 1, wherein the at least one metal catalyst is chosen from platinum catalysts. 16. The skin tightening composition of claim 1, further comprising at least one additional components chosen from volatile solvents, emulsifiers, colorants, silicone elastomers, and humectants. 17. The skin tightening composition of claim 16, wherein the at least one solvent is chosen from volatile solvents. 18. The skin tightening composition of claim 17, wherein the at least one solvent is chosen from volatile hydrocarbon-based oils and volatile silicone oils. 19. A skin tightening film formed from the composition of claim 1, wherein the film has a Young Modulus greater than about 500 kPa. 20. The skin tightening film of claim 19, wherein the Young Modulus of the film is greater than about 1000 kPa. 21. The skin tightening film of claim 20, wherein the Young Modulus of the film is greater than about 5000 kPa. 22. A method for improving the appearance of the skin, said method comprising forming a film on the skin by applying to the skin a composition comprising:
(A) (a) at least one vinyl-terminated polysiloxane and at least one hydride-functionalized polysiloxane;
(b) at least one filler; and
(B) (a) at least one vinyl-terminated polysiloxane;
(b) at least one filler; and
(c) at least one at least one metal catalyst,
wherein the viscosity of the at least one vinyl-terminated polysiloxane ranges from about 50,000 to about 100,000 cSt at 25° C., and wherein the specific surface area of the at least one filler is greater than about 300 m2/g. 23. The method of claim 22, wherein the Young Modulus of the film ranges from about 500 kPa to about 2000 kPa. 24. The method of claim 22, wherein the Young Modulus of the film ranges from about 500 kPa to about 50,000 kPa. 25. A kit comprising a composition comprising:
(A) (a) at least one vinyl-terminated polysiloxane and at least one hydride-functionalized polysiloxane;
(b) at least one filler; and
(B) (a) at least one vinyl-terminated polysiloxane;
(b) at least one filler; and
(c) at least one at least one metal catalyst,
wherein the viscosity of the at least one vinyl-terminated polysiloxane ranges from about 50,000 to about 100,000 cSt at 25° C., and wherein the specific surface area of the at least one filler is greater than about 300 m2/g; wherein parts (A) and (B) are packaged in separate compartments.
| 1,600 |
942 | 16,354,739 | 1,648 |
The invention relates to VLP derived from human polyoma virus loaded with a drug (cargo) as a drug delivery system for transporting said drug into the CNS, in particular of living humans.
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1. A method of treating a subject having a central nervous system (CNS) disease or a neurological, neuronal or neurodegenerative disorder, the method comprising:
intravenously administering a drug delivery system composed of VLP loaded with a drug into a subject, wherein, the VLP crosses the blood-brain barrier (BBB) of the subject together with the drug, the VLP are composed of VP1 comprising an amino acid sequence which is at least 80% identical to the amino acid sequence according to SEQ ID NO: 1 over its entire length, and the drug delivery system is provided without the use of additives. 2. The method as recited in claim 1, wherein the drug is detectable in the CNS within two days after administration. 3. The method as recited in claim 1, wherein the method does not require a loss of integrity or an increased permeability of the BBB. 4. The method as recited in claim 1, wherein the drug delivery system crosses a physiologically intact BBB. 5. The method as recited in claim 1, wherein the drug is transported into cells of the central nervous system (CNS). 6. The method as recited in claim 1, wherein the drug is transported to oligodendrocytes or into oligodendrocytes. 7. The method as recited in claim 1, wherein the drug is selected from the group consisting of
a cytotoxic agent, a detectable agent, a protein, a peptide and a nucleic acid. 8. The method as recited in claim 7, wherein the nucleic acid
encodes a desired protein, is an inhibitory nucleic acid, or is a nucleic acid having catalytic activity. 9. The method as recited in claim 8, wherein,
the detectable agent is a radionuclide, the nucleic acid which encodes the desired protein is selected from mRNA, cDNA, a plasmid or a vector, the inhibitory nucleic acid is siRNA or miRNA, or the nucleic acid having catalytic activity is a ribozyme. 10. The method as recited in claim 1, wherein,
the VLP comprise a hull, and at least 1% or at least 15% or at least 50% or at least 95% of a total amount of the drug is fully encapsulated in the hull of the VLP. 11. The method as recited in claim 1, wherein the subject is a human patient. 12. The method as recited in claim 1, wherein the VLP are non-aggregated.
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The invention relates to VLP derived from human polyoma virus loaded with a drug (cargo) as a drug delivery system for transporting said drug into the CNS, in particular of living humans.1. A method of treating a subject having a central nervous system (CNS) disease or a neurological, neuronal or neurodegenerative disorder, the method comprising:
intravenously administering a drug delivery system composed of VLP loaded with a drug into a subject, wherein, the VLP crosses the blood-brain barrier (BBB) of the subject together with the drug, the VLP are composed of VP1 comprising an amino acid sequence which is at least 80% identical to the amino acid sequence according to SEQ ID NO: 1 over its entire length, and the drug delivery system is provided without the use of additives. 2. The method as recited in claim 1, wherein the drug is detectable in the CNS within two days after administration. 3. The method as recited in claim 1, wherein the method does not require a loss of integrity or an increased permeability of the BBB. 4. The method as recited in claim 1, wherein the drug delivery system crosses a physiologically intact BBB. 5. The method as recited in claim 1, wherein the drug is transported into cells of the central nervous system (CNS). 6. The method as recited in claim 1, wherein the drug is transported to oligodendrocytes or into oligodendrocytes. 7. The method as recited in claim 1, wherein the drug is selected from the group consisting of
a cytotoxic agent, a detectable agent, a protein, a peptide and a nucleic acid. 8. The method as recited in claim 7, wherein the nucleic acid
encodes a desired protein, is an inhibitory nucleic acid, or is a nucleic acid having catalytic activity. 9. The method as recited in claim 8, wherein,
the detectable agent is a radionuclide, the nucleic acid which encodes the desired protein is selected from mRNA, cDNA, a plasmid or a vector, the inhibitory nucleic acid is siRNA or miRNA, or the nucleic acid having catalytic activity is a ribozyme. 10. The method as recited in claim 1, wherein,
the VLP comprise a hull, and at least 1% or at least 15% or at least 50% or at least 95% of a total amount of the drug is fully encapsulated in the hull of the VLP. 11. The method as recited in claim 1, wherein the subject is a human patient. 12. The method as recited in claim 1, wherein the VLP are non-aggregated.
| 1,600 |
943 | 14,633,067 | 1,618 |
The present invention relates to a method for preparing a 2-fluoropurine marked with the radioisotope 18 F comprising a fluorination step for a 2-nitropurine derivative. The present invention comprises a 2-fluoropurine derivative marked with the radioisotope 18 F which can be obtained by or during a method according to the invention and its various uses.
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1-22. (canceled) 23. A method for performing PET imaging studies in a subject comprising administering to the subject a fludarabine marked with the radioisotope 18F of the formula (B) or one of its salts
and detecting said marked fludarabine. 24. The method according to claim 23, wherein PET imaging studies are applied to the fields of neurobiology, cardiology, or oncology. 25. The method according to claim 24, wherein PET imaging studies are applied to the fields of chronic lymphoid leukemia and related illnesses. 26. The method according to claim 23, wherein PET imaging studies are
used for evaluating the treatment of the chronic lymphoid leukemia and related illnesses. 27. The method according to claim 23, wherein PET imaging studies are used for the in vivo mapping of malignant hematopoietic cells.
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The present invention relates to a method for preparing a 2-fluoropurine marked with the radioisotope 18 F comprising a fluorination step for a 2-nitropurine derivative. The present invention comprises a 2-fluoropurine derivative marked with the radioisotope 18 F which can be obtained by or during a method according to the invention and its various uses.1-22. (canceled) 23. A method for performing PET imaging studies in a subject comprising administering to the subject a fludarabine marked with the radioisotope 18F of the formula (B) or one of its salts
and detecting said marked fludarabine. 24. The method according to claim 23, wherein PET imaging studies are applied to the fields of neurobiology, cardiology, or oncology. 25. The method according to claim 24, wherein PET imaging studies are applied to the fields of chronic lymphoid leukemia and related illnesses. 26. The method according to claim 23, wherein PET imaging studies are
used for evaluating the treatment of the chronic lymphoid leukemia and related illnesses. 27. The method according to claim 23, wherein PET imaging studies are used for the in vivo mapping of malignant hematopoietic cells.
| 1,600 |
944 | 15,515,857 | 1,617 |
An encapsulated perfume composition in the form of a slurry comprising one or more core-shell capsules, dispersed in an aqueous dispersing medium, wherein the core contains a perfume and the shell contains a polyurea resin, and wherein the capsules are in the form of a stable suspension having a viscosity of up to 3000 centipoise, and more particularly about 150 to 3000 centipoise when measured on a rheometer, using rotating disks at a shear rate of 21 s −1 at a temperature of 25° C.
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1. An encapsulated perfume composition in the form of a slurry comprising one or more core-shell capsules, each having a core and a shell, dispersed in an aqueous dispersing medium, wherein the core contains a perfume and the shell contains a polyurea resin, and wherein the capsules are in the form of a stable suspension having a viscosity of up to 3000 centipoise, when measured on a rheometer; using rotating disks at a shear rate of 21 s−1 at a temperature of 25° C. 2. An encapsulated perfume composition according to claim 1 wherein the aqueous dispersing medium contains a hydroxyethyl cellulose dispersing aid. 3. An encapsulated perfume composition according to claim 2 wherein the hydroxyethyl cellulose is present in an amount of about 0.05% weight to about 1.0% weight based on the total weight of the slurry. 4. An encapsulated perfume composition according to claim 2 wherein the hydroxyethyl cellulose is a Natrosol™ hydroxyethyl cellulose. 5. An encapsulated perfume composition according to claim 1 wherein the polyurea capsules have a volume average diameter of about 20 to 250 microns. 6. An encapsulated perfume composition according to claim 1 wherein the weight of the capsule shells is 5% weight to 40% weight based on the total weight of the capsules. 7. An encapsulated perfume composition according to claim 1, wherein the encapsulated perfume comprises at least 60% by weight of perfume ingredients having a solubility in water of 15000 ppm or less. 8. An encapsulated perfume composition according to claim 1 wherein the capsules contain no encapsulated solvent. 9. An encapsulated perfume composition according to claim 1, wherein the encapsulated perfume comprises: an aldehyde-containing perfume ingredient, a non-aromatic cyclic perfume ingredient, and an alkyl salicylate and/or a 2,2,2-trisubstituted acetal, wherein said acetal has the general formula
R1R2R3C—CH(OR4)(OR5)
wherein R1 is a saturated or unsaturated alkyl or aromatic residue having at least 4 and up to 10 carbon atoms; R2 and R3 are independently selected from a saturated and an unsaturated alkyl residue having at least on carbon atom; and R4 and R5 are independently selected from a methyl group and an ethyl group. 10. An encapsulated perfume composition according to claim 9 wherein the aldehyde perfume ingredients are present in amounts of 0.01% to about 6% by weight of the total perfume ingredients. 11. A consumer product comprising an encapsulated perfume composition as defined in claim 1. 12. A consumer product according to claim 11, which is a leave-on personal care product. 13. A leave-on product according to claim 10 in the form of a deodorant product. 14. A leave on product according to claim 10 in the form of an anti-perspirant. 15. An encapsulated perfume according to claim 1, wherein the capsules are in the form of a stable suspension having a viscosity of 150 to 3000 centipoise, when measured on a rheometer using rotating disks at a shear rate of 21 s−1 at a temperature of 25° C.
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An encapsulated perfume composition in the form of a slurry comprising one or more core-shell capsules, dispersed in an aqueous dispersing medium, wherein the core contains a perfume and the shell contains a polyurea resin, and wherein the capsules are in the form of a stable suspension having a viscosity of up to 3000 centipoise, and more particularly about 150 to 3000 centipoise when measured on a rheometer, using rotating disks at a shear rate of 21 s −1 at a temperature of 25° C.1. An encapsulated perfume composition in the form of a slurry comprising one or more core-shell capsules, each having a core and a shell, dispersed in an aqueous dispersing medium, wherein the core contains a perfume and the shell contains a polyurea resin, and wherein the capsules are in the form of a stable suspension having a viscosity of up to 3000 centipoise, when measured on a rheometer; using rotating disks at a shear rate of 21 s−1 at a temperature of 25° C. 2. An encapsulated perfume composition according to claim 1 wherein the aqueous dispersing medium contains a hydroxyethyl cellulose dispersing aid. 3. An encapsulated perfume composition according to claim 2 wherein the hydroxyethyl cellulose is present in an amount of about 0.05% weight to about 1.0% weight based on the total weight of the slurry. 4. An encapsulated perfume composition according to claim 2 wherein the hydroxyethyl cellulose is a Natrosol™ hydroxyethyl cellulose. 5. An encapsulated perfume composition according to claim 1 wherein the polyurea capsules have a volume average diameter of about 20 to 250 microns. 6. An encapsulated perfume composition according to claim 1 wherein the weight of the capsule shells is 5% weight to 40% weight based on the total weight of the capsules. 7. An encapsulated perfume composition according to claim 1, wherein the encapsulated perfume comprises at least 60% by weight of perfume ingredients having a solubility in water of 15000 ppm or less. 8. An encapsulated perfume composition according to claim 1 wherein the capsules contain no encapsulated solvent. 9. An encapsulated perfume composition according to claim 1, wherein the encapsulated perfume comprises: an aldehyde-containing perfume ingredient, a non-aromatic cyclic perfume ingredient, and an alkyl salicylate and/or a 2,2,2-trisubstituted acetal, wherein said acetal has the general formula
R1R2R3C—CH(OR4)(OR5)
wherein R1 is a saturated or unsaturated alkyl or aromatic residue having at least 4 and up to 10 carbon atoms; R2 and R3 are independently selected from a saturated and an unsaturated alkyl residue having at least on carbon atom; and R4 and R5 are independently selected from a methyl group and an ethyl group. 10. An encapsulated perfume composition according to claim 9 wherein the aldehyde perfume ingredients are present in amounts of 0.01% to about 6% by weight of the total perfume ingredients. 11. A consumer product comprising an encapsulated perfume composition as defined in claim 1. 12. A consumer product according to claim 11, which is a leave-on personal care product. 13. A leave-on product according to claim 10 in the form of a deodorant product. 14. A leave on product according to claim 10 in the form of an anti-perspirant. 15. An encapsulated perfume according to claim 1, wherein the capsules are in the form of a stable suspension having a viscosity of 150 to 3000 centipoise, when measured on a rheometer using rotating disks at a shear rate of 21 s−1 at a temperature of 25° C.
| 1,600 |
945 | 14,865,257 | 1,615 |
The present invention relates to personal care compositions comprising malodor reduction compositions and methods of making and using such personal care compositions. Such personal care compositions comprising the malodor control technologies disclosed herein provide malodor control without leaving an undesirable scent and when perfume is used to scent such compositions, such scent is not unduly altered by the malodor control technology.
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1. A personal care composition comprising, based on total composition weight,
a) a sum total of from about 0.0001% to about 2%, preferably from about 0.0001% to about 0.75%, more preferably from about 0.001% to about 0.5%, most preferably from about 0.007% to about 0.25% of 1 or more malodor reduction materials, preferably 1 to about 75 malodor reduction materials, more preferably 1 to about 50 malodor reduction materials, more preferably 1 to about 35 malodor reduction materials, most preferably 1 to about 20 malodor reduction materials, each of said malodor reduction materials having a MORV of at least 0.5, preferably from 0.5 to 10, more preferably from 1 to 10, most preferably from 1 to 5, and preferably each of said malodor reduction materials having a Universal MORV, or said sum total of malodor reduction materials having a Blocker Index of less than 3, more preferable less than about 2.5 even more preferably less than about 2 and still more preferably less than about 1 and most preferably 0 and/or a Blocker Index average of 3 to about 0.001; and b) from about 0% to about 12%, preferably from about 0% to about 8%, more preferably from about 0.1% to about 4%, of one or more perfume raw materials having a MORV of less than 0.5, preferably less than 0, more preferably less than −2, most preferably less than −5; c) from about 0.1% to about 99%, preferably from about 1% to about 80%, more preferably from about 5% to about 70%, most preferably from about 10% to about 50% of a solvent, preferably said solvent is selected from, water, glycerin, and mixtures thereof; d) from about 0% to about 50%, preferably from about 0% to about 40%, more preferably from about 0.1% to about 30%, most preferably from about 0.1% to about 15% of a material selected from the group consisting of a structurant, a humectant, a surfactant, an antimicrobial, and mixtures thereof. 2. A personal care composition according to claim 1, wherein said sum total of malodor reduction materials has a Blocker Index of less than 3, more preferable less than about 2.5 even more preferably less than about 2 and still more preferably less than about 1 and most preferably 0 and/or a Blocker Index average of 3 to about 0.001. 3. A personal care composition according to any preceding claim, wherein each of said malodor reduction materials has a MORV of at least 0.5, preferably from 0.5 to 10, more preferably from 1 to 10, most preferably from 1 to 5, and preferably each of said malodor reduction materials having a Universal MORV. 4. A personal care composition according to any preceding claim wherein, said sum total of malodor reduction materials has a Fragrance Fidelity Index average of 3 to about 0.001 Fragrance Fidelity Index, preferably each malodor reduction material in said sum total of malodor reduction materials has a Fragrance Fidelity Index of less than 3, preferably less than 2, more preferably less than 1 and most preferably each malodor reduction material in said sum total of malodor reduction materials has a Fragrance Fidelity Index of 0. 5. A personal care composition according to any preceding claim, wherein said malodor reduction materials are selected from the group consisting of 2-ethylhexyl (Z)-(3-(4-methoxyphenyl)acrylate; 2,4-dimethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolane; 1,1-dimethoxynon-2-yne; 2-(p-tolyl)propan-2-ol; 3-methoxy-7,7-dimethyl-10-methylenebicyclo[4.3.1]decane; methoxycyclododecane; 1,1-dimethoxycyclododecane; (Z)-tridec-2-enenitrile; (2-hydroxy-4-methoxyphenyl)(phenyl)methanone; 2,4a,5,8a-tetramethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl formate; 4-methyl-1-oxaspiro[5.5]undecan-4-ol; 7-methyl-2H-benzo[b][1,4]dioxepin-3(4H)-one; 1,8-dioxacycloheptadecan-9-one; 4-(tert-pentyl)cyclohexan-1-one; 2-methoxy-1,1′-biphenyl; 3a,5,6,7,8,8b-hexahydro-2,2,6,6,7,8,8-heptamethyl-4H-indeno(4,5-d)-1,3-dioxole; 7-isopropyl-8,8-dimethyl-6,10-dioxaspiro[4.5]decane; octyl furan-2-carboxylate; octyl acetate; 2-heptyl-4-methyl-1,3-dioxolane; octanal; 1,1-dimethoxyoctane; 7-methyl-3-methyleneocta-1,6-diene; 2-methyl-6-methyleneoct-7-en-2-ol; 2-methyl-6-methyleneoct-7-en-2-yl acetate; tetradecanal; 4-methoxy-6-prop-2-enyl-1,3-benzodioxole; tetradecanenitrile; 2,2,6,8-tetramethyl-1,2,3,4,4a,5,8,8a-octahydronaphthalen-1-ol; (E)-2,6-dimethylocta-5,7-dien-2-ol; (E)-2,7-dimethylocta-1,5,7-trien-3-ol; 2-((1S,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethyl acetate; (4R,4aS,6R)-4,4a-dimethyl-6-(prop-1-en-2-yl)-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one; nonan-1-ol; nonanal; 12-methyl-14-tetradec-9-enolide; N-ethyl-2-isopropyl-5-methylcyclohexane-1-carboxamide; 1-(3-methylbenzofuran-2-yl)ethan-1-one; 2-methoxynaphthalene; (E)-3,7,11-trimethyldodeca-1,6,10-trien-3-ol; (Z)-3,7-dimethylocta-2,6-dien-1-ol; 1-ethyl-3-methoxytricyclo[2.2.1.02,6]heptane; methyl (E)-non-2-enoate; 10-isopropyl-2,7-dimethyl-1-oxaspiro[4.5]deca-3,6-diene; 2-(2-(4-methylcyclohex-3-en-1-yl)propyl)cyclopentan-1-one; 6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-carbaldehyde; (E)-4-(2,2,3,6-tetramethylcyclohexyl)but-3-en-2-one; (4-(4-methylpent-3-en-1-yl)cyclohex-3-en-1-yl)methyl acetate; 2-(tert-butyl)-4,5,6-trimethyl-1,3-phenylene dinitrite; 1,7-dioxacycloheptadecan-8-one; 1-(4-(tert-butyl)-2,6-dimethyl-3,5-dinitrophenyl)ethan-1-one; 1-(tert-butyl)-2-methoxy-4-methyl-3,5-dinitrobenzene; 3-methylcyclopentadecan-1-one; (E)-3-methylcyclopentadec-4-en-1-one; 3-methyl-4-phenylbutan-2-ol; 1-(4-isopropylcyclohexyl)ethan-1-ol; (E)-dec-5-enoic acid; methyl non-2-ynoate; 2-methyldecanal; 6,6-dimethoxy-2,5,5-trimethylhex-2-ene; 4-phenylbutan-2-ol; methyl stearate; 1,1-dimethoxy-2-methylundecane; undecan-2-one; 2-methylundecanal; methyl tetradecanoate; methyl (9Z,12Z)-octadeca-9,12-dienoate; 1-hydroxydecan-3-one; (Z)-1,2-dimethoxy-4-(prop-1-en-1-yl)benzene; methyl palmitate; 4-allyl-1,2-dimethoxybenzene; methyl 2-((1R,2R)-3-oxo-2-((Z)-pent-2-en-1-yl)cyclopentyl)acetate; methyl 2-(3-oxo-2-pentylcyclopentyl)acetate; 1-methyl-2-phenoxybenzene; methyl cinnamate; 1-allyl-4-methoxybenzene; 1-(naphthalen-2-yl)ethan-1-one; methyloct-2-ynoate; methyl 2,6,6-trimethylcyclohex-2-ene-1-carboxylate; 7-methoxy-3,7-dimethyloctanal; 7-isopropyl-10-methyl-1,5-dioxaspiro[5.5]undecan-3-ol; octahydro-1H-4,7-methanoindene-1-carbaldehyde; 3-(3-(tert-butyl)phenyl)-2-methylpropanal; (E)-4-(4,8-dimethylnona-3,7-dien-1-yl)pyridine; (E)-trideca-3,12-dienenitrile; 2,2-dimethyl-3-(m-tolyl)propan-1-ol; 2,4-dimethyl-4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; 8-isopropyl-6-methylbicyclo[2.2.2]oct-5-ene-2-carbaldehyde; 4-(4-hydroxy-4-methylpentyl)cyclohex-3-ene-1-carbaldehyde; (S)-1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene; (Z)-3-hexen-1-yl-2-cyclopenten-1-one; 3,7-dimethylocta-1,6-dien-3-yl octanoate; 3,7-dimethylocta-1,6-dien-3-yl isobutyrate; 3,7-dimethylocta-1,6-dien-3-yl benzoate; 3,7-dimethylocta-1,6-dien-3-yl 2-aminobenzoate; 2-(5-methyl-5-vinyltetrahydrofuran-2-yl)propan-2-ol; 6-methyl-2-(oxiran-2-yl)hept-5-en-2-ol; (2Z,6E)-3,7-dimethylnona-2,6-dienenitrile; 3-(4-methylcyclohex-3-en-1-yl)butanal; (2,5-dimethyl-1,3-dihydroinden-2-yl)methanol; 3-(4-(tert-butyl)phenyl)-2-methylpropanal; (E)-1-(1-methoxypropoxy)hex-3-ene; (E)-1-(1-ethoxyethoxy)hex-3-ene; (1S,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-ol; dodecan-1-ol; dodecyl acetate; dodecanoic acid; 5-hexyl-5-methyldihydrofuran-2(3H)-one; dodecanal; 3,6-dimethylhexahydrobenzofuran-2(3H)-one; 4-(1-ethoxyvinyl)-3,3,5,5-tetramethylcyclohexan-1-one; ((3S,3aR,6R,8aS)-7,7-dimethyl-8-methyleneoctahydro-1H-3a,6-methanoazulen-3-yl)methanol; 5-(sec-butyl)-2-(2,4-dimethylcyclohex-3-en-1-yl)-5-methyl-1,3-dioxane; (1-methyl-2-((1,2,2-trimethylbicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methanol; 2-propylheptanenitrile; (E)-6-(pent-3-en-1-yl)tetrahydro-2H-pyran-2-one; 2-hexylcyclopentan-1-one; 2-methyl-4-phenyl-1,3-dioxolane; 2,6,9,10-tetramethyl-1-oxaspiro(4.5)deca-3,6-diene; (1R,2S,5R)-5-methyl-2-(prop-1-en-2-yl)cyclohexan-1-ol; isopropyl palmitate; isopropyl tetradecanoate; isopropyl dodecanoate; 4,9-dimethoxy-7H-furo[3,2-g]chromen-7-one; (E)-cyclohexadec-8-en-1-one; (2S,5S)-2-isopropyl-5-methylcyclohexan-1-one; 2-hexylcyclopent-2-en-1-one; (2S,5S)-2-isopropyl-5-methylcyclohexan-1-one; 4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; (Z)-1-(benzyloxy)-2-methoxy-4-(prop-1-en-1-yl)benzene; 1-((2S,3S)-2,3,8,8-tetramethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-yl)ethan-1-one; 2,5,6-trimethylcyclohex-3-ene-1-carbaldehyde; 6-(sec-butyl)quinoline; 2-(cyclohexyloxy)-1,7,7-trimethylbicyclo[2.2.1]heptane; (1R,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl propionate; (1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate; 4-((2R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)cyclohexan-1-ol; (1R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 2-(4-isopropylcyclohexa-1,4-dien-1-yl)ethyl formate; isopentyl (E)-undec-6-enoate; isopentyl dodecanoate; (E)-oxacycloheptadec-10-en-2-one; (E)-non-2-enenitrile; (E)-8-(1H-indol-1-yl)-2,6-dimethyloct-7-en-2-ol; 8,8-di(1H-indol-1-yl)-2,6-dimethyloctan-2-ol; 4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; 3,7-dimethyloctane-1,7-diol; 2-cyclododecylpropan-1-ol; 3-methyl-5-phenylpentanenitrile; 3-phenylpropan-1-ol; (1,1-dimethoxypropan-2-yl)benzene; 5-ethyl-4-hydroxy-2-methylfuran-3(2H)-one; 2,3-dihydro-3,3-dimethyl-1H-indene-5-propanal; 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)propanal; hexyl octanoate; hexyl hexanoate; (Z)-2-benzylideneoctanal; hexyl benzoate; (Z)-hex-1-en-1-yl (Z)-2-methylbut-2-enoate; (E)-3,7-dimethylocta-2,6-dien-1-yl palmitate; oxacycloheptadecan-2-one; 2-butyl-4,4,6-trimethyl-1,3-dioxane; ethyl (1R,2R,3R,4R)-3-isopropylbicyclo[2.2.1]hept-5-ene-2-carboxylate; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl acetate; 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropyl propionate; 5-(diethoxymethyl)benzo[d][1,3]dioxole; 3-(benzo[d][1,3]dioxol-5-yl)-2-methylpropanal; (E)-oxacyclohexadec-13-en-2-one; 6-butyl-2,4-dimethyl-3,6-dihydro-2H-pyran; 2-((3S,5R,8S)-3,8-dimethyl-1,2,3,4,5,6,7,8-octahydroazulen-5-yl)propan-2-ol; 1-(2,6,6-trimethylcyclohex-2-en-1-yl)pentan-3-one; ethyl 2-ethyl-6,6-dimethylcyclohex-2-ene-1-carboxylate; (1Z,5Z)-1,5-dimethyl-8-(propan-2-ylidene)cyclodeca-1,5-diene; (1E,6E)-8-isopropyl-1-methyl-5-methylenecyclodeca-1,6-diene; (E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate; (E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate; (6E,10E)-3,7,11,15-tetramethylhexadeca-1,6,10,14-tetraen-3-ol; (E)-2-(3,7-dimethylocta-2,6-dien-1-yl)cyclopentan-1-one; 5-heptyldihydrofuran-2(3H)-one; 1-methyl-4-(propan-2-ylidene)cyclohexyl acetate; 1-methyl-4-(propan-2-ylidene)cyclohexan-1-ol; 5-pentyldihydrofuran-2(3H)-one; (1R,4aR,8aS)-1-isopropyl-7-methyl-4-methylene-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 5-[(Z)-hex-3-enyl]oxolan-2-one; (Z)-4-(2,2-dimethyl-6-methylenecyclohexyl)but-3-en-2-one; (4aS,9aR)-3,5,5,9-tetramethyl-2,4a,5,6,7,9a-hexahydro-1H-benzo[7]annulene; (1R,3aR,4R,7R)-1,4-dimethyl-7-(prop-1-en-2-yl)-1,2,3,3a,4,5,6,7-octahydroazulene; 2-((2R,4aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)propan-2-ol; 5-octyldihydrofuran-2(3H)-one; (Z)-1-(2,2-dimethyl-6-methylenecyclohexyl)but-2-en-1-one; 5-hexyldihydrofuran-2(3H)-one; (1R,4aS,8aS)-1-isopropyl-7-methyl-4-methylene-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 1-(3,3-dimethylcyclohexyl)pent-4-en-1-one; 4,6,6,7,8,8-hexamethyl-1,3,4,6,7,8-hexahydrocyclopenta[g]isochromene; furan-2-ylmethyl octanoate; furan-2-ylmethyl hexanoate; furan-2-ylmethyl heptanoate; 2-methyldecanenitrile; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; ethyl (3aR,4S,7R,7aR)-octahydro-3aH-4,7-methanoindene-3a-carboxylate; diethyl cyclohexane-1,4-dicarboxylate; (6-isopropyl-9-methyl-1,4-dioxaspiro[4.5]decan-2-yl)methanol; 2-isobutyl-4-methyltetrahydro-2H-pyran-4-ol; undec-10-enenitrile; (Z)-6-ethylideneoctahydro-2H-5,8-methanochromen-2-one; 3-(2-ethylphenyl)-2,2-dimethylpropanal; (E)-4,8-dimethyldeca-4,9-dienal; (E)-4-((3aR,4R,7R,7aR)-1,3a,4,6,7,7a-hexahydro-5H-4,7-methanoinden-5-ylidene)-3-methylbutan-2-ol; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl acetate; 3-(4-ethylphenyl)-2,2-dimethylpropanenitrile; 2-heptylcyclopentan-1-one; 1-ethoxyethoxy Cyclododecane; 3-cyclohexene-1-carboxylic acid, 2,6,6-trimethyl-, methyl ester; (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl acetate; (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol; oxacyclohexadecan-2-one; (E)-cyclopentadec-4-en-1-one; 1-cyclopentadec-4-en-1-one; 2-methoxy-4-(4-methylenetetrahydro-2H-pyran-2-yl)phenol; 4-allyl-2-methoxyphenyl acetate; 4-allyl-2-methoxyphenol; ethyl 3-methyl-3-phenyloxirane-2-carboxylate; 1,4-dioxacycloheptadecane-5,17-dione; ethyl undec-10-enoate; ethyl palmitate; ethyl nonanoate; ethyl tetradecanoate; (E)-3,7-dimethylnona-1,6-dien-3-ol; ethyl dodecanoate; nonan-3-one; ethyl decanoate; ethyl 6,6-dimethyl-2-methylenecyclohex-3-ene-1-carboxylate; ethyl 3-phenyloxirane-2-carboxylate; 6-ethyl-2,10,10-trimethyl-1-oxaspiro[4.5]deca-3,6-diene; 2-((1R,3S,4S)-4-methyl-3-(prop-1-en-2-yl)-4-vinylcyclohexyl)propan-2-ol; (2-(1-ethoxyethoxy)ethyl)benzene; (E)-3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pent-4-en-2-ol; (2R,3S,4R)-2,3,4,5-tetrahydroxypentanal; (E)-4-((3aS,7aS)-octahydro-5H-4,7-methanoinden-5-ylidene)butanal; 1,1-dimethoxydodecane; (R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene; 2-(2-hydroxypropoxy)propan-1-ol; 7,9-dimethylspiro[5.5]undecan-3-one; oxydibenzene; diphenylmethane; 2-methyl-1-phenylpropan-2-yl butyrate; 2,6-dimethyloct-7-en-4-one; octahydro-1H-4,7-methanoinden-5-yl acetate; 2-methyl-5-(prop-1-en-2-yl)cyclohexyl acetate; 2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-ol; 3,7-dimethyloct-6-en-3-ol; methyl 2-hexyl-3-oxocyclopentane-1-carboxylate; dibutylsulfane; 1,2-diphenylethane; 6-hexyltetrahydro-2H-pyran-2-one; (3R,4R)-1-isopropyl-4-methyl-3-(prop-1-en-2-yl)-4-vinylcyclohex-1-ene; (3S,3aS,5R)-3,8-dimethyl-5-(prop-1-en-2-yl)-1,2,3,3a,4,5,6,7-octahydroazulene; 6-heptyltetrahydro-2H-pyran-2-one; 6-pentyltetrahydro-2H-pyran-2-one; (1S,8aR)-4,7-dimethyl-1-(propan-2-yl)-1,2,3,5,6,8a-hexahydronaphthalene; (Z)-1-((1R,2S)-2,6,6-trimethylcyclohex-3-en-1-yl)but-2-en-1-one; (1S,8aS)-1-isopropyl-4,7-dimethyl-1,2,3,5,6,8a-hexahydronaphthalene; 3,7,7-trimethylbicyclo[4.1.0]hept-3-ene; dec-9-en-1-ol; decyl propionate; 1,1-diethoxydecane; decahydronaphthalen-2-ol; 1-cyclohexylethyl (E)-but-2-enoate; 3-(4-isopropylphenyl)-2-methylpropanal; cyclotetradecane; cyclopentadecanone; cyclohexyl 2-hydroxybenzoate; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl butyrate; 1,4-dioxacyclohexadecane-5,16-dione; 8,8-dimethyl-1,2,3,4,5,6,7,8-octahydronaphthalene-2-carbaldehyde; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl isobutyrate; (5R,6R)-3,6-dimethyl-5-(prop-1-en-2-yl)-6-vinyl-4,5,6,7-tetrahydrobenzofuran; (4-isopropylphenyl)methanol; 1-(benzofuran-2-yl)ethan-1-one; 2-(3-phenylpropyl)pyridine; dodecanenitrile; (E)-cycloheptadec-9-en-1-one; 3-(4-methylcyclohex-3-en-1-yl)but-3-en-1-yl acetate; 3-(4-methylcyclohex-3-en-1-yl)butan-1-ol; (E)-3-methyl-5-phenylpent-2-enenitrile; (E)-2-(2,6-dimethylhepta-1,5-dien-1-yl)-4-methyl-1,3-dioxolane; (E)-1,1-dimethoxy-3,7-dimethylocta-2,6-diene; (E)-1,1-diethoxy-3,7-dimethylocta-2,6-diene; (E)-3,7-dimethylocta-1,3,6-triene; (1R,4R,6S)-1-methyl-4-(prop-1-en-2-yl)-7-oxabicyclo[4.1.0]heptane; (E)-oxacycloheptadec-11-en-2-one; (Z)-non-6-en-1-ol; (1R,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-ol; (Z)-dec-4-enal; (E)-hex-3-en-1-yl (E)-hex-3-enoate; (Z)-hex-3-en-1-yl 2-hydroxybenzoate; (Z)-hex-3-en-1-yl benzoate; (Z)-hex-3-en-1-yl 2-methylbutanoate; (3Z,6Z)-nona-3,6-dien-1-ol; cinnamyl propionate; cinnamyl isobutyrate; cinnamyl formate; cinnamyl cinnamate; cinnamyl acetate; (E)-3-phenylprop-2-en-1-ol; hexadecan-1-ol; (E)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)hepta-1,6-dien-3-one; 2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butanal; (3aR,5aR,9aR,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; 1,6-dioxacycloheptadecan-7-one; 1-(6-(tert-butyl)-1,1-dimethyl-2,3-dihydro-1H-inden-4-yl)ethan-1-one; (3R,3aR,6S,7S,8aS)-6-methoxy-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-3-yl formate; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl acetate; (4Z,8Z)-1,5,9-trimethyl-13-oxabicyclo[10.1.0]trideca-4,8-diene; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-ol; 5-methyl-1-(2,2,3-trimethylcyclopent-3-en-1-yl)-6-oxabicyclo[3.2.1]octane; 5-methyl-1-(2,2,3-trimethylcyclopent-3-en-1-yl)-6-oxabicyclo[3.2.1]octane; 1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-4H-inden-4-one; (Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-3-en-5-yl acetate; (1S,2S,5R,8S)-4,4,8-trimethyltricyclo[6.3.1.02,5]dodecan-1-ol; 2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-yl acetate; octanenitrile; octan-1-ol; octanoic acid; decanoic acid; decanal; 3-(4-methoxyphenyl)-2-methylpropanal; 1,7,7-trimethylbicyclo[2.2.1]heptane-2,3-dione; 2,2-dimethyl-3-methylenebicyclo[2.2.1]heptane; ethyl 2-methyl-4-oxo-6-pentylcyclohex-2-ene-1-carboxylate; 2,6-di-tert-butyl-4-methylphenol; butyl stearate; 1-butoxy-1-oxopropan-2-yl butyrate; butyl undec-10-enoate; 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)butan-1-ol; 3-(4-(tert-butyl)phenyl)propanal; (1S,2S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate; 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 2-ethoxy-2,6,6-trimethyl-9-methylenebicyclo[3.3.1]nonane; (ethoxymethoxy)cyclododecane; (E)-1-methyl-4-(6-methylhept-5-en-2-ylidene)cyclohex-1-ene; 3,3,6,7-tetramethyloctahydro-2H-chromene; (5R,10R)-6,10-dimethyl-2-(propan-2-ylidene)spiro[4.5]dec-6-en-8-one; 1-methyl-4-(prop-1-en-2-yl)cyclohexyl acetate; 1-methyl-4-(prop-1-en-2-yl)cyclohexan-1-ol; (2Z,6E)-2,6-dimethyl-10-methylenedodeca-2,6,11-trienal; (R)-3-methylene-6-((S)-6-methylhept-5-en-2-yl)cyclohex-1-ene; (4aR,7R,8aS)-4a-methyl-1-methylene-7-(prop-1-en-2-yl)decahydronaphthalene; (Z)-2-methyl-5-((1S,2R,4R)-2-methyl-3-methylenebicyclo[2.2.1]heptan-2-yl)pent-2-en-1-ol; 6,6-dimethyl-2-methylenebicyclo[3.1.1]heptane; 2-ethoxynaphthalene; (1S,4R,7R)-1,4,9,9-tetramethyl-1,2,3,4,5,6,7,8-octahydro-4,7-methanoazulene; (1aS,5aR,9aR)-1a,5,5,7-tetramethyl-1a,2,3,4,5,5a,8,9-octahydrobenzo[1,7]cyclohepta[1,2-b]oxirene; (R)-3,5,5,9-tetramethyl-2,4a,5,6,7,8-hexahydro-1H-benzo[7]annulene; (1S,4S)-1,4-dimethyl-7-(propan-2-ylidene)-1,2,3,4,5,6,7,8-octahydroazulene; (2,2-dimethoxyethyl)benzene; (E)-7,11-dimethyl-3-methylenedodeca-1,6,10-triene; (1R,2S,6S,7S,8S)-8-isopropyl-1-methyl-3-methylenetricyclo[4.4.0.02,7]decane; (3R,3aS,7S,8aS)-3,8,8-trimethyl-6-methyleneoctahydro-1H-3a,7-methanoazulene; (1R,9S,Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-4-ene; (S)-4-methyl-1-((S)-6-methylhept-5-en-2-yl)cyclohex-3-en-1-ol; (Z)-4-(2,2,6-trimethyl-7-oxabicyclo[4.1.0]heptan-1-yl)but-3-en-2-one; 4-methoxy-7H-furo[3,2-g]chromen-7-one; 2-methyl-4-phenylbutan-2-ol; benzyldodecanoate; 2-methyl-1-phenylpropan-2-ol; benzyl cinnamate; benzyl benzoate; benzophenone; 7-isopentyl-2H-benzo[b][1,4]dioxepin-3(4H)-one; 2′-isopropyl-1,7,7-trimethylspiro[bicyclo[2.2.1]heptane-2,4′-[1,3]dioxane]/A; 4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbonitrile; methyl (E)-2-((7-hydroxy-3,7-dimethyloctylidene)amino)benzoate; 4-methoxybenzyl 2-phenylacetate; methyl (E)-octa-4,7-dienoate; pentyl (Z)-3-phenylacrylate; (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; (4aR,5R,7aS,9R)-2,2,5,8,8,9a-hexamethyloctahydro-4H-4a,9-methanoazuleno[5,6-d][1,3]dioxole; 2,5,5-trimethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-ol; 2,5,5-trimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-ol; 1-((2-(tert-butyl)cyclohexyl)oxy)butan-2-ol; (3S,5aR,7aS,11aS,11bR)-3,8,8,11a-tetramethyldodecahydro-5H-3,5a-epoxynaphtho[2,1-c]oxepine; 2,2,6,6,7,8,8-heptamethyldecahydro-2H-indeno[4,5-b]furan; 2,2,7,7,8,9,9-heptamethyldecahydroindeno[4,3a-b]furan; 2-(sec-butyl)-1-vinylcyclohexyl acetate; (1S,4R,5R)-1-isopropyl-4-methylbicyclo[3.1.0]hexan-3-one; (4R,4aS)-4,4a-dimethyl-6-(propan-2-ylidene)-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one; 2-(4-methylcyclohex-3-en-1-yl)propan-2-yl propionate; (2Z,6E,9E)-2,6,10-trimethyldodeca-2,6,9,11-tetraenal; (2R,4aR,8aR)-4a,8-dimethyl-2-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 1,7-dimethyl-7-(4-methylpent-3-en-1-yl)tricyclo[2.2.1.02,6]heptane; (E)-5-(2,3-dimethyltricyclo[2.2.1.02,6]heptan-3-yl)-2-methylpent-2-en-1-ol; (1R,3aS,7S,8aR)-1,4,9,9-tetramethyl-2,3,6,7,8,8a-hexahydro-1H-3a,7-methanoazulene; 1-(5,5-dimethylcyclohex-1-en-1-yl)pent-4-en-1-one; (1S,4aS,8aR)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (R,Z)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)pent-1-en-3-one; 1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene; (Z)-4-(2,5,6,6-tetramethylcyclohex-2-en-1-yl)but-3-en-2-one; (1Z,4E,8Z)-2,6,6,9-tetramethylcycloundeca-1,4,8-triene; (4aR,8S,9aS)-3,5,5,8-tetramethyl-9-methylene-2,4a,5,6,7,8,9,9a-octahydro-1H-benzo[7]annulene; (1aR,4R,4aR,7bS)-1,1,4,7-tetramethyl-1a,2,3,4,4a,5,6,7b-octahydro-1H-cyclopropa[e]azulene; 1,4-dimethyl-7-(prop-1-en-2-yl)-1,2,3,4,5,6,7,8-octahydroazulene; (3E,6E)-3,7,11-trimethyldodeca-1,3,6,10-tetraene; 7,7-dimethyl-2-methylenebicyclo[2.2.1]heptane; 2-((2R,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl)propan-2-ol; (R)-1-methyl-4-(6-methylhept-5-en-2-yl)benzene; (3aR,3bR,4S,7R,7aS)-4-isopropyl-7-methyl-3a,3b,4,5,6,7-hexahydro-1H-cyclopenta[1,3]cyclopropa[1,2]benzene; (1aS,2aR,3R,5aS,7R,7aR)-3,6,6,7a-tetramethyloctahydro-2H-2a,7-methanoazuleno[5,6-b]oxirene; (1R,4S,4aR,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; (1S,4aR,8aR)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (R)-2-((R)-4-methylcyclohex-3-en-1-yl)hex-5-en-2-ol; (Z)-1-methyl-4-(6-methylhepta-2,5-dien-2-yl)cyclohex-1-ene; 2,6-dimethyl-6-(4-methylpent-3-en-1-yl)bicyclo[3.1.1]hept-2-ene; (E)-2-benzylideneheptan-1-ol; (E)-2-benzylideneheptyl acetate; (Z)-(2-(diethoxymethyl)hept-1-en-1-yl)benzene; (E)-2-benzylideneheptanal; (1S,4aR,8aS)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (3R,5aS,9aR)-2,2,5a,9-tetramethyl-3,4,5,5a,6,7-hexahydro-2H-3,9a-methanobenzo[b]oxepine; 1-methyl-4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carb aldehyde; 1-phenylpentan-2-ol; 3-methyl-1-phenylpentan-3-ol; 2,3,4-trimethoxybenzaldehyde; 2,4,5-trimethoxybenzaldehyde; 2,4,6-trimethoxybenzaldehyde; Trans,Trans-2,4-Nonadienal; 2,6,10-trimethylundecanal; alpha-4-Dimethyl benzenepropanal; allyl 3-cyclohexylpropanoate; allyl 2-(isopentyloxy)acetate; (1aR,4aS,7R,7aR,7bS)-1,1,7-trimethyl-4-methylenedecahydro-1H-cyclopropa[e]azulene; (E)-undec-9-enal; methyl (E)-2-(((3,5-dimethylcyclohex-3-en-1-yl)methylene)amino)benzoate; 2,6,10-trimethylundec-9-enal; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methyl acetate; nonyl acetate; (2-(1-propoxyethoxy)ethyl)benzene; 1-(1-propoxyethoxy)propane; ((1-(2-methoxyethoxy)ethoxy)methyl)benzene; (Z)-2-(4-methylbenzylidene)heptanal; dec-9-enal; (Z)-oxacycloheptadec-8-en-2-one; 7-methoxy-2H-chromen-2-one; (2S,4aR,8aR)-4a,8-dimethyl-2-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 2-((2S,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl)propan-2-ol; 1-(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethan-1-one; 6-isopropylquinoline; 3-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)propanal; 6,10,14-trimethylpentadecan-2-one; 2-methyl-5-(prop-1-en-2-yl)-2-vinyltetrahydrofuran; (E)-cyclohexadec-5-en-1-one; 1-isopropyl-4-methylcyclohex-3-en-1-ol; 1-phenylpent-4-en-1-one; 1-isopropyl-4-methylcyclohex-3-en-1-ol; 3,6-dimethyl-4,5,6,7-tetrahydrobenzofuran; 4-(4-methoxyphenyl)butan-2-one; (1aR,2S,4aS)-2,4a,8,8-tetramethyloctahydrocyclopropa[d]naphthalen-3(1H)-one; (E)-3-propylideneisobenzofuran-1(3H)-one; (Z)-dodec-2-enal; 3-methyl-5-phenylpentanal; (E)-hex-3-en-1-yl 3-methylbutanoate; 3,6-dimethyloctan-3-yl acetate; 3,4,5-trimethoxybenzaldehyde; 3-(4-isopropylphenyl)propanal; (Z)-undec-2-enenitrile; (E)-undec-2-enal; (2E,6E)-nona-2,6-dienal; phenethyl butyrate; (Z)-3-(furan-2-yl)-2-phenylacrylaldehyde; 2-phenoxyethan-1-ol; (Z)-non-2-enal; nonan-2-ol; nonan-2-one; 2-isobutylquinoline; (E)-2-hexylidenecyclopentan-1-one; 2-heptyltetrahydrofuran; (E)-dec-2-enal; (2E,6E)-nona-2,6-dienal; (2E,6E)-nona-2,6-dien-1-ol; 2,6-dimethyloctanal; decan-1-ol; (E)-hept-1-en-1-yl acetate; undec-10-en-1-ol; undec-10-enal; 2-((2R,4aS)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)propan-2-ol; 1-isopropyl-4-methyl-7-thiabicyclo[2.2.1]heptane; (3E,5Z)-undeca-1,3,5-triene; 3,7-dimethyloct-6-en-3-ol; 1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 1,1,2,3,3-pentamethyl-2,3-dihydro-1H-indene; (Z)-6,10-dimethylundeca-5,9-dien-2-yl acetate; (Z)-dodec-3-enal; (S)-5-heptyldihydrofuran-2(3H)-one; (R)-5-heptyldihydrofuran-2(3H)-one; (E)-6,10-dimethylundeca-5,9-dien-2-yl acetate; (Z)-3-methyl-5-phenylpent-2-enenitrile; (2S,5S,6S)-2,6,10,10-tetramethyl-1-oxaspiro[4.5]decan-6-ol; (2E)-3-methyl-5-phenyl-2-pentenenitrile; (1S,2S,5S)-2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-ol; (2S,5R)-2-isopropyl-5-methylcyclohexan-1-one; (R,E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 2-(8-isopropyl-6-methylbicyclo[2.2.2]oct-5-en-2-yl)-1,3-dioxolane; (E)-4-(2,2-dimethyl-6-methylenecyclohexyl)-3-methylbut-3-en-2-one; 3-(3-isopropylphenyl)butanal; 3-(1-ethoxyethoxy)-3,7-dimethylocta-1,6-diene; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; 2-((3S,3aS,5R)-3,8-dimethyl-1,2,3,3a,4,5,6,7-octahydroazulen-5-yl)propan-2-ol; benzyl 2-phenylacetate; 2-hydroxy-1,2-diphenylethan-1-one; (E)-1,2,4-trimethoxy-5-(prop-1-en-1-yl)benzene; 3-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-2,2-dimethylpropanal; 2-methyl-5-(6-methylhept-5-en-2-yl)bicyclo[3.1.0]hex-2-ene; 1-(1,1,2,3,3,6-hexamethyl-2,3-dihydro-1H-inden-5-yl)ethan-1-one; 2-(m-tolyl)ethan-1-ol; (3E,6E)-nona-3,6-dien-1-ol; (E)-tridec-2-enal; (1R,4S,4aS,6R,8aS)-4,8a,9,9-tetramethyloctahydro-1,6-methanonaphthalen-1(2H)-ol; p-tolyl isobutyrate; p-tolyl hexanoate; 5-hexyl-4-methyldihydrofuran-2(3H)-one; ethyl (2Z,4E)-deca-2,4-dienoate; 2,4-dimethyl-6-phenyl-3,6-dihydro-2H-pyran; 2-cyclohexylidene-2-phenylacetonitrile; 4-(prop-1-en-2-yl)cyclohex-1-ene-1-carbaldehyde; (4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methyl acetate; (4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methanol; (2-isopropoxyethyl)benzene; 2-cyclohexylhepta-1,6-dien-3-one; (2-(cyclohexyloxy)ethyl)benzene; phenethyl 2-methylbutanoate; 2-phenylethan-1-ol; phenethyl 2-phenylacetate; 3-methyl-5-phenylpentan-1-ol; phenyl benzoate; phenethyl benzoate; 2-benzyl-1,3-dioxolane; 2-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)acetaldehyde; 6,6-dimethyl-2-methylenebicyclo[3.1.1]heptan-3-ol; 4-(benzo[d][1,3]dioxol-5-yl)butan-2-one; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-ylpivalate; (4aR,8aS)-7-methyloctahydro-1,4-methanonaphthalen-6(2H)-one; 4-isopropyl-1-methylcyclohex-3-en-1-ol; (E)-3,3-dimethyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pent-4-en-2-ol; 1-methyl-4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; propane-1,2-diol; p-tolyl 2-phenylacetate; Ethyl 2,4,7-decatrienoate; 2-benzyl-4,4,6-trimethyl-1,3-dioxane; 2,4-dimethyl-4-phenyltetrahydrofuran; (2R,4a′R,8a′R)-3,7′-dimethyl-3′,4′,4a′,5′,8′,8a′-hexahydro-1′H-spiro[oxirane-2,2′-[1,4]methanonaphthalene]; (Z)-6-ethylideneoctahydro-2H-5,8-methanochromene; 2-((S)-1-((S)-3,3-dimethylcyclohexyl)ethoxy)-2-oxoethyl propionate; methyl 2,2-dimethyl-6-methylenecyclohexane-1-carboxylate; 2-methyl-5-phenylpentan-1-ol; 4-methyl-2-phenyl-3,6-dihydro-2H-pyran; (1S,3R,5S)-1-isopropyl-4-methylenebicyclo[3.1.0]hexan-3-ol; 5-allylbenzo[d][1,3]dioxole; 2,2,7,9-tetramethylspiro(5.5)undec-8-en-1-one; 3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pentan-2-ol; (Z)-2-ethyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; (E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carb aldehyde; 1-(3-hydroxy-3-methylpent-4-en-1-yl)-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol; (4aR,6aS,10aS,10bR)-3,4a,7,7,10a-pentamethyl-4a,5,6,6a,7,8,9,10,10a,10b-decahydro-1H-benzo[f]chromene; (4aR,8aR)-4a,8-dimethyl-2-(propan-2-ylidene)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropyl cyclopropanecarboxylate; 3-(4-isobutylphenyl)-2-methylprop anal; (1aR,4aR,7S,7aR,7bR)-1,1,7-trimethyl-4-methylenedecahydro-1H-cyclopropa[e]azulen-7-ol; (1R,3R,6R)-2′,2′,3,7,7-pentamethylspiro[bicyclo[4.1.0]heptane-2,5′-[1,3]dioxane]; 2-methyl-1,5-dioxaspiro[5.5]undecane; 1-(spiro[4.5]dec-7-en-7-yl)pent-4-en-1-one; 2-(4-methylthiazol-5-yl)ethan-1-ol; 2-(heptan-3-yl)-1,3-dioxolane; (Z)-dodec-4-enal; (1S,4S,4aR,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; (1S,4S,4aR,8aS)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; 3-methyl-2-pentylcyclopentan-1-one; 2,6,10,10-tetramethyl-1-oxaspiro[4.5]dec-6-ene; 2-(2-mercaptopropan-2-yl)-5-methylcyclohexan-1-one; (1aR,4aS)-2,4a,8,8-tetramethyl-1,1a,4,4a,5,6,7,8-octahydrocyclopropa[d]naphthalene; 1-isopropyl-2-methoxy-4-methylbenzene; 1-(2,2,6-trimethylcyclohexyl)hexan-3-ol; (2Z,4E)-nona-2,4-dienal; (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol; (2E,6Z)-nona-2,6-dienal; (Z)-dec-2-enal; (E)-non-2-enal; (3E,6Z)-nona-3,6-dien-1-ol; (E)-dec-4-enal; (Z)-oxacycloheptadec-8-en-2-one; (Z)-3,7-dimethylocta-1,3,6-triene; (Z)-3,7-dimethylocta-1,3,6-triene; (E)-3,7-dimethylocta-2,6-dien-1-ol; methyl 2-((1S,2S)-3-oxo-2-pentylcyclopentyl)acetate; 7-(1,1-Dimethylethyl)-2H-1,5-benzodioxepin-3(4H)-one; (1R-(1alpha,3alpha,4aalpha))-2,3,4,4a,5,6-hexahydro-2,2-dimethyl-1,3-methanonaphthalen-7(1H)-one; tridecan-1-ol; triethyl 2-hydroxypropane-1,2,3-tricarboxylate; methyl 2-((1-hydroxy-3-phenylbutyl)amino)benzoate; 1-((2E,5Z,9Z)-2,6,10-trimethylcyclododeca-2,5,9-trien-1-yl)ethan-1-one; decahydro-2,6,6,7,8,8-hexamethyl-2h-indeno(4,5-b)furan; 13-methyl oxacyclopentadec-10-en-2-one; undecanal; (E)-4-methyldec-3-en-5-ol; (3R,4aS,5R)-4a,5-dimethyl-3-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,7-octahydronaphthalene; 2-((2R,8R,8aS)-8,8a-dimethyl-1,2,3,4,6,7,8,8a-octahydronaphthalen-2-yl)propan-2-ol; 4-formyl-2-methoxyphenyl isobutyrate; (Z)-2-methyl-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-enal; methyl 2,4-dihydroxy-3,6-dimethylbenzoate; 1-methoxy-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoindene; methyl (Z)-2-((3-(4-(tert-butyl)phenyl)-2-methylpropylidene)amino)benzoate; (Z)-hex-3-en-1-yl isobutyrate; 2,4,6-trimethyl-4-phenyl-1,3-dioxane; 1-((3R,3aR,7R,8aS)-3,6,8,8-tetramethyl-2,3,4,7,8,8a-hexahydro-1H-3a,7-methanoazulen-5-yl)ethan-1-one; methyl (Z)-2-(((2,4-dimethylcyclohex-3-en-1-yl)methylene)amino)benzoate; 4,8-dimethyl-2-(propan-2-ylidene)-1,2,3,3a,4,5,6,8a-octahydroazulen-6-ol; 4,8-dimethyl-2-(propan-2-ylidene)-1,2,3,3a,4,5,6,8a-octahydroazulen-6-yl acetate; decahydro-3H-spiro[furan-2,5′-[4,7]methanoindene]; (2Z,6E)-nona-2,6-dienenitrile; (Z)-cyclooct-4-en-1-yl methyl carbonate; (1aR,4S,4aS,7R,7aS,7bS)-1,1,4,7-tetramethyldecahydro-1H-cyclopropa[e]azulen-4-ol; 3,5,5,6,7,8,8-heptamethyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile; (1S,2S,3S,5R)-2,6,6-trimethylspiro[bicyclo[3.1.1]heptane-3,1′-cyclohexan]-2′-en-4′-one; 1′,1′,5′,5′-tetramethylhexahydro-2′H,5′H-spiro[[1,3]dioxolane-2,8′-[2,4a]methanonaphthalene]; (2'S,4a'S,8a'S)-1′,1′,5′,5′-tetramethylhexahydro-2′H,5′H-spiro[[1,3]dioxolane-2,8′-[2,4a]methanonaphthalene]; 4-(4-hydroxy-3-methoxyphenyl)butan-2-one; (1R,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,7,8,8a-hexahydronaphthalene; 2,4-dimethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolane; 3a,5,6,7,8,8b-hexahydro-2,2,6,6,7,8,8-heptamethyl-4H-indeno(4,5-d)-1,3-dioxole; 2,4-dimethyl-4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; (1-methyl-2-((1,2,2-trimethylbicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methanol; 2-(cyclohexyloxy)-1,7,7-trimethylbicyclo[2.2.1]heptane; 4-((2R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)cyclohexan-1-ol; 8,8-di(1H-indol-1-yl)-2,6-dimethyloctan-2-ol; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methanol; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; (E)-4-((3aR,4R,7R,7aR)-1,3a,4,6,7,7a-hexahydro-5H-4,7-methanoinden-5-ylidene)-3-methylbutan-2-ol; (3R,3aR,6S,7S,8aS)-6-methoxy-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene; (1R,2S,6S,7S,8S)-8-isopropyl-1-methyl-3-methylenetricyclo[4.4.0.02,7]decane; 2′-isopropyl-1,7,7-trimethylspiro[bicyclo[2.2.1]heptane-2,4′-[1,3]dioxane]; (4aR,5R,7aS,9R)-2,2,5,8,8,9a-hexamethyloctahydro-4H-4a,9-methanoazuleno[5,6-d][1,3]dioxole; (3S,5aR,7aS,11aS,11bR)-3,8,8,11a-tetramethyldodecahydro-5H-3,5a-epoxynaphtho[2,1-c]oxepine; 2,2,6,6,7,8,8-heptamethyldecahydro-2H-indeno[4,5-b]furan; (1aS,2aR,3R,5aS,7R,7aR)-3,6,6,7a-tetramethyloctahydro-2H-2a,7-methanoazuleno[5,6-b]oxirene; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methyl acetate; 1-(3-hydroxy-3-methylpent-4-en-1-yl)-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol; decahydro-2,6,6,7,8,8-hexamethyl-2h-indeno(4,5-b)furan; 2-ethylhexyl (Z)-3-(4-methoxyphenyl)acrylate; methoxycyclododecane; 1-ethoxy-4-(tert-pentyl)cyclohexane; (2-hydroxy-4-methoxyphenyl)(phenyl)methanone; (3Z)-1-(2-buten-1-yloxy)-3-hexene; 4-(2-methoxypropan-2-yl)-1-methylcyclohex-1-ene; 4-(tert-pentyl)cyclohexan-1-one; 3-methoxy-3,7-dimethylocta-1,6-diene; 7-isopropyl-8,8-dimethyl-6,10-dioxaspiro[4.5]decane; (E)-3-(2-methoxyphenyl)acrylaldehyde; 3,7-dimethyloctanal; 1,1-dimethoxyoctane; 2-methyl-6-methyleneoct-7-en-2-ol; 4-methoxy-6-prop-2-enyl-1,3-benzodioxole; tetradecanenitrile; (E)-2,7-dimethylocta-1,5,7-trien-3-ol; 3,3-Dimethyl-5(2,2,3-Trimethyl-3-Cyclopenten-1yl)-4-Penten-2-ol; hexyl 2-hydroxybenzoate; hexyl (Z)-but-2-enoate; (Z)-3,7-dimethylocta-2,6-dien-1-yl formate; (Z)-3,7-dimethylocta-2,6-dien-1-ol; 1-ethyl-3-methoxytricyclo[2.2.1.02,6]heptane; 10-isopropyl-2,7-dimethyl-1-oxaspiro[4.5]deca-3,6-diene; 6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-carbaldehyde; (E)-4-(2,2,3,6-tetramethylcyclohexyl)but-3-en-2-one; (Z)-1-(2,6,6-trimethylcyclohex-1-en-1-yl)pent-1-en-3-one; (E)-2,2-dimethyl-3-(3-methylpenta-2,4-dien-1-yl)oxirane; 3-methylcyclopentadecan-1-one; (E)-3,7-dimethylocta-4,6-dien-3-ol; 3-methyl-4-phenylbutan-2-ol; 1-(4-isopropylcyclohexyl)ethan-1-ol; (Z)-hex-3-en-1-yl cyclopropanecarboxylate; (E)-dec-5-enoic acid; 1-phenylethyl propionate; methyl 2-phenylacetate; 4-phenylbutan-2-ol; methyl stearate; methyl (9Z,12Z)-octadeca-9,12-dienoate; 1-hydroxydecan-3-one; 2-methyl-6-oxaspiro[4.5]decan-7-one; (Z)-1,2-dimethoxy-4-(prop-1-en-1-yl)benzene; methyl palmitate; 4-allyl-1,2-dimethoxybenzene; methyl (Z)-3,7-dimethylocta-2,6-dienoate; 1-methyl-2-phenoxybenzene; 2-ethoxy-4-(methoxymethyl)phenol; methyl 2-cyclopentylideneacetate; 1-allyl-4-methoxybenzene; 6-methoxy-2,6-dimethylheptanal; 7-methoxy-3,7-dimethyloctanal; ((1s,4s)-4-isopropylcyclohexyl)methanol; 3-(3-(tert-butyl)phenyl)-2-methylpropanal; (E)-4-(4,8-dimethylnona-3,7-dien-1-yl)pyridine; (E)-trideca-3,12-dienenitrile; 2,2-dimethyl-3-(m-tolyl)propan-1-ol; 8-isopropyl-6-methylbicyclo[2.2.2]oct-5-ene-2-carbaldehyde; 4-(4-hydroxy-4-methylpentyl)cyclohex-3-ene-1-carbaldehyde; (Z)-3-hexen-1-yl-2-cyclopenten-1-one; 3,7-dimethylocta-1,6-dien-3-yl propionate; 3,7-dimethylocta-1,6-dien-3-yl octanoate; 3,7-dimethylocta-1,6-dien-3-yl formate; 3,7-dimethylocta-1,6-dien-3-yl butyrate; 3,7-dimethylocta-1,6-dien-3-yl benzoate; 3,7-dimethylocta-1,6-dien-3-yl 2-aminobenzoate; 3,7-dimethylocta-1,6-dien-3-yl acetate; 3,7-dimethylocta-1,6-dien-3-ol; 3-(4-methylcyclohex-3-en-1-yl)butanal; 3-(4-(tert-butyl)phenyl)-2-methylpropanal; (Z)-hex-3-en-1-yl methyl carbonate; 4-methylquinoline; (E)-1-(1-methoxypropoxy)hex-3-ene; 2-Methyl-5-(1-methylethenyl)-2-cyclohexenone; dodecanal; 2,2-dimethyl-5-phenylhexanenitrile; (E)-6-(pent-3-en-1-yl)tetrahydro-2H-pyran-2-one; 2-hexylcyclopentan-1-one; (Z)-4-(6,6-dimethylcyclohex-2-en-1-yl)-3-methylbut-3-en-2-one; 2,6,9,10-tetramethyl-1-oxaspiro(4.5)deca-3,6-diene; 4-methylpent-1-en-3-ol; isopropyl palmitate; isopropyl dodecanoate; isopropyl 2-methylbutanoate; 4-methylpent-4-en-2-yl isobutyrate; 7-methyloctyl acetate; 7-methyloctan-1-ol; 4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; (Z)-2-methoxy-4-(prop-1-en-1-yl)phenyl acetate; (Z)-2-methoxy-4-(prop-1-en-1-yl)phenol; (1R,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl propionate; (1R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol; 2-(4-isopropylcyclohexa-1,4-dien-1-yl)ethyl formate; isopentyl (E)-undec-6-enoate; isopentyl octanoate; isopentyl dodecanoate; isopentyl isobutyrate; (E)-oxacycloheptadec-10-en-2-one; 8,8-di(1H-indol-1-yl)-2,6-dimethyloctan-2-ol; 2-cyclododecylpropan-1-ol; 3-phenylpropan-1-ol; 3-phenylpropanoic acid; (1,1-dimethoxypropan-2-yl)benzene; 2-phenylpropan-1-ol; hexyl propionate; hexyl butyrate; hexyl 2-methylbutanoate; hexyl furan-2-carboxylate; oxacycloheptadecan-2-one; heptan-1-ol; heptyl acetate; heptanal; 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropyl propionate; 5-(diethoxymethyl)benzo[d][1,3]dioxole; benzo[d][1,3]dioxole-5-carbaldehyde; 3-(benzo[d][1,3]dioxol-5-yl)-2-methylpropanal; (E)-oxacyclohexadec-13-en-2-one; 6-butyl-2,4-dimethyl-3,6-dihydro-2H-pyran; 2-((3S,5R,8S)-3,8-dimethyl-1,2,3,4,5,6,7,8-octahydroazulen-5-yl)propan-2-ol; 1-(2,6,6-trimethylcyclohex-2-en-1-yl)pentan-3-one; (1Z,5Z)-1,5-dimethyl-8-(propan-2-ylidene)cyclodeca-1,5-diene; (E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate; (E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate; (Z)-3,7-dimethylocta-2,6-dienenitrile; (E)-3,7-dimethylocta-2,6-dien-1-yl formate; (E)-3,7-dimethylocta-2,6-dien-1-yl octanoate; (E)-3,7-dimethylocta-2,6-dien-1-yl benzoate; (E)-3,7-dimethylocta-2,6-dienal; N,2-dimethyl-N-phenylbutanamide; 1-isopropyl-4-methylcyclohexa-1,4-diene; (1R,4aR,8aS)-1-isopropyl-7-methyl-4-methylene-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 5-[(Z)-hex-3-enyl]oxolan-2-one; (4aS,9aR)-3,5,5,9-tetramethyl-2,4a,5,6,7,9a-hexahydro-1H-benzo[7]annulene; (Z)-1-(2,2-dimethyl-6-methylenecyclohexyl)but-2-en-1-one; (1R,4aS,8aS)-1-isopropyl-7-methyl-4-methylene-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 1-(3,3-dimethylcyclohexyl)pent-4-en-1-one; furan-2-ylmethyl octanoate; furan-2-ylmethyl hexanoate; furan-2-ylmethyl heptanoate; ethyl (3aR,4S,7R,7aR)-octahydro-3aH-4,7-methanoindene-3a-carboxylate; 2-(sec-butyl)cyclohexan-1-one; 3-(2-ethylphenyl)-2,2-dimethylpropanal; 2-(tert-butyl)cyclohexyl ethyl carbonate; 3-(2-ethylphenyl)-2,2-dimethylpropanal; (E)-4,8-dimethyldeca-4,9-dienal; 3-(4-ethylphenyl)-2,2-dimethylpropanenitrile; 2-heptylcyclopentan-1-one; 1-ethoxyethoxy Cyclododecane; (Z)-5-methylhept-2-en-4-one; 1,3,3-trimethylbicyclo[2.2.1]heptan-2-ol; oxacyclohexadecan-2-one; (E)-cyclopentadec-4-en-1-one; 1-cyclopentadec-4-en-1-one; 4-allyl-2-methoxyphenyl acetate; 4-allyl-2-methoxyphenol; 1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane; ethyl 3-methyl-3-phenyloxirane-2-carboxylate; 1,4-dioxacycloheptadecane-5,17-dione; 2-ethoxy-4-formylphenyl acetate; ethyl undec-10-enoate; ethyl palmitate; ethyl octanoate; ethyl tetradecanoate; (E)-3,7-dimethylnona-1,6-dien-3-ol; ethyl cinnamate; ethyl 3-phenyloxirane-2-carboxylate; ethyl 2-cyclohexylpropanoate; 6-ethyl-2,10,10-trimethyl-1-oxaspiro[4.5]deca-3,6-diene; (2R,3S,4R)-2,3,4,5-tetrahydroxypentanal; (E)-4-((3aS,7aS)-octahydro-5H-4,7-methanoinden-5-ylidene)butanal; (2R,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-one; 4-methyl-2-phenyltetrahydro-2H-pyran; oxydibenzene; diphenylmethane; 2-methyl-1-phenylpropan-2-yl butyrate; 2,6-dimethyloct-7-en-2-ol; 3-methyl-2-pentylcyclopent-2-en-1-one; 3,3,5-trimethylcyclohexan-1-one; 2-methoxy-4-propylphenol; chroman-2-one; 2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-one; 2-methyl-5-(prop-1-en-2-yl)cyclohexyl acetate; 2-(4-methylcyclohexyl)propan-2-yl acetate; 4-(2,6,6-trimethylcyclohex-2-en-1-yl)butan-2-one; (oxybis(methylene))dibenzene; dibutyl phthalate; 1,2-diphenylethane; (3R,4R)-1-isopropyl-4-methyl-3-(prop-1-en-2-yl)-4-vinylcyclohex-1-ene; (1S,8aR)-4,7-dimethyl-1-(propan-2-yl)-1,2,3,5,6,8a-hexahydronaphthalene; (1S,8aS)-1-isopropyl-4,7-dimethyl-1,2,3,5,6,8a-hexahydronaphthalene; 2-pentylcyclopentan-1-one; decyl 2-aminobenzoate; decahydronaphthalen-2-ol; methyl (1s,4s)-1,4-dimethylcyclohexane-1-carboxylate; 3-(4-isopropylphenyl)-2-methylpropanal; cyclotetradecane; cyclopentadecanone; 2-cyclohexylethyl acetate; cyclohexyl 2-hydroxybenzoate; 1,4-dioxacyclohexadecane-5,16-dione; (4-isopropylphenyl)methanol; 2-methoxy-4-methylphenol; (3Z,5Z)-2,6-dimethylocta-1,3,5,7-tetraene; 4-cyclohexyl-2-methylbutan-2-ol; 2-(3-phenylpropyl)pyridine; 3-(4-methylcyclohex-3-en-1-yl)but-3-en-1-yl acetate; 3-(4-methylcyclohex-3-en-1-yl)butan-1-ol; 2-benzyl-2-methylbut-3-enenitrile; 3,7-dimethyloct-6-enenitrile; 3,7-dimethyloct-6-en-1-yl 2-phenylacetate; 3,7-dimethyloct-6-en-1-yl formate; 3,7-dimethyloct-6-en-1-yl benzoate; 3,7-dimethyloct-6-en-1-ol; 3,7-dimethyloct-6-enal; (E)-3,7-dimethylocta-2,6-dienal; (1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptane; (Z)-3-methyl-2-(pent-2-en-1-yl)cyclopent-2-en-1-one; (E)-2-methoxy-4-(prop-1-en-1-yl)phenol; (E)-oxacycloheptadec-11-en-2-one; (Z)-non-6-en-1-ol; (Z)-hex-3-en-1-yl pentanoate; (E)-hex-3-en-1-yl (E)-2-methylbut-2-enoate; (Z)-hex-3-en-1-yl 2-hydroxybenzoate; (Z)-hex-3-en-1-yl propionate; (Z)-hex-3-en-1-yl butyrate; (Z)-hex-3-en-1-yl benzoate; (Z)-hex-3-en-1-ol; (Z)-hex-3-en-1-yl 2-methylbutanoate; (Z)-hex-2-en-1-ol; cinnamonitrile; cinnamyl isobutyrate; cinnamaldehyde; (E)-3-phenylprop-2-en-1-ol; cinnamonitrile; 4-chloro-3,5-dimethylphenol; hexadecan-1-ol; (E)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)hepta-1,6-dien-3-one; 2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butanal; (3aR,5aR,9aR,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; (4Z,8Z)-1,5,9-trimethyl-13-oxabicyclo[10.1.0]trideca-4,8-diene; 5-methyl-1-(2,2,3-trimethylcyclopent-3-en-1-yl)-6-oxabicyclo[3.2.1]octane; 1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-4H-inden-4-one; 5-isopropyl-2-methylphenol; 2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-one; 2-(2-ethoxyethoxy)ethan-1-ol; hexan-1-ol; 2-(2,2,3-trimethylcyclopent-3-en-1-yl)acetonitrile; 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one; 2,2-dimethyl-3-methylenebicyclo[2.2.1]heptane; 2,6-di-tert-butyl-4-methylphenol; butyl stearate; butyl undec-10-enoate; 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)butan-1-ol; (E)-2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)but-2-enal; 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate; (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol; 3,3,6,7-tetramethyloctahydro-2H-chromene; 6,6-dimethylspiro[bicyclo[3.1.1]heptane-2,2′-oxirane]; 3-isopropyl-6-methylenecyclohex-1-ene; 2-ethoxynaphthalene; (R)-3,5,5,9-tetramethyl-2,4a,5,6,7,8-hexahydro-1H-benzo[7]annulene; (1S,4S)-1,4-dimethyl-7-(propan-2-ylidene)-1,2,3,4,5,6,7,8-octahydroazulene; (1R,9S,Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-4-ene; (Z)-4-(2,2,6-trimethyl-7-oxabicyclo[4.1.0]heptan-1-yl)but-3-en-2-one; 4-methoxy-7H-furo[3,2-g]chromen-7-one; 4-phenylbutan-2-one; benzyl 2-hydroxybenzoate; benzyl dodecanoate; benzyl 3-methylbutanoate; benzyl isobutyrate; benzyl cinnamate; benzyl butyrate; phenylmethanol; benzyl benzoate; 1-(3,3-dimethylcyclohexyl)ethyl formate; 4-methoxybenzyl acetate; 4-methoxybenzyl formate; (Z)-1-methoxy-4-(prop-1-en-1-yl)benzene; pentyl benzoate; (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; 2,5,5-trimethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-ol; 2,5,5-trimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-ol; 2-(sec-butyl)-1-vinylcyclohexyl acetate; (1S,4R,5R)-1-isopropyl-4-methylbicyclo[3.1.0]hexan-3-one; 2-(4-methylcyclohex-3-en-1-yl)propan-2-yl propionate; 2-(4-methylcyclohex-3-en-1-yl)propan-2-yl acetate; 1,7-dimethyl-7-(4-methylpent-3-en-1-yl)tricyclo[2.2.1.02,6]heptane; 1-(5,5-dimethylcyclohex-1-en-1-yl)pent-4-en-1-one; (1S,4aS,8aR)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; 4-cyclohexylbutan-2-ol; (R,Z)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)pent-1-en-3-one; (E)-2-methyl-3-phenylacrylaldehyde; (Z)-3-methyl-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-3-en-2-one; (Z)-4-(2,5,6,6-tetramethylcyclohex-2-en-1-yl)but-3-en-2-one; (1Z,4E,8Z)-2,6,6,9-tetramethylcycloundeca-1,4,8-triene; (4aR,8S,9aS)-3,5,5,8-tetramethyl-9-methylene-2,4a,5,6,7,8,9,9a-octahydro-1H-benzo[7]annulene; (1R,4S,4aR,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; (1S,4aR,8aR)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (R)-2-((R)-4-methylcyclohex-3-en-1-yl)hex-5-en-2-ol; (E)-2-benzylideneheptyl acetate; (1S,4aR,8aS)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; 1-phenylpentan-2-ol; 4-methoxy-2,5-dimethylfuran-3(2H)-one; alpha-4-Dimethyl benzenepropanal; allyl 2-phenoxyacetate; (2-(allyloxy)ethyl)benzene; allyl heptanoate; allyl 3-cyclohexylpropanoate; N-ethyl-N-(m-tolyl)propionamide; 2,6,10-trimethylundec-9-enal; 3-hydroxybutan-2-one; 1-(4-methoxyphenyl)ethan-1-one; (Z)-2-(4-methylbenzylidene)heptanal; (Z)-oxacycloheptadec-8-en-2-one; 7-methoxy-2H-chromen-2-one; 6-methylquinoline; 6,8-dimethylnonan-2-ol; 6,10,14-trimethylpentadecan-2-one; 5-methylheptan-3-one; 4-vinylphenol; 1-phenylpent-4-en-1-one; (E)-3-(4-hydroxy-3-methoxyphenyl)acrylaldehyde; 4-ethyl-2-methoxyphenol; 5-methyl-5-phenylhexan-3-one; 4-(4-methoxyphenyl)butan-2-one; (E)-3-propylideneisobenzofuran-1(3H)-one; (Z)-dodec-2-enal; 3-methyl-5-phenylpentanal; 3-methyl-4-phenyl-1H-pyrazole; 3-methylcyclopentane-1,2-dione; 3-methoxy-5-methylphenol; 3-methoxy-3-methylbutan-1-ol; (E)-hex-3-en-1-ol; 3,7-dimethyl-2-methyleneoct-6-enal; 3,7-dimethyloctan-1-ol; (Z)-undec-2-enenitrile; (E)-undec-2-enal; phenethyl acetate; (Z)-3-(furan-2-yl)-2-phenylacrylaldehyde; phenethyl propionate; 2-pentylcyclopentan-1-ol; (2S,4S)-2-heptyl-2,4-dimethyl-1,3-dioxolane; nonan-2-ol; 2-(sec-butyl)-3-methoxypyrazine; 2-isopropyl-N,2,3-trimethylbutanamide; (E)-2-isopropyl-5-methylhex-2-enal; 2-isopropyl-4-methylthiazole; (E)-2-hexylidenecyclopentan-1-one; (E)-hex-2-en-1-ol; 2-butoxyethan-1-ol; (2E,6E)-nona-2,6-dien-1-ol; 1-isopropyl-4-methyl-7-oxabicyclo[2.2.1]heptane; 1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 1,1,2,3,3-pentamethyl-2,3-dihydro-1H-indene; (Z)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-en-1-one; (Z)-6,10-dimethylundeca-5,9-dien-2-yl acetate; (Z)-hept-3-en-1-yl acetate; (1S,5S)-4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-one; (R)-3,7-dimethylocta-1,6-dien-3-ol; 3,7-dimethyloct-6-enal; (E)-6,10-dimethylundeca-5,9-dien-2-yl acetate; (R)-3,7-dimethyloct-6-enal; (2S,5S,6S)-2,6,10,10-tetramethyl-1-oxaspiro[4.5]decan-6-ol; 3,7-dimethyloct-6-en-1-ol; 3,7-dimethyloct-6-en-1-ol; (1R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene; (S)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-one; (1S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene; methyl 2-methylbutanoate; hexyl (Z)-2-methylbut-2-enoate; 2-(8-isopropyl-6-methylbicyclo[2.2.2]oct-5-en-2-yl)-1,3-dioxolane; 3-(3-isopropylphenyl)butanal; allyl 2-(cyclohexyloxy)acetate; 2-((3S,3aS,5R)-3,8-dimethyl-1,2,3,3a,4,5,6,7-octahydroazulen-5-yl)propan-2-ol; 1,5-dimethylbicyclo[3.2.1]octan-8-one oxime; benzyl 2-phenylacetate; 2-hydroxy-1,2-diphenylethan-1-one; (E)-tridec-2-enal; 1-phenylvinyl acetate; p-tolyl isobutyrate; p-tolyl hexanoate; p-cymene; 5-hexyl-4-methyldihydrofuran-2(3H)-one; 2-cyclohexylidene-2-phenylacetonitrile; 4-(prop-1-en-2-yl)cyclohex-1-ene-1-carbaldehyde; (4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methyl acetate; (4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methanol; (2-(cyclohexyloxy)ethyl)benzene; phenethyl 2-methylbutanoate; phenethyl formate; phenethyl isobutyrate; phenethyl 2-phenylacetate; phenethyl (Z)-2-methylbut-2-enoate; phenyl benzoate; phenethyl benzoate; phenethyl methacrylate; 2-(4-isopropylphenyl)acetaldehyde; 1,2-dimethyl-3-(prop-1-en-2-yl)cyclopentan-1-ol; 1-(4-methoxyphenyl)propan-2-one; (2Z,5Z)-5,6,7-trimethylocta-2,5-dien-4-one; 1-methoxy-4-propylbenzene; 2-(4-(tert-butyl)phenyl)acetaldehyde; 4-(tert-pentyl)cyclohexan-1-ol; p-tolyl 2-phenylacetate; Ethyl 2,4,7-decatrienoate; 2,6,6-trimethylbicyclo[3.1.1]hept-2-ene; 4-(4-hydroxyphenyl)butan-2-one; 2-benzyl-4,4,6-trimethyl-1,3-dioxane; 3,7-dimethyloct-7-en-1-ol; ethyl (2,3,6-trimethylcyclohexyl) carbonate; (Z)-6-ethylideneoctahydro-2H-5,8-methanochromene; 2-((S)-1-((S)-3,3-dimethylcyclohexyl)ethoxy)-2-oxoethyl propionate; methyl 2,2-dimethyl-6-methylenecyclohexane-1-carboxylate; 1-(3,3-dimethylcyclohexyl)ethyl acetate; (S)-3,7-dimethylocta-1,6-dien-3-ol; 1-isopropyl-4-methylenebicyclo[3.1.0]hexane; 5-isopropyl-2-methylbicyclo[3.1.0]hexan-2-ol; (1S,3R,5S)-1-isopropyl-4-methylenebicyclo[3.1.0]hexan-3-ol; 3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pentan-2-ol; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; propyl (S)-2-(tert-pentyloxy)propanoate; (4aR,8aR)-4a,8-dimethyl-2-(propan-2-ylidene)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropyl cyclopropanecarboxylate; (1R,3R,6R)-2′,2′,3,7,7-pentamethylspiro[bicyclo[4.1.0]heptane-2,5′-[1,3]dioxane]; 1-oxaspiro(4,5)decan-2-one; (Z)-5-methylheptan-3-one oxime; 1-phenylethyl acetate; (1S,4S,4aR,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; (1S,4S,4aR,8aS)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; 3,7-dimethyloctanal; 4-(2,2,6-trimethylcyclohexyl)butan-2-ol; 3-methyl-2-pentylcyclopentan-1-one; 3,7-dimethyloctan-3-ol; 3,7-dimethyloctan-3-yl acetate; 2,6,10,10-tetramethyl-1-oxaspiro[4.5]dec-6-ene; ethyl (1R,6S)-2,2,6-trimethylcyclohexane-1-carboxylate; 2-isopropyl-5-methylphenol; 1-isopropyl-2-methoxy-4-methylbenzene; 1-(2,2,6-trimethylcyclohexyl)hexan-3-ol; (E)-hex-2-en-1-ol; (1R,2S)-2-(tert-butyl)cyclohexan-1-ol; (Z)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-en-1-one; (Z)-oxacycloheptadec-8-en-2-one; (Z)-1-methoxy-4-(prop-1-en-1-yl)benzene; cinnamic acid; (2R,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-one; (E)-3,7-dimethylocta-2,6-dien-1-ol; (Z)-2-methoxy-4-(prop-1-en-1-yl)phenol; 2,2,2-trichloro-1-phenylethyl acetate; triethyl 2-hydroxypropane-1,2,3-tricarboxylate; methyl 2-((1-hydroxy-3-phenylbutyl)amino)benzoate; 1-((2E,5Z,9Z)-2,6,10-trimethylcyclododeca-2,5,9-trien-1-yl)ethan-1-one; 2-mercapto-2-methylpentan-1-ol; 13-methyl oxacyclopentadec-10-en-2-one; undecanal; (E)-4-methyldec-3-en-5-ol; (3R,4aS,5R)-4a,5-dimethyl-3-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,7-octahydronaphthalene; 4-formyl-2-methoxyphenyl acetate; 4-formyl-2-methoxyphenyl isobutyrate; (Z)-2-ethoxy-5-(prop-1-en-1-yl)phenol; 2,2,5-trimethyl-5-pentylcyclopentan-1-one; (Z)-2-methyl-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-enal; 3,4-dimethoxybenzaldehyde; (1R,5R)-4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-one; 1-methoxy-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoindene; 2-(tert-butyl)cyclohexan-1-ol; cis-(4-tert-butylcyclohexyl)acetate; 4-(tert-butyl)cyclohexyl acetate; 2,4-diethoxy-5-methylpyrimidine; 4-methyl-4-phenylpentan-2-yl acetate; 4,8-dimethyl-2-(propan-2-ylidene)-1,2,3,3a,4,5,6,8a-octahydroazulen-6-ol; (Z)-cyclooct-4-en-1-yl methyl carbonate; (Z)-1-((2-methylallyl)oxy)hex-3-ene; 4-(4-hydroxy-3-methoxyphenyl)butan-2-one; (1R,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,7,8,8a-hexahydronaphthalene; 4,5-epoxy-4,11,11-trimethyl-8-methylenebicyclo(7.2.0)undecane; 1,3,4,6,7,8alpha-hexahydro-1,1,5,5-tetramethyl-2H-2,4alpha-methanophtalen-8(5H)-one preferably said malodor reduction materials are selected from the group consisting of: 2-ethylhexyl (Z)-3-(4-methoxyphenyl)acrylate; 2,4-dimethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolane; 1,1-dimethoxynon-2-yne; 2-(p-tolyl)propan-2-ol; 3-methoxy-7,7-dimethyl-10-methylenebicyclo[4.3.1]decane; methoxycyclododecane; 1,1-dimethoxycyclododecane; (Z)-tridec-2-enenitrile; (2-hydroxy-4-methoxyphenyl)(phenyl)methanone; 2,4a,5,8a-tetramethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl formate; 4-methyl-1-oxaspiro[5.5]undecan-4-ol; 7-methyl-2H-benzo[b][1,4]dioxepin-3(4H)-one; 1,8-dioxacycloheptadecan-9-one; 4-(tert-pentyl)cyclohexan-1-one; 2-methoxy-1,1′-biphenyl; 3a,5,6,7,8,8b-hexahydro-2,2,6,6,7,8,8-heptamethyl-4H-indeno(4,5-d)-1,3-dioxole; 7-isopropyl-8,8-dimethyl-6,10-dioxaspiro[4.5]decane; octyl furan-2-carboxylate; octyl acetate; 2-heptyl-4-methyl-1,3-dioxolane; octanal; 1,1-dimethoxyoctane; 7-methyl-3-methyleneocta-1,6-diene; 2-methyl-6-methyleneoct-7-en-2-ol; 2-methyl-6-methyleneoct-7-en-2-yl acetate; tetradecanal; 4-methoxy-6-prop-2-enyl-1,3-benzodioxole; tetradecanenitrile; 2,2,6,8-tetramethyl-1,2,3,4,4a,5,8,8a-octahydronaphthalen-1-ol; (E)-2,6-dimethylocta-5,7-dien-2-ol; (E)-2,7-dimethylocta-1,5,7-trien-3-ol; 2-((1S,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethyl acetate; (4R,4aS,6R)-4,4a-dimethyl-6-(prop-1-en-2-yl)-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one; nonan-1-ol; nonanal; 12-methyl-14-tetradec-9-enolide; N-ethyl-2-isopropyl-5-methylcyclohexane-1-carboxamide; 1-(3-methylbenzofuran-2-yl)ethan-1-one; 2-methoxynaphthalene; (E)-3,7,11-trimethyldodeca-1,6,10-trien-3-ol; (Z)-3,7-dimethylocta-2,6-dien-1-ol; 1-ethyl-3-methoxytricyclo[2.2.1.02,6]heptane; methyl (E)-non-2-enoate; 10-isopropyl-2,7-dimethyl-1-oxaspiro[4.5]deca-3,6-diene; 2-(2-(4-methylcyclohex-3-en-1-yl)propyl)cyclopentan-1-one; 6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-carbaldehyde; (E)-4-(2,2,3,6-tetramethylcyclohexyl)but-3-en-2-one; (4-(4-methylpent-3-en-1-yl)cyclohex-3-en-1-yl)methyl acetate; 2-(tert-butyl)-4,5,6-trimethyl-1,3-phenylene dinitrite; 1,7-dioxacycloheptadecan-8-one; 1-(4-(tert-butyl)-2,6-dimethyl-3,5-dinitrophenyl)ethan-1-one; 1-(tert-butyl)-2-methoxy-4-methyl-3,5-dinitrobenzene; 3-methylcyclopentadecan-1-one; (E)-3-methylcyclopentadec-4-en-1-one; 3-methyl-4-phenylbutan-2-ol; 1-(4-isopropylcyclohexyl)ethan-1-ol; (E)-dec-5-enoic acid; methyl non-2-ynoate; 2-methyldecanal; 6,6-dimethoxy-2,5,5-trimethylhex-2-ene; 4-phenylbutan-2-ol; methyl stearate; 1,1-dimethoxy-2-methylundecane; undecan-2-one; 2-methylundecanal; methyl tetradecanoate; methyl (9Z,12Z)-octadeca-9,12-dienoate; 1-hydroxydecan-3-one; (Z)-1,2-dimethoxy-4-(prop-1-en-1-yl)benzene; methyl palmitate; 4-allyl-1,2-dimethoxybenzene; methyl 2-((1R,2R)-3-oxo-2-((Z)-pent-2-en-1-yl)cyclopentyl)acetate; methyl 2-(3-oxo-2-pentylcyclopentyl)acetate; 1-methyl-2-phenoxybenzene; methyl cinnamate; 1-allyl-4-methoxybenzene; 1-(naphthalen-2-yl)ethan-1-one; methyl oct-2-ynoate; methyl 2,6,6-trimethylcyclohex-2-ene-1-carboxylate; 7-methoxy-3,7-dimethyloctanal; 7-isopropyl-10-methyl-1,5-dioxaspiro[5.5]undecan-3-ol; octahydro-1H-4,7-methanoindene-1-carbaldehyde; 3-(3-(tert-butyl)phenyl)-2-methylpropanal; (E)-4-(4,8-dimethylnona-3,7-dien-1-yl)pyridine; (E)-trideca-3,12-dienenitrile; 2,2-dimethyl-3-(m-tolyl)propan-1-ol; 2,4-dimethyl-4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; 8-isopropyl-6-methylbicyclo[2.2.2]oct-5-ene-2-carbaldehyde; 4-(4-hydroxy-4-methylpentyl)cyclohex-3-ene-1-carbaldehyde; (S)-1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene; (Z)-3-hexen-1-yl-2-cyclopenten-1-one; 3,7-dimethylocta-1,6-dien-3-yl octanoate; 3,7-dimethylocta-1,6-dien-3-yl isobutyrate; 3,7-dimethylocta-1,6-dien-3-yl benzoate; 3,7-dimethylocta-1,6-dien-3-yl 2-aminobenzoate; 2-(5-methyl-5-vinyltetrahydrofuran-2-yl)propan-2-ol; 6-methyl-2-(oxiran-2-yl)hept-5-en-2-ol; (2Z,6E)-3,7-dimethylnona-2,6-dienenitrile; 3-(4-methylcyclohex-3-en-1-yl)butanal; (2,5-dimethyl-1,3-dihydroinden-2-yl)methanol; 3-(4-(tert-butyl)phenyl)-2-methylpropanal; (E)-1-(1-methoxypropoxy)hex-3-ene; (E)-1-(1-ethoxyethoxy)hex-3-ene; (1S,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-ol; dodecan-1-ol; dodecyl acetate; dodecanoic acid; 5-hexyl-5-methyldihydrofuran-2(3H)-one; dodecanal; 3,6-dimethylhexahydrobenzofuran-2(3H)-one; 4-(1-ethoxyvinyl)-3,3,5,5-tetramethylcyclohexan-1-one; ((3S,3aR,6R,8aS)-7,7-dimethyl-8-methyleneoctahydro-1H-3a,6-methanoazulen-3-yl)methanol; 5-(sec-butyl)-2-(2,4-dimethylcyclohex-3-en-1-yl)-5-methyl-1,3-dioxane; (1-methyl-2-((1,2,2-trimethylbicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methanol; 2-propylheptanenitrile; (E)-6-(pent-3-en-1-yl)tetrahydro-2H-pyran-2-one; 2-hexylcyclopentan-1-one; 2-methyl-4-phenyl-1,3-dioxolane; 2,6,9,10-tetramethyl-1-oxaspiro(4.5)deca-3,6-diene; (1R,2S,5R)-5-methyl-2-(prop-1-en-2-yl)cyclohexan-1-ol; isopropyl palmitate; isopropyl tetradecanoate; isopropyl dodecanoate; 4,9-dimethoxy-7H-furo[3,2-g]chromen-7-one; (E)-cyclohexadec-8-en-1-one; (2S,5S)-2-isopropyl-5-methylcyclohexan-1-one; 2-hexylcyclopent-2-en-1-one; (2S,5S)-2-isopropyl-5-methylcyclohexan-1-one; 4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; (Z)-1-(benzyloxy)-2-methoxy-4-(prop-1-en-1-yl)benzene; 1-((2S,3S)-2,3,8,8-tetramethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-yl)ethan-1-one; 2,5,6-trimethylcyclohex-3-ene-1-carbaldehyde; 6-(sec-butyl)quinoline; 2-(cyclohexyloxy)-1,7,7-trimethylbicyclo[2.2.1]heptane; (1R,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl propionate; (1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate; 4-((2R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)cyclohexan-1-ol; (1R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 2-(4-isopropylcyclohexa-1,4-dien-1-yl)ethyl formate; isopentyl (E)-undec-6-enoate; isopentyl dodecanoate; (E)-oxacycloheptadec-10-en-2-one; (E)-non-2-enenitrile; (E)-8-(1H-indol-1-yl)-2,6-dimethyloct-7-en-2-ol; 8,8-di(1H-indol-1-yl)-2,6-dimethyloctan-2-ol; 4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; 3,7-dimethyloctane-1,7-diol; 2-cyclododecylpropan-1-ol; 3-methyl-5-phenylpentanenitrile; 3-phenylpropan-1-ol; (1,1-dimethoxypropan-2-yl)benzene; 5-ethyl-4-hydroxy-2-methylfuran-3(2H)-one; 2,3-dihydro-3,3-dimethyl-1H-indene-5-propanal; 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)propanal; hexyl octanoate; hexyl hexanoate; (Z)-2-benzylideneoctanal; hexyl benzoate; (Z)-hex-1-en-1-yl (Z)-2-methylbut-2-enoate; (E)-3,7-dimethylocta-2,6-dien-1-yl palmitate; oxacycloheptadecan-2-one; 2-butyl-4,4,6-trimethyl-1,3-dioxane; ethyl (1R,2R,3R,4R)-3-isopropylbicyclo[2.2.1]hept-5-ene-2-carboxylate; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl acetate; 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropyl propionate; 5-(diethoxymethyl)benzo[d][1,3]dioxole; 3-(benzo[d][1,3]dioxol-5-yl)-2-methylpropanal; (E)-oxacyclohexadec-13-en-2-one; 6-butyl-2,4-dimethyl-3,6-dihydro-2H-pyran; 2-((3S,5R,8S)-3,8-dimethyl-1,2,3,4,5,6,7,8-octahydroazulen-5-yl)propan-2-ol; 1-(2,6,6-trimethylcyclohex-2-en-1-yl)pentan-3-one; ethyl 2-ethyl-6,6-dimethylcyclohex-2-ene-1-carboxylate; (1Z,5Z)-1,5-dimethyl-8-(propan-2-ylidene)cyclodeca-1,5-diene; (1E,6E)-8-isopropyl-1-methyl-5-methylenecyclodeca-1,6-diene; (E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate; (E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate; (6E,10E)-3,7,11,15-tetramethylhexadeca-1,6,10,14-tetraen-3-ol; (E)-2-(3,7-dimethylocta-2,6-dien-1-yl)cyclopentan-1-one; 5-heptyldihydrofuran-2(3H)-one; 1-methyl-4-(propan-2-ylidene)cyclohexyl acetate; 1-methyl-4-(propan-2-ylidene)cyclohexan-1-ol; 5-pentyldihydrofuran-2(3H)-one; (1R,4aR,8aS)-1-isopropyl-7-methyl-4-methylene-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 5-[(Z)-hex-3-enyl]oxolan-2-one; (Z)-4-(2,2-dimethyl-6-methylenecyclohexyl)but-3-en-2-one; (4aS,9aR)-3,5,5,9-tetramethyl-2,4a,5,6,7,9a-hexahydro-1H-benzo[7]annulene; (1R,3aR,4R,7R)-1,4-dimethyl-7-(prop-1-en-2-yl)-1,2,3,3a,4,5,6,7-octahydroazulene; 2-((2R,4aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)propan-2-ol; 5-octyldihydrofuran-2(3H)-one; (Z)-1-(2,2-dimethyl-6-methylenecyclohexyl)but-2-en-1-one; 5-hexyldihydrofuran-2(3H)-one; (1R,4aS,8aS)-1-isopropyl-7-methyl-4-methylene-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 1-(3,3-dimethylcyclohexyl)pent-4-en-1-one; 4,6,6,7,8,8-hexamethyl-1,3,4,6,7,8-hexahydrocyclopenta[g]isochromene; furan-2-ylmethyl octanoate; furan-2-ylmethyl hexanoate; furan-2-ylmethyl heptanoate; 2-methyldecanenitrile; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; ethyl (3aR,4S,7R,7aR)-octahydro-3aH-4,7-methanoindene-3a-carboxylate; diethyl cyclohexane-1,4-dicarboxylate; (6-isopropyl-9-methyl-1,4-dioxaspiro[4.5]decan-2-yl)methanol; 2-isobutyl-4-methyltetrahydro-2H-pyran-4-ol; undec-10-enenitrile; (Z)-6-ethylideneoctahydro-2H-5,8-methanochromen-2-one; 3-(2-ethylphenyl)-2,2-dimethylpropanal; (E)-4,8-dimethyldeca-4,9-dienal; (E)-4-((3aR,4R,7R,7aR)-1,3a,4,6,7,7a-hexahydro-5H-4,7-methanoinden-5-ylidene)-3-methylbutan-2-ol; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl acetate; 3-(4-ethylphenyl)-2,2-dimethylpropanenitrile; 2-heptylcyclopentan-1-one; 1-ethoxyethoxy Cyclododecane; 3-cyclohexene-1-carboxylic acid, 2,6,6-trimethyl-, methyl ester; (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl acetate; (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol; oxacyclohexadecan-2-one; (E)-cyclopentadec-4-en-1-one; 1-cyclopentadec-4-en-1-one; 2-methoxy-4-(4-methylenetetrahydro-2H-pyran-2-yl)phenol; 4-allyl-2-methoxyphenyl acetate; 4-allyl-2-methoxyphenol; ethyl 3-methyl-3-phenyloxirane-2-carboxylate; 1,4-dioxacycloheptadecane-5,17-dione; ethyl undec-10-enoate; ethyl palmitate; ethyl nonanoate; ethyl tetradecanoate; (E)-3,7-dimethylnona-1,6-dien-3-ol; ethyl dodecanoate; nonan-3-one; ethyl decanoate; ethyl 6,6-dimethyl-2-methylenecyclohex-3-ene-1-carboxylate; ethyl 3-phenyloxirane-2-carboxylate; 6-ethyl-2,10,10-trimethyl-1-oxaspiro[4.5]deca-3,6-diene; 2-((1R,3S,4S)-4-methyl-3-(prop-1-en-2-yl)-4-vinylcyclohexyl)propan-2-ol; (2-(1-ethoxyethoxy)ethyl)benzene; (E)-3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pent-4-en-2-ol; (2R,3S,4R)-2,3,4,5-tetrahydroxypentanal; (E)-4-((3aS,7aS)-octahydro-5H-4,7-methanoinden-5-ylidene)butanal; 1,1-dimethoxydodecane; (R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene; 2-(2-hydroxypropoxy)propan-1-ol; 7,9-dimethylspiro[5.5]undecan-3-one; oxydibenzene; diphenylmethane; 2-methyl-1-phenylpropan-2-yl butyrate; 2,6-dimethyloct-7-en-4-one; octahydro-1H-4,7-methanoinden-5-yl acetate; 2-methyl-5-(prop-1-en-2-yl)cyclohexyl acetate; 2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-ol; 3,7-dimethyloct-6-en-3-ol; methyl 2-hexyl-3-oxocyclopentane-1-carboxylate; dibutylsulfane; 1,2-diphenylethane; 6-hexyltetrahydro-2H-pyran-2-one; (3R,4R)-1-isopropyl-4-methyl-3-(prop-1-en-2-yl)-4-vinylcyclohex-1-ene; (3S,3aS,5R)-3,8-dimethyl-5-(prop-1-en-2-yl)-1,2,3,3a,4,5,6,7-octahydroazulene; 6-heptyltetrahydro-2H-pyran-2-one; 6-pentyltetrahydro-2H-pyran-2-one; (1S,8aR)-4,7-dimethyl-1-(propan-2-yl)-1,2,3,5,6,8a-hexahydronaphthalene; (Z)-1-((1R,2S)-2,6,6-trimethylcyclohex-3-en-1-yl)but-2-en-1-one; (1S,8aS)-1-isopropyl-4,7-dimethyl-1,2,3,5,6,8a-hexahydronaphthalene; 3,7,7-trimethylbicyclo[4.1.0]hept-3-ene; dec-9-en-1-ol; decyl propionate; 1,1-diethoxydecane; decahydronaphthalen-2-ol; 1-cyclohexylethyl (E)-but-2-enoate; 3-(4-isopropylphenyl)-2-methylpropanal; cyclotetradecane; cyclopentadecanone; cyclohexyl 2-hydroxybenzoate; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl butyrate; 1,4-dioxacyclohexadecane-5,16-dione; 8,8-dimethyl-1,2,3,4,5,6,7,8-octahydronaphthalene-2-carbaldehyde; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl isobutyrate; (5R,6R)-3,6-dimethyl-5-(prop-1-en-2-yl)-6-vinyl-4,5,6,7-tetrahydrobenzofuran; (4-isopropylphenyl)methanol; 1-(benzofuran-2-yl)ethan-1-one; 2-(3-phenylpropyl)pyridine; dodecanenitrile; (E)-cycloheptadec-9-en-1-one; 3-(4-methylcyclohex-3-en-1-yl)but-3-en-1-yl acetate; 3-(4-methylcyclohex-3-en-1-yl)butan-1-ol; (E)-3-methyl-5-phenylpent-2-enenitrile; (E)-2-(2,6-dimethylhepta-1,5-dien-1-yl)-4-methyl-1,3-dioxolane; (E)-1,1-dimethoxy-3,7-dimethylocta-2,6-diene; (E)-1,1-diethoxy-3,7-dimethylocta-2,6-diene; (E)-3,7-dimethylocta-1,3,6-triene; (1R,4R,6S)-1-methyl-4-(prop-1-en-2-yl)-7-oxabicyclo[4.1.0]heptane; (E)-oxacycloheptadec-11-en-2-one; (Z)-non-6-en-1-ol; (1R,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-ol; (Z)-dec-4-enal; (E)-hex-3-en-1-yl (E)-hex-3-enoate; (Z)-hex-3-en-1-yl 2-hydroxybenzoate; (Z)-hex-3-en-1-yl benzoate; (Z)-hex-3-en-1-yl 2-methylbutanoate; (3Z,6Z)-nona-3,6-dien-1-ol; cinnamyl propionate; cinnamyl isobutyrate; cinnamyl formate; cinnamyl cinnamate; cinnamyl acetate; (E)-3-phenylprop-2-en-1-ol; hexadecan-1-ol; (E)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)hepta-1,6-dien-3-one; 2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butanal; (3aR,5aR,9aR,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; 1,6-dioxacycloheptadecan-7-one; 1-(6-(tert-butyl)-1,1-dimethyl-2,3-dihydro-1H-inden-4-yl)ethan-1-one; (3R,3aR,6S,7S,8aS)-6-methoxy-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-3-yl formate; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl acetate; (4Z,8Z)-1,5,9-trimethyl-13-oxabicyclo[10.1.0]trideca-4,8-diene; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-ol; 5-methyl-1-(2,2,3-trimethylcyclopent-3-en-1-yl)-6-oxabicyclo[3.2.1]octane; 5-methyl-1-(2,2,3-trimethylcyclopent-3-en-1-yl)-6-oxabicyclo[3.2.1]octane; 1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-4H-inden-4-one; (Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-3-en-5-yl acetate; (1S,2S,5R,8S)-4,4,8-trimethyltricyclo[6.3.1.02,5]dodecan-1-ol; 2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-yl acetate; octanenitrile; octan-1-ol; octanoic acid; decanoic acid; decanal; 3-(4-methoxyphenyl)-2-methylpropanal; 1,7,7-trimethylbicyclo[2.2.1]heptane-2,3-dione; 2,2-dimethyl-3-methylenebicyclo[2.2.1]heptane; ethyl 2-methyl-4-oxo-6-pentylcyclohex-2-ene-1-carboxylate; 2,6-di-tert-butyl-4-methylphenol; butyl stearate; 1-butoxy-1-oxopropan-2-yl butyrate; butyl undec-10-enoate; 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)butan-1-ol; 3-(4-(tert-butyl)phenyl)propanal; (1S,2S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate; 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 2-ethoxy-2,6,6-trimethyl-9-methylenebicyclo[3.3.1]nonane; (ethoxymethoxy)cyclododecane; (E)-1-methyl-4-(6-methylhept-5-en-2-ylidene)cyclohex-1-ene; 3,3,6,7-tetramethyloctahydro-2H-chromene; (5R,10R)-6,10-dimethyl-2-(propan-2-ylidene)spiro[4.5]dec-6-en-8-one; 1-methyl-4-(prop-1-en-2-yl)cyclohexyl acetate; 1-methyl-4-(prop-1-en-2-yl)cyclohexan-1-ol; (2Z,6E)-2,6-dimethyl-10-methylenedodeca-2,6,11-trienal; (R)-3-methylene-6-((S)-6-methylhept-5-en-2-yl)cyclohex-1-ene; (4aR,7R,8aS)-4a-methyl-1-methylene-7-(prop-1-en-2-yl)decahydronaphthalene; (Z)-2-methyl-5-((1S,2R,4R)-2-methyl-3-methylenebicyclo[2.2.1]heptan-2-yl)pent-2-en-1-ol; 6,6-dimethyl-2-methylenebicyclo[3.1.1]heptane; 2-ethoxynaphthalene; (1S,4R,7R)-1,4,9,9-tetramethyl-1,2,3,4,5,6,7,8-octahydro-4,7-methanoazulene; (1aS,5aR,9aR)-1a,5,5,7-tetramethyl-1a,2,3,4,5,5a,8,9-octahydrobenzo[1,7]cyclohepta[1,2-b]oxirene; (R)-3,5,5,9-tetramethyl-2,4a,5,6,7,8-hexahydro-1H-benzo[7]annulene; (1S,4S)-1,4-dimethyl-7-(propan-2-ylidene)-1,2,3,4,5,6,7,8-octahydroazulene; (2,2-dimethoxyethyl)benzene; (E)-7,11-dimethyl-3-methylenedodeca-1,6,10-triene; (1R,2S,6S,7S,8S)-8-isopropyl-1-methyl-3-methylenetricyclo[4.4.0.02,7]decane; (3R,3aS,7S,8aS)-3,8,8-trimethyl-6-methyleneoctahydro-1H-3a,7-methanoazulene; (1R,9S,Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-4-ene; (S)-4-methyl-1-((S)-6-methylhept-5-en-2-yl)cyclohex-3-en-1-ol; (Z)-4-(2,2,6-trimethyl-7-oxabicyclo[4.1.0]heptan-1-yl)but-3-en-2-one; 4-methoxy-7H-furo[3,2-g]chromen-7-one; 2-methyl-4-phenylbutan-2-ol; benzyl dodecanoate; 2-methyl-1-phenylpropan-2-ol; benzyl cinnamate; benzyl benzoate; benzophenone; 7-isopentyl-2H-benzo[b][1,4]dioxepin-3(4H)-one; 2′-isopropyl-1,7,7-trimethylspiro[bicyclo[2.2.1]heptane-2,4′-[1,3]dioxane]/A; 4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbonitrile; methyl (E)-2-((7-hydroxy-3,7-dimethyloctylidene)amino)benzoate; 4-methoxybenzyl 2-phenylacetate; methyl (E)-octa-4,7-dienoate; pentyl (Z)-3-phenylacrylate; (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; (4aR,5R,7aS,9R)-2,2,5,8,8,9a-hexamethyloctahydro-4H-4a,9-methanoazuleno[5,6-d][1,3]dioxole; 2,5,5-trimethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-ol; 2,5,5-trimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-ol; 1-((2-(tert-butyl)cyclohexyl)oxy)butan-2-ol; (3S,5aR,7aS,11aS,11bR)-3,8,8,11a-tetramethyldodecahydro-5H-3,5a-epoxynaphtho[2,1-c]oxepine; 2,2,6,6,7,8,8-heptamethyldecahydro-2H-indeno[4,5-b]furan; 2,2,7,7,8,9,9-heptamethyldecahydroindeno[4,3a-b]furan; 2-(sec-butyl)-1-vinylcyclohexyl acetate; (1S,4R,5R)-1-isopropyl-4-methylbicyclo[3.1.0]hexan-3-one; (4R,4aS)-4,4a-dimethyl-6-(propan-2-ylidene)-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one; 2-(4-methylcyclohex-3-en-1-yl)propan-2-yl propionate; (2Z,6E,9E)-2,6,10-trimethyldodeca-2,6,9,11-tetraenal; (2R,4aR,8aR)-4a,8-dimethyl-2-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 1,7-dimethyl-7-(4-methylpent-3-en-1-yl)tricyclo[2.2.1.02,6]heptane; (E)-5-(2,3-dimethyltricyclo[2.2.1.02,6]heptan-3-yl)-2-methylpent-2-en-1-ol; (1R,3aS,7S,8aR)-1,4,9,9-tetramethyl-2,3,6,7,8,8a-hexahydro-1H-3a,7-methanoazulene; 1-(5,5-dimethylcyclohex-1-en-1-yl)pent-4-en-1-one; (1S,4aS,8aR)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (R,Z)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)pent-1-en-3-one; 1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene; (Z)-4-(2,5,6,6-tetramethylcyclohex-2-en-1-yl)but-3-en-2-one; (1Z,4E,8Z)-2,6,6,9-tetramethylcycloundeca-1,4,8-triene; (4aR,8S,9aS)-3,5,5,8-tetramethyl-9-methylene-2,4a,5,6,7,8,9,9a-octahydro-1H-benzo[7]annulene; (1aR,4R,4aR,7bS)-1,1,4,7-tetramethyl-1a,2,3,4,4a,5,6,7b-octahydro-1H-cyclopropa[e]azulene; 1,4-dimethyl-7-(prop-1-en-2-yl)-1,2,3,4,5,6,7,8-octahydroazulene; (3E,6E)-3,7,11-trimethyldodeca-1,3,6,10-tetraene; 7,7-dimethyl-2-methylenebicyclo[2.2.1]heptane; 2-((2R,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl)propan-2-ol; (R)-1-methyl-4-(6-methylhept-5-en-2-yl)benzene; (3aR,3bR,4S,7R,7aS)-4-isopropyl-7-methyl-3a,3b,4,5,6,7-hexahydro-1H-cyclopenta[1,3]cyclopropa[1,2]benzene; (1aS,2aR,3R,5aS,7R,7aR)-3,6,6,7a-tetramethyloctahydro-2H-2a,7-methanoazuleno[5,6-b]oxirene; (1R,4S,4aR,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; (1S,4aR,8aR)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (R)-2-((R)-4-methylcyclohex-3-en-1-yl)hex-5-en-2-ol; (Z)-1-methyl-4-(6-methylhepta-2,5-dien-2-yl)cyclohex-1-ene; 2,6-dimethyl-6-(4-methylpent-3-en-1-yl)bicyclo[3.1.1]hept-2-ene; (E)-2-benzylideneheptan-1-ol; (E)-2-benzylideneheptyl acetate; (Z)-(2-(diethoxymethyl)hept-1-en-1-yl)benzene; (E)-2-benzylideneheptanal; (1S,4aR,8aS)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (3R,5aS,9aR)-2,2,5a,9-tetramethyl-3,4,5,5a,6,7-hexahydro-2H-3,9a-methanobenzo[b]oxepine; 1-methyl-4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; 1-phenylpentan-2-ol; 3-methyl-1-phenylpentan-3-ol; 2,3,4-trimethoxybenzaldehyde; 2,4,5-trimethoxybenzaldehyde; 2,4,6-trimethoxybenzaldehyde; Trans,Trans-2,4-Nonadienal; 2,6,10-trimethylundecanal; alpha-4-Dimethyl benzenepropanal; allyl 3-cyclohexylpropanoate; allyl 2-(isopentyloxy)acetate; (1aR,4aS,7R,7aR,7bS)-1,1,7-trimethyl-4-methylenedecahydro-1H-cyclopropa[e]azulene; (E)-undec-9-enal; methyl (E)-2-(((3,5-dimethylcyclohex-3-en-1-yl)methylene)amino)benzoate; 2,6,10-trimethylundec-9-enal; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methyl acetate; nonyl acetate; (2-(1-propoxyethoxy)ethyl)benzene; 1-(1-propoxyethoxy)propane; ((1-(2-methoxyethoxy)ethoxy)methyl)benzene; (Z)-2-(4-methylbenzylidene)heptanal; dec-9-enal; (Z)-oxacycloheptadec-8-en-2-one; 7-methoxy-2H-chromen-2-one; (2S,4aR,8aR)-4a,8-dimethyl-2-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 2-((2S,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl)propan-2-ol; 1-(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethan-1-one; 6-isopropylquinoline; 3-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)propanal; 6,10,14-trimethylpentadecan-2-one; 2-methyl-5-(prop-1-en-2-yl)-2-vinyltetrahydrofuran; (E)-cyclohexadec-5-en-1-one; 1-isopropyl-4-methylcyclohex-3-en-1-ol; 1-phenylpent-4-en-1-one; 1-isopropyl-4-methylcyclohex-3-en-1-ol; 3,6-dimethyl-4,5,6,7-tetrahydrobenzofuran; 4-(4-methoxyphenyl)butan-2-one; (1aR,2S,4aS)-2,4a,8,8-tetramethyloctahydrocyclopropa[d]naphthalen-3(1H)-one; (E)-3-propylideneisobenzofuran-1(3H)-one; (Z)-dodec-2-enal; 3-methyl-5-phenylpentanal; (E)-hex-3-en-1-yl 3-methylbutanoate; 3,6-dimethyloctan-3-yl acetate; 3,4,5-trimethoxybenzaldehyde; 3-(4-isopropylphenyl)propanal; (Z)-undec-2-enenitrile; (E)-undec-2-enal; (2E,6E)-nona-2,6-dienal; phenethyl butyrate; (Z)-3-(furan-2-yl)-2-phenylacrylaldehyde; 2-phenoxyethan-1-ol; (Z)-non-2-enal; nonan-2-ol; nonan-2-one; 2-isobutylquinoline; (E)-2-hexylidenecyclopentan-1-one; 2-heptyltetrahydrofuran; (E)-dec-2-enal; (2E,6E)-nona-2,6-dienal; (2E,6E)-nona-2,6-dien-1-ol; 2,6-dimethyloctanal; decan-1-ol; (E)-hept-1-en-1-yl acetate; undec-10-en-1-ol; undec-10-enal; 2-((2R,4aS)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)propan-2-ol; 1-isopropyl-4-methyl-7-thiabicyclo[2.2.1]heptane; (3E,5Z)-undeca-1,3,5-triene; 3,7-dimethyloct-6-en-3-ol; 1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 1,1,2,3,3-pentamethyl-2,3-dihydro-1H-indene; (Z)-6,10-dimethylundeca-5,9-dien-2-yl acetate; (Z)-dodec-3-enal; (S)-5-heptyldihydrofuran-2(3H)-one; (R)-5-heptyldihydrofuran-2(3H)-one; (E)-6,10-dimethylundeca-5,9-dien-2-yl acetate; (Z)-3-methyl-5-phenylpent-2-enenitrile; (2S,5S,6S)-2,6,10,10-tetramethyl-1-oxaspiro[4.5]decan-6-ol; (2E)-3-methyl-5-phenyl-2-pentenenitrile; (1S,2S,5S)-2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-ol; (2S,5R)-2-isopropyl-5-methylcyclohexan-1-one; (R,E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 2-(8-isopropyl-6-methylbicyclo[2.2.2]oct-5-en-2-yl)-1,3-dioxolane; (E)-4-(2,2-dimethyl-6-methylenecyclohexyl)-3-methylbut-3-en-2-one; 3-(3-isopropylphenyl)butanal; 3-(1-ethoxyethoxy)-3,7-dimethylocta-1,6-diene; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; 2-((3S,3aS,5R)-3,8-dimethyl-1,2,3,3a,4,5,6,7-octahydroazulen-5-yl)propan-2-ol; benzyl 2-phenylacetate; 2-hydroxy-1,2-diphenylethan-1-one; (E)-1,2,4-trimethoxy-5-(prop-1-en-1-yl)benzene; 3-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-2,2-dimethylpropanal; 2-methyl-5-(6-methylhept-5-en-2-yl)bicyclo[3.1.0]hex-2-ene; 1-(1,1,2,3,3,6-hexamethyl-2,3-dihydro-1H-inden-5-yl)ethan-1-one; 2-(m-tolyl)ethan-1-ol; (3E,6E)-nona-3,6-dien-1-ol; (E)-tridec-2-enal; (1R,4S,4aS,6R,8aS)-4,8a,9,9-tetramethyloctahydro-1,6-methanonaphthalen-1(2H)-ol; p-tolyl isobutyrate; p-tolyl hexanoate; 5-hexyl-4-methyldihydrofuran-2(3H)-one; ethyl (2Z,4E)-deca-2,4-dienoate; 2,4-dimethyl-6-phenyl-3,6-dihydro-2H-pyran; 2-cyclohexylidene-2-phenylacetonitrile; 4-(prop-1-en-2-yl)cyclohex-1-ene-1-carbaldehyde; (4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methyl acetate; (4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methanol; (2-isopropoxyethyl)benzene; 2-cyclohexylhepta-1,6-dien-3-one; (2-(cyclohexyloxy)ethyl)benzene; phenethyl 2-methylbutanoate; 2-phenylethan-1-ol; phenethyl 2-phenylacetate; 3-methyl-5-phenylpentan-1-ol; phenyl benzoate; phenethyl benzoate; 2-benzyl-1,3-dioxolane; 2-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)acetaldehyde; 6,6-dimethyl-2-methylenebicyclo[3.1.1]heptan-3-ol; 4-(benzo[d][1,3]dioxol-5-yl)butan-2-one; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-ylpivalate; (4aR,8aS)-7-methyloctahydro-1,4-methanonaphthalen-6(2H)-one; 4-isopropyl-1-methylcyclohex-3-en-1-ol; (E)-3,3-dimethyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pent-4-en-2-ol; 1-methyl-4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; propane-1,2-diol; p-tolyl 2-phenylacetate; Ethyl 2,4,7-decatrienoate; 2-benzyl-4,4,6-trimethyl-1,3-dioxane; 2,4-dimethyl-4-phenyltetrahydrofuran; (2R,4a′R,8a′R)-3,7′-dimethyl-3′,4′,4a′,5′,8′,8a′-hexahydro-1′H-spiro[oxirane-2,2′-[1,4]methanonaphthalene]; (Z)-6-ethylideneoctahydro-2H-5,8-methanochromene; 2-((S)-1-((S)-3,3-dimethylcyclohexyl)ethoxy)-2-oxoethyl propionate; methyl 2,2-dimethyl-6-methylenecyclohexane-1-carboxylate; 2-methyl-5-phenylpentan-1-ol; 4-methyl-2-phenyl-3,6-dihydro-2H-pyran; (1S,3R,5S)-1-isopropyl-4-methylenebicyclo[3.1.0]hexan-3-ol; 5-allylbenzo[d][1,3]dioxole; 2,2,7,9-tetramethylspiro(5.5)undec-8-en-1-one; 3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pentan-2-ol; (Z)-2-ethyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; (E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; 1-(3-hydroxy-3-methylpent-4-en-1-yl)-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol; (4aR,6aS,10aS,10bR)-3,4a,7,7,10a-pentamethyl-4a,5,6,6a,7,8,9,10,10a,10b-decahydro-1H-benzo[f]chromene; (4aR,8aR)-4a,8-dimethyl-2-(propan-2-ylidene)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropyl cyclopropanecarboxylate; 3-(4-isobutylphenyl)-2-methylpropanal; (1aR,4aR,7S,7aR,7bR)-1,1,7-trimethyl-4-methylenedecahydro-1H-cyclopropa[e]azulen-7-ol; (1R,3R,6R)-2′,2′,3,7,7-pentamethylspiro[bicyclo[4.1.0]heptane-2,5′-[1,3]dioxane]; 2-methyl-1,5-dioxaspiro[5.5]undecane; 1-(spiro[4.5]dec-7-en-7-yl)pent-4-en-1-one; 2-(4-methylthiazol-5-yl)ethan-1-ol; 2-(heptan-3-yl)-1,3-dioxolane; (Z)-dodec-4-enal; (1S,4S,4aR,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; (1S,4S,4aR,8aS)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; 3-methyl-2-pentylcyclopentan-1-one; 2,6,10,10-tetramethyl-1-oxaspiro[4.5]dec-6-ene; 2-(2-mercaptopropan-2-yl)-5-methylcyclohexan-1-one; (1aR,4aS)-2,4a,8,8-tetramethyl-1,1a,4,4a,5,6,7,8-octahydrocyclopropa[d]naphthalene; 1-isopropyl-2-methoxy-4-methylbenzene; 1-(2,2,6-trimethylcyclohexyl)hexan-3-ol; (2Z,4E)-nona-2,4-dienal; (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol; (2E,6Z)-nona-2,6-dienal; (Z)-dec-2-enal; (E)-non-2-enal; (3E,6Z)-nona-3,6-dien-1-ol; (E)-dec-4-enal; (Z)-oxacycloheptadec-8-en-2-one; (Z)-3,7-dimethylocta-1,3,6-triene; (Z)-3,7-dimethylocta-1,3,6-triene; (E)-3,7-dimethylocta-2,6-dien-1-ol; methyl 2-((1S,2S)-3-oxo-2-pentylcyclopentyl)acetate; 7-(1,1-Dimethylethyl)-2H-1,5-benzodioxepin-3(4H)-one; (1R-(1alpha,3alpha,4aalpha))-2,3,4,4a,5,6-hexahydro-2,2-dimethyl-1,3-methanonaphthalen-7(1H)-one; tridecan-1-ol; triethyl 2-hydroxypropane-1,2,3-tricarboxylate; methyl 2-((1-hydroxy-3-phenylbutyl)amino)benzoate; 1-((2E,5Z,9Z)-2,6,10-trimethylcyclododeca-2,5,9-trien-1-yl)ethan-1-one; decahydro-2,6,6,7,8,8-hexamethyl-2h-indeno(4,5-b)furan; 13-methyl oxacyclopentadec-10-en-2-one; undecanal; (E)-4-methyldec-3-en-5-ol; (3R,4aS,5R)-4a,5-dimethyl-3-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,7-octahydronaphthalene; 2-((2R,8R,8aS)-8,8a-dimethyl-1,2,3,4,6,7,8,8a-octahydronaphthalen-2-yl)propan-2-ol; 4-formyl-2-methoxyphenyl isobutyrate; (Z)-2-methyl-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-enal; methyl 2,4-dihydroxy-3,6-dimethylbenzoate; 1-methoxy-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoindene; methyl (Z)-2-((3-(4-(tert-butyl)phenyl)-2-methylpropylidene)amino)benzoate; (Z)-hex-3-en-1-yl isobutyrate; 2,4,6-trimethyl-4-phenyl-1,3-dioxane; 1-((3R,3aR,7R,8aS)-3,6,8,8-tetramethyl-2,3,4,7,8,8a-hexahydro-1H-3a,7-methanoazulen-5-yl)ethan-1-one; methyl (Z)-2-(((2,4-dimethylcyclohex-3-en-1-yl)methylene)amino)benzoate; 4,8-dimethyl-2-(propan-2-ylidene)-1,2,3,3a,4,5,6,8a-octahydroazulen-6-ol; 4,8-dimethyl-2-(propan-2-ylidene)-1,2,3,3a,4,5,6,8a-octahydroazulen-6-yl acetate; decahydro-3H-spiro[furan-2,5′-[4,7]methanoindene]; (2Z,6E)-nona-2,6-dienenitrile; (Z)-cyclooct-4-en-1-yl methyl carbonate; (1aR,4S,4aS,7R,7aS,7bS)-1,1,4,7-tetramethyldecahydro-1H-cyclopropa[e]azulen-4-ol; 3,5,5,6,7,8,8-heptamethyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile; (1S,2S,3S,5R)-2,6,6-trimethylspiro[bicyclo[3.1.1]heptane-3,1′-cyclohexan]-2′-en-4′-one; 1′,1′,5′,5′-tetramethylhexahydro-2′H,5′H-spiro[[1,3]dioxolane-2,8′-[2,4a]methanonaphthalene]; (2'S,4a'S,8a'S)-1′,1′,5′,5′-tetramethylhexahydro-2′H,5′H-spiro[[1,3]dioxolane-2,8′-[2,4a]methanonaphthalene]; 4-(4-hydroxy-3-methoxyphenyl)butan-2-one; (1R,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,7,8,8a-hexahydronaphthalene; 2,4-dimethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolane; 3a,5,6,7,8,8b-hexahydro-2,2,6,6,7,8,8-heptamethyl-4H-indeno(4,5-d)-1,3-dioxole; 2,4-dimethyl-4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; (1-methyl-2-((1,2,2-trimethylbicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methanol; 2-(cyclohexyloxy)-1,7,7-trimethylbicyclo[2.2.1]heptane; 4-((2R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)cyclohexan-1-ol; 8,8-di(1H-indol-1-yl)-2,6-dimethyloctan-2-ol; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methanol; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; (E)-4-((3aR,4R,7R,7aR)-1,3a,4,6,7,7a-hexahydro-5H-4,7-methanoinden-5-ylidene)-3-methylbutan-2-ol; (3R,3aR,6S,7S,8aS)-6-methoxy-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene; (1R,2S,6S,7S,8S)-8-isopropyl-1-methyl-3-methylenetricyclo[4.4.0.02,7]decane; 2′-isopropyl-1,7,7-trimethylspiro[bicyclo[2.2.1]heptane-2,4′-[1,3]dioxane]; (4aR,5R,7aS,9R)-2,2,5,8,8,9a-hexamethyloctahydro-4H-4a,9-methanoazuleno[5,6-d][1,3]dioxole; (3S,5aR,7aS,11aS,11bR)-3,8,8,11a-tetramethyldodecahydro-5H-3,5a-epoxynaphtho[2,1-c]oxepine; 2,2,6,6,7,8,8-heptamethyldecahydro-2H-indeno[4,5-b]furan; (1aS,2aR,3R,5aS,7R,7aR)-3,6,6,7a-tetramethyloctahydro-2H-2a,7-methanoazuleno[5,6-b]oxirene; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methyl acetate; 1-(3-hydroxy-3-methylpent-4-en-1-yl)-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol; decahydro-2,6,6,7,8,8-hexamethyl-2h-indeno(4,5-b)furan; 4,5-epoxy-4,11,11-trimethyl-8-methylenebicyclo(7.2.0)undecane; 1,3,4,6,7,8alpha-hexahydro-1,1,5,5-tetramethyl-2H-2,4alpha-methanophtalen-8(5H)-one, more preferably said malodor reduction materials are selected from the group consisting of: 3-methoxy-7,7-dimethyl-10-methylenebicyclo[4.3.1]decane; 2,4a,5,8a-tetramethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl formate; 2,2,6,8-tetramethyl-1,2,3,4,4a,5,8,8a-octahydronaphthalen-1-ol; (4R,4aS,6R)-4,4a-dimethyl-6-(prop-1-en-2-yl)-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one; ((3S,3aR,6R,8aS)-7,7-dimethyl-8-methyleneoctahydro-1H-3a,6-methanoazulen-3-yl)methanol; 4,9-dimethoxy-7H-furo[3,2-g]chromen-7-one; (E)-cyclohexadec-8-en-1-one; (Z)-1-(benzyloxy)-2-methoxy-4-(prop-1-en-1-yl)benzene; 1-((2S,3S)-2,3,8,8-tetramethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-yl)ethan-1-one; (1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate; 2,3-dihydro-3,3-dimethyl-1H-indene-5-propanal; 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)propanal; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl acetate; 2-((2R,4aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)propan-2-ol; 4,6,6,7,8,8-hexamethyl-1,3,4,6,7,8-hexahydrocyclopenta[g]isochromene; (Z)-6-ethylideneoctahydro-2H-5,8-methanochromen-2-one; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl acetate; octahydro-1H-4,7-methanoinden-5-yl acetate; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl butyrate; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl isobutyrate; (5R,6R)-3,6-dimethyl-5-(prop-1-en-2-yl)-6-vinyl-4,5,6,7-tetrahydrobenzofuran; (E)-cycloheptadec-9-en-1-one; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-3-yl formate; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl acetate; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-ol; 5-methyl-1-(2,2,3-trimethylcyclopent-3-en-1-yl)-6-oxabicyclo[3.2.1]octane; (Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-3-en-5-yl acetate; (1S,2S,5R,8S)-4,4,8-trimethyltricyclo[6.3.1.02,5]dodecan-1-ol; (1S,2S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate; (Z)-2-methyl-5-((1S,2R,4R)-2-methyl-3-methylenebicyclo[2.2.1]heptan-2-yl)pent-2-en-1-ol; (1S,4R,7R)-1,4,9,9-tetramethyl-1,2,3,4,5,6,7,8-octahydro-4,7-methanoazulene; (1aS,5aR,9aR)-1a,5,5,7-tetramethyl-1a,2,3,4,5,5a,8,9-octahydrobenzo[1,7]cyclohepta[1,2-b]oxirene; (2,2-dimethoxyethyl)benzene; (3R,3aS,7S,8aS)-3,8,8-trimethyl-6-methyleneoctahydro-1H-3a,7-methanoazulene; 4-methoxybenzyl 2-phenylacetate; 2,2,7,7,8,9,9-heptamethyldecahydroindeno[4,3a-b]furan; (4R,4aS)-4,4a-dimethyl-6-(propan-2-ylidene)-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one; (E)-5-(2,3-dimethyltricyclo[2.2.1.02,6]heptan-3-yl)-2-methylpent-2-en-1-ol; (1R,3aS,7S,8aR)-1,4,9,9-tetramethyl-2,3,6,7,8,8a-hexahydro-1H-3a,7-methanoazulene; (1aR,4R,4aR,7bS)-1,1,4,7-tetramethyl-1a,2,3,4,4a,5,6,7b-octahydro-1H-cyclopropa[e]azulene; 2-((2R,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl)propan-2-ol; (3aR,3bR,4S,7R,7aS)-4-isopropyl-7-methyl-3a,3b,4,5,6,7-hexahydro-1H-cyclopenta[1,3]cyclopropa[1,2]benzene; (3R,5aS,9aR)-2,2,5a,9-tetramethyl-3,4,5,5a,6,7-hexahydro-2H-3,9a-methanobenzo[b]oxepine; (1aR,4aS,7R,7aR,7bS)-1,1,7-trimethyl-4-methylenedecahydro-1H-cyclopropa[e]azulene; 2-((2S,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl)propan-2-ol; 1-(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethan-1-one; (E)-cyclohexadec-5-en-1-one; (1aR,2S,4aS)-2,4a,8,8-tetramethyloctahydrocyclopropa[d]naphthalen-3(1H)-one; 2-((2R,4aS)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)propan-2-ol; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; 1-(1,1,2,3,3,6-hexamethyl-2,3-dihydro-1H-inden-5-yl)ethan-1-one; (1R,4S,4aS,6R,8aS)-4,8a,9,9-tetramethyloctahydro-1,6-methanonaphthalen-1(2H)-ol; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl pivalate; (2R,4a′R,8a′R)-3,7′-dimethyl-3′,4′,4a′,5′,8′,8a′-hexahydro-1′H-spiro[oxirane-2,2′-[1,4]methanonaphthalene]; 2,2,7,9-tetramethylspiro(5.5)undec-8-en-1-one; (Z)-2-ethyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; (4aR,6aS,10aS,10bR)-3,4a,7,7,10a-pentamethyl-4a,5,6,6a,7,8,9,10,10a,10b-decahydro-1H-benzo[f]chromene; (1aR,4aR,7S,7aR,7bR)-1,1,7-trimethyl-4-methylenedecahydro-1H-cyclopropa[e]azulen-7-ol; 1-(spiro[4.5]dec-7-en-7-yl)pent-4-en-1-one; (1 aR,4aS)-2,4a,8,8-tetramethyl-1,1a,4,4a,5,6,7,8-octahydrocyclopropa[d]naphthalene; (1R-(1alpha,3alpha,4aalpha))-2,3,4,4a,5,6-hexahydro-2,2-dimethyl-1,3-methanonaphthalen-7(1H)-one; 2-((2R,8R,8aS)-8,8a-dimethyl-1,2,3,4,6,7,8,8a-octahydronaphthalen-2-yl)propan-2-ol; 1-((3R,3aR,7R,8aS)-3,6,8,8-tetramethyl-2,3,4,7,8,8a-hexahydro-1H-3a,7-methanoazulen-5-yl)ethan-1-one; methyl (Z)-2-(((2,4-dimethylcyclohex-3-en-1-yl)methylene)amino)benzoate; 4,8-dimethyl-2-(propan-2-ylidene)-1,2,3,3a,4,5,6,8a-octahydroazulen-6-yl acetate; decahydro-3H-spiro[furan-2,5′-[4,7]methanoindene]; (1aR,4S,4aS,7R,7aS,7bS)-1,1,4,7-tetramethyldecahydro-1H-cyclopropa[e]azulen-4-ol; 3,5,5,6,7,8,8-heptamethyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile; (1S,2S,3S,5R)-2,6,6-trimethylspiro[bicyclo[3.1.1]heptane-3,1′-cyclohexan]-2′-en-4′-one; 1′,1′,5′,5′-tetramethylhexahydro-2′H,5′H-spiro[[1,3]dioxolane-2,8′-[2,4a]methanonaphthalene]; (2'S,4a'S,8a'S)-1′,1′,5′,5′-tetramethylhexahydro-2′H,5′H-spiro[[1,3]dioxolane-2,8′-[2,4a]methanonaphthalene]; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methanol; 4,5-epoxy-4,11,11-trimethyl-8-methylenebicyclo(7.2.0)undecane; 1,3,4,6,7,8alpha-hexahydro-1,1,5,5-tetramethyl-2H-2,4alpha-methanophtalen-8(5H)-one, most preferably said malodor reduction materials are selected from the group consisting of: (E)-cyclohexadec-5-en-1-one; 2,2,7,7,8,9,9-heptamethyldecahydroindeno[4,3a-b]furan; 2,3-dihydro-3,3-dimethyl-1H-indene-5-propanal; 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)propanal; 4,5-epoxy-4,11,11-trimethyl-8-methylenebicyclo(7.2.0)undecane; 1,3,4,6,7,8alpha-hexahydro-1,1,5,5-tetramethyl-2H-2,4alpha-methanophtalen-8(5H)-one and mixtures thereof. 6. A personal care composition according to any preceeding claim, said composition comprising one or more perfume raw materials. 7. A personal care composition according to any preceeding claim wherein, said sum total of malodor reduction materials has an average Log P, based on weight percent of each malodor reduction material in said sum total of malodor reduction materials, of from about 2.5 to about 8, preferably from about 3 to about 8, more preferably from about 3.5 to about 7, most preferably, each of said malodor reduction materials in said sum total of malodor reduction materials and each of said one or more perfume raw materials has a Log P from about 3.5 to about 7. 8. A personal care composition according to any preceding claim wherein, the ratio of said one or more perfume raw materials to said sum total of malodor reduction material being from about 1000:1 to about 1:1, preferably from about 100:1 to about 1:1, more preferably from about 10:1 to about 1:1, most preferably from about 2:1 to about 1:1. 9. A personal care composition according to any preceding claim, wherein less than 10%, preferably less than 5%, more preferably less than 1% of said malodor reduction materials and said one or more perfume raw materials, based on total combined weight of malodor reduction materials and said one or more perfume raw materials comprise an ionone moiety. 10. A personal care composition according to any preceding claim, wherein said malodor reduction materials are not a material selected from the group consisting of geranyl nitrile; helional; nonanal; linalool; (S)-(+)-linalool; (R)-(−)-linalool; nerol; tetrahydrolinalool; 2-phenylethyl acetate; eugenol; ethyl linalool; allyl heptoate; agrumen nitrile; citronitrile; 2,2-dimethyl-3-(m-tolyl)propan-1-ol; 2-methyl-5-phenylpentan-1-ol; dodecanenitrile; 2-heptylcyclopentan-1-one; methyl nonyl acetaldehyde; 3-(2-ethylphenyl)-2,2-dimethylpropanal; (Z)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-en-1-one; (R,E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 4-(tert-butyl)cyclohexyl acetate; 1-cyclohexylethyl (E)-but-2-enoate; allyl 2-(cyclohexyloxy)acetate; alpha terpinyl acetate; beta terpinyl acetate; gamma terpinyl acetate; methyl dodecyl ether; 2,4-dimethyl-4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; cinnamyl isobutyrate; (E)-2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)but-2-enal; gamma methyl ionone; ethyl 2,3,6-trimethyl cyclohexyl carbonate ethyl 2,3,6-trimethyl cyclohexyl carbonate; Citral diethyl acetal; Dimethoxycyclododecane; 1-((2S,3S)-2,3,8,8-tetramethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-yl)ethan-1-one; oxacyclohexadecan-2-one; 4,6,6,7,8,8-hexamethyl-1,3,4,6,7,8-hexahydrocyclopenta[g]isochromene; Ethylene brassylate; Methyl (Z)-2-((3-(4-(tert-butyl)phenyl)-2-methylpropylidene)amino)benzoate; 4,7-Methano-1H-inden-5-ol, 3a,4,5,6,7,7a-hexahydro-, 5-acetate; cedryl methyl ether; vetivert acetate; 1-((3R,3aR,7R,8aS)-3,6,8,8-tetramethyl-2,3,4,7,8,8a-hexahydro-1H-3a,7-methanoazulen-5-yl)ethan-1-one; Benzophenone; Farnesol; trans,trans-farnesol; 3-(3-isopropylphenyl)butanal; 2,6,10-trimethylundec-9-enal; 3-(4-(tert-butyl)phenyl)propanal; 3-(4-isopropylphenyl)-2-methylpropanal; Citronellal (1); Citronellal (d); (E)-4,8-dimethyldeca-4,9-dienal; Pino Acetaldehyde; 3-(4-(tert-butyl)phenyl)-2-methylpropanal; Cinnamic aldehyde; Citral; Geranial; MethoxyMelonal; o-methoxycinnamaldehyde; (E)-4-((3aS,7aS)-octahydro-5H-4,7-methanoinden-5-ylidene)butanal; Methyl Octyl Acetaldehyde; 3-(4-methoxyphenyl)-2-methylpropanal; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; Iso Cyclocitral; Octanal; 2-Undecenal; 10-Undecenal; Trans-trans-2,6-Nonadienal; Trans-2,cis-6-nondienal; Heliotropin; Hexyl Cinnamic aldehyde; p-methyl-alpha-pentylcinnamaldehyde; Alpha-methyl cinnamaldehyde; 3,4-dimethoxybenzaldehyde; Myrtenal; Perillaldehyde; Maceal; Methyl palmitate; Methyl iso eugenol and mixtures thereof. 11. A personal care composition according to any preceeding claim, said composition comprising a total, based on total personal care composition weight, of from about 0.1% to about 7% of one or more of said malodor reduction materials and from about 3% to 30% of a surfactant, and, optionally, a miscellar phase and/or lamellar phase. 12. A personal care composition according to any preceeding claim said composition comprising a total, based on total personal care composition weight, of from about 0.1% to about 50% of a material selected from structurants, humectants, fatty acids, inorganic salts, antimicrobial agents, antimicrobial actives and mixtures thereof. 13. A personal care composition according to any preceding claim, said composition comprising an adjunct ingredient selected from the group consisting of clay mineral powders, pearl pigments, organic powders, emulsifiers, distributing agents, pharmaceutical active, topical active, preservatives, surfactants and mixtures thereof. 14. A method of controlling malodors comprising: contacting a situs comprising a malodor and/or a situs that will become malodorous with a personal care composition selected from the group consisting of the personal care composition of claims 1 to 13. 15. The method of claim 14 wherein, said situs is a body or head of hair and said contacting step comprises contacting said body or head of hair with a sufficient amount of Applicants' personal care composition to provide said body or hair with a level of malodor reduction material at least 0.0001 mg of malodor reduction material per body or head of hair, preferably from about 0.0001 mg of malodor reduction material per body or head of hair to about 1 mg of malodor reduction material per body or head of hair, more preferably from about 0.001 mg of malodor reduction material per body or head of hair about 0.5 mg of malodor reduction material per body or head of hair, most preferably from about 0.01 of malodor reduction material per body or head of hair to about 0.2 mg of malodor reduction material per body or head of hair.
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The present invention relates to personal care compositions comprising malodor reduction compositions and methods of making and using such personal care compositions. Such personal care compositions comprising the malodor control technologies disclosed herein provide malodor control without leaving an undesirable scent and when perfume is used to scent such compositions, such scent is not unduly altered by the malodor control technology.1. A personal care composition comprising, based on total composition weight,
a) a sum total of from about 0.0001% to about 2%, preferably from about 0.0001% to about 0.75%, more preferably from about 0.001% to about 0.5%, most preferably from about 0.007% to about 0.25% of 1 or more malodor reduction materials, preferably 1 to about 75 malodor reduction materials, more preferably 1 to about 50 malodor reduction materials, more preferably 1 to about 35 malodor reduction materials, most preferably 1 to about 20 malodor reduction materials, each of said malodor reduction materials having a MORV of at least 0.5, preferably from 0.5 to 10, more preferably from 1 to 10, most preferably from 1 to 5, and preferably each of said malodor reduction materials having a Universal MORV, or said sum total of malodor reduction materials having a Blocker Index of less than 3, more preferable less than about 2.5 even more preferably less than about 2 and still more preferably less than about 1 and most preferably 0 and/or a Blocker Index average of 3 to about 0.001; and b) from about 0% to about 12%, preferably from about 0% to about 8%, more preferably from about 0.1% to about 4%, of one or more perfume raw materials having a MORV of less than 0.5, preferably less than 0, more preferably less than −2, most preferably less than −5; c) from about 0.1% to about 99%, preferably from about 1% to about 80%, more preferably from about 5% to about 70%, most preferably from about 10% to about 50% of a solvent, preferably said solvent is selected from, water, glycerin, and mixtures thereof; d) from about 0% to about 50%, preferably from about 0% to about 40%, more preferably from about 0.1% to about 30%, most preferably from about 0.1% to about 15% of a material selected from the group consisting of a structurant, a humectant, a surfactant, an antimicrobial, and mixtures thereof. 2. A personal care composition according to claim 1, wherein said sum total of malodor reduction materials has a Blocker Index of less than 3, more preferable less than about 2.5 even more preferably less than about 2 and still more preferably less than about 1 and most preferably 0 and/or a Blocker Index average of 3 to about 0.001. 3. A personal care composition according to any preceding claim, wherein each of said malodor reduction materials has a MORV of at least 0.5, preferably from 0.5 to 10, more preferably from 1 to 10, most preferably from 1 to 5, and preferably each of said malodor reduction materials having a Universal MORV. 4. A personal care composition according to any preceding claim wherein, said sum total of malodor reduction materials has a Fragrance Fidelity Index average of 3 to about 0.001 Fragrance Fidelity Index, preferably each malodor reduction material in said sum total of malodor reduction materials has a Fragrance Fidelity Index of less than 3, preferably less than 2, more preferably less than 1 and most preferably each malodor reduction material in said sum total of malodor reduction materials has a Fragrance Fidelity Index of 0. 5. A personal care composition according to any preceding claim, wherein said malodor reduction materials are selected from the group consisting of 2-ethylhexyl (Z)-(3-(4-methoxyphenyl)acrylate; 2,4-dimethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolane; 1,1-dimethoxynon-2-yne; 2-(p-tolyl)propan-2-ol; 3-methoxy-7,7-dimethyl-10-methylenebicyclo[4.3.1]decane; methoxycyclododecane; 1,1-dimethoxycyclododecane; (Z)-tridec-2-enenitrile; (2-hydroxy-4-methoxyphenyl)(phenyl)methanone; 2,4a,5,8a-tetramethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl formate; 4-methyl-1-oxaspiro[5.5]undecan-4-ol; 7-methyl-2H-benzo[b][1,4]dioxepin-3(4H)-one; 1,8-dioxacycloheptadecan-9-one; 4-(tert-pentyl)cyclohexan-1-one; 2-methoxy-1,1′-biphenyl; 3a,5,6,7,8,8b-hexahydro-2,2,6,6,7,8,8-heptamethyl-4H-indeno(4,5-d)-1,3-dioxole; 7-isopropyl-8,8-dimethyl-6,10-dioxaspiro[4.5]decane; octyl furan-2-carboxylate; octyl acetate; 2-heptyl-4-methyl-1,3-dioxolane; octanal; 1,1-dimethoxyoctane; 7-methyl-3-methyleneocta-1,6-diene; 2-methyl-6-methyleneoct-7-en-2-ol; 2-methyl-6-methyleneoct-7-en-2-yl acetate; tetradecanal; 4-methoxy-6-prop-2-enyl-1,3-benzodioxole; tetradecanenitrile; 2,2,6,8-tetramethyl-1,2,3,4,4a,5,8,8a-octahydronaphthalen-1-ol; (E)-2,6-dimethylocta-5,7-dien-2-ol; (E)-2,7-dimethylocta-1,5,7-trien-3-ol; 2-((1S,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethyl acetate; (4R,4aS,6R)-4,4a-dimethyl-6-(prop-1-en-2-yl)-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one; nonan-1-ol; nonanal; 12-methyl-14-tetradec-9-enolide; N-ethyl-2-isopropyl-5-methylcyclohexane-1-carboxamide; 1-(3-methylbenzofuran-2-yl)ethan-1-one; 2-methoxynaphthalene; (E)-3,7,11-trimethyldodeca-1,6,10-trien-3-ol; (Z)-3,7-dimethylocta-2,6-dien-1-ol; 1-ethyl-3-methoxytricyclo[2.2.1.02,6]heptane; methyl (E)-non-2-enoate; 10-isopropyl-2,7-dimethyl-1-oxaspiro[4.5]deca-3,6-diene; 2-(2-(4-methylcyclohex-3-en-1-yl)propyl)cyclopentan-1-one; 6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-carbaldehyde; (E)-4-(2,2,3,6-tetramethylcyclohexyl)but-3-en-2-one; (4-(4-methylpent-3-en-1-yl)cyclohex-3-en-1-yl)methyl acetate; 2-(tert-butyl)-4,5,6-trimethyl-1,3-phenylene dinitrite; 1,7-dioxacycloheptadecan-8-one; 1-(4-(tert-butyl)-2,6-dimethyl-3,5-dinitrophenyl)ethan-1-one; 1-(tert-butyl)-2-methoxy-4-methyl-3,5-dinitrobenzene; 3-methylcyclopentadecan-1-one; (E)-3-methylcyclopentadec-4-en-1-one; 3-methyl-4-phenylbutan-2-ol; 1-(4-isopropylcyclohexyl)ethan-1-ol; (E)-dec-5-enoic acid; methyl non-2-ynoate; 2-methyldecanal; 6,6-dimethoxy-2,5,5-trimethylhex-2-ene; 4-phenylbutan-2-ol; methyl stearate; 1,1-dimethoxy-2-methylundecane; undecan-2-one; 2-methylundecanal; methyl tetradecanoate; methyl (9Z,12Z)-octadeca-9,12-dienoate; 1-hydroxydecan-3-one; (Z)-1,2-dimethoxy-4-(prop-1-en-1-yl)benzene; methyl palmitate; 4-allyl-1,2-dimethoxybenzene; methyl 2-((1R,2R)-3-oxo-2-((Z)-pent-2-en-1-yl)cyclopentyl)acetate; methyl 2-(3-oxo-2-pentylcyclopentyl)acetate; 1-methyl-2-phenoxybenzene; methyl cinnamate; 1-allyl-4-methoxybenzene; 1-(naphthalen-2-yl)ethan-1-one; methyloct-2-ynoate; methyl 2,6,6-trimethylcyclohex-2-ene-1-carboxylate; 7-methoxy-3,7-dimethyloctanal; 7-isopropyl-10-methyl-1,5-dioxaspiro[5.5]undecan-3-ol; octahydro-1H-4,7-methanoindene-1-carbaldehyde; 3-(3-(tert-butyl)phenyl)-2-methylpropanal; (E)-4-(4,8-dimethylnona-3,7-dien-1-yl)pyridine; (E)-trideca-3,12-dienenitrile; 2,2-dimethyl-3-(m-tolyl)propan-1-ol; 2,4-dimethyl-4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; 8-isopropyl-6-methylbicyclo[2.2.2]oct-5-ene-2-carbaldehyde; 4-(4-hydroxy-4-methylpentyl)cyclohex-3-ene-1-carbaldehyde; (S)-1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene; (Z)-3-hexen-1-yl-2-cyclopenten-1-one; 3,7-dimethylocta-1,6-dien-3-yl octanoate; 3,7-dimethylocta-1,6-dien-3-yl isobutyrate; 3,7-dimethylocta-1,6-dien-3-yl benzoate; 3,7-dimethylocta-1,6-dien-3-yl 2-aminobenzoate; 2-(5-methyl-5-vinyltetrahydrofuran-2-yl)propan-2-ol; 6-methyl-2-(oxiran-2-yl)hept-5-en-2-ol; (2Z,6E)-3,7-dimethylnona-2,6-dienenitrile; 3-(4-methylcyclohex-3-en-1-yl)butanal; (2,5-dimethyl-1,3-dihydroinden-2-yl)methanol; 3-(4-(tert-butyl)phenyl)-2-methylpropanal; (E)-1-(1-methoxypropoxy)hex-3-ene; (E)-1-(1-ethoxyethoxy)hex-3-ene; (1S,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-ol; dodecan-1-ol; dodecyl acetate; dodecanoic acid; 5-hexyl-5-methyldihydrofuran-2(3H)-one; dodecanal; 3,6-dimethylhexahydrobenzofuran-2(3H)-one; 4-(1-ethoxyvinyl)-3,3,5,5-tetramethylcyclohexan-1-one; ((3S,3aR,6R,8aS)-7,7-dimethyl-8-methyleneoctahydro-1H-3a,6-methanoazulen-3-yl)methanol; 5-(sec-butyl)-2-(2,4-dimethylcyclohex-3-en-1-yl)-5-methyl-1,3-dioxane; (1-methyl-2-((1,2,2-trimethylbicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methanol; 2-propylheptanenitrile; (E)-6-(pent-3-en-1-yl)tetrahydro-2H-pyran-2-one; 2-hexylcyclopentan-1-one; 2-methyl-4-phenyl-1,3-dioxolane; 2,6,9,10-tetramethyl-1-oxaspiro(4.5)deca-3,6-diene; (1R,2S,5R)-5-methyl-2-(prop-1-en-2-yl)cyclohexan-1-ol; isopropyl palmitate; isopropyl tetradecanoate; isopropyl dodecanoate; 4,9-dimethoxy-7H-furo[3,2-g]chromen-7-one; (E)-cyclohexadec-8-en-1-one; (2S,5S)-2-isopropyl-5-methylcyclohexan-1-one; 2-hexylcyclopent-2-en-1-one; (2S,5S)-2-isopropyl-5-methylcyclohexan-1-one; 4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; (Z)-1-(benzyloxy)-2-methoxy-4-(prop-1-en-1-yl)benzene; 1-((2S,3S)-2,3,8,8-tetramethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-yl)ethan-1-one; 2,5,6-trimethylcyclohex-3-ene-1-carbaldehyde; 6-(sec-butyl)quinoline; 2-(cyclohexyloxy)-1,7,7-trimethylbicyclo[2.2.1]heptane; (1R,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl propionate; (1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate; 4-((2R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)cyclohexan-1-ol; (1R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 2-(4-isopropylcyclohexa-1,4-dien-1-yl)ethyl formate; isopentyl (E)-undec-6-enoate; isopentyl dodecanoate; (E)-oxacycloheptadec-10-en-2-one; (E)-non-2-enenitrile; (E)-8-(1H-indol-1-yl)-2,6-dimethyloct-7-en-2-ol; 8,8-di(1H-indol-1-yl)-2,6-dimethyloctan-2-ol; 4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; 3,7-dimethyloctane-1,7-diol; 2-cyclododecylpropan-1-ol; 3-methyl-5-phenylpentanenitrile; 3-phenylpropan-1-ol; (1,1-dimethoxypropan-2-yl)benzene; 5-ethyl-4-hydroxy-2-methylfuran-3(2H)-one; 2,3-dihydro-3,3-dimethyl-1H-indene-5-propanal; 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)propanal; hexyl octanoate; hexyl hexanoate; (Z)-2-benzylideneoctanal; hexyl benzoate; (Z)-hex-1-en-1-yl (Z)-2-methylbut-2-enoate; (E)-3,7-dimethylocta-2,6-dien-1-yl palmitate; oxacycloheptadecan-2-one; 2-butyl-4,4,6-trimethyl-1,3-dioxane; ethyl (1R,2R,3R,4R)-3-isopropylbicyclo[2.2.1]hept-5-ene-2-carboxylate; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl acetate; 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropyl propionate; 5-(diethoxymethyl)benzo[d][1,3]dioxole; 3-(benzo[d][1,3]dioxol-5-yl)-2-methylpropanal; (E)-oxacyclohexadec-13-en-2-one; 6-butyl-2,4-dimethyl-3,6-dihydro-2H-pyran; 2-((3S,5R,8S)-3,8-dimethyl-1,2,3,4,5,6,7,8-octahydroazulen-5-yl)propan-2-ol; 1-(2,6,6-trimethylcyclohex-2-en-1-yl)pentan-3-one; ethyl 2-ethyl-6,6-dimethylcyclohex-2-ene-1-carboxylate; (1Z,5Z)-1,5-dimethyl-8-(propan-2-ylidene)cyclodeca-1,5-diene; (1E,6E)-8-isopropyl-1-methyl-5-methylenecyclodeca-1,6-diene; (E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate; (E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate; (6E,10E)-3,7,11,15-tetramethylhexadeca-1,6,10,14-tetraen-3-ol; (E)-2-(3,7-dimethylocta-2,6-dien-1-yl)cyclopentan-1-one; 5-heptyldihydrofuran-2(3H)-one; 1-methyl-4-(propan-2-ylidene)cyclohexyl acetate; 1-methyl-4-(propan-2-ylidene)cyclohexan-1-ol; 5-pentyldihydrofuran-2(3H)-one; (1R,4aR,8aS)-1-isopropyl-7-methyl-4-methylene-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 5-[(Z)-hex-3-enyl]oxolan-2-one; (Z)-4-(2,2-dimethyl-6-methylenecyclohexyl)but-3-en-2-one; (4aS,9aR)-3,5,5,9-tetramethyl-2,4a,5,6,7,9a-hexahydro-1H-benzo[7]annulene; (1R,3aR,4R,7R)-1,4-dimethyl-7-(prop-1-en-2-yl)-1,2,3,3a,4,5,6,7-octahydroazulene; 2-((2R,4aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)propan-2-ol; 5-octyldihydrofuran-2(3H)-one; (Z)-1-(2,2-dimethyl-6-methylenecyclohexyl)but-2-en-1-one; 5-hexyldihydrofuran-2(3H)-one; (1R,4aS,8aS)-1-isopropyl-7-methyl-4-methylene-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 1-(3,3-dimethylcyclohexyl)pent-4-en-1-one; 4,6,6,7,8,8-hexamethyl-1,3,4,6,7,8-hexahydrocyclopenta[g]isochromene; furan-2-ylmethyl octanoate; furan-2-ylmethyl hexanoate; furan-2-ylmethyl heptanoate; 2-methyldecanenitrile; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; ethyl (3aR,4S,7R,7aR)-octahydro-3aH-4,7-methanoindene-3a-carboxylate; diethyl cyclohexane-1,4-dicarboxylate; (6-isopropyl-9-methyl-1,4-dioxaspiro[4.5]decan-2-yl)methanol; 2-isobutyl-4-methyltetrahydro-2H-pyran-4-ol; undec-10-enenitrile; (Z)-6-ethylideneoctahydro-2H-5,8-methanochromen-2-one; 3-(2-ethylphenyl)-2,2-dimethylpropanal; (E)-4,8-dimethyldeca-4,9-dienal; (E)-4-((3aR,4R,7R,7aR)-1,3a,4,6,7,7a-hexahydro-5H-4,7-methanoinden-5-ylidene)-3-methylbutan-2-ol; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl acetate; 3-(4-ethylphenyl)-2,2-dimethylpropanenitrile; 2-heptylcyclopentan-1-one; 1-ethoxyethoxy Cyclododecane; 3-cyclohexene-1-carboxylic acid, 2,6,6-trimethyl-, methyl ester; (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl acetate; (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol; oxacyclohexadecan-2-one; (E)-cyclopentadec-4-en-1-one; 1-cyclopentadec-4-en-1-one; 2-methoxy-4-(4-methylenetetrahydro-2H-pyran-2-yl)phenol; 4-allyl-2-methoxyphenyl acetate; 4-allyl-2-methoxyphenol; ethyl 3-methyl-3-phenyloxirane-2-carboxylate; 1,4-dioxacycloheptadecane-5,17-dione; ethyl undec-10-enoate; ethyl palmitate; ethyl nonanoate; ethyl tetradecanoate; (E)-3,7-dimethylnona-1,6-dien-3-ol; ethyl dodecanoate; nonan-3-one; ethyl decanoate; ethyl 6,6-dimethyl-2-methylenecyclohex-3-ene-1-carboxylate; ethyl 3-phenyloxirane-2-carboxylate; 6-ethyl-2,10,10-trimethyl-1-oxaspiro[4.5]deca-3,6-diene; 2-((1R,3S,4S)-4-methyl-3-(prop-1-en-2-yl)-4-vinylcyclohexyl)propan-2-ol; (2-(1-ethoxyethoxy)ethyl)benzene; (E)-3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pent-4-en-2-ol; (2R,3S,4R)-2,3,4,5-tetrahydroxypentanal; (E)-4-((3aS,7aS)-octahydro-5H-4,7-methanoinden-5-ylidene)butanal; 1,1-dimethoxydodecane; (R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene; 2-(2-hydroxypropoxy)propan-1-ol; 7,9-dimethylspiro[5.5]undecan-3-one; oxydibenzene; diphenylmethane; 2-methyl-1-phenylpropan-2-yl butyrate; 2,6-dimethyloct-7-en-4-one; octahydro-1H-4,7-methanoinden-5-yl acetate; 2-methyl-5-(prop-1-en-2-yl)cyclohexyl acetate; 2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-ol; 3,7-dimethyloct-6-en-3-ol; methyl 2-hexyl-3-oxocyclopentane-1-carboxylate; dibutylsulfane; 1,2-diphenylethane; 6-hexyltetrahydro-2H-pyran-2-one; (3R,4R)-1-isopropyl-4-methyl-3-(prop-1-en-2-yl)-4-vinylcyclohex-1-ene; (3S,3aS,5R)-3,8-dimethyl-5-(prop-1-en-2-yl)-1,2,3,3a,4,5,6,7-octahydroazulene; 6-heptyltetrahydro-2H-pyran-2-one; 6-pentyltetrahydro-2H-pyran-2-one; (1S,8aR)-4,7-dimethyl-1-(propan-2-yl)-1,2,3,5,6,8a-hexahydronaphthalene; (Z)-1-((1R,2S)-2,6,6-trimethylcyclohex-3-en-1-yl)but-2-en-1-one; (1S,8aS)-1-isopropyl-4,7-dimethyl-1,2,3,5,6,8a-hexahydronaphthalene; 3,7,7-trimethylbicyclo[4.1.0]hept-3-ene; dec-9-en-1-ol; decyl propionate; 1,1-diethoxydecane; decahydronaphthalen-2-ol; 1-cyclohexylethyl (E)-but-2-enoate; 3-(4-isopropylphenyl)-2-methylpropanal; cyclotetradecane; cyclopentadecanone; cyclohexyl 2-hydroxybenzoate; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl butyrate; 1,4-dioxacyclohexadecane-5,16-dione; 8,8-dimethyl-1,2,3,4,5,6,7,8-octahydronaphthalene-2-carbaldehyde; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl isobutyrate; (5R,6R)-3,6-dimethyl-5-(prop-1-en-2-yl)-6-vinyl-4,5,6,7-tetrahydrobenzofuran; (4-isopropylphenyl)methanol; 1-(benzofuran-2-yl)ethan-1-one; 2-(3-phenylpropyl)pyridine; dodecanenitrile; (E)-cycloheptadec-9-en-1-one; 3-(4-methylcyclohex-3-en-1-yl)but-3-en-1-yl acetate; 3-(4-methylcyclohex-3-en-1-yl)butan-1-ol; (E)-3-methyl-5-phenylpent-2-enenitrile; (E)-2-(2,6-dimethylhepta-1,5-dien-1-yl)-4-methyl-1,3-dioxolane; (E)-1,1-dimethoxy-3,7-dimethylocta-2,6-diene; (E)-1,1-diethoxy-3,7-dimethylocta-2,6-diene; (E)-3,7-dimethylocta-1,3,6-triene; (1R,4R,6S)-1-methyl-4-(prop-1-en-2-yl)-7-oxabicyclo[4.1.0]heptane; (E)-oxacycloheptadec-11-en-2-one; (Z)-non-6-en-1-ol; (1R,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-ol; (Z)-dec-4-enal; (E)-hex-3-en-1-yl (E)-hex-3-enoate; (Z)-hex-3-en-1-yl 2-hydroxybenzoate; (Z)-hex-3-en-1-yl benzoate; (Z)-hex-3-en-1-yl 2-methylbutanoate; (3Z,6Z)-nona-3,6-dien-1-ol; cinnamyl propionate; cinnamyl isobutyrate; cinnamyl formate; cinnamyl cinnamate; cinnamyl acetate; (E)-3-phenylprop-2-en-1-ol; hexadecan-1-ol; (E)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)hepta-1,6-dien-3-one; 2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butanal; (3aR,5aR,9aR,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; 1,6-dioxacycloheptadecan-7-one; 1-(6-(tert-butyl)-1,1-dimethyl-2,3-dihydro-1H-inden-4-yl)ethan-1-one; (3R,3aR,6S,7S,8aS)-6-methoxy-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-3-yl formate; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl acetate; (4Z,8Z)-1,5,9-trimethyl-13-oxabicyclo[10.1.0]trideca-4,8-diene; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-ol; 5-methyl-1-(2,2,3-trimethylcyclopent-3-en-1-yl)-6-oxabicyclo[3.2.1]octane; 5-methyl-1-(2,2,3-trimethylcyclopent-3-en-1-yl)-6-oxabicyclo[3.2.1]octane; 1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-4H-inden-4-one; (Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-3-en-5-yl acetate; (1S,2S,5R,8S)-4,4,8-trimethyltricyclo[6.3.1.02,5]dodecan-1-ol; 2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-yl acetate; octanenitrile; octan-1-ol; octanoic acid; decanoic acid; decanal; 3-(4-methoxyphenyl)-2-methylpropanal; 1,7,7-trimethylbicyclo[2.2.1]heptane-2,3-dione; 2,2-dimethyl-3-methylenebicyclo[2.2.1]heptane; ethyl 2-methyl-4-oxo-6-pentylcyclohex-2-ene-1-carboxylate; 2,6-di-tert-butyl-4-methylphenol; butyl stearate; 1-butoxy-1-oxopropan-2-yl butyrate; butyl undec-10-enoate; 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)butan-1-ol; 3-(4-(tert-butyl)phenyl)propanal; (1S,2S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate; 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 2-ethoxy-2,6,6-trimethyl-9-methylenebicyclo[3.3.1]nonane; (ethoxymethoxy)cyclododecane; (E)-1-methyl-4-(6-methylhept-5-en-2-ylidene)cyclohex-1-ene; 3,3,6,7-tetramethyloctahydro-2H-chromene; (5R,10R)-6,10-dimethyl-2-(propan-2-ylidene)spiro[4.5]dec-6-en-8-one; 1-methyl-4-(prop-1-en-2-yl)cyclohexyl acetate; 1-methyl-4-(prop-1-en-2-yl)cyclohexan-1-ol; (2Z,6E)-2,6-dimethyl-10-methylenedodeca-2,6,11-trienal; (R)-3-methylene-6-((S)-6-methylhept-5-en-2-yl)cyclohex-1-ene; (4aR,7R,8aS)-4a-methyl-1-methylene-7-(prop-1-en-2-yl)decahydronaphthalene; (Z)-2-methyl-5-((1S,2R,4R)-2-methyl-3-methylenebicyclo[2.2.1]heptan-2-yl)pent-2-en-1-ol; 6,6-dimethyl-2-methylenebicyclo[3.1.1]heptane; 2-ethoxynaphthalene; (1S,4R,7R)-1,4,9,9-tetramethyl-1,2,3,4,5,6,7,8-octahydro-4,7-methanoazulene; (1aS,5aR,9aR)-1a,5,5,7-tetramethyl-1a,2,3,4,5,5a,8,9-octahydrobenzo[1,7]cyclohepta[1,2-b]oxirene; (R)-3,5,5,9-tetramethyl-2,4a,5,6,7,8-hexahydro-1H-benzo[7]annulene; (1S,4S)-1,4-dimethyl-7-(propan-2-ylidene)-1,2,3,4,5,6,7,8-octahydroazulene; (2,2-dimethoxyethyl)benzene; (E)-7,11-dimethyl-3-methylenedodeca-1,6,10-triene; (1R,2S,6S,7S,8S)-8-isopropyl-1-methyl-3-methylenetricyclo[4.4.0.02,7]decane; (3R,3aS,7S,8aS)-3,8,8-trimethyl-6-methyleneoctahydro-1H-3a,7-methanoazulene; (1R,9S,Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-4-ene; (S)-4-methyl-1-((S)-6-methylhept-5-en-2-yl)cyclohex-3-en-1-ol; (Z)-4-(2,2,6-trimethyl-7-oxabicyclo[4.1.0]heptan-1-yl)but-3-en-2-one; 4-methoxy-7H-furo[3,2-g]chromen-7-one; 2-methyl-4-phenylbutan-2-ol; benzyldodecanoate; 2-methyl-1-phenylpropan-2-ol; benzyl cinnamate; benzyl benzoate; benzophenone; 7-isopentyl-2H-benzo[b][1,4]dioxepin-3(4H)-one; 2′-isopropyl-1,7,7-trimethylspiro[bicyclo[2.2.1]heptane-2,4′-[1,3]dioxane]/A; 4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbonitrile; methyl (E)-2-((7-hydroxy-3,7-dimethyloctylidene)amino)benzoate; 4-methoxybenzyl 2-phenylacetate; methyl (E)-octa-4,7-dienoate; pentyl (Z)-3-phenylacrylate; (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; (4aR,5R,7aS,9R)-2,2,5,8,8,9a-hexamethyloctahydro-4H-4a,9-methanoazuleno[5,6-d][1,3]dioxole; 2,5,5-trimethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-ol; 2,5,5-trimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-ol; 1-((2-(tert-butyl)cyclohexyl)oxy)butan-2-ol; (3S,5aR,7aS,11aS,11bR)-3,8,8,11a-tetramethyldodecahydro-5H-3,5a-epoxynaphtho[2,1-c]oxepine; 2,2,6,6,7,8,8-heptamethyldecahydro-2H-indeno[4,5-b]furan; 2,2,7,7,8,9,9-heptamethyldecahydroindeno[4,3a-b]furan; 2-(sec-butyl)-1-vinylcyclohexyl acetate; (1S,4R,5R)-1-isopropyl-4-methylbicyclo[3.1.0]hexan-3-one; (4R,4aS)-4,4a-dimethyl-6-(propan-2-ylidene)-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one; 2-(4-methylcyclohex-3-en-1-yl)propan-2-yl propionate; (2Z,6E,9E)-2,6,10-trimethyldodeca-2,6,9,11-tetraenal; (2R,4aR,8aR)-4a,8-dimethyl-2-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 1,7-dimethyl-7-(4-methylpent-3-en-1-yl)tricyclo[2.2.1.02,6]heptane; (E)-5-(2,3-dimethyltricyclo[2.2.1.02,6]heptan-3-yl)-2-methylpent-2-en-1-ol; (1R,3aS,7S,8aR)-1,4,9,9-tetramethyl-2,3,6,7,8,8a-hexahydro-1H-3a,7-methanoazulene; 1-(5,5-dimethylcyclohex-1-en-1-yl)pent-4-en-1-one; (1S,4aS,8aR)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (R,Z)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)pent-1-en-3-one; 1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene; (Z)-4-(2,5,6,6-tetramethylcyclohex-2-en-1-yl)but-3-en-2-one; (1Z,4E,8Z)-2,6,6,9-tetramethylcycloundeca-1,4,8-triene; (4aR,8S,9aS)-3,5,5,8-tetramethyl-9-methylene-2,4a,5,6,7,8,9,9a-octahydro-1H-benzo[7]annulene; (1aR,4R,4aR,7bS)-1,1,4,7-tetramethyl-1a,2,3,4,4a,5,6,7b-octahydro-1H-cyclopropa[e]azulene; 1,4-dimethyl-7-(prop-1-en-2-yl)-1,2,3,4,5,6,7,8-octahydroazulene; (3E,6E)-3,7,11-trimethyldodeca-1,3,6,10-tetraene; 7,7-dimethyl-2-methylenebicyclo[2.2.1]heptane; 2-((2R,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl)propan-2-ol; (R)-1-methyl-4-(6-methylhept-5-en-2-yl)benzene; (3aR,3bR,4S,7R,7aS)-4-isopropyl-7-methyl-3a,3b,4,5,6,7-hexahydro-1H-cyclopenta[1,3]cyclopropa[1,2]benzene; (1aS,2aR,3R,5aS,7R,7aR)-3,6,6,7a-tetramethyloctahydro-2H-2a,7-methanoazuleno[5,6-b]oxirene; (1R,4S,4aR,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; (1S,4aR,8aR)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (R)-2-((R)-4-methylcyclohex-3-en-1-yl)hex-5-en-2-ol; (Z)-1-methyl-4-(6-methylhepta-2,5-dien-2-yl)cyclohex-1-ene; 2,6-dimethyl-6-(4-methylpent-3-en-1-yl)bicyclo[3.1.1]hept-2-ene; (E)-2-benzylideneheptan-1-ol; (E)-2-benzylideneheptyl acetate; (Z)-(2-(diethoxymethyl)hept-1-en-1-yl)benzene; (E)-2-benzylideneheptanal; (1S,4aR,8aS)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (3R,5aS,9aR)-2,2,5a,9-tetramethyl-3,4,5,5a,6,7-hexahydro-2H-3,9a-methanobenzo[b]oxepine; 1-methyl-4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carb aldehyde; 1-phenylpentan-2-ol; 3-methyl-1-phenylpentan-3-ol; 2,3,4-trimethoxybenzaldehyde; 2,4,5-trimethoxybenzaldehyde; 2,4,6-trimethoxybenzaldehyde; Trans,Trans-2,4-Nonadienal; 2,6,10-trimethylundecanal; alpha-4-Dimethyl benzenepropanal; allyl 3-cyclohexylpropanoate; allyl 2-(isopentyloxy)acetate; (1aR,4aS,7R,7aR,7bS)-1,1,7-trimethyl-4-methylenedecahydro-1H-cyclopropa[e]azulene; (E)-undec-9-enal; methyl (E)-2-(((3,5-dimethylcyclohex-3-en-1-yl)methylene)amino)benzoate; 2,6,10-trimethylundec-9-enal; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methyl acetate; nonyl acetate; (2-(1-propoxyethoxy)ethyl)benzene; 1-(1-propoxyethoxy)propane; ((1-(2-methoxyethoxy)ethoxy)methyl)benzene; (Z)-2-(4-methylbenzylidene)heptanal; dec-9-enal; (Z)-oxacycloheptadec-8-en-2-one; 7-methoxy-2H-chromen-2-one; (2S,4aR,8aR)-4a,8-dimethyl-2-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 2-((2S,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl)propan-2-ol; 1-(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethan-1-one; 6-isopropylquinoline; 3-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)propanal; 6,10,14-trimethylpentadecan-2-one; 2-methyl-5-(prop-1-en-2-yl)-2-vinyltetrahydrofuran; (E)-cyclohexadec-5-en-1-one; 1-isopropyl-4-methylcyclohex-3-en-1-ol; 1-phenylpent-4-en-1-one; 1-isopropyl-4-methylcyclohex-3-en-1-ol; 3,6-dimethyl-4,5,6,7-tetrahydrobenzofuran; 4-(4-methoxyphenyl)butan-2-one; (1aR,2S,4aS)-2,4a,8,8-tetramethyloctahydrocyclopropa[d]naphthalen-3(1H)-one; (E)-3-propylideneisobenzofuran-1(3H)-one; (Z)-dodec-2-enal; 3-methyl-5-phenylpentanal; (E)-hex-3-en-1-yl 3-methylbutanoate; 3,6-dimethyloctan-3-yl acetate; 3,4,5-trimethoxybenzaldehyde; 3-(4-isopropylphenyl)propanal; (Z)-undec-2-enenitrile; (E)-undec-2-enal; (2E,6E)-nona-2,6-dienal; phenethyl butyrate; (Z)-3-(furan-2-yl)-2-phenylacrylaldehyde; 2-phenoxyethan-1-ol; (Z)-non-2-enal; nonan-2-ol; nonan-2-one; 2-isobutylquinoline; (E)-2-hexylidenecyclopentan-1-one; 2-heptyltetrahydrofuran; (E)-dec-2-enal; (2E,6E)-nona-2,6-dienal; (2E,6E)-nona-2,6-dien-1-ol; 2,6-dimethyloctanal; decan-1-ol; (E)-hept-1-en-1-yl acetate; undec-10-en-1-ol; undec-10-enal; 2-((2R,4aS)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)propan-2-ol; 1-isopropyl-4-methyl-7-thiabicyclo[2.2.1]heptane; (3E,5Z)-undeca-1,3,5-triene; 3,7-dimethyloct-6-en-3-ol; 1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 1,1,2,3,3-pentamethyl-2,3-dihydro-1H-indene; (Z)-6,10-dimethylundeca-5,9-dien-2-yl acetate; (Z)-dodec-3-enal; (S)-5-heptyldihydrofuran-2(3H)-one; (R)-5-heptyldihydrofuran-2(3H)-one; (E)-6,10-dimethylundeca-5,9-dien-2-yl acetate; (Z)-3-methyl-5-phenylpent-2-enenitrile; (2S,5S,6S)-2,6,10,10-tetramethyl-1-oxaspiro[4.5]decan-6-ol; (2E)-3-methyl-5-phenyl-2-pentenenitrile; (1S,2S,5S)-2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-ol; (2S,5R)-2-isopropyl-5-methylcyclohexan-1-one; (R,E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 2-(8-isopropyl-6-methylbicyclo[2.2.2]oct-5-en-2-yl)-1,3-dioxolane; (E)-4-(2,2-dimethyl-6-methylenecyclohexyl)-3-methylbut-3-en-2-one; 3-(3-isopropylphenyl)butanal; 3-(1-ethoxyethoxy)-3,7-dimethylocta-1,6-diene; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; 2-((3S,3aS,5R)-3,8-dimethyl-1,2,3,3a,4,5,6,7-octahydroazulen-5-yl)propan-2-ol; benzyl 2-phenylacetate; 2-hydroxy-1,2-diphenylethan-1-one; (E)-1,2,4-trimethoxy-5-(prop-1-en-1-yl)benzene; 3-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-2,2-dimethylpropanal; 2-methyl-5-(6-methylhept-5-en-2-yl)bicyclo[3.1.0]hex-2-ene; 1-(1,1,2,3,3,6-hexamethyl-2,3-dihydro-1H-inden-5-yl)ethan-1-one; 2-(m-tolyl)ethan-1-ol; (3E,6E)-nona-3,6-dien-1-ol; (E)-tridec-2-enal; (1R,4S,4aS,6R,8aS)-4,8a,9,9-tetramethyloctahydro-1,6-methanonaphthalen-1(2H)-ol; p-tolyl isobutyrate; p-tolyl hexanoate; 5-hexyl-4-methyldihydrofuran-2(3H)-one; ethyl (2Z,4E)-deca-2,4-dienoate; 2,4-dimethyl-6-phenyl-3,6-dihydro-2H-pyran; 2-cyclohexylidene-2-phenylacetonitrile; 4-(prop-1-en-2-yl)cyclohex-1-ene-1-carbaldehyde; (4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methyl acetate; (4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methanol; (2-isopropoxyethyl)benzene; 2-cyclohexylhepta-1,6-dien-3-one; (2-(cyclohexyloxy)ethyl)benzene; phenethyl 2-methylbutanoate; 2-phenylethan-1-ol; phenethyl 2-phenylacetate; 3-methyl-5-phenylpentan-1-ol; phenyl benzoate; phenethyl benzoate; 2-benzyl-1,3-dioxolane; 2-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)acetaldehyde; 6,6-dimethyl-2-methylenebicyclo[3.1.1]heptan-3-ol; 4-(benzo[d][1,3]dioxol-5-yl)butan-2-one; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-ylpivalate; (4aR,8aS)-7-methyloctahydro-1,4-methanonaphthalen-6(2H)-one; 4-isopropyl-1-methylcyclohex-3-en-1-ol; (E)-3,3-dimethyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pent-4-en-2-ol; 1-methyl-4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; propane-1,2-diol; p-tolyl 2-phenylacetate; Ethyl 2,4,7-decatrienoate; 2-benzyl-4,4,6-trimethyl-1,3-dioxane; 2,4-dimethyl-4-phenyltetrahydrofuran; (2R,4a′R,8a′R)-3,7′-dimethyl-3′,4′,4a′,5′,8′,8a′-hexahydro-1′H-spiro[oxirane-2,2′-[1,4]methanonaphthalene]; (Z)-6-ethylideneoctahydro-2H-5,8-methanochromene; 2-((S)-1-((S)-3,3-dimethylcyclohexyl)ethoxy)-2-oxoethyl propionate; methyl 2,2-dimethyl-6-methylenecyclohexane-1-carboxylate; 2-methyl-5-phenylpentan-1-ol; 4-methyl-2-phenyl-3,6-dihydro-2H-pyran; (1S,3R,5S)-1-isopropyl-4-methylenebicyclo[3.1.0]hexan-3-ol; 5-allylbenzo[d][1,3]dioxole; 2,2,7,9-tetramethylspiro(5.5)undec-8-en-1-one; 3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pentan-2-ol; (Z)-2-ethyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; (E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carb aldehyde; 1-(3-hydroxy-3-methylpent-4-en-1-yl)-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol; (4aR,6aS,10aS,10bR)-3,4a,7,7,10a-pentamethyl-4a,5,6,6a,7,8,9,10,10a,10b-decahydro-1H-benzo[f]chromene; (4aR,8aR)-4a,8-dimethyl-2-(propan-2-ylidene)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropyl cyclopropanecarboxylate; 3-(4-isobutylphenyl)-2-methylprop anal; (1aR,4aR,7S,7aR,7bR)-1,1,7-trimethyl-4-methylenedecahydro-1H-cyclopropa[e]azulen-7-ol; (1R,3R,6R)-2′,2′,3,7,7-pentamethylspiro[bicyclo[4.1.0]heptane-2,5′-[1,3]dioxane]; 2-methyl-1,5-dioxaspiro[5.5]undecane; 1-(spiro[4.5]dec-7-en-7-yl)pent-4-en-1-one; 2-(4-methylthiazol-5-yl)ethan-1-ol; 2-(heptan-3-yl)-1,3-dioxolane; (Z)-dodec-4-enal; (1S,4S,4aR,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; (1S,4S,4aR,8aS)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; 3-methyl-2-pentylcyclopentan-1-one; 2,6,10,10-tetramethyl-1-oxaspiro[4.5]dec-6-ene; 2-(2-mercaptopropan-2-yl)-5-methylcyclohexan-1-one; (1aR,4aS)-2,4a,8,8-tetramethyl-1,1a,4,4a,5,6,7,8-octahydrocyclopropa[d]naphthalene; 1-isopropyl-2-methoxy-4-methylbenzene; 1-(2,2,6-trimethylcyclohexyl)hexan-3-ol; (2Z,4E)-nona-2,4-dienal; (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol; (2E,6Z)-nona-2,6-dienal; (Z)-dec-2-enal; (E)-non-2-enal; (3E,6Z)-nona-3,6-dien-1-ol; (E)-dec-4-enal; (Z)-oxacycloheptadec-8-en-2-one; (Z)-3,7-dimethylocta-1,3,6-triene; (Z)-3,7-dimethylocta-1,3,6-triene; (E)-3,7-dimethylocta-2,6-dien-1-ol; methyl 2-((1S,2S)-3-oxo-2-pentylcyclopentyl)acetate; 7-(1,1-Dimethylethyl)-2H-1,5-benzodioxepin-3(4H)-one; (1R-(1alpha,3alpha,4aalpha))-2,3,4,4a,5,6-hexahydro-2,2-dimethyl-1,3-methanonaphthalen-7(1H)-one; tridecan-1-ol; triethyl 2-hydroxypropane-1,2,3-tricarboxylate; methyl 2-((1-hydroxy-3-phenylbutyl)amino)benzoate; 1-((2E,5Z,9Z)-2,6,10-trimethylcyclododeca-2,5,9-trien-1-yl)ethan-1-one; decahydro-2,6,6,7,8,8-hexamethyl-2h-indeno(4,5-b)furan; 13-methyl oxacyclopentadec-10-en-2-one; undecanal; (E)-4-methyldec-3-en-5-ol; (3R,4aS,5R)-4a,5-dimethyl-3-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,7-octahydronaphthalene; 2-((2R,8R,8aS)-8,8a-dimethyl-1,2,3,4,6,7,8,8a-octahydronaphthalen-2-yl)propan-2-ol; 4-formyl-2-methoxyphenyl isobutyrate; (Z)-2-methyl-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-enal; methyl 2,4-dihydroxy-3,6-dimethylbenzoate; 1-methoxy-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoindene; methyl (Z)-2-((3-(4-(tert-butyl)phenyl)-2-methylpropylidene)amino)benzoate; (Z)-hex-3-en-1-yl isobutyrate; 2,4,6-trimethyl-4-phenyl-1,3-dioxane; 1-((3R,3aR,7R,8aS)-3,6,8,8-tetramethyl-2,3,4,7,8,8a-hexahydro-1H-3a,7-methanoazulen-5-yl)ethan-1-one; methyl (Z)-2-(((2,4-dimethylcyclohex-3-en-1-yl)methylene)amino)benzoate; 4,8-dimethyl-2-(propan-2-ylidene)-1,2,3,3a,4,5,6,8a-octahydroazulen-6-ol; 4,8-dimethyl-2-(propan-2-ylidene)-1,2,3,3a,4,5,6,8a-octahydroazulen-6-yl acetate; decahydro-3H-spiro[furan-2,5′-[4,7]methanoindene]; (2Z,6E)-nona-2,6-dienenitrile; (Z)-cyclooct-4-en-1-yl methyl carbonate; (1aR,4S,4aS,7R,7aS,7bS)-1,1,4,7-tetramethyldecahydro-1H-cyclopropa[e]azulen-4-ol; 3,5,5,6,7,8,8-heptamethyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile; (1S,2S,3S,5R)-2,6,6-trimethylspiro[bicyclo[3.1.1]heptane-3,1′-cyclohexan]-2′-en-4′-one; 1′,1′,5′,5′-tetramethylhexahydro-2′H,5′H-spiro[[1,3]dioxolane-2,8′-[2,4a]methanonaphthalene]; (2'S,4a'S,8a'S)-1′,1′,5′,5′-tetramethylhexahydro-2′H,5′H-spiro[[1,3]dioxolane-2,8′-[2,4a]methanonaphthalene]; 4-(4-hydroxy-3-methoxyphenyl)butan-2-one; (1R,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,7,8,8a-hexahydronaphthalene; 2,4-dimethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolane; 3a,5,6,7,8,8b-hexahydro-2,2,6,6,7,8,8-heptamethyl-4H-indeno(4,5-d)-1,3-dioxole; 2,4-dimethyl-4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; (1-methyl-2-((1,2,2-trimethylbicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methanol; 2-(cyclohexyloxy)-1,7,7-trimethylbicyclo[2.2.1]heptane; 4-((2R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)cyclohexan-1-ol; 8,8-di(1H-indol-1-yl)-2,6-dimethyloctan-2-ol; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methanol; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; (E)-4-((3aR,4R,7R,7aR)-1,3a,4,6,7,7a-hexahydro-5H-4,7-methanoinden-5-ylidene)-3-methylbutan-2-ol; (3R,3aR,6S,7S,8aS)-6-methoxy-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene; (1R,2S,6S,7S,8S)-8-isopropyl-1-methyl-3-methylenetricyclo[4.4.0.02,7]decane; 2′-isopropyl-1,7,7-trimethylspiro[bicyclo[2.2.1]heptane-2,4′-[1,3]dioxane]; (4aR,5R,7aS,9R)-2,2,5,8,8,9a-hexamethyloctahydro-4H-4a,9-methanoazuleno[5,6-d][1,3]dioxole; (3S,5aR,7aS,11aS,11bR)-3,8,8,11a-tetramethyldodecahydro-5H-3,5a-epoxynaphtho[2,1-c]oxepine; 2,2,6,6,7,8,8-heptamethyldecahydro-2H-indeno[4,5-b]furan; (1aS,2aR,3R,5aS,7R,7aR)-3,6,6,7a-tetramethyloctahydro-2H-2a,7-methanoazuleno[5,6-b]oxirene; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methyl acetate; 1-(3-hydroxy-3-methylpent-4-en-1-yl)-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol; decahydro-2,6,6,7,8,8-hexamethyl-2h-indeno(4,5-b)furan; 2-ethylhexyl (Z)-3-(4-methoxyphenyl)acrylate; methoxycyclododecane; 1-ethoxy-4-(tert-pentyl)cyclohexane; (2-hydroxy-4-methoxyphenyl)(phenyl)methanone; (3Z)-1-(2-buten-1-yloxy)-3-hexene; 4-(2-methoxypropan-2-yl)-1-methylcyclohex-1-ene; 4-(tert-pentyl)cyclohexan-1-one; 3-methoxy-3,7-dimethylocta-1,6-diene; 7-isopropyl-8,8-dimethyl-6,10-dioxaspiro[4.5]decane; (E)-3-(2-methoxyphenyl)acrylaldehyde; 3,7-dimethyloctanal; 1,1-dimethoxyoctane; 2-methyl-6-methyleneoct-7-en-2-ol; 4-methoxy-6-prop-2-enyl-1,3-benzodioxole; tetradecanenitrile; (E)-2,7-dimethylocta-1,5,7-trien-3-ol; 3,3-Dimethyl-5(2,2,3-Trimethyl-3-Cyclopenten-1yl)-4-Penten-2-ol; hexyl 2-hydroxybenzoate; hexyl (Z)-but-2-enoate; (Z)-3,7-dimethylocta-2,6-dien-1-yl formate; (Z)-3,7-dimethylocta-2,6-dien-1-ol; 1-ethyl-3-methoxytricyclo[2.2.1.02,6]heptane; 10-isopropyl-2,7-dimethyl-1-oxaspiro[4.5]deca-3,6-diene; 6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-carbaldehyde; (E)-4-(2,2,3,6-tetramethylcyclohexyl)but-3-en-2-one; (Z)-1-(2,6,6-trimethylcyclohex-1-en-1-yl)pent-1-en-3-one; (E)-2,2-dimethyl-3-(3-methylpenta-2,4-dien-1-yl)oxirane; 3-methylcyclopentadecan-1-one; (E)-3,7-dimethylocta-4,6-dien-3-ol; 3-methyl-4-phenylbutan-2-ol; 1-(4-isopropylcyclohexyl)ethan-1-ol; (Z)-hex-3-en-1-yl cyclopropanecarboxylate; (E)-dec-5-enoic acid; 1-phenylethyl propionate; methyl 2-phenylacetate; 4-phenylbutan-2-ol; methyl stearate; methyl (9Z,12Z)-octadeca-9,12-dienoate; 1-hydroxydecan-3-one; 2-methyl-6-oxaspiro[4.5]decan-7-one; (Z)-1,2-dimethoxy-4-(prop-1-en-1-yl)benzene; methyl palmitate; 4-allyl-1,2-dimethoxybenzene; methyl (Z)-3,7-dimethylocta-2,6-dienoate; 1-methyl-2-phenoxybenzene; 2-ethoxy-4-(methoxymethyl)phenol; methyl 2-cyclopentylideneacetate; 1-allyl-4-methoxybenzene; 6-methoxy-2,6-dimethylheptanal; 7-methoxy-3,7-dimethyloctanal; ((1s,4s)-4-isopropylcyclohexyl)methanol; 3-(3-(tert-butyl)phenyl)-2-methylpropanal; (E)-4-(4,8-dimethylnona-3,7-dien-1-yl)pyridine; (E)-trideca-3,12-dienenitrile; 2,2-dimethyl-3-(m-tolyl)propan-1-ol; 8-isopropyl-6-methylbicyclo[2.2.2]oct-5-ene-2-carbaldehyde; 4-(4-hydroxy-4-methylpentyl)cyclohex-3-ene-1-carbaldehyde; (Z)-3-hexen-1-yl-2-cyclopenten-1-one; 3,7-dimethylocta-1,6-dien-3-yl propionate; 3,7-dimethylocta-1,6-dien-3-yl octanoate; 3,7-dimethylocta-1,6-dien-3-yl formate; 3,7-dimethylocta-1,6-dien-3-yl butyrate; 3,7-dimethylocta-1,6-dien-3-yl benzoate; 3,7-dimethylocta-1,6-dien-3-yl 2-aminobenzoate; 3,7-dimethylocta-1,6-dien-3-yl acetate; 3,7-dimethylocta-1,6-dien-3-ol; 3-(4-methylcyclohex-3-en-1-yl)butanal; 3-(4-(tert-butyl)phenyl)-2-methylpropanal; (Z)-hex-3-en-1-yl methyl carbonate; 4-methylquinoline; (E)-1-(1-methoxypropoxy)hex-3-ene; 2-Methyl-5-(1-methylethenyl)-2-cyclohexenone; dodecanal; 2,2-dimethyl-5-phenylhexanenitrile; (E)-6-(pent-3-en-1-yl)tetrahydro-2H-pyran-2-one; 2-hexylcyclopentan-1-one; (Z)-4-(6,6-dimethylcyclohex-2-en-1-yl)-3-methylbut-3-en-2-one; 2,6,9,10-tetramethyl-1-oxaspiro(4.5)deca-3,6-diene; 4-methylpent-1-en-3-ol; isopropyl palmitate; isopropyl dodecanoate; isopropyl 2-methylbutanoate; 4-methylpent-4-en-2-yl isobutyrate; 7-methyloctyl acetate; 7-methyloctan-1-ol; 4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; (Z)-2-methoxy-4-(prop-1-en-1-yl)phenyl acetate; (Z)-2-methoxy-4-(prop-1-en-1-yl)phenol; (1R,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl propionate; (1R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol; 2-(4-isopropylcyclohexa-1,4-dien-1-yl)ethyl formate; isopentyl (E)-undec-6-enoate; isopentyl octanoate; isopentyl dodecanoate; isopentyl isobutyrate; (E)-oxacycloheptadec-10-en-2-one; 8,8-di(1H-indol-1-yl)-2,6-dimethyloctan-2-ol; 2-cyclododecylpropan-1-ol; 3-phenylpropan-1-ol; 3-phenylpropanoic acid; (1,1-dimethoxypropan-2-yl)benzene; 2-phenylpropan-1-ol; hexyl propionate; hexyl butyrate; hexyl 2-methylbutanoate; hexyl furan-2-carboxylate; oxacycloheptadecan-2-one; heptan-1-ol; heptyl acetate; heptanal; 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropyl propionate; 5-(diethoxymethyl)benzo[d][1,3]dioxole; benzo[d][1,3]dioxole-5-carbaldehyde; 3-(benzo[d][1,3]dioxol-5-yl)-2-methylpropanal; (E)-oxacyclohexadec-13-en-2-one; 6-butyl-2,4-dimethyl-3,6-dihydro-2H-pyran; 2-((3S,5R,8S)-3,8-dimethyl-1,2,3,4,5,6,7,8-octahydroazulen-5-yl)propan-2-ol; 1-(2,6,6-trimethylcyclohex-2-en-1-yl)pentan-3-one; (1Z,5Z)-1,5-dimethyl-8-(propan-2-ylidene)cyclodeca-1,5-diene; (E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate; (E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate; (Z)-3,7-dimethylocta-2,6-dienenitrile; (E)-3,7-dimethylocta-2,6-dien-1-yl formate; (E)-3,7-dimethylocta-2,6-dien-1-yl octanoate; (E)-3,7-dimethylocta-2,6-dien-1-yl benzoate; (E)-3,7-dimethylocta-2,6-dienal; N,2-dimethyl-N-phenylbutanamide; 1-isopropyl-4-methylcyclohexa-1,4-diene; (1R,4aR,8aS)-1-isopropyl-7-methyl-4-methylene-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 5-[(Z)-hex-3-enyl]oxolan-2-one; (4aS,9aR)-3,5,5,9-tetramethyl-2,4a,5,6,7,9a-hexahydro-1H-benzo[7]annulene; (Z)-1-(2,2-dimethyl-6-methylenecyclohexyl)but-2-en-1-one; (1R,4aS,8aS)-1-isopropyl-7-methyl-4-methylene-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 1-(3,3-dimethylcyclohexyl)pent-4-en-1-one; furan-2-ylmethyl octanoate; furan-2-ylmethyl hexanoate; furan-2-ylmethyl heptanoate; ethyl (3aR,4S,7R,7aR)-octahydro-3aH-4,7-methanoindene-3a-carboxylate; 2-(sec-butyl)cyclohexan-1-one; 3-(2-ethylphenyl)-2,2-dimethylpropanal; 2-(tert-butyl)cyclohexyl ethyl carbonate; 3-(2-ethylphenyl)-2,2-dimethylpropanal; (E)-4,8-dimethyldeca-4,9-dienal; 3-(4-ethylphenyl)-2,2-dimethylpropanenitrile; 2-heptylcyclopentan-1-one; 1-ethoxyethoxy Cyclododecane; (Z)-5-methylhept-2-en-4-one; 1,3,3-trimethylbicyclo[2.2.1]heptan-2-ol; oxacyclohexadecan-2-one; (E)-cyclopentadec-4-en-1-one; 1-cyclopentadec-4-en-1-one; 4-allyl-2-methoxyphenyl acetate; 4-allyl-2-methoxyphenol; 1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane; ethyl 3-methyl-3-phenyloxirane-2-carboxylate; 1,4-dioxacycloheptadecane-5,17-dione; 2-ethoxy-4-formylphenyl acetate; ethyl undec-10-enoate; ethyl palmitate; ethyl octanoate; ethyl tetradecanoate; (E)-3,7-dimethylnona-1,6-dien-3-ol; ethyl cinnamate; ethyl 3-phenyloxirane-2-carboxylate; ethyl 2-cyclohexylpropanoate; 6-ethyl-2,10,10-trimethyl-1-oxaspiro[4.5]deca-3,6-diene; (2R,3S,4R)-2,3,4,5-tetrahydroxypentanal; (E)-4-((3aS,7aS)-octahydro-5H-4,7-methanoinden-5-ylidene)butanal; (2R,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-one; 4-methyl-2-phenyltetrahydro-2H-pyran; oxydibenzene; diphenylmethane; 2-methyl-1-phenylpropan-2-yl butyrate; 2,6-dimethyloct-7-en-2-ol; 3-methyl-2-pentylcyclopent-2-en-1-one; 3,3,5-trimethylcyclohexan-1-one; 2-methoxy-4-propylphenol; chroman-2-one; 2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-one; 2-methyl-5-(prop-1-en-2-yl)cyclohexyl acetate; 2-(4-methylcyclohexyl)propan-2-yl acetate; 4-(2,6,6-trimethylcyclohex-2-en-1-yl)butan-2-one; (oxybis(methylene))dibenzene; dibutyl phthalate; 1,2-diphenylethane; (3R,4R)-1-isopropyl-4-methyl-3-(prop-1-en-2-yl)-4-vinylcyclohex-1-ene; (1S,8aR)-4,7-dimethyl-1-(propan-2-yl)-1,2,3,5,6,8a-hexahydronaphthalene; (1S,8aS)-1-isopropyl-4,7-dimethyl-1,2,3,5,6,8a-hexahydronaphthalene; 2-pentylcyclopentan-1-one; decyl 2-aminobenzoate; decahydronaphthalen-2-ol; methyl (1s,4s)-1,4-dimethylcyclohexane-1-carboxylate; 3-(4-isopropylphenyl)-2-methylpropanal; cyclotetradecane; cyclopentadecanone; 2-cyclohexylethyl acetate; cyclohexyl 2-hydroxybenzoate; 1,4-dioxacyclohexadecane-5,16-dione; (4-isopropylphenyl)methanol; 2-methoxy-4-methylphenol; (3Z,5Z)-2,6-dimethylocta-1,3,5,7-tetraene; 4-cyclohexyl-2-methylbutan-2-ol; 2-(3-phenylpropyl)pyridine; 3-(4-methylcyclohex-3-en-1-yl)but-3-en-1-yl acetate; 3-(4-methylcyclohex-3-en-1-yl)butan-1-ol; 2-benzyl-2-methylbut-3-enenitrile; 3,7-dimethyloct-6-enenitrile; 3,7-dimethyloct-6-en-1-yl 2-phenylacetate; 3,7-dimethyloct-6-en-1-yl formate; 3,7-dimethyloct-6-en-1-yl benzoate; 3,7-dimethyloct-6-en-1-ol; 3,7-dimethyloct-6-enal; (E)-3,7-dimethylocta-2,6-dienal; (1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptane; (Z)-3-methyl-2-(pent-2-en-1-yl)cyclopent-2-en-1-one; (E)-2-methoxy-4-(prop-1-en-1-yl)phenol; (E)-oxacycloheptadec-11-en-2-one; (Z)-non-6-en-1-ol; (Z)-hex-3-en-1-yl pentanoate; (E)-hex-3-en-1-yl (E)-2-methylbut-2-enoate; (Z)-hex-3-en-1-yl 2-hydroxybenzoate; (Z)-hex-3-en-1-yl propionate; (Z)-hex-3-en-1-yl butyrate; (Z)-hex-3-en-1-yl benzoate; (Z)-hex-3-en-1-ol; (Z)-hex-3-en-1-yl 2-methylbutanoate; (Z)-hex-2-en-1-ol; cinnamonitrile; cinnamyl isobutyrate; cinnamaldehyde; (E)-3-phenylprop-2-en-1-ol; cinnamonitrile; 4-chloro-3,5-dimethylphenol; hexadecan-1-ol; (E)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)hepta-1,6-dien-3-one; 2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butanal; (3aR,5aR,9aR,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; (4Z,8Z)-1,5,9-trimethyl-13-oxabicyclo[10.1.0]trideca-4,8-diene; 5-methyl-1-(2,2,3-trimethylcyclopent-3-en-1-yl)-6-oxabicyclo[3.2.1]octane; 1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-4H-inden-4-one; 5-isopropyl-2-methylphenol; 2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-one; 2-(2-ethoxyethoxy)ethan-1-ol; hexan-1-ol; 2-(2,2,3-trimethylcyclopent-3-en-1-yl)acetonitrile; 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one; 2,2-dimethyl-3-methylenebicyclo[2.2.1]heptane; 2,6-di-tert-butyl-4-methylphenol; butyl stearate; butyl undec-10-enoate; 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)butan-1-ol; (E)-2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)but-2-enal; 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate; (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol; 3,3,6,7-tetramethyloctahydro-2H-chromene; 6,6-dimethylspiro[bicyclo[3.1.1]heptane-2,2′-oxirane]; 3-isopropyl-6-methylenecyclohex-1-ene; 2-ethoxynaphthalene; (R)-3,5,5,9-tetramethyl-2,4a,5,6,7,8-hexahydro-1H-benzo[7]annulene; (1S,4S)-1,4-dimethyl-7-(propan-2-ylidene)-1,2,3,4,5,6,7,8-octahydroazulene; (1R,9S,Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-4-ene; (Z)-4-(2,2,6-trimethyl-7-oxabicyclo[4.1.0]heptan-1-yl)but-3-en-2-one; 4-methoxy-7H-furo[3,2-g]chromen-7-one; 4-phenylbutan-2-one; benzyl 2-hydroxybenzoate; benzyl dodecanoate; benzyl 3-methylbutanoate; benzyl isobutyrate; benzyl cinnamate; benzyl butyrate; phenylmethanol; benzyl benzoate; 1-(3,3-dimethylcyclohexyl)ethyl formate; 4-methoxybenzyl acetate; 4-methoxybenzyl formate; (Z)-1-methoxy-4-(prop-1-en-1-yl)benzene; pentyl benzoate; (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; 2,5,5-trimethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-ol; 2,5,5-trimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-ol; 2-(sec-butyl)-1-vinylcyclohexyl acetate; (1S,4R,5R)-1-isopropyl-4-methylbicyclo[3.1.0]hexan-3-one; 2-(4-methylcyclohex-3-en-1-yl)propan-2-yl propionate; 2-(4-methylcyclohex-3-en-1-yl)propan-2-yl acetate; 1,7-dimethyl-7-(4-methylpent-3-en-1-yl)tricyclo[2.2.1.02,6]heptane; 1-(5,5-dimethylcyclohex-1-en-1-yl)pent-4-en-1-one; (1S,4aS,8aR)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; 4-cyclohexylbutan-2-ol; (R,Z)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)pent-1-en-3-one; (E)-2-methyl-3-phenylacrylaldehyde; (Z)-3-methyl-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-3-en-2-one; (Z)-4-(2,5,6,6-tetramethylcyclohex-2-en-1-yl)but-3-en-2-one; (1Z,4E,8Z)-2,6,6,9-tetramethylcycloundeca-1,4,8-triene; (4aR,8S,9aS)-3,5,5,8-tetramethyl-9-methylene-2,4a,5,6,7,8,9,9a-octahydro-1H-benzo[7]annulene; (1R,4S,4aR,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; (1S,4aR,8aR)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (R)-2-((R)-4-methylcyclohex-3-en-1-yl)hex-5-en-2-ol; (E)-2-benzylideneheptyl acetate; (1S,4aR,8aS)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; 1-phenylpentan-2-ol; 4-methoxy-2,5-dimethylfuran-3(2H)-one; alpha-4-Dimethyl benzenepropanal; allyl 2-phenoxyacetate; (2-(allyloxy)ethyl)benzene; allyl heptanoate; allyl 3-cyclohexylpropanoate; N-ethyl-N-(m-tolyl)propionamide; 2,6,10-trimethylundec-9-enal; 3-hydroxybutan-2-one; 1-(4-methoxyphenyl)ethan-1-one; (Z)-2-(4-methylbenzylidene)heptanal; (Z)-oxacycloheptadec-8-en-2-one; 7-methoxy-2H-chromen-2-one; 6-methylquinoline; 6,8-dimethylnonan-2-ol; 6,10,14-trimethylpentadecan-2-one; 5-methylheptan-3-one; 4-vinylphenol; 1-phenylpent-4-en-1-one; (E)-3-(4-hydroxy-3-methoxyphenyl)acrylaldehyde; 4-ethyl-2-methoxyphenol; 5-methyl-5-phenylhexan-3-one; 4-(4-methoxyphenyl)butan-2-one; (E)-3-propylideneisobenzofuran-1(3H)-one; (Z)-dodec-2-enal; 3-methyl-5-phenylpentanal; 3-methyl-4-phenyl-1H-pyrazole; 3-methylcyclopentane-1,2-dione; 3-methoxy-5-methylphenol; 3-methoxy-3-methylbutan-1-ol; (E)-hex-3-en-1-ol; 3,7-dimethyl-2-methyleneoct-6-enal; 3,7-dimethyloctan-1-ol; (Z)-undec-2-enenitrile; (E)-undec-2-enal; phenethyl acetate; (Z)-3-(furan-2-yl)-2-phenylacrylaldehyde; phenethyl propionate; 2-pentylcyclopentan-1-ol; (2S,4S)-2-heptyl-2,4-dimethyl-1,3-dioxolane; nonan-2-ol; 2-(sec-butyl)-3-methoxypyrazine; 2-isopropyl-N,2,3-trimethylbutanamide; (E)-2-isopropyl-5-methylhex-2-enal; 2-isopropyl-4-methylthiazole; (E)-2-hexylidenecyclopentan-1-one; (E)-hex-2-en-1-ol; 2-butoxyethan-1-ol; (2E,6E)-nona-2,6-dien-1-ol; 1-isopropyl-4-methyl-7-oxabicyclo[2.2.1]heptane; 1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 1,1,2,3,3-pentamethyl-2,3-dihydro-1H-indene; (Z)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-en-1-one; (Z)-6,10-dimethylundeca-5,9-dien-2-yl acetate; (Z)-hept-3-en-1-yl acetate; (1S,5S)-4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-one; (R)-3,7-dimethylocta-1,6-dien-3-ol; 3,7-dimethyloct-6-enal; (E)-6,10-dimethylundeca-5,9-dien-2-yl acetate; (R)-3,7-dimethyloct-6-enal; (2S,5S,6S)-2,6,10,10-tetramethyl-1-oxaspiro[4.5]decan-6-ol; 3,7-dimethyloct-6-en-1-ol; 3,7-dimethyloct-6-en-1-ol; (1R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene; (S)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-one; (1S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene; methyl 2-methylbutanoate; hexyl (Z)-2-methylbut-2-enoate; 2-(8-isopropyl-6-methylbicyclo[2.2.2]oct-5-en-2-yl)-1,3-dioxolane; 3-(3-isopropylphenyl)butanal; allyl 2-(cyclohexyloxy)acetate; 2-((3S,3aS,5R)-3,8-dimethyl-1,2,3,3a,4,5,6,7-octahydroazulen-5-yl)propan-2-ol; 1,5-dimethylbicyclo[3.2.1]octan-8-one oxime; benzyl 2-phenylacetate; 2-hydroxy-1,2-diphenylethan-1-one; (E)-tridec-2-enal; 1-phenylvinyl acetate; p-tolyl isobutyrate; p-tolyl hexanoate; p-cymene; 5-hexyl-4-methyldihydrofuran-2(3H)-one; 2-cyclohexylidene-2-phenylacetonitrile; 4-(prop-1-en-2-yl)cyclohex-1-ene-1-carbaldehyde; (4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methyl acetate; (4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methanol; (2-(cyclohexyloxy)ethyl)benzene; phenethyl 2-methylbutanoate; phenethyl formate; phenethyl isobutyrate; phenethyl 2-phenylacetate; phenethyl (Z)-2-methylbut-2-enoate; phenyl benzoate; phenethyl benzoate; phenethyl methacrylate; 2-(4-isopropylphenyl)acetaldehyde; 1,2-dimethyl-3-(prop-1-en-2-yl)cyclopentan-1-ol; 1-(4-methoxyphenyl)propan-2-one; (2Z,5Z)-5,6,7-trimethylocta-2,5-dien-4-one; 1-methoxy-4-propylbenzene; 2-(4-(tert-butyl)phenyl)acetaldehyde; 4-(tert-pentyl)cyclohexan-1-ol; p-tolyl 2-phenylacetate; Ethyl 2,4,7-decatrienoate; 2,6,6-trimethylbicyclo[3.1.1]hept-2-ene; 4-(4-hydroxyphenyl)butan-2-one; 2-benzyl-4,4,6-trimethyl-1,3-dioxane; 3,7-dimethyloct-7-en-1-ol; ethyl (2,3,6-trimethylcyclohexyl) carbonate; (Z)-6-ethylideneoctahydro-2H-5,8-methanochromene; 2-((S)-1-((S)-3,3-dimethylcyclohexyl)ethoxy)-2-oxoethyl propionate; methyl 2,2-dimethyl-6-methylenecyclohexane-1-carboxylate; 1-(3,3-dimethylcyclohexyl)ethyl acetate; (S)-3,7-dimethylocta-1,6-dien-3-ol; 1-isopropyl-4-methylenebicyclo[3.1.0]hexane; 5-isopropyl-2-methylbicyclo[3.1.0]hexan-2-ol; (1S,3R,5S)-1-isopropyl-4-methylenebicyclo[3.1.0]hexan-3-ol; 3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pentan-2-ol; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; propyl (S)-2-(tert-pentyloxy)propanoate; (4aR,8aR)-4a,8-dimethyl-2-(propan-2-ylidene)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropyl cyclopropanecarboxylate; (1R,3R,6R)-2′,2′,3,7,7-pentamethylspiro[bicyclo[4.1.0]heptane-2,5′-[1,3]dioxane]; 1-oxaspiro(4,5)decan-2-one; (Z)-5-methylheptan-3-one oxime; 1-phenylethyl acetate; (1S,4S,4aR,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; (1S,4S,4aR,8aS)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; 3,7-dimethyloctanal; 4-(2,2,6-trimethylcyclohexyl)butan-2-ol; 3-methyl-2-pentylcyclopentan-1-one; 3,7-dimethyloctan-3-ol; 3,7-dimethyloctan-3-yl acetate; 2,6,10,10-tetramethyl-1-oxaspiro[4.5]dec-6-ene; ethyl (1R,6S)-2,2,6-trimethylcyclohexane-1-carboxylate; 2-isopropyl-5-methylphenol; 1-isopropyl-2-methoxy-4-methylbenzene; 1-(2,2,6-trimethylcyclohexyl)hexan-3-ol; (E)-hex-2-en-1-ol; (1R,2S)-2-(tert-butyl)cyclohexan-1-ol; (Z)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-en-1-one; (Z)-oxacycloheptadec-8-en-2-one; (Z)-1-methoxy-4-(prop-1-en-1-yl)benzene; cinnamic acid; (2R,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-one; (E)-3,7-dimethylocta-2,6-dien-1-ol; (Z)-2-methoxy-4-(prop-1-en-1-yl)phenol; 2,2,2-trichloro-1-phenylethyl acetate; triethyl 2-hydroxypropane-1,2,3-tricarboxylate; methyl 2-((1-hydroxy-3-phenylbutyl)amino)benzoate; 1-((2E,5Z,9Z)-2,6,10-trimethylcyclododeca-2,5,9-trien-1-yl)ethan-1-one; 2-mercapto-2-methylpentan-1-ol; 13-methyl oxacyclopentadec-10-en-2-one; undecanal; (E)-4-methyldec-3-en-5-ol; (3R,4aS,5R)-4a,5-dimethyl-3-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,7-octahydronaphthalene; 4-formyl-2-methoxyphenyl acetate; 4-formyl-2-methoxyphenyl isobutyrate; (Z)-2-ethoxy-5-(prop-1-en-1-yl)phenol; 2,2,5-trimethyl-5-pentylcyclopentan-1-one; (Z)-2-methyl-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-enal; 3,4-dimethoxybenzaldehyde; (1R,5R)-4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-one; 1-methoxy-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoindene; 2-(tert-butyl)cyclohexan-1-ol; cis-(4-tert-butylcyclohexyl)acetate; 4-(tert-butyl)cyclohexyl acetate; 2,4-diethoxy-5-methylpyrimidine; 4-methyl-4-phenylpentan-2-yl acetate; 4,8-dimethyl-2-(propan-2-ylidene)-1,2,3,3a,4,5,6,8a-octahydroazulen-6-ol; (Z)-cyclooct-4-en-1-yl methyl carbonate; (Z)-1-((2-methylallyl)oxy)hex-3-ene; 4-(4-hydroxy-3-methoxyphenyl)butan-2-one; (1R,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,7,8,8a-hexahydronaphthalene; 4,5-epoxy-4,11,11-trimethyl-8-methylenebicyclo(7.2.0)undecane; 1,3,4,6,7,8alpha-hexahydro-1,1,5,5-tetramethyl-2H-2,4alpha-methanophtalen-8(5H)-one preferably said malodor reduction materials are selected from the group consisting of: 2-ethylhexyl (Z)-3-(4-methoxyphenyl)acrylate; 2,4-dimethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolane; 1,1-dimethoxynon-2-yne; 2-(p-tolyl)propan-2-ol; 3-methoxy-7,7-dimethyl-10-methylenebicyclo[4.3.1]decane; methoxycyclododecane; 1,1-dimethoxycyclododecane; (Z)-tridec-2-enenitrile; (2-hydroxy-4-methoxyphenyl)(phenyl)methanone; 2,4a,5,8a-tetramethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl formate; 4-methyl-1-oxaspiro[5.5]undecan-4-ol; 7-methyl-2H-benzo[b][1,4]dioxepin-3(4H)-one; 1,8-dioxacycloheptadecan-9-one; 4-(tert-pentyl)cyclohexan-1-one; 2-methoxy-1,1′-biphenyl; 3a,5,6,7,8,8b-hexahydro-2,2,6,6,7,8,8-heptamethyl-4H-indeno(4,5-d)-1,3-dioxole; 7-isopropyl-8,8-dimethyl-6,10-dioxaspiro[4.5]decane; octyl furan-2-carboxylate; octyl acetate; 2-heptyl-4-methyl-1,3-dioxolane; octanal; 1,1-dimethoxyoctane; 7-methyl-3-methyleneocta-1,6-diene; 2-methyl-6-methyleneoct-7-en-2-ol; 2-methyl-6-methyleneoct-7-en-2-yl acetate; tetradecanal; 4-methoxy-6-prop-2-enyl-1,3-benzodioxole; tetradecanenitrile; 2,2,6,8-tetramethyl-1,2,3,4,4a,5,8,8a-octahydronaphthalen-1-ol; (E)-2,6-dimethylocta-5,7-dien-2-ol; (E)-2,7-dimethylocta-1,5,7-trien-3-ol; 2-((1S,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethyl acetate; (4R,4aS,6R)-4,4a-dimethyl-6-(prop-1-en-2-yl)-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one; nonan-1-ol; nonanal; 12-methyl-14-tetradec-9-enolide; N-ethyl-2-isopropyl-5-methylcyclohexane-1-carboxamide; 1-(3-methylbenzofuran-2-yl)ethan-1-one; 2-methoxynaphthalene; (E)-3,7,11-trimethyldodeca-1,6,10-trien-3-ol; (Z)-3,7-dimethylocta-2,6-dien-1-ol; 1-ethyl-3-methoxytricyclo[2.2.1.02,6]heptane; methyl (E)-non-2-enoate; 10-isopropyl-2,7-dimethyl-1-oxaspiro[4.5]deca-3,6-diene; 2-(2-(4-methylcyclohex-3-en-1-yl)propyl)cyclopentan-1-one; 6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-carbaldehyde; (E)-4-(2,2,3,6-tetramethylcyclohexyl)but-3-en-2-one; (4-(4-methylpent-3-en-1-yl)cyclohex-3-en-1-yl)methyl acetate; 2-(tert-butyl)-4,5,6-trimethyl-1,3-phenylene dinitrite; 1,7-dioxacycloheptadecan-8-one; 1-(4-(tert-butyl)-2,6-dimethyl-3,5-dinitrophenyl)ethan-1-one; 1-(tert-butyl)-2-methoxy-4-methyl-3,5-dinitrobenzene; 3-methylcyclopentadecan-1-one; (E)-3-methylcyclopentadec-4-en-1-one; 3-methyl-4-phenylbutan-2-ol; 1-(4-isopropylcyclohexyl)ethan-1-ol; (E)-dec-5-enoic acid; methyl non-2-ynoate; 2-methyldecanal; 6,6-dimethoxy-2,5,5-trimethylhex-2-ene; 4-phenylbutan-2-ol; methyl stearate; 1,1-dimethoxy-2-methylundecane; undecan-2-one; 2-methylundecanal; methyl tetradecanoate; methyl (9Z,12Z)-octadeca-9,12-dienoate; 1-hydroxydecan-3-one; (Z)-1,2-dimethoxy-4-(prop-1-en-1-yl)benzene; methyl palmitate; 4-allyl-1,2-dimethoxybenzene; methyl 2-((1R,2R)-3-oxo-2-((Z)-pent-2-en-1-yl)cyclopentyl)acetate; methyl 2-(3-oxo-2-pentylcyclopentyl)acetate; 1-methyl-2-phenoxybenzene; methyl cinnamate; 1-allyl-4-methoxybenzene; 1-(naphthalen-2-yl)ethan-1-one; methyl oct-2-ynoate; methyl 2,6,6-trimethylcyclohex-2-ene-1-carboxylate; 7-methoxy-3,7-dimethyloctanal; 7-isopropyl-10-methyl-1,5-dioxaspiro[5.5]undecan-3-ol; octahydro-1H-4,7-methanoindene-1-carbaldehyde; 3-(3-(tert-butyl)phenyl)-2-methylpropanal; (E)-4-(4,8-dimethylnona-3,7-dien-1-yl)pyridine; (E)-trideca-3,12-dienenitrile; 2,2-dimethyl-3-(m-tolyl)propan-1-ol; 2,4-dimethyl-4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; 8-isopropyl-6-methylbicyclo[2.2.2]oct-5-ene-2-carbaldehyde; 4-(4-hydroxy-4-methylpentyl)cyclohex-3-ene-1-carbaldehyde; (S)-1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene; (Z)-3-hexen-1-yl-2-cyclopenten-1-one; 3,7-dimethylocta-1,6-dien-3-yl octanoate; 3,7-dimethylocta-1,6-dien-3-yl isobutyrate; 3,7-dimethylocta-1,6-dien-3-yl benzoate; 3,7-dimethylocta-1,6-dien-3-yl 2-aminobenzoate; 2-(5-methyl-5-vinyltetrahydrofuran-2-yl)propan-2-ol; 6-methyl-2-(oxiran-2-yl)hept-5-en-2-ol; (2Z,6E)-3,7-dimethylnona-2,6-dienenitrile; 3-(4-methylcyclohex-3-en-1-yl)butanal; (2,5-dimethyl-1,3-dihydroinden-2-yl)methanol; 3-(4-(tert-butyl)phenyl)-2-methylpropanal; (E)-1-(1-methoxypropoxy)hex-3-ene; (E)-1-(1-ethoxyethoxy)hex-3-ene; (1S,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-ol; dodecan-1-ol; dodecyl acetate; dodecanoic acid; 5-hexyl-5-methyldihydrofuran-2(3H)-one; dodecanal; 3,6-dimethylhexahydrobenzofuran-2(3H)-one; 4-(1-ethoxyvinyl)-3,3,5,5-tetramethylcyclohexan-1-one; ((3S,3aR,6R,8aS)-7,7-dimethyl-8-methyleneoctahydro-1H-3a,6-methanoazulen-3-yl)methanol; 5-(sec-butyl)-2-(2,4-dimethylcyclohex-3-en-1-yl)-5-methyl-1,3-dioxane; (1-methyl-2-((1,2,2-trimethylbicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methanol; 2-propylheptanenitrile; (E)-6-(pent-3-en-1-yl)tetrahydro-2H-pyran-2-one; 2-hexylcyclopentan-1-one; 2-methyl-4-phenyl-1,3-dioxolane; 2,6,9,10-tetramethyl-1-oxaspiro(4.5)deca-3,6-diene; (1R,2S,5R)-5-methyl-2-(prop-1-en-2-yl)cyclohexan-1-ol; isopropyl palmitate; isopropyl tetradecanoate; isopropyl dodecanoate; 4,9-dimethoxy-7H-furo[3,2-g]chromen-7-one; (E)-cyclohexadec-8-en-1-one; (2S,5S)-2-isopropyl-5-methylcyclohexan-1-one; 2-hexylcyclopent-2-en-1-one; (2S,5S)-2-isopropyl-5-methylcyclohexan-1-one; 4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; (Z)-1-(benzyloxy)-2-methoxy-4-(prop-1-en-1-yl)benzene; 1-((2S,3S)-2,3,8,8-tetramethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-yl)ethan-1-one; 2,5,6-trimethylcyclohex-3-ene-1-carbaldehyde; 6-(sec-butyl)quinoline; 2-(cyclohexyloxy)-1,7,7-trimethylbicyclo[2.2.1]heptane; (1R,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl propionate; (1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate; 4-((2R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)cyclohexan-1-ol; (1R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 2-(4-isopropylcyclohexa-1,4-dien-1-yl)ethyl formate; isopentyl (E)-undec-6-enoate; isopentyl dodecanoate; (E)-oxacycloheptadec-10-en-2-one; (E)-non-2-enenitrile; (E)-8-(1H-indol-1-yl)-2,6-dimethyloct-7-en-2-ol; 8,8-di(1H-indol-1-yl)-2,6-dimethyloctan-2-ol; 4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; 3,7-dimethyloctane-1,7-diol; 2-cyclododecylpropan-1-ol; 3-methyl-5-phenylpentanenitrile; 3-phenylpropan-1-ol; (1,1-dimethoxypropan-2-yl)benzene; 5-ethyl-4-hydroxy-2-methylfuran-3(2H)-one; 2,3-dihydro-3,3-dimethyl-1H-indene-5-propanal; 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)propanal; hexyl octanoate; hexyl hexanoate; (Z)-2-benzylideneoctanal; hexyl benzoate; (Z)-hex-1-en-1-yl (Z)-2-methylbut-2-enoate; (E)-3,7-dimethylocta-2,6-dien-1-yl palmitate; oxacycloheptadecan-2-one; 2-butyl-4,4,6-trimethyl-1,3-dioxane; ethyl (1R,2R,3R,4R)-3-isopropylbicyclo[2.2.1]hept-5-ene-2-carboxylate; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl acetate; 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropyl propionate; 5-(diethoxymethyl)benzo[d][1,3]dioxole; 3-(benzo[d][1,3]dioxol-5-yl)-2-methylpropanal; (E)-oxacyclohexadec-13-en-2-one; 6-butyl-2,4-dimethyl-3,6-dihydro-2H-pyran; 2-((3S,5R,8S)-3,8-dimethyl-1,2,3,4,5,6,7,8-octahydroazulen-5-yl)propan-2-ol; 1-(2,6,6-trimethylcyclohex-2-en-1-yl)pentan-3-one; ethyl 2-ethyl-6,6-dimethylcyclohex-2-ene-1-carboxylate; (1Z,5Z)-1,5-dimethyl-8-(propan-2-ylidene)cyclodeca-1,5-diene; (1E,6E)-8-isopropyl-1-methyl-5-methylenecyclodeca-1,6-diene; (E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate; (E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate; (6E,10E)-3,7,11,15-tetramethylhexadeca-1,6,10,14-tetraen-3-ol; (E)-2-(3,7-dimethylocta-2,6-dien-1-yl)cyclopentan-1-one; 5-heptyldihydrofuran-2(3H)-one; 1-methyl-4-(propan-2-ylidene)cyclohexyl acetate; 1-methyl-4-(propan-2-ylidene)cyclohexan-1-ol; 5-pentyldihydrofuran-2(3H)-one; (1R,4aR,8aS)-1-isopropyl-7-methyl-4-methylene-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 5-[(Z)-hex-3-enyl]oxolan-2-one; (Z)-4-(2,2-dimethyl-6-methylenecyclohexyl)but-3-en-2-one; (4aS,9aR)-3,5,5,9-tetramethyl-2,4a,5,6,7,9a-hexahydro-1H-benzo[7]annulene; (1R,3aR,4R,7R)-1,4-dimethyl-7-(prop-1-en-2-yl)-1,2,3,3a,4,5,6,7-octahydroazulene; 2-((2R,4aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)propan-2-ol; 5-octyldihydrofuran-2(3H)-one; (Z)-1-(2,2-dimethyl-6-methylenecyclohexyl)but-2-en-1-one; 5-hexyldihydrofuran-2(3H)-one; (1R,4aS,8aS)-1-isopropyl-7-methyl-4-methylene-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 1-(3,3-dimethylcyclohexyl)pent-4-en-1-one; 4,6,6,7,8,8-hexamethyl-1,3,4,6,7,8-hexahydrocyclopenta[g]isochromene; furan-2-ylmethyl octanoate; furan-2-ylmethyl hexanoate; furan-2-ylmethyl heptanoate; 2-methyldecanenitrile; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; ethyl (3aR,4S,7R,7aR)-octahydro-3aH-4,7-methanoindene-3a-carboxylate; diethyl cyclohexane-1,4-dicarboxylate; (6-isopropyl-9-methyl-1,4-dioxaspiro[4.5]decan-2-yl)methanol; 2-isobutyl-4-methyltetrahydro-2H-pyran-4-ol; undec-10-enenitrile; (Z)-6-ethylideneoctahydro-2H-5,8-methanochromen-2-one; 3-(2-ethylphenyl)-2,2-dimethylpropanal; (E)-4,8-dimethyldeca-4,9-dienal; (E)-4-((3aR,4R,7R,7aR)-1,3a,4,6,7,7a-hexahydro-5H-4,7-methanoinden-5-ylidene)-3-methylbutan-2-ol; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl acetate; 3-(4-ethylphenyl)-2,2-dimethylpropanenitrile; 2-heptylcyclopentan-1-one; 1-ethoxyethoxy Cyclododecane; 3-cyclohexene-1-carboxylic acid, 2,6,6-trimethyl-, methyl ester; (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl acetate; (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol; oxacyclohexadecan-2-one; (E)-cyclopentadec-4-en-1-one; 1-cyclopentadec-4-en-1-one; 2-methoxy-4-(4-methylenetetrahydro-2H-pyran-2-yl)phenol; 4-allyl-2-methoxyphenyl acetate; 4-allyl-2-methoxyphenol; ethyl 3-methyl-3-phenyloxirane-2-carboxylate; 1,4-dioxacycloheptadecane-5,17-dione; ethyl undec-10-enoate; ethyl palmitate; ethyl nonanoate; ethyl tetradecanoate; (E)-3,7-dimethylnona-1,6-dien-3-ol; ethyl dodecanoate; nonan-3-one; ethyl decanoate; ethyl 6,6-dimethyl-2-methylenecyclohex-3-ene-1-carboxylate; ethyl 3-phenyloxirane-2-carboxylate; 6-ethyl-2,10,10-trimethyl-1-oxaspiro[4.5]deca-3,6-diene; 2-((1R,3S,4S)-4-methyl-3-(prop-1-en-2-yl)-4-vinylcyclohexyl)propan-2-ol; (2-(1-ethoxyethoxy)ethyl)benzene; (E)-3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pent-4-en-2-ol; (2R,3S,4R)-2,3,4,5-tetrahydroxypentanal; (E)-4-((3aS,7aS)-octahydro-5H-4,7-methanoinden-5-ylidene)butanal; 1,1-dimethoxydodecane; (R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene; 2-(2-hydroxypropoxy)propan-1-ol; 7,9-dimethylspiro[5.5]undecan-3-one; oxydibenzene; diphenylmethane; 2-methyl-1-phenylpropan-2-yl butyrate; 2,6-dimethyloct-7-en-4-one; octahydro-1H-4,7-methanoinden-5-yl acetate; 2-methyl-5-(prop-1-en-2-yl)cyclohexyl acetate; 2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-ol; 3,7-dimethyloct-6-en-3-ol; methyl 2-hexyl-3-oxocyclopentane-1-carboxylate; dibutylsulfane; 1,2-diphenylethane; 6-hexyltetrahydro-2H-pyran-2-one; (3R,4R)-1-isopropyl-4-methyl-3-(prop-1-en-2-yl)-4-vinylcyclohex-1-ene; (3S,3aS,5R)-3,8-dimethyl-5-(prop-1-en-2-yl)-1,2,3,3a,4,5,6,7-octahydroazulene; 6-heptyltetrahydro-2H-pyran-2-one; 6-pentyltetrahydro-2H-pyran-2-one; (1S,8aR)-4,7-dimethyl-1-(propan-2-yl)-1,2,3,5,6,8a-hexahydronaphthalene; (Z)-1-((1R,2S)-2,6,6-trimethylcyclohex-3-en-1-yl)but-2-en-1-one; (1S,8aS)-1-isopropyl-4,7-dimethyl-1,2,3,5,6,8a-hexahydronaphthalene; 3,7,7-trimethylbicyclo[4.1.0]hept-3-ene; dec-9-en-1-ol; decyl propionate; 1,1-diethoxydecane; decahydronaphthalen-2-ol; 1-cyclohexylethyl (E)-but-2-enoate; 3-(4-isopropylphenyl)-2-methylpropanal; cyclotetradecane; cyclopentadecanone; cyclohexyl 2-hydroxybenzoate; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl butyrate; 1,4-dioxacyclohexadecane-5,16-dione; 8,8-dimethyl-1,2,3,4,5,6,7,8-octahydronaphthalene-2-carbaldehyde; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl isobutyrate; (5R,6R)-3,6-dimethyl-5-(prop-1-en-2-yl)-6-vinyl-4,5,6,7-tetrahydrobenzofuran; (4-isopropylphenyl)methanol; 1-(benzofuran-2-yl)ethan-1-one; 2-(3-phenylpropyl)pyridine; dodecanenitrile; (E)-cycloheptadec-9-en-1-one; 3-(4-methylcyclohex-3-en-1-yl)but-3-en-1-yl acetate; 3-(4-methylcyclohex-3-en-1-yl)butan-1-ol; (E)-3-methyl-5-phenylpent-2-enenitrile; (E)-2-(2,6-dimethylhepta-1,5-dien-1-yl)-4-methyl-1,3-dioxolane; (E)-1,1-dimethoxy-3,7-dimethylocta-2,6-diene; (E)-1,1-diethoxy-3,7-dimethylocta-2,6-diene; (E)-3,7-dimethylocta-1,3,6-triene; (1R,4R,6S)-1-methyl-4-(prop-1-en-2-yl)-7-oxabicyclo[4.1.0]heptane; (E)-oxacycloheptadec-11-en-2-one; (Z)-non-6-en-1-ol; (1R,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-ol; (Z)-dec-4-enal; (E)-hex-3-en-1-yl (E)-hex-3-enoate; (Z)-hex-3-en-1-yl 2-hydroxybenzoate; (Z)-hex-3-en-1-yl benzoate; (Z)-hex-3-en-1-yl 2-methylbutanoate; (3Z,6Z)-nona-3,6-dien-1-ol; cinnamyl propionate; cinnamyl isobutyrate; cinnamyl formate; cinnamyl cinnamate; cinnamyl acetate; (E)-3-phenylprop-2-en-1-ol; hexadecan-1-ol; (E)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)hepta-1,6-dien-3-one; 2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butanal; (3aR,5aR,9aR,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; 1,6-dioxacycloheptadecan-7-one; 1-(6-(tert-butyl)-1,1-dimethyl-2,3-dihydro-1H-inden-4-yl)ethan-1-one; (3R,3aR,6S,7S,8aS)-6-methoxy-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-3-yl formate; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl acetate; (4Z,8Z)-1,5,9-trimethyl-13-oxabicyclo[10.1.0]trideca-4,8-diene; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-ol; 5-methyl-1-(2,2,3-trimethylcyclopent-3-en-1-yl)-6-oxabicyclo[3.2.1]octane; 5-methyl-1-(2,2,3-trimethylcyclopent-3-en-1-yl)-6-oxabicyclo[3.2.1]octane; 1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-4H-inden-4-one; (Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-3-en-5-yl acetate; (1S,2S,5R,8S)-4,4,8-trimethyltricyclo[6.3.1.02,5]dodecan-1-ol; 2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-yl acetate; octanenitrile; octan-1-ol; octanoic acid; decanoic acid; decanal; 3-(4-methoxyphenyl)-2-methylpropanal; 1,7,7-trimethylbicyclo[2.2.1]heptane-2,3-dione; 2,2-dimethyl-3-methylenebicyclo[2.2.1]heptane; ethyl 2-methyl-4-oxo-6-pentylcyclohex-2-ene-1-carboxylate; 2,6-di-tert-butyl-4-methylphenol; butyl stearate; 1-butoxy-1-oxopropan-2-yl butyrate; butyl undec-10-enoate; 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)butan-1-ol; 3-(4-(tert-butyl)phenyl)propanal; (1S,2S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate; 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 2-ethoxy-2,6,6-trimethyl-9-methylenebicyclo[3.3.1]nonane; (ethoxymethoxy)cyclododecane; (E)-1-methyl-4-(6-methylhept-5-en-2-ylidene)cyclohex-1-ene; 3,3,6,7-tetramethyloctahydro-2H-chromene; (5R,10R)-6,10-dimethyl-2-(propan-2-ylidene)spiro[4.5]dec-6-en-8-one; 1-methyl-4-(prop-1-en-2-yl)cyclohexyl acetate; 1-methyl-4-(prop-1-en-2-yl)cyclohexan-1-ol; (2Z,6E)-2,6-dimethyl-10-methylenedodeca-2,6,11-trienal; (R)-3-methylene-6-((S)-6-methylhept-5-en-2-yl)cyclohex-1-ene; (4aR,7R,8aS)-4a-methyl-1-methylene-7-(prop-1-en-2-yl)decahydronaphthalene; (Z)-2-methyl-5-((1S,2R,4R)-2-methyl-3-methylenebicyclo[2.2.1]heptan-2-yl)pent-2-en-1-ol; 6,6-dimethyl-2-methylenebicyclo[3.1.1]heptane; 2-ethoxynaphthalene; (1S,4R,7R)-1,4,9,9-tetramethyl-1,2,3,4,5,6,7,8-octahydro-4,7-methanoazulene; (1aS,5aR,9aR)-1a,5,5,7-tetramethyl-1a,2,3,4,5,5a,8,9-octahydrobenzo[1,7]cyclohepta[1,2-b]oxirene; (R)-3,5,5,9-tetramethyl-2,4a,5,6,7,8-hexahydro-1H-benzo[7]annulene; (1S,4S)-1,4-dimethyl-7-(propan-2-ylidene)-1,2,3,4,5,6,7,8-octahydroazulene; (2,2-dimethoxyethyl)benzene; (E)-7,11-dimethyl-3-methylenedodeca-1,6,10-triene; (1R,2S,6S,7S,8S)-8-isopropyl-1-methyl-3-methylenetricyclo[4.4.0.02,7]decane; (3R,3aS,7S,8aS)-3,8,8-trimethyl-6-methyleneoctahydro-1H-3a,7-methanoazulene; (1R,9S,Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-4-ene; (S)-4-methyl-1-((S)-6-methylhept-5-en-2-yl)cyclohex-3-en-1-ol; (Z)-4-(2,2,6-trimethyl-7-oxabicyclo[4.1.0]heptan-1-yl)but-3-en-2-one; 4-methoxy-7H-furo[3,2-g]chromen-7-one; 2-methyl-4-phenylbutan-2-ol; benzyl dodecanoate; 2-methyl-1-phenylpropan-2-ol; benzyl cinnamate; benzyl benzoate; benzophenone; 7-isopentyl-2H-benzo[b][1,4]dioxepin-3(4H)-one; 2′-isopropyl-1,7,7-trimethylspiro[bicyclo[2.2.1]heptane-2,4′-[1,3]dioxane]/A; 4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbonitrile; methyl (E)-2-((7-hydroxy-3,7-dimethyloctylidene)amino)benzoate; 4-methoxybenzyl 2-phenylacetate; methyl (E)-octa-4,7-dienoate; pentyl (Z)-3-phenylacrylate; (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; (4aR,5R,7aS,9R)-2,2,5,8,8,9a-hexamethyloctahydro-4H-4a,9-methanoazuleno[5,6-d][1,3]dioxole; 2,5,5-trimethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-ol; 2,5,5-trimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-ol; 1-((2-(tert-butyl)cyclohexyl)oxy)butan-2-ol; (3S,5aR,7aS,11aS,11bR)-3,8,8,11a-tetramethyldodecahydro-5H-3,5a-epoxynaphtho[2,1-c]oxepine; 2,2,6,6,7,8,8-heptamethyldecahydro-2H-indeno[4,5-b]furan; 2,2,7,7,8,9,9-heptamethyldecahydroindeno[4,3a-b]furan; 2-(sec-butyl)-1-vinylcyclohexyl acetate; (1S,4R,5R)-1-isopropyl-4-methylbicyclo[3.1.0]hexan-3-one; (4R,4aS)-4,4a-dimethyl-6-(propan-2-ylidene)-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one; 2-(4-methylcyclohex-3-en-1-yl)propan-2-yl propionate; (2Z,6E,9E)-2,6,10-trimethyldodeca-2,6,9,11-tetraenal; (2R,4aR,8aR)-4a,8-dimethyl-2-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 1,7-dimethyl-7-(4-methylpent-3-en-1-yl)tricyclo[2.2.1.02,6]heptane; (E)-5-(2,3-dimethyltricyclo[2.2.1.02,6]heptan-3-yl)-2-methylpent-2-en-1-ol; (1R,3aS,7S,8aR)-1,4,9,9-tetramethyl-2,3,6,7,8,8a-hexahydro-1H-3a,7-methanoazulene; 1-(5,5-dimethylcyclohex-1-en-1-yl)pent-4-en-1-one; (1S,4aS,8aR)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (R,Z)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)pent-1-en-3-one; 1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene; (Z)-4-(2,5,6,6-tetramethylcyclohex-2-en-1-yl)but-3-en-2-one; (1Z,4E,8Z)-2,6,6,9-tetramethylcycloundeca-1,4,8-triene; (4aR,8S,9aS)-3,5,5,8-tetramethyl-9-methylene-2,4a,5,6,7,8,9,9a-octahydro-1H-benzo[7]annulene; (1aR,4R,4aR,7bS)-1,1,4,7-tetramethyl-1a,2,3,4,4a,5,6,7b-octahydro-1H-cyclopropa[e]azulene; 1,4-dimethyl-7-(prop-1-en-2-yl)-1,2,3,4,5,6,7,8-octahydroazulene; (3E,6E)-3,7,11-trimethyldodeca-1,3,6,10-tetraene; 7,7-dimethyl-2-methylenebicyclo[2.2.1]heptane; 2-((2R,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl)propan-2-ol; (R)-1-methyl-4-(6-methylhept-5-en-2-yl)benzene; (3aR,3bR,4S,7R,7aS)-4-isopropyl-7-methyl-3a,3b,4,5,6,7-hexahydro-1H-cyclopenta[1,3]cyclopropa[1,2]benzene; (1aS,2aR,3R,5aS,7R,7aR)-3,6,6,7a-tetramethyloctahydro-2H-2a,7-methanoazuleno[5,6-b]oxirene; (1R,4S,4aR,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; (1S,4aR,8aR)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (R)-2-((R)-4-methylcyclohex-3-en-1-yl)hex-5-en-2-ol; (Z)-1-methyl-4-(6-methylhepta-2,5-dien-2-yl)cyclohex-1-ene; 2,6-dimethyl-6-(4-methylpent-3-en-1-yl)bicyclo[3.1.1]hept-2-ene; (E)-2-benzylideneheptan-1-ol; (E)-2-benzylideneheptyl acetate; (Z)-(2-(diethoxymethyl)hept-1-en-1-yl)benzene; (E)-2-benzylideneheptanal; (1S,4aR,8aS)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (3R,5aS,9aR)-2,2,5a,9-tetramethyl-3,4,5,5a,6,7-hexahydro-2H-3,9a-methanobenzo[b]oxepine; 1-methyl-4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; 1-phenylpentan-2-ol; 3-methyl-1-phenylpentan-3-ol; 2,3,4-trimethoxybenzaldehyde; 2,4,5-trimethoxybenzaldehyde; 2,4,6-trimethoxybenzaldehyde; Trans,Trans-2,4-Nonadienal; 2,6,10-trimethylundecanal; alpha-4-Dimethyl benzenepropanal; allyl 3-cyclohexylpropanoate; allyl 2-(isopentyloxy)acetate; (1aR,4aS,7R,7aR,7bS)-1,1,7-trimethyl-4-methylenedecahydro-1H-cyclopropa[e]azulene; (E)-undec-9-enal; methyl (E)-2-(((3,5-dimethylcyclohex-3-en-1-yl)methylene)amino)benzoate; 2,6,10-trimethylundec-9-enal; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methyl acetate; nonyl acetate; (2-(1-propoxyethoxy)ethyl)benzene; 1-(1-propoxyethoxy)propane; ((1-(2-methoxyethoxy)ethoxy)methyl)benzene; (Z)-2-(4-methylbenzylidene)heptanal; dec-9-enal; (Z)-oxacycloheptadec-8-en-2-one; 7-methoxy-2H-chromen-2-one; (2S,4aR,8aR)-4a,8-dimethyl-2-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 2-((2S,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl)propan-2-ol; 1-(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethan-1-one; 6-isopropylquinoline; 3-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)propanal; 6,10,14-trimethylpentadecan-2-one; 2-methyl-5-(prop-1-en-2-yl)-2-vinyltetrahydrofuran; (E)-cyclohexadec-5-en-1-one; 1-isopropyl-4-methylcyclohex-3-en-1-ol; 1-phenylpent-4-en-1-one; 1-isopropyl-4-methylcyclohex-3-en-1-ol; 3,6-dimethyl-4,5,6,7-tetrahydrobenzofuran; 4-(4-methoxyphenyl)butan-2-one; (1aR,2S,4aS)-2,4a,8,8-tetramethyloctahydrocyclopropa[d]naphthalen-3(1H)-one; (E)-3-propylideneisobenzofuran-1(3H)-one; (Z)-dodec-2-enal; 3-methyl-5-phenylpentanal; (E)-hex-3-en-1-yl 3-methylbutanoate; 3,6-dimethyloctan-3-yl acetate; 3,4,5-trimethoxybenzaldehyde; 3-(4-isopropylphenyl)propanal; (Z)-undec-2-enenitrile; (E)-undec-2-enal; (2E,6E)-nona-2,6-dienal; phenethyl butyrate; (Z)-3-(furan-2-yl)-2-phenylacrylaldehyde; 2-phenoxyethan-1-ol; (Z)-non-2-enal; nonan-2-ol; nonan-2-one; 2-isobutylquinoline; (E)-2-hexylidenecyclopentan-1-one; 2-heptyltetrahydrofuran; (E)-dec-2-enal; (2E,6E)-nona-2,6-dienal; (2E,6E)-nona-2,6-dien-1-ol; 2,6-dimethyloctanal; decan-1-ol; (E)-hept-1-en-1-yl acetate; undec-10-en-1-ol; undec-10-enal; 2-((2R,4aS)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)propan-2-ol; 1-isopropyl-4-methyl-7-thiabicyclo[2.2.1]heptane; (3E,5Z)-undeca-1,3,5-triene; 3,7-dimethyloct-6-en-3-ol; 1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 1,1,2,3,3-pentamethyl-2,3-dihydro-1H-indene; (Z)-6,10-dimethylundeca-5,9-dien-2-yl acetate; (Z)-dodec-3-enal; (S)-5-heptyldihydrofuran-2(3H)-one; (R)-5-heptyldihydrofuran-2(3H)-one; (E)-6,10-dimethylundeca-5,9-dien-2-yl acetate; (Z)-3-methyl-5-phenylpent-2-enenitrile; (2S,5S,6S)-2,6,10,10-tetramethyl-1-oxaspiro[4.5]decan-6-ol; (2E)-3-methyl-5-phenyl-2-pentenenitrile; (1S,2S,5S)-2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-ol; (2S,5R)-2-isopropyl-5-methylcyclohexan-1-one; (R,E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 2-(8-isopropyl-6-methylbicyclo[2.2.2]oct-5-en-2-yl)-1,3-dioxolane; (E)-4-(2,2-dimethyl-6-methylenecyclohexyl)-3-methylbut-3-en-2-one; 3-(3-isopropylphenyl)butanal; 3-(1-ethoxyethoxy)-3,7-dimethylocta-1,6-diene; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; 2-((3S,3aS,5R)-3,8-dimethyl-1,2,3,3a,4,5,6,7-octahydroazulen-5-yl)propan-2-ol; benzyl 2-phenylacetate; 2-hydroxy-1,2-diphenylethan-1-one; (E)-1,2,4-trimethoxy-5-(prop-1-en-1-yl)benzene; 3-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-2,2-dimethylpropanal; 2-methyl-5-(6-methylhept-5-en-2-yl)bicyclo[3.1.0]hex-2-ene; 1-(1,1,2,3,3,6-hexamethyl-2,3-dihydro-1H-inden-5-yl)ethan-1-one; 2-(m-tolyl)ethan-1-ol; (3E,6E)-nona-3,6-dien-1-ol; (E)-tridec-2-enal; (1R,4S,4aS,6R,8aS)-4,8a,9,9-tetramethyloctahydro-1,6-methanonaphthalen-1(2H)-ol; p-tolyl isobutyrate; p-tolyl hexanoate; 5-hexyl-4-methyldihydrofuran-2(3H)-one; ethyl (2Z,4E)-deca-2,4-dienoate; 2,4-dimethyl-6-phenyl-3,6-dihydro-2H-pyran; 2-cyclohexylidene-2-phenylacetonitrile; 4-(prop-1-en-2-yl)cyclohex-1-ene-1-carbaldehyde; (4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methyl acetate; (4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methanol; (2-isopropoxyethyl)benzene; 2-cyclohexylhepta-1,6-dien-3-one; (2-(cyclohexyloxy)ethyl)benzene; phenethyl 2-methylbutanoate; 2-phenylethan-1-ol; phenethyl 2-phenylacetate; 3-methyl-5-phenylpentan-1-ol; phenyl benzoate; phenethyl benzoate; 2-benzyl-1,3-dioxolane; 2-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)acetaldehyde; 6,6-dimethyl-2-methylenebicyclo[3.1.1]heptan-3-ol; 4-(benzo[d][1,3]dioxol-5-yl)butan-2-one; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-ylpivalate; (4aR,8aS)-7-methyloctahydro-1,4-methanonaphthalen-6(2H)-one; 4-isopropyl-1-methylcyclohex-3-en-1-ol; (E)-3,3-dimethyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pent-4-en-2-ol; 1-methyl-4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; propane-1,2-diol; p-tolyl 2-phenylacetate; Ethyl 2,4,7-decatrienoate; 2-benzyl-4,4,6-trimethyl-1,3-dioxane; 2,4-dimethyl-4-phenyltetrahydrofuran; (2R,4a′R,8a′R)-3,7′-dimethyl-3′,4′,4a′,5′,8′,8a′-hexahydro-1′H-spiro[oxirane-2,2′-[1,4]methanonaphthalene]; (Z)-6-ethylideneoctahydro-2H-5,8-methanochromene; 2-((S)-1-((S)-3,3-dimethylcyclohexyl)ethoxy)-2-oxoethyl propionate; methyl 2,2-dimethyl-6-methylenecyclohexane-1-carboxylate; 2-methyl-5-phenylpentan-1-ol; 4-methyl-2-phenyl-3,6-dihydro-2H-pyran; (1S,3R,5S)-1-isopropyl-4-methylenebicyclo[3.1.0]hexan-3-ol; 5-allylbenzo[d][1,3]dioxole; 2,2,7,9-tetramethylspiro(5.5)undec-8-en-1-one; 3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pentan-2-ol; (Z)-2-ethyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; (E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; 1-(3-hydroxy-3-methylpent-4-en-1-yl)-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol; (4aR,6aS,10aS,10bR)-3,4a,7,7,10a-pentamethyl-4a,5,6,6a,7,8,9,10,10a,10b-decahydro-1H-benzo[f]chromene; (4aR,8aR)-4a,8-dimethyl-2-(propan-2-ylidene)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropyl cyclopropanecarboxylate; 3-(4-isobutylphenyl)-2-methylpropanal; (1aR,4aR,7S,7aR,7bR)-1,1,7-trimethyl-4-methylenedecahydro-1H-cyclopropa[e]azulen-7-ol; (1R,3R,6R)-2′,2′,3,7,7-pentamethylspiro[bicyclo[4.1.0]heptane-2,5′-[1,3]dioxane]; 2-methyl-1,5-dioxaspiro[5.5]undecane; 1-(spiro[4.5]dec-7-en-7-yl)pent-4-en-1-one; 2-(4-methylthiazol-5-yl)ethan-1-ol; 2-(heptan-3-yl)-1,3-dioxolane; (Z)-dodec-4-enal; (1S,4S,4aR,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; (1S,4S,4aR,8aS)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; 3-methyl-2-pentylcyclopentan-1-one; 2,6,10,10-tetramethyl-1-oxaspiro[4.5]dec-6-ene; 2-(2-mercaptopropan-2-yl)-5-methylcyclohexan-1-one; (1aR,4aS)-2,4a,8,8-tetramethyl-1,1a,4,4a,5,6,7,8-octahydrocyclopropa[d]naphthalene; 1-isopropyl-2-methoxy-4-methylbenzene; 1-(2,2,6-trimethylcyclohexyl)hexan-3-ol; (2Z,4E)-nona-2,4-dienal; (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol; (2E,6Z)-nona-2,6-dienal; (Z)-dec-2-enal; (E)-non-2-enal; (3E,6Z)-nona-3,6-dien-1-ol; (E)-dec-4-enal; (Z)-oxacycloheptadec-8-en-2-one; (Z)-3,7-dimethylocta-1,3,6-triene; (Z)-3,7-dimethylocta-1,3,6-triene; (E)-3,7-dimethylocta-2,6-dien-1-ol; methyl 2-((1S,2S)-3-oxo-2-pentylcyclopentyl)acetate; 7-(1,1-Dimethylethyl)-2H-1,5-benzodioxepin-3(4H)-one; (1R-(1alpha,3alpha,4aalpha))-2,3,4,4a,5,6-hexahydro-2,2-dimethyl-1,3-methanonaphthalen-7(1H)-one; tridecan-1-ol; triethyl 2-hydroxypropane-1,2,3-tricarboxylate; methyl 2-((1-hydroxy-3-phenylbutyl)amino)benzoate; 1-((2E,5Z,9Z)-2,6,10-trimethylcyclododeca-2,5,9-trien-1-yl)ethan-1-one; decahydro-2,6,6,7,8,8-hexamethyl-2h-indeno(4,5-b)furan; 13-methyl oxacyclopentadec-10-en-2-one; undecanal; (E)-4-methyldec-3-en-5-ol; (3R,4aS,5R)-4a,5-dimethyl-3-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,7-octahydronaphthalene; 2-((2R,8R,8aS)-8,8a-dimethyl-1,2,3,4,6,7,8,8a-octahydronaphthalen-2-yl)propan-2-ol; 4-formyl-2-methoxyphenyl isobutyrate; (Z)-2-methyl-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-enal; methyl 2,4-dihydroxy-3,6-dimethylbenzoate; 1-methoxy-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoindene; methyl (Z)-2-((3-(4-(tert-butyl)phenyl)-2-methylpropylidene)amino)benzoate; (Z)-hex-3-en-1-yl isobutyrate; 2,4,6-trimethyl-4-phenyl-1,3-dioxane; 1-((3R,3aR,7R,8aS)-3,6,8,8-tetramethyl-2,3,4,7,8,8a-hexahydro-1H-3a,7-methanoazulen-5-yl)ethan-1-one; methyl (Z)-2-(((2,4-dimethylcyclohex-3-en-1-yl)methylene)amino)benzoate; 4,8-dimethyl-2-(propan-2-ylidene)-1,2,3,3a,4,5,6,8a-octahydroazulen-6-ol; 4,8-dimethyl-2-(propan-2-ylidene)-1,2,3,3a,4,5,6,8a-octahydroazulen-6-yl acetate; decahydro-3H-spiro[furan-2,5′-[4,7]methanoindene]; (2Z,6E)-nona-2,6-dienenitrile; (Z)-cyclooct-4-en-1-yl methyl carbonate; (1aR,4S,4aS,7R,7aS,7bS)-1,1,4,7-tetramethyldecahydro-1H-cyclopropa[e]azulen-4-ol; 3,5,5,6,7,8,8-heptamethyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile; (1S,2S,3S,5R)-2,6,6-trimethylspiro[bicyclo[3.1.1]heptane-3,1′-cyclohexan]-2′-en-4′-one; 1′,1′,5′,5′-tetramethylhexahydro-2′H,5′H-spiro[[1,3]dioxolane-2,8′-[2,4a]methanonaphthalene]; (2'S,4a'S,8a'S)-1′,1′,5′,5′-tetramethylhexahydro-2′H,5′H-spiro[[1,3]dioxolane-2,8′-[2,4a]methanonaphthalene]; 4-(4-hydroxy-3-methoxyphenyl)butan-2-one; (1R,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,7,8,8a-hexahydronaphthalene; 2,4-dimethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolane; 3a,5,6,7,8,8b-hexahydro-2,2,6,6,7,8,8-heptamethyl-4H-indeno(4,5-d)-1,3-dioxole; 2,4-dimethyl-4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; (1-methyl-2-((1,2,2-trimethylbicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methanol; 2-(cyclohexyloxy)-1,7,7-trimethylbicyclo[2.2.1]heptane; 4-((2R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)cyclohexan-1-ol; 8,8-di(1H-indol-1-yl)-2,6-dimethyloctan-2-ol; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methanol; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; (E)-4-((3aR,4R,7R,7aR)-1,3a,4,6,7,7a-hexahydro-5H-4,7-methanoinden-5-ylidene)-3-methylbutan-2-ol; (3R,3aR,6S,7S,8aS)-6-methoxy-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene; (1R,2S,6S,7S,8S)-8-isopropyl-1-methyl-3-methylenetricyclo[4.4.0.02,7]decane; 2′-isopropyl-1,7,7-trimethylspiro[bicyclo[2.2.1]heptane-2,4′-[1,3]dioxane]; (4aR,5R,7aS,9R)-2,2,5,8,8,9a-hexamethyloctahydro-4H-4a,9-methanoazuleno[5,6-d][1,3]dioxole; (3S,5aR,7aS,11aS,11bR)-3,8,8,11a-tetramethyldodecahydro-5H-3,5a-epoxynaphtho[2,1-c]oxepine; 2,2,6,6,7,8,8-heptamethyldecahydro-2H-indeno[4,5-b]furan; (1aS,2aR,3R,5aS,7R,7aR)-3,6,6,7a-tetramethyloctahydro-2H-2a,7-methanoazuleno[5,6-b]oxirene; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methyl acetate; 1-(3-hydroxy-3-methylpent-4-en-1-yl)-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol; decahydro-2,6,6,7,8,8-hexamethyl-2h-indeno(4,5-b)furan; 4,5-epoxy-4,11,11-trimethyl-8-methylenebicyclo(7.2.0)undecane; 1,3,4,6,7,8alpha-hexahydro-1,1,5,5-tetramethyl-2H-2,4alpha-methanophtalen-8(5H)-one, more preferably said malodor reduction materials are selected from the group consisting of: 3-methoxy-7,7-dimethyl-10-methylenebicyclo[4.3.1]decane; 2,4a,5,8a-tetramethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl formate; 2,2,6,8-tetramethyl-1,2,3,4,4a,5,8,8a-octahydronaphthalen-1-ol; (4R,4aS,6R)-4,4a-dimethyl-6-(prop-1-en-2-yl)-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one; ((3S,3aR,6R,8aS)-7,7-dimethyl-8-methyleneoctahydro-1H-3a,6-methanoazulen-3-yl)methanol; 4,9-dimethoxy-7H-furo[3,2-g]chromen-7-one; (E)-cyclohexadec-8-en-1-one; (Z)-1-(benzyloxy)-2-methoxy-4-(prop-1-en-1-yl)benzene; 1-((2S,3S)-2,3,8,8-tetramethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-yl)ethan-1-one; (1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate; 2,3-dihydro-3,3-dimethyl-1H-indene-5-propanal; 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)propanal; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl acetate; 2-((2R,4aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)propan-2-ol; 4,6,6,7,8,8-hexamethyl-1,3,4,6,7,8-hexahydrocyclopenta[g]isochromene; (Z)-6-ethylideneoctahydro-2H-5,8-methanochromen-2-one; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl acetate; octahydro-1H-4,7-methanoinden-5-yl acetate; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl butyrate; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl isobutyrate; (5R,6R)-3,6-dimethyl-5-(prop-1-en-2-yl)-6-vinyl-4,5,6,7-tetrahydrobenzofuran; (E)-cycloheptadec-9-en-1-one; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-3-yl formate; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl acetate; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-ol; 5-methyl-1-(2,2,3-trimethylcyclopent-3-en-1-yl)-6-oxabicyclo[3.2.1]octane; (Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-3-en-5-yl acetate; (1S,2S,5R,8S)-4,4,8-trimethyltricyclo[6.3.1.02,5]dodecan-1-ol; (1S,2S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate; (Z)-2-methyl-5-((1S,2R,4R)-2-methyl-3-methylenebicyclo[2.2.1]heptan-2-yl)pent-2-en-1-ol; (1S,4R,7R)-1,4,9,9-tetramethyl-1,2,3,4,5,6,7,8-octahydro-4,7-methanoazulene; (1aS,5aR,9aR)-1a,5,5,7-tetramethyl-1a,2,3,4,5,5a,8,9-octahydrobenzo[1,7]cyclohepta[1,2-b]oxirene; (2,2-dimethoxyethyl)benzene; (3R,3aS,7S,8aS)-3,8,8-trimethyl-6-methyleneoctahydro-1H-3a,7-methanoazulene; 4-methoxybenzyl 2-phenylacetate; 2,2,7,7,8,9,9-heptamethyldecahydroindeno[4,3a-b]furan; (4R,4aS)-4,4a-dimethyl-6-(propan-2-ylidene)-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one; (E)-5-(2,3-dimethyltricyclo[2.2.1.02,6]heptan-3-yl)-2-methylpent-2-en-1-ol; (1R,3aS,7S,8aR)-1,4,9,9-tetramethyl-2,3,6,7,8,8a-hexahydro-1H-3a,7-methanoazulene; (1aR,4R,4aR,7bS)-1,1,4,7-tetramethyl-1a,2,3,4,4a,5,6,7b-octahydro-1H-cyclopropa[e]azulene; 2-((2R,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl)propan-2-ol; (3aR,3bR,4S,7R,7aS)-4-isopropyl-7-methyl-3a,3b,4,5,6,7-hexahydro-1H-cyclopenta[1,3]cyclopropa[1,2]benzene; (3R,5aS,9aR)-2,2,5a,9-tetramethyl-3,4,5,5a,6,7-hexahydro-2H-3,9a-methanobenzo[b]oxepine; (1aR,4aS,7R,7aR,7bS)-1,1,7-trimethyl-4-methylenedecahydro-1H-cyclopropa[e]azulene; 2-((2S,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl)propan-2-ol; 1-(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethan-1-one; (E)-cyclohexadec-5-en-1-one; (1aR,2S,4aS)-2,4a,8,8-tetramethyloctahydrocyclopropa[d]naphthalen-3(1H)-one; 2-((2R,4aS)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)propan-2-ol; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; 1-(1,1,2,3,3,6-hexamethyl-2,3-dihydro-1H-inden-5-yl)ethan-1-one; (1R,4S,4aS,6R,8aS)-4,8a,9,9-tetramethyloctahydro-1,6-methanonaphthalen-1(2H)-ol; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl pivalate; (2R,4a′R,8a′R)-3,7′-dimethyl-3′,4′,4a′,5′,8′,8a′-hexahydro-1′H-spiro[oxirane-2,2′-[1,4]methanonaphthalene]; 2,2,7,9-tetramethylspiro(5.5)undec-8-en-1-one; (Z)-2-ethyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; (4aR,6aS,10aS,10bR)-3,4a,7,7,10a-pentamethyl-4a,5,6,6a,7,8,9,10,10a,10b-decahydro-1H-benzo[f]chromene; (1aR,4aR,7S,7aR,7bR)-1,1,7-trimethyl-4-methylenedecahydro-1H-cyclopropa[e]azulen-7-ol; 1-(spiro[4.5]dec-7-en-7-yl)pent-4-en-1-one; (1 aR,4aS)-2,4a,8,8-tetramethyl-1,1a,4,4a,5,6,7,8-octahydrocyclopropa[d]naphthalene; (1R-(1alpha,3alpha,4aalpha))-2,3,4,4a,5,6-hexahydro-2,2-dimethyl-1,3-methanonaphthalen-7(1H)-one; 2-((2R,8R,8aS)-8,8a-dimethyl-1,2,3,4,6,7,8,8a-octahydronaphthalen-2-yl)propan-2-ol; 1-((3R,3aR,7R,8aS)-3,6,8,8-tetramethyl-2,3,4,7,8,8a-hexahydro-1H-3a,7-methanoazulen-5-yl)ethan-1-one; methyl (Z)-2-(((2,4-dimethylcyclohex-3-en-1-yl)methylene)amino)benzoate; 4,8-dimethyl-2-(propan-2-ylidene)-1,2,3,3a,4,5,6,8a-octahydroazulen-6-yl acetate; decahydro-3H-spiro[furan-2,5′-[4,7]methanoindene]; (1aR,4S,4aS,7R,7aS,7bS)-1,1,4,7-tetramethyldecahydro-1H-cyclopropa[e]azulen-4-ol; 3,5,5,6,7,8,8-heptamethyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile; (1S,2S,3S,5R)-2,6,6-trimethylspiro[bicyclo[3.1.1]heptane-3,1′-cyclohexan]-2′-en-4′-one; 1′,1′,5′,5′-tetramethylhexahydro-2′H,5′H-spiro[[1,3]dioxolane-2,8′-[2,4a]methanonaphthalene]; (2'S,4a'S,8a'S)-1′,1′,5′,5′-tetramethylhexahydro-2′H,5′H-spiro[[1,3]dioxolane-2,8′-[2,4a]methanonaphthalene]; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methanol; 4,5-epoxy-4,11,11-trimethyl-8-methylenebicyclo(7.2.0)undecane; 1,3,4,6,7,8alpha-hexahydro-1,1,5,5-tetramethyl-2H-2,4alpha-methanophtalen-8(5H)-one, most preferably said malodor reduction materials are selected from the group consisting of: (E)-cyclohexadec-5-en-1-one; 2,2,7,7,8,9,9-heptamethyldecahydroindeno[4,3a-b]furan; 2,3-dihydro-3,3-dimethyl-1H-indene-5-propanal; 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)propanal; 4,5-epoxy-4,11,11-trimethyl-8-methylenebicyclo(7.2.0)undecane; 1,3,4,6,7,8alpha-hexahydro-1,1,5,5-tetramethyl-2H-2,4alpha-methanophtalen-8(5H)-one and mixtures thereof. 6. A personal care composition according to any preceeding claim, said composition comprising one or more perfume raw materials. 7. A personal care composition according to any preceeding claim wherein, said sum total of malodor reduction materials has an average Log P, based on weight percent of each malodor reduction material in said sum total of malodor reduction materials, of from about 2.5 to about 8, preferably from about 3 to about 8, more preferably from about 3.5 to about 7, most preferably, each of said malodor reduction materials in said sum total of malodor reduction materials and each of said one or more perfume raw materials has a Log P from about 3.5 to about 7. 8. A personal care composition according to any preceding claim wherein, the ratio of said one or more perfume raw materials to said sum total of malodor reduction material being from about 1000:1 to about 1:1, preferably from about 100:1 to about 1:1, more preferably from about 10:1 to about 1:1, most preferably from about 2:1 to about 1:1. 9. A personal care composition according to any preceding claim, wherein less than 10%, preferably less than 5%, more preferably less than 1% of said malodor reduction materials and said one or more perfume raw materials, based on total combined weight of malodor reduction materials and said one or more perfume raw materials comprise an ionone moiety. 10. A personal care composition according to any preceding claim, wherein said malodor reduction materials are not a material selected from the group consisting of geranyl nitrile; helional; nonanal; linalool; (S)-(+)-linalool; (R)-(−)-linalool; nerol; tetrahydrolinalool; 2-phenylethyl acetate; eugenol; ethyl linalool; allyl heptoate; agrumen nitrile; citronitrile; 2,2-dimethyl-3-(m-tolyl)propan-1-ol; 2-methyl-5-phenylpentan-1-ol; dodecanenitrile; 2-heptylcyclopentan-1-one; methyl nonyl acetaldehyde; 3-(2-ethylphenyl)-2,2-dimethylpropanal; (Z)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-en-1-one; (R,E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 4-(tert-butyl)cyclohexyl acetate; 1-cyclohexylethyl (E)-but-2-enoate; allyl 2-(cyclohexyloxy)acetate; alpha terpinyl acetate; beta terpinyl acetate; gamma terpinyl acetate; methyl dodecyl ether; 2,4-dimethyl-4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; cinnamyl isobutyrate; (E)-2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)but-2-enal; gamma methyl ionone; ethyl 2,3,6-trimethyl cyclohexyl carbonate ethyl 2,3,6-trimethyl cyclohexyl carbonate; Citral diethyl acetal; Dimethoxycyclododecane; 1-((2S,3S)-2,3,8,8-tetramethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-yl)ethan-1-one; oxacyclohexadecan-2-one; 4,6,6,7,8,8-hexamethyl-1,3,4,6,7,8-hexahydrocyclopenta[g]isochromene; Ethylene brassylate; Methyl (Z)-2-((3-(4-(tert-butyl)phenyl)-2-methylpropylidene)amino)benzoate; 4,7-Methano-1H-inden-5-ol, 3a,4,5,6,7,7a-hexahydro-, 5-acetate; cedryl methyl ether; vetivert acetate; 1-((3R,3aR,7R,8aS)-3,6,8,8-tetramethyl-2,3,4,7,8,8a-hexahydro-1H-3a,7-methanoazulen-5-yl)ethan-1-one; Benzophenone; Farnesol; trans,trans-farnesol; 3-(3-isopropylphenyl)butanal; 2,6,10-trimethylundec-9-enal; 3-(4-(tert-butyl)phenyl)propanal; 3-(4-isopropylphenyl)-2-methylpropanal; Citronellal (1); Citronellal (d); (E)-4,8-dimethyldeca-4,9-dienal; Pino Acetaldehyde; 3-(4-(tert-butyl)phenyl)-2-methylpropanal; Cinnamic aldehyde; Citral; Geranial; MethoxyMelonal; o-methoxycinnamaldehyde; (E)-4-((3aS,7aS)-octahydro-5H-4,7-methanoinden-5-ylidene)butanal; Methyl Octyl Acetaldehyde; 3-(4-methoxyphenyl)-2-methylpropanal; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; Iso Cyclocitral; Octanal; 2-Undecenal; 10-Undecenal; Trans-trans-2,6-Nonadienal; Trans-2,cis-6-nondienal; Heliotropin; Hexyl Cinnamic aldehyde; p-methyl-alpha-pentylcinnamaldehyde; Alpha-methyl cinnamaldehyde; 3,4-dimethoxybenzaldehyde; Myrtenal; Perillaldehyde; Maceal; Methyl palmitate; Methyl iso eugenol and mixtures thereof. 11. A personal care composition according to any preceeding claim, said composition comprising a total, based on total personal care composition weight, of from about 0.1% to about 7% of one or more of said malodor reduction materials and from about 3% to 30% of a surfactant, and, optionally, a miscellar phase and/or lamellar phase. 12. A personal care composition according to any preceeding claim said composition comprising a total, based on total personal care composition weight, of from about 0.1% to about 50% of a material selected from structurants, humectants, fatty acids, inorganic salts, antimicrobial agents, antimicrobial actives and mixtures thereof. 13. A personal care composition according to any preceding claim, said composition comprising an adjunct ingredient selected from the group consisting of clay mineral powders, pearl pigments, organic powders, emulsifiers, distributing agents, pharmaceutical active, topical active, preservatives, surfactants and mixtures thereof. 14. A method of controlling malodors comprising: contacting a situs comprising a malodor and/or a situs that will become malodorous with a personal care composition selected from the group consisting of the personal care composition of claims 1 to 13. 15. The method of claim 14 wherein, said situs is a body or head of hair and said contacting step comprises contacting said body or head of hair with a sufficient amount of Applicants' personal care composition to provide said body or hair with a level of malodor reduction material at least 0.0001 mg of malodor reduction material per body or head of hair, preferably from about 0.0001 mg of malodor reduction material per body or head of hair to about 1 mg of malodor reduction material per body or head of hair, more preferably from about 0.001 mg of malodor reduction material per body or head of hair about 0.5 mg of malodor reduction material per body or head of hair, most preferably from about 0.01 of malodor reduction material per body or head of hair to about 0.2 mg of malodor reduction material per body or head of hair.
| 1,600 |
946 | 15,708,205 | 1,615 |
The present invention relates to personal care compositions comprising malodor reduction compositions and methods of making and using such personal care compositions. Such personal care compositions comprising the malodor control technologies disclosed herein provide malodor control without leaving an undesireable scent and when perfume is used to scent such compositions, such scent is not unduely altered by the malodor control technology.
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1. A personal care composition comprising, based on total composition weight,
a) a sum total of from about 0.0001% to about 2%, preferably from about 0.0001% to about 0.75%, more preferably from about 0.001% to about 0.5%, most preferably from about 0.007% to about 0.25% of 1 or more malodor reduction materials, preferably 1 to about 75 malodor reduction materials, more preferably 1 to about 50 malodor reduction materials, more preferably 1 to about 35 malodor reduction materials, most preferably 1 to about 20 malodor reduction materials, each of said malodor reduction materials having a MORV of at least 0.5, preferably from 0.5 to 10, more preferably from 1 to 10, most preferably from 1 to 5, and preferably each of said malodor reduction materials having a Universal MORV, or said sum total of malodor reduction materials having a Blocker Index of less than 3, more preferable less than about 2.5 even more preferably less than about 2 and still more preferably less than about 1 and most preferably 0 and/or a Blocker Index average of 3 to about 0.001; and b) from about 0% to about 12%, preferably from about 0% to about 8%, more preferably from about 0.1% to about 4%, of one or more perfume raw materials having a MORV of less than 0.5, preferably less than 0, more preferably less than −2, most preferably less than −5; c) from about 0.1% to about 99%, preferably from about 1% to about 80%, more preferably from about 5% to about 70%, most preferably from about 10% to about 50% of a solvent, preferably said solvent is selected from, water, glycerin, and mixtures thereof; d) from about 0% to about 50%, preferably from about 0% to about 40%, more preferably from about 0.1% to about 30%, most preferably from about 0.1% to about 15% of a material selected from the group consisting of a structurant, a humectant, a surfactant, an antimicrobial, and mixtures thereof. 2. A personal care composition according to claim 1, wherein said sum total of malodor reduction materials has a Blocker Index of less than 3, more preferable less than about 2.5 even more preferably less than about 2 and still more preferably less than about 1 and most preferably 0 and/or a Blocker Index average of 3 to about 0.001. 3. A personal care composition according to any preceding claim, wherein each of said malodor reduction materials has a MORV of at least 0.5, preferably from 0.5 to 10, more preferably from 1 to 10, most preferably from 1 to 5, and preferably each of said malodor reduction materials having a Universal MORV. 4. A personal care composition according to any preceding claim wherein, said sum total of malodor reduction materials has a Fragrance Fidelity Index average of 3 to about 0.001 Fragrance Fidelity Index, preferably each malodor reduction material in said sum total of malodor reduction materials has a Fragrance Fidelity Index of less than 3, preferably less than 2, more preferably less than 1 and most preferably each malodor reduction material in said sum total of malodor reduction materials has a Fragrance Fidelity Index of 0. 5. A personal care composition according to any preceding claim, wherein said malodor reduction materials are selected from the group consisting of 2-ethylhexyl (Z)-(3-(4-methoxyphenyl)acrylate; 2,4-dimethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolane; 1,1-dimethoxynon-2-yne; 2-(p-tolyl)propan-2-ol; 3-methoxy-7,7-dimethyl-10-methylenebicyclo[4.3.1]decane; methoxycyclododecane; 1,1-dimethoxycyclododecane; (Z)-tridec-2-enenitrile; (2-hydroxy-4-methoxyphenyl)(phenyl)methanone; 2,4a,5,8a-tetramethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl formate; 4-methyl-1-oxaspiro[5.5]undecan-4-ol; 7-methyl-2H-benzo[b][1,4]dioxepin-3(4H)-one; 1,8-dioxacycloheptadecan-9-one; 4-(tert-pentyl)cyclohexan-1-one; 2-methoxy-1,1′-biphenyl; 3a,5,6,7,8,8b-hexahydro-2,2,6,6,7,8,8-heptamethyl-4H-indeno(4,5-d)-1,3-dioxole; 7-isopropyl-8,8-dimethyl-6,10-dioxaspiro[4.5]decane; octyl furan-2-carboxylate; octyl acetate; 2-heptyl-4-methyl-1,3-dioxolane; octanal; 1,1-dimethoxyoctane; 7-methyl-3-methyleneocta-1,6-diene; 2-methyl-6-methyleneoct-7-en-2-ol; 2-methyl-6-methyleneoct-7-en-2-yl acetate; tetradecanal; 4-methoxy-6-prop-2-enyl-1,3-benzodioxole; tetradecanenitrile; 2,2,6,8-tetramethyl-1,2,3,4,4a,5,8,8a-octahydronaphthalen-1-ol; (E)-2,6-dimethylocta-5,7-dien-2-ol; (E)-2,7-dimethylocta-1,5,7-trien-3-ol; 2-((1S,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethyl acetate; (4R,4aS,6R)-4,4a-dimethyl-6-(prop-1-en-2-yl)-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one; nonan-1-ol; nonanal; 12-methyl-14-tetradec-9-enolide; N-ethyl-2-isopropyl-5-methylcyclohexane-1-carboxamide; 1-(3-methylbenzofuran-2-yl)ethan-1-one; 2-methoxynaphthalene; (E)-3,7,11-trimethyldodeca-1,6,10-trien-3-ol; (Z)-3,7-dimethylocta-2,6-dien-1-ol; 1-ethyl-3-methoxytricyclo[2.2.1.02,6]heptane; methyl (E)-non-2-enoate; 10-isopropyl-2,7-dimethyl-1-oxaspiro[4.5]deca-3,6-diene; 2-(2-(4-methylcyclohex-3-en-1-yl)propyl)cyclopentan-1-one; 6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-carbaldehyde; (E)-4-(2,2,3,6-tetramethylcyclohexyl)but-3-en-2-one; (4-(4-methylpent-3-en-1-yl)cyclohex-3-en-1-yl)methyl acetate; 2-(tert-butyl)-4,5,6-trimethyl-1,3-phenylene dinitrite; 1,7-dioxacycloheptadecan-8-one; 1-(4-(tert-butyl)-2,6-dimethyl-3,5-dinitrophenyl)ethan-1-one; 1-(tert-butyl)-2-methoxy-4-methyl-3,5-dinitrobenzene; 3-methylcyclopentadecan-1-one; (E)-3-methylcyclopentadec-4-en-1-one; 3-methyl-4-phenylbutan-2-ol; 1-(4-isopropylcyclohexyl)ethan-1-ol; (E)-dec-5-enoic acid; methyl non-2-ynoate; 2-methyldecanal; 6,6-dimethoxy-2,5,5-trimethylhex-2-ene; 4-phenylbutan-2-ol; methyl stearate; 1,1-dimethoxy-2-methylundecane; undecan-2-one; 2-methylundecanal; methyl tetradecanoate; methyl (9Z,12Z)-octadeca-9,12-dienoate; 1-hydroxydecan-3-one; (Z)-1,2-dimethoxy-4-(prop-1-en-1-yl)benzene; methyl palmitate; 4-allyl-1,2-dimethoxybenzene; methyl 2-((1R,2R)-3-oxo-2-((Z)-pent-2-en-1-yl)cyclopentyl)acetate; methyl 2-(3-oxo-2-pentylcyclopentyl)acetate; 1-methyl-2-phenoxybenzene; methyl cinnamate; 1-allyl-4-methoxybenzene; 1-(naphthalen-2-yl)ethan-1-one; methyl oct-2-ynoate; methyl 2,6,6-trimethylcyclohex-2-ene-1-carboxylate; 7-methoxy-3,7-dimethyloctanal; 7-isopropyl-10-methyl-1,5-dioxaspiro[5.5]undecan-3-ol; octahydro-1H-4,7-methanoindene-1-carbaldehyde; 3-(3-(tert-butyl)phenyl)-2-methylpropanal; (E)-4-(4,8-dimethylnona-3,7-dien-1-yl)pyridine; (E)-trideca-3,12-dienenitrile; 2,2-dimethyl-3-(m-tolyl)propan-1-ol; 2,4-dimethyl-4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; 8-isopropyl-6-methylbicyclo[2.2.2]oct-5-ene-2-carbaldehyde; 4-(4-hydroxy-4-methylpentyl)cyclohex-3-ene-1-carbaldehyde; (S)-1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene; (Z)-3-hexen-1-yl-2-cyclopenten-1-one; 3,7-dimethylocta-1,6-dien-3-yl octanoate; 3,7-dimethylocta-1,6-dien-3-yl isobutyrate; 3,7-dimethylocta-1,6-dien-3-yl benzoate; 3,7-dimethylocta-1,6-dien-3-yl 2-aminobenzoate; 2-(5-methyl-5-vinyltetrahydrofuran-2-yl)propan-2-ol; 6-methyl-2-(oxiran-2-yl)hept-5-en-2-ol; (2Z,6E)-3,7-dimethylnona-2,6-dienenitrile; 3-(4-methylcyclohex-3-en-1-yl)butanal; (2,5-dimethyl-1,3-dihydroinden-2-yl)methanol; 3-(4-(tert-butyl)phenyl)-2-methylpropanal; (E)-1-(1-methoxypropoxy)hex-3-ene; (E)-1-(1-ethoxyethoxy)hex-3-ene; (1S,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-ol; dodecan-1-ol; dodecyl acetate; dodecanoic acid; 5-hexyl-5-methyldihydrofuran-2(3H)-one; dodecanal; 3,6-dimethylhexahydrobenzofuran-2(3H)-one; 4-(1-ethoxyvinyl)-3,3,5,5-tetramethylcyclohexan-1-one; ((3S,3aR,6R,8aS)-7,7-dimethyl-8-methyleneoctahydro-1H-3a,6-methanoazulen-3-yl)methanol; 5-(sec-butyl)-2-(2,4-dimethylcyclohex-3-en-1-yl)-5-methyl-1,3-dioxane; (1-methyl-2-((1,2,2-trimethylbicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methanol; 2-propylheptanenitrile; (E)-6-(pent-3-en-1-yl)tetrahydro-2H-pyran-2-one; 2-hexylcyclopentan-1-one; 2-methyl-4-phenyl-1,3-dioxolane; 2,6,9,10-tetramethyl-1-oxaspiro(4.5)deca-3,6-diene; (1R,2S,5R)-5-methyl-2-(prop-1-en-2-yl)cyclohexan-1-ol; isopropyl palmitate; isopropyl tetradecanoate; isopropyl dodecanoate; 4,9-dimethoxy-7H-furo[3,2-g]chromen-7-one; (E)-cyclohexadec-8-en-1-one; (2S,5S)-2-isopropyl-5-methylcyclohexan-1-one; 2-hexylcyclopent-2-en-1-one; (2S,5 S)-2-isopropyl-5-methylcyclohexan-1-one; 4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; (Z)-1-(benzyloxy)-2-methoxy-4-(prop-1-en-1-yl)benzene; 1-((2S,3S)-2,3,8,8-tetramethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-yl)ethan-1-one; 2,5,6-trimethylcyclohex-3-ene-1-carbaldehyde; 6-(sec-butyl)quinoline; 2-(cyclohexyloxy)-1,7,7-trimethylbicyclo[2.2.1]heptane; (1R,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl propionate; (1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate; 4-((2R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)cyclohexan-1-ol; (1R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 2-(4-isopropylcyclohexa-1,4-dien-1-yl)ethyl formate; isopentyl (E)-undec-6-enoate; isopentyl dodecanoate; (E)-oxacycloheptadec-10-en-2-one; (E)-non-2-enenitrile; (E)-8-(1H-indol-1-yl)-2,6-dimethyloct-7-en-2-ol; 8,8-di(1H-indol-1-yl)-2,6-dimethyloctan-2-ol; 4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; 3,7-dimethyloctane-1,7-diol; 2-cyclododecylpropan-1-ol; 3-methyl-5-phenylpentanenitrile; 3-phenylpropan-1-ol; (1,1-dimethoxypropan-2-yl)benzene; 5-ethyl-4-hydroxy-2-methylfuran-3(2H)-one; 2,3-dihydro-3,3-dimethyl-1H-indene-5-propanal; 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)propanal; hexyl octanoate; hexyl hexanoate; (Z)-2-benzylideneoctanal; hexyl benzoate; (Z)-hex-1-en-1-yl (Z)-2-methylbut-2-enoate; (E)-3,7-dimethylocta-2,6-dien-1-yl palmitate; oxacycloheptadecan-2-one; 2-butyl-4,4,6-trimethyl-1,3-dioxane; ethyl (1R,2R,3R,4R)-3-isopropylbicyclo[2.2.1]hept-5-ene-2-carboxylate; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl acetate; 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropyl propionate; 5-(diethoxymethyl)benzo[d][1,3]dioxole; 3-(benzo[d][1,3]dioxol-5-yl)-2-methylpropanal; (E)-oxacyclohexadec-13-en-2-one; 6-butyl-2,4-dimethyl-3,6-dihydro-2H-pyran; 2-((3S,5R,8S)-3,8-dimethyl-1,2,3,4,5,6,7,8-octahydroazulen-5-yl)propan-2-ol; 1-(2,6,6-trimethylcyclohex-2-en-1-yl)pentan-3-one; ethyl 2-ethyl-6,6-dimethylcyclohex-2-ene-1-carboxylate; (1Z,5Z)-1,5-dimethyl-8-(propan-2-ylidene)cyclodeca-1,5-diene; (1E,6E)-8-isopropyl-1-methyl-5-methylenecyclodeca-1,6-diene; (E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate; (E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate; (6E,10E)-3,7,11,15-tetramethylhexadeca-1,6,10,14-tetraen-3-ol; (E)-2-(3,7-dimethylocta-2,6-dien-1-yl)cyclopentan-1-one; 5-heptyldihydrofuran-2(3H)-one; 1-methyl-4-(propan-2-ylidene)cyclohexyl acetate; 1-methyl-4-(propan-2-ylidene)cyclohexan-1-ol; 5-pentyldihydrofuran-2(3H)-one; (1R,4aR,8aS)-1-isopropyl-7-methyl-4-methylene-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 5-[(Z)-hex-3-enyl]oxolan-2-one; (Z)-4-(2,2-dimethyl-6-methylenecyclohexyl)but-3-en-2-one; (4aS,9aR)-3,5,5,9-tetramethyl-2,4a,5,6,7,9a-hexahydro-1H-benzo[7]annulene; (1R,3aR,4R,7R)-1,4-dimethyl-7-(prop-1-en-2-yl)-1,2,3,3a,4,5,6,7-octahydroazulene; 2-((2R,4aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)propan-2-ol; 5-octyldihydrofuran-2(3H)-one; (Z)-1-(2,2-dimethyl-6-methylenecyclohexyl)but-2-en-1-one; 5-hexyldihydrofuran-2(3H)-one; (1R,4aS,8aS)-1-isopropyl-7-methyl-4-methylene-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 1-(3,3-dimethylcyclohexyl)pent-4-en-1-one; 4,6,6,7,8,8-hexamethyl-1,3,4,6,7,8-hexahydrocyclopenta[g]isochromene; furan-2-ylmethyl octanoate; furan-2-ylmethyl hexanoate; furan-2-ylmethyl heptanoate; 2-methyldecanenitrile; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; ethyl (3aR,4S,7R,7aR)-octahydro-3aH-4,7-methanoindene-3a-carboxylate; diethyl cyclohexane-1,4-dicarboxylate; (6-isopropyl-9-methyl-1,4-dioxaspiro[4.5]decan-2-yl)methanol; 2-isobutyl-4-methyltetrahydro-2H-pyran-4-ol; undec-10-enenitrile; (Z)-6-ethylideneoctahydro-2H-5,8-methanochromen-2-one; 3-(2-ethylphenyl)-2,2-dimethylpropanal; (E)-4,8-dimethyldeca-4,9-dienal; (E)-4-((3aR,4R,7R,7aR)-1,3a,4,6,7,7a-hexahydro-5H-4,7-methanoinden-5-ylidene)-3-methylbutan-2-ol; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl acetate; 3-(4-ethylphenyl)-2,2-dimethylpropanenitrile; 2-heptylcyclopentan-1-one; 1-ethoxyethoxy Cyclododecane; 3-cyclohexene-1-carboxylic acid, 2,6,6-trimethyl-, methyl ester; (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl acetate; (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol; oxacyclohexadecan-2-one; (E)-cyclopentadec-4-en-1-one; 1-cyclopentadec-4-en-1-one; 2-methoxy-4-(4-methylenetetrahydro-2H-pyran-2-yl)phenol; 4-allyl-2-methoxyphenyl acetate; 4-allyl-2-methoxyphenol; ethyl 3-methyl-3-phenyloxirane-2-carboxylate; 1,4-dioxacycloheptadecane-5,17-dione; ethyl undec-10-enoate; ethyl palmitate; ethyl nonanoate; ethyl tetradecanoate; (E)-3,7-dimethylnona-1,6-dien-3-ol; ethyl dodecanoate; nonan-3-one; ethyl decanoate; ethyl 6,6-dimethyl-2-methylenecyclohex-3-ene-1-carboxylate; ethyl 3-phenyloxirane-2-carboxylate; 6-ethyl-2,10,10-trimethyl-1-oxaspiro[4.5]deca-3,6-diene; 2-((1R,3S,4S)-4-methyl-3-(prop-1-en-2-yl)-4-vinylcyclohexyl)propan-2-ol; (2-(1-ethoxyethoxy)ethyl)benzene; (E)-3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pent-4-en-2-ol; (2R,3S,4R)-2,3,4,5-tetrahydroxypentanal; (E)-4-((3aS,7aS)-octahydro-5H-4,7-methanoinden-5-ylidene)butanal; 1,1-dimethoxydodecane; (R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene; 2-(2-hydroxypropoxy)propan-1-ol; 7,9-dimethylspiro[5.5]undecan-3-one; oxydibenzene; diphenylmethane; 2-methyl-1-phenylpropan-2-yl butyrate; 2,6-dimethyloct-7-en-4-one; octahydro-1H-4,7-methanoinden-5-yl acetate; 2-methyl-5-(prop-1-en-2-yl)cyclohexyl acetate; 2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-ol; 3,7-dimethyloct-6-en-3-ol; methyl 2-hexyl-3-oxocyclopentane-1-carboxylate; dibutylsulfane; 1,2-diphenylethane; 6-hexyltetrahydro-2H-pyran-2-one; (3R,4R)-1-isopropyl-4-methyl-3-(prop-1-en-2-yl)-4-vinylcyclohex-1-ene; (3S,3aS,5R)-3,8-dimethyl-5-(prop-1-en-2-yl)-1,2,3,3a,4,5,6,7-octahydroazulene; 6-heptyltetrahydro-2H-pyran-2-one; 6-pentyltetrahydro-2H-pyran-2-one; (1S,8aR)-4,7-dimethyl-1-(propan-2-yl)-1,2,3,5,6,8a-hexahydronaphthalene; (Z)-1-((1R,2S)-2,6,6-trimethylcyclohex-3-en-1-yl)but-2-en-1-one; (1S,8aS)-1-isopropyl-4,7-dimethyl-1,2,3,5,6,8a-hexahydronaphthalene; 3,7,7-trimethylbicyclo[4.1.0]hept-3-ene; dec-9-en-1-ol; decyl propionate; 1,1-diethoxydecane; decahydronaphthalen-2-ol; 1-cyclohexylethyl (E)-but-2-enoate; 3-(4-isopropylphenyl)-2-methylpropanal; cyclotetradecane; cyclopentadecanone; cyclohexyl 2-hydroxybenzoate; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl butyrate; 1,4-dioxacyclohexadecane-5,16-dione; 8,8-dimethyl-1,2,3,4,5,6,7,8-octahydronaphthalene-2-carbaldehyde; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl isobutyrate; (5R,6R)-3,6-dimethyl-5-(prop-1-en-2-yl)-6-vinyl-4,5,6,7-tetrahydrobenzofuran; (4-isopropylphenyl)methanol; 1-(benzofuran-2-yl)ethan-1-one; 2-(3-phenylpropyl)pyridine; dodecanenitrile; (E)-cycloheptadec-9-en-1-one; 3-(4-methylcyclohex-3-en-1-yl)but-3-en-1-yl acetate; 3-(4-methylcyclohex-3-en-1-yl)butan-1-ol; (E)-3-methyl-5-phenylpent-2-enenitrile; (E)-2-(2,6-dimethylhepta-1,5-dien-1-yl)-4-methyl-1,3-dioxolane; (E)-1,1-dimethoxy-3,7-dimethylocta-2,6-diene; (E)-1,1-diethoxy-3,7-dimethylocta-2,6-diene; (E)-3,7-dimethylocta-1,3,6-triene; (1R,4R,6S)-1-methyl-4-(prop-1-en-2-yl)-7-oxabicyclo[4.1.0]heptane; (E)-oxacycloheptadec-11-en-2-one; (Z)-non-6-en-1-ol; (1R,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-ol; (Z)-dec-4-enal; (E)-hex-3-en-1-yl (E)-hex-3-enoate; (Z)-hex-3-en-1-yl 2-hydroxybenzoate; (Z)-hex-3-en-1-yl benzoate; (Z)-hex-3-en-1-yl 2-methylbutanoate; (3Z,6Z)-nona-3,6-dien-1-ol; cinnamyl propionate; cinnamyl isobutyrate; cinnamyl formate; cinnamyl cinnamate; cinnamyl acetate; (E)-3-phenylprop-2-en-1-ol; hexadecan-1-ol; (E)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)hepta-1,6-dien-3-one; 2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butanal; (3aR,5aR,9aR,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; 1,6-dioxacycloheptadecan-7-one; 1-(6-(tert-butyl)-1,1-dimethyl-2,3-dihydro-1H-inden-4-yl)ethan-1-one; (3R,3aR,6S,7S,8aS)-6-methoxy-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-3-yl formate; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl acetate; (4Z,8Z)-1,5,9-trimethyl-13-oxabicyclo[10.1.0]trideca-4,8-diene; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-ol; 5-methyl-1-(2,2,3-trimethylcyclopent-3-en-1-yl)-6-oxabicyclo[3.2.1]octane; 5-methyl-1-(2,2,3-trimethylcyclopent-3-en-1-yl)-6-oxabicyclo[3.2.1]octane; 1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-4H-inden-4-one; (Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-3-en-5-yl acetate; (1S,2S,5R,8S)-4,4,8-trimethyltricyclo[6.3.1.02,5]dodecan-1-ol; 2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-yl acetate; octanenitrile; octan-1-ol; octanoic acid; decanoic acid; decanal; 3-(4-methoxyphenyl)-2-methylpropanal; 1,7,7-trimethylbicyclo[2.2.1]heptane-2,3-dione; 2,2-dimethyl-3-methylenebicyclo[2.2.1]heptane; ethyl 2-methyl-4-oxo-6-pentylcyclohex-2-ene-1-carboxylate; 2,6-di-tert-butyl-4-methylphenol; butyl stearate; 1-butoxy-1-oxopropan-2-yl butyrate; butyl undec-10-enoate; 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)butan-1-ol; 3-(4-(tert-butyl)phenyl)propanal; (1S,2S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate; 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 2-ethoxy-2,6,6-trimethyl-9-methylenebicyclo[3.3.1]nonane; (ethoxymethoxy)cyclododecane; (E)-1-methyl-4-(6-methylhept-5-en-2-ylidene)cyclohex-1-ene; 3,3,6,7-tetramethyloctahydro-2H-chromene; (5R,10R)-6,10-dimethyl-2-(propan-2-ylidene)spiro[4.5]dec-6-en-8-one; 1-methyl-4-(prop-1-en-2-yl)cyclohexyl acetate; 1-methyl-4-(prop-1-en-2-yl)cyclohexan-1-ol; (2Z,6E)-2,6-dimethyl-10-methylenedodeca-2,6,11-trienal; (R)-3-methylene-6-((S)-6-methylhept-5-en-2-yl)cyclohex-1-ene; (4aR,7R,8aS)-4a-methyl-1-methylene-7-(prop-1-en-2-yl)decahydronaphthalene; (Z)-2-methyl-5-((1S,2R,4R)-2-methyl-3-methylenebicyclo[2.2.1]heptan-2-yl)pent-2-en-1-ol; 6,6-dimethyl-2-methylenebicyclo[3.1.1]heptane; 2-ethoxynaphthalene; (1S,4R,7R)-1,4,9,9-tetramethyl-1,2,3,4,5,6,7,8-octahydro-4,7-methanoazulene; (1 aS,5aR,9aR)-1a,5,5,7-tetramethyl-1a,2,3,4,5,5a,8,9-octahydrobenzo[1,7]cyclohepta[1,2-b]oxirene; (R)-3,5,5,9-tetramethyl-2,4a,5,6,7,8-hexahydro-1H-benzo[7]annulene; (1S,4S)-1,4-dimethyl-7-(propan-2-ylidene)-1,2,3,4,5,6,7,8-octahydroazulene; (2,2-dimethoxyethyl)benzene; (E)-7,11-dimethyl-3-methylenedodeca-1,6,10-triene; (1R,2S,6S,7S,8S)-8-isopropyl-1-methyl-3-methylenetricyclo[4.4.0.02,7]decane; (3R,3aS,7S,8aS)-3,8,8-trimethyl-6-methyleneoctahydro-1H-3a,7-methanoazulene; (1R,9S,Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-4-ene; (S)-4-methyl-1-((S)-6-methylhept-5-en-2-yl)cyclohex-3-en-1-ol; (Z)-4-(2,2,6-trimethyl-7-oxabicyclo[4.1.0]heptan-1-yl)but-3-en-2-one; 4-methoxy-7H-furo[3,2-g]chromen-7-one; 2-methyl-4-phenylbutan-2-ol; benzyl dodecanoate; 2-methyl-1-phenylpropan-2-ol; benzyl cinnamate; benzyl benzoate; benzophenone; 7-isopentyl-2H-benzo[b][1,4]dioxepin-3(4H)-one; 2′-isopropyl-1,7,7-trimethylspiro[bicyclo[2.2.1]heptane-2,4′-[1,3]dioxane]/A; 4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbonitrile; methyl (E)-2-((7-hydroxy-3,7-dimethyloctylidene)amino)benzoate; 4-methoxybenzyl 2-phenylacetate; methyl (E)-octa-4,7-dienoate; pentyl (Z)-3-phenylacrylate; (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; (4aR,5R,7aS,9R)-2,2,5,8,8,9a-hexamethyloctahydro-4H-4a,9-methanoazuleno[5,6-d][1,3]dioxole; 2,5,5-trimethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-ol; 2,5,5-trimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-ol; 1-((2-(tert-butyl)cyclohexyl)oxy)butan-2-ol; (3S,5aR,7aS,11aS,11bR)-3,8,8,11a-tetramethyldodecahydro-5H-3,5a-epoxynaphtho[2,1-c]oxepine; 2,2,6,6,7,8,8-heptamethyldecahydro-2H-indeno[4,5-b]furan; 2,2,7,7,8,9,9-heptamethyldecahydroindeno[4,3a-b]furan; 2-(sec-butyl)-1-vinylcyclohexyl acetate; (1S,4R,5R)-1-isopropyl-4-methylbicyclo[3.1.0]hexan-3-one; (4R,4aS)-4,4a-dimethyl-6-(propan-2-ylidene)-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one; 2-(4-methylcyclohex-3-en-1-yl)propan-2-yl propionate; (2Z,6E,9E)-2,6,10-trimethyldodeca-2,6,9,11-tetraenal; (2R,4aR,8aR)-4a,8-dimethyl-2-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 1,7-dimethyl-7-(4-methylpent-3-en-1-yl)tricyclo[2.2.1.02,6]heptane; (E)-5-(2,3-dimethyltricyclo[2.2.1.02,6]heptan-3-yl)-2-methylpent-2-en-1-ol; (1R,3aS,7S,8aR)-1,4,9,9-tetramethyl-2,3,6,7,8,8a-hexahydro-1H-3a,7-methanoazulene; 1-(5,5-dimethylcyclohex-1-en-1-yl)pent-4-en-1-one; (1S,4aS,8aR)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (R,Z)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)pent-1-en-3-one; 1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene; (Z)-4-(2,5,6,6-tetramethylcyclohex-2-en-1-yl)but-3-en-2-one; (1Z,4E,8Z)-2,6,6,9-tetramethylcycloundeca-1,4,8-triene; (4aR,8S,9aS)-3,5,5,8-tetramethyl-9-methylene-2,4a,5,6,7,8,9,9a-octahydro-1H-benzo[7]annulene; (1aR,4R,4aR,7bS)-1,1,4,7-tetramethyl-1a,2,3,4,4a,5,6,7b-octahydro-1H-cyclopropa[e]azulene; 1,4-dimethyl-7-(prop-1-en-2-yl)-1,2,3,4,5,6,7,8-octahydroazulene; (3E,6E)-3,7,11-trimethyldodeca-1,3,6,10-tetraene; 7,7-dimethyl-2-methylenebicyclo[2.2.1]heptane; 2-((2R,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl)propan-2-ol; (R)-1-methyl-4-(6-methylhept-5-en-2-yl)benzene; (3aR,3bR,4S,7R,7aS)-4-isopropyl-7-methyl-3a,3b,4,5,6,7-hexahydro-1H-cyclopenta[1,3]cyclopropa[1,2]benzene; (1aS,2aR,3R,5aS,7R,7aR)-3,6,6,7a-tetramethyloctahydro-2H-2a,7-methanoazuleno[5,6-b]oxirene; (1R,4S,4aR,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; (1S,4aR,8aR)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (R)-2-((R)-4-methylcyclohex-3-en-1-yl)hex-5-en-2-ol; (Z)-1-methyl-4-(6-methylhepta-2,5-dien-2-yl)cyclohex-1-ene; 2,6-dimethyl-6-(4-methylpent-3-en-1-yl)bicyclo[3.1.1]hept-2-ene; (E)-2-benzylideneheptan-1-ol; (E)-2-benzylideneheptyl acetate; (Z)-(2-(diethoxymethyl)hept-1-en-1-yl)benzene; (E)-2-benzylideneheptanal; (1S,4aR,8aS)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (3R,5aS,9aR)-2,2,5a,9-tetramethyl-3,4,5,5a,6,7-hexahydro-2H-3,9a-methanobenzo[b]oxepine; 1-methyl-4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; 1-phenylpentan-2-ol; 3-methyl-1-phenylpentan-3-ol; 2,3,4-trimethoxybenzaldehyde; 2,4,5-trimethoxybenzaldehyde; 2,4,6-trimethoxybenzaldehyde; Trans,Trans-2,4-Nonadienal; 2,6,10-trimethylundecanal; alpha-4-Dimethyl benzenepropanal; allyl 3-cyclohexylpropanoate; allyl 2-(isopentyloxy)acetate; (1aR,4aS,7R,7aR,7bS)-1,1,7-trimethyl-4-methylenedecahydro-1H-cyclopropa[e]azulene; (E)-undec-9-enal; methyl (E)-2-(((3,5-dimethylcyclohex-3-en-1-yl)methylene)amino)benzoate; 2,6,10-trimethylundec-9-enal; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methyl acetate; nonyl acetate; (2-(1-propoxyethoxy)ethyl)benzene; 1-(1-propoxyethoxy)propane; ((1-(2-methoxyethoxy)ethoxy)methyl)benzene; (Z)-2-(4-methylbenzylidene)heptanal; dec-9-enal; (Z)-oxacycloheptadec-8-en-2-one; 7-methoxy-2H-chromen-2-one; (2S,4aR,8aR)-4a,8-dimethyl-2-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 2-((2S,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl)propan-2-ol; 1-(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethan-1-one; 6-isopropylquinoline; 3-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)propanal; 6,10,14-trimethylpentadecan-2-one; 2-methyl-5-(prop-1-en-2-yl)-2-vinyltetrahydrofuran; (E)-cyclohexadec-5-en-1-one; 1-isopropyl-4-methylcyclohex-3-en-1-ol; 1-phenylpent-4-en-1-one; 1-isopropyl-4-methylcyclohex-3-en-1-ol; 3,6-dimethyl-4,5,6,7-tetrahydrobenzofuran; 4-(4-methoxyphenyl)butan-2-one; (1aR,2S,4aS)-2,4a,8,8-tetramethyloctahydrocyclopropa[d]naphthalen-3(1H)-one; (E)-3-propylideneisobenzofuran-1(3H)-one; (Z)-dodec-2-enal; 3-methyl-5-phenylpentanal; (E)-hex-3-en-1-yl 3-methylbutanoate; 3,6-dimethyloctan-3-yl acetate; 3,4,5-trimethoxybenzaldehyde; 3-(4-isopropylphenyl)propanal; (Z)-undec-2-enenitrile; (E)-undec-2-enal; (2E,6E)-nona-2,6-dienal; phenethyl butyrate; (Z)-3-(furan-2-yl)-2-phenylacrylaldehyde; 2-phenoxyethan-1-ol; (Z)-non-2-enal; nonan-2-ol; nonan-2-one; 2-isobutylquinoline; (E)-2-hexylidenecyclopentan-1-one; 2-heptyltetrahydrofuran; (E)-dec-2-enal; (2E,6E)-nona-2,6-dienal; (2E,6E)-nona-2,6-dien-1-ol; 2,6-dimethyloctanal; decan-1-ol; (E)-hept-1-en-1-yl acetate; undec-10-en-1-ol; undec-10-enal; 2-((2R,4aS)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)propan-2-ol; 1-isopropyl-4-methyl-7-thiabicyclo[2.2.1]heptane; (3E,5Z)-undeca-1,3,5-triene; 3,7-dimethyloct-6-en-3-ol; 1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 1,1,2,3,3-pentamethyl-2,3-dihydro-1H-indene; (Z)-6,10-dimethylundeca-5,9-dien-2-yl acetate; (Z)-dodec-3-enal; (S)-5-heptyldihydrofuran-2(3H)-one; (R)-5-heptyldihydrofuran-2(3H)-one; (E)-6,10-dimethylundeca-5,9-dien-2-yl acetate; (Z)-3-methyl-5-phenylpent-2-enenitrile; (2S,5S,6S)-2,6,10,10-tetramethyl-1-oxaspiro[4.5]decan-6-ol; (2E)-3-methyl-5-phenyl-2-pentenenitrile; (1 S,2S,5S)-2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-ol; (2S,5R)-2-isopropyl-5-methylcyclohexan-1-one; (R,E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 2-(8-isopropyl-6-methylbicyclo[2.2.2]oct-5-en-2-yl)-1,3-dioxolane; (E)-4-(2,2-dimethyl-6-methylenecyclohexyl)-3-methylbut-3-en-2-one; 3-(3-isopropylphenyl)butanal; 3-(1-ethoxyethoxy)-3,7-dimethylocta-1,6-diene; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; 2-((3S,3aS,5R)-3,8-dimethyl-1,2,3,3a,4,5,6,7-octahydroazulen-5-yl)propan-2-ol; benzyl 2-phenylacetate; 2-hydroxy-1,2-diphenylethan-1-one; (E)-1,2,4-trimethoxy-5-(prop-1-en-1-yl)benzene; 3-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-2,2-dimethylpropanal; 2-methyl-5-(6-methylhept-5-en-2-yl)bicyclo[3.1.0]hex-2-ene; 1-(1,1,2,3,3,6-hexamethyl-2,3-dihydro-1H-inden-5-yl)ethan-1-one; 2-(m-tolyl)ethan-1-ol; (3E,6E)-nona-3,6-dien-1-ol; (E)-tridec-2-enal; (1R,4S,4aS,6R,8aS)-4,8a,9,9-tetramethyloctahydro-1,6-methanonaphthalen-1(2H)-ol; p-tolyl isobutyrate; p-tolyl hexanoate; 5-hexyl-4-methyldihydrofuran-2(3H)-one; ethyl (2Z,4E)-deca-2,4-dienoate; 2,4-dimethyl-6-phenyl-3,6-dihydro-2H-pyran; 2-cyclohexylidene-2-phenylacetonitrile; 4-(prop-1-en-2-yl)cyclohex-1-ene-1-carbaldehyde; (4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methyl acetate; (4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methanol; (2-isopropoxyethyl)benzene; 2-cyclohexylhepta-1,6-dien-3-one; (2-(cyclohexyloxy)ethyl)benzene; phenethyl 2-methylbutanoate; 2-phenylethan-1-ol; phenethyl 2-phenylacetate; 3-methyl-5-phenylpentan-1-ol; phenyl benzoate; phenethyl benzoate; 2-benzyl-1,3-dioxolane; 2-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)acetaldehyde; 6,6-dimethyl-2-methylenebicyclo[3.1.1]heptan-3-ol; 4-(benzo[d][1,3]dioxol-5-yl)butan-2-one; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl pivalate; (4aR,8aS)-7-methyloctahydro-1,4-methanonaphthalen-6(2H)-one; 4-isopropyl-1-methylcyclohex-3-en-1-ol; (E)-3,3-dimethyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pent-4-en-2-ol; 1-methyl-4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; propane-1,2-diol; p-tolyl 2-phenylacetate; Ethyl 2,4,7-decatrienoate; 2-benzyl-4,4,6-trimethyl-1,3-dioxane; 2,4-dimethyl-4-phenyltetrahydrofuran; (2R,4a′R,8a′R)-3,7′-dimethyl-3′,4′,4a′,5′,8′,8a′-hexahydro-1′H-spiro[oxirane-2,2′-[1,4]methanonaphthalene]; (Z)-6-ethylideneoctahydro-2H-5,8-methanochromene; 2-((S)-1-((S)-3,3-dimethylcyclohexyl)ethoxy)-2-oxoethyl propionate; methyl 2,2-dimethyl-6-methylenecyclohexane-1-carboxylate; 2-methyl-5-phenylpentan-1-ol; 4-methyl-2-phenyl-3,6-dihydro-2H-pyran; (1S,3R,5S)-1-isopropyl-4-methylenebicyclo[3.1.0]hexan-3-ol; 5-allylbenzo[d][1,3]dioxole; 2,2,7,9-tetramethylspiro(5.5)undec-8-en-1-one; 3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pentan-2-ol; (Z)-2-ethyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; (E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; 1-(3-hydroxy-3-methylpent-4-en-1-yl)-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol; (4aR,6aS,10aS,10bR)-3,4a,7,7,10a-pentamethyl-4a,5,6,6a,7,8,9,10,10a, 10b-decahydro-1H-benzo[f]chromene; (4aR,8aR)-4a,8-dimethyl-2-(propan-2-ylidene)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropyl cyclopropanecarboxylate; 3-(4-isobutylphenyl)-2-methylpropanal; (1aR,4aR,7S,7aR,7bR)-1,1,7-trimethyl-4-methylenedecahydro-1H-cyclopropa[e]azulen-7-ol; (1R,3R,6R)-2′,2′,3,7,7-pentamethylspiro[bicyclo[4.1.0]heptane-2,5′-[1,3]dioxane]; 2-methyl-1,5-dioxaspiro[5.5]undecane; 1-(spiro[4.5]dec-7-en-7-yl)pent-4-en-1-one; 2-(4-methylthiazol-5-yl)ethan-1-ol; 2-(heptan-3-yl)-1,3-dioxolane; (Z)-dodec-4-enal; (1 S,4S,4aR,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; (1S,4S,4aR,8aS)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; 3-methyl-2-pentylcyclopentan-1-one; 2,6,10,10-tetramethyl-1-oxaspiro[4.5]dec-6-ene; 2-(2-mercaptopropan-2-yl)-5-methylcyclohexan-1-one; (1aR,4aS)-2,4a,8,8-tetramethyl-1,1a,4,4a,5,6,7,8-octahydrocyclopropa[d]naphthalene; 1-isopropyl-2-methoxy-4-methylbenzene; 1-(2,2,6-trimethylcyclohexyl)hexan-3-ol; (2Z,4E)-nona-2,4-dienal; (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol; (2E,6Z)-nona-2,6-dienal; (Z)-dec-2-enal; (E)-non-2-enal; (3E,6Z)-nona-3,6-dien-1-ol; (E)-dec-4-enal; (Z)-oxacycloheptadec-8-en-2-one; (Z)-3,7-dimethylocta-1,3,6-triene; (Z)-3,7-dimethylocta-1,3,6-triene; (E)-3,7-dimethylocta-2,6-dien-1-ol; methyl 2-((1S,2S)-3-oxo-2-pentylcyclopentyl)acetate; 7-(1,1-Dimethylethyl)-2H-1,5-benzodioxepin-3 (4H)-one; (1R-(1alpha,3alpha,4aalpha))-2,3,4,4a,5,6-hexahydro-2,2-dimethyl-1,3-methanonaphthalen-7(1H)-one; tridecan-1-ol; triethyl 2-hydroxypropane-1,2,3-tricarboxylate; methyl 2-((1-hydroxy-3-phenylbutyl)amino)benzoate; 1-((2E,5Z,9Z)-2,6,10-trimethylcyclododeca-2,5,9-trien-1-yl)ethan-1-one; decahydro-2,6,6,7,8,8-hexamethyl-2h-indeno(4,5-b)furan; 13-methyl oxacyclopentadec-10-en-2-one; undecanal; (E)-4-methyldec-3-en-5-ol; (3R,4aS,5R)-4a,5-dimethyl-3-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,7-octahydronaphthalene; 2-((2R,8R,8aS)-8,8a-dimethyl-1,2,3,4,6,7,8,8a-octahydronaphthalen-2-yl)propan-2-ol; 4-formyl-2-methoxyphenyl isobutyrate; (Z)-2-methyl-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-enal; methyl 2,4-dihydroxy-3,6-dimethylbenzoate; 1-methoxy-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoindene; methyl (Z)-2-((3-(4-(tert-butyl)phenyl)-2-methylpropylidene)amino)benzoate; (Z)-hex-3-en-1-yl isobutyrate; 2,4,6-trimethyl-4-phenyl-1,3-dioxane; 1-((3R,3aR,7R,8aS)-3,6,8,8-tetramethyl-2,3,4,7,8,8a-hexahydro-1H-3a,7-methanoazulen-5-yl)ethan-1-one; methyl (Z)-2-(((2,4-dimethylcyclohex-3-en-1-yl)methylene)amino)benzoate; 4,8-dimethyl-2-(propan-2-ylidene)-1,2,3,3a,4,5,6,8a-octahydroazulen-6-ol; 4,8-dimethyl-2-(propan-2-ylidene)-1,2,3,3a,4,5,6,8a-octahydroazulen-6-yl acetate; decahydro-3H-spiro[furan-2,5′-[4,7]methanoindene]; (2Z,6E)-nona-2,6-dienenitrile; (Z)-cyclooct-4-en-1-yl methyl carbonate; (1aR,4S,4aS,7R,7aS,7bS)-1,1,4,7-tetramethyldecahydro-1H-cyclopropa[e]azulen-4-ol; 3,5,5,6,7,8,8-heptamethyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile; (1S,2S,3S,5R)-2,6,6-trimethylspiro[bicyclo[3.1.1]heptane-3,1′-cyclohexan]-2′-en-4′-one; 1′,1′,5′,5′-tetramethylhexahydro-2′H,5′H-spiro[[1,3]dioxolane-2,8′-[2,4a]methanonaphthalene]; (2'S,4a'S,8a'S)-1′,1′,5′,5′-tetramethylhexahydro-2′H,5′H-spiro[[1,3]dioxolane-2,8′-[2,4a]methanonaphthalene]; 4-(4-hydroxy-3-methoxyphenyl)butan-2-one; (1R,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,7,8,8a-hexahydronaphthalene; 2,4-dimethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolane; 3a,5,6,7,8,8b-hexahydro-2,2,6,6,7,8,8-heptamethyl-4H-indeno(4,5-d)-1,3-dioxole; 2,4-dimethyl-4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; (1-methyl-2-((1,2,2-trimethylbicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methanol; 2-(cyclohexyloxy)-1,7,7-trimethylbicyclo[2.2.1]heptane; 4-((2R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)cyclohexan-1-ol; 8,8-di(1H-indol-1-yl)-2,6-dimethyloctan-2-ol; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methanol; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; (E)-4-((3aR,4R,7R,7aR)-1,3a,4,6,7,7a-hexahydro-5H-4,7-methanoinden-5-ylidene)-3-methylbutan-2-ol; (3R,3aR,6S,7S,8aS)-6-methoxy-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene; (1R,2S,6S,7S,8S)-8-isopropyl-1-methyl-3-methylenetricyclo[4.4.0.02,7]decane; 2′-isopropyl-1,7,7-trimethylspiro[bicyclo[2.2.1]heptane-2,4′-[1,3]dioxane]; (4aR,5R,7aS,9R)-2,2,5,8,8,9a-hexamethyloctahydro-4H-4a,9-methanoazuleno[5,6-d][1,3]dioxole; (3S,5aR,7aS,11aS,11bR)-3,8,8,11a-tetramethyldodecahydro-5H-3,5a-epoxynaphtho[2,1-c]oxepine; 2,2,6,6,7,8,8-heptamethyldecahydro-2H-indeno[4,5-b]furan; (1 aS,2aR,3R,5aS,7R,7aR)-3,6,6,7a-tetramethyloctahydro-2H-2a,7-methanoazuleno[5,6-b]oxirene; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methyl acetate; 1-(3-hydroxy-3-methylpent-4-en-1-yl)-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol; decahydro-2,6,6,7,8,8-hexamethyl-2h-indeno(4,5-b)furan; 2-ethylhexyl (Z)-3-(4-methoxyphenyl)acrylate; methoxycyclododecane; 1-ethoxy-4-(tert-pentyl)cyclohexane; (2-hydroxy-4-methoxyphenyl)(phenyl)methanone; (3Z)-1-(2-buten-1-yloxy)-3-hexene; 4-(2-methoxypropan-2-yl)-1-methylcyclohex-1-ene; 4-(tert-pentyl)cyclohexan-1-one; 3-methoxy-3,7-dimethylocta-1,6-diene; 7-isopropyl-8,8-dimethyl-6,10-dioxaspiro[4.5]decane; (E)-3-(2-methoxyphenyl)acrylaldehyde; 3,7-dimethyloctanal; 1,1-dimethoxyoctane; 2-methyl-6-methyleneoct-7-en-2-ol; 4-methoxy-6-prop-2-enyl-1,3-benzodioxole; tetradecanenitrile; (E)-2,7-dimethylocta-1,5,7-trien-3-ol; 3,3-Dimethyl-5(2,2,3-Trimethyl-3-Cyclopenten-1yl)-4-Penten-2-ol; hexyl 2-hydroxybenzoate; hexyl (Z)-but-2-enoate; (Z)-3,7-dimethylocta-2,6-dien-1-yl formate; (Z)-3,7-dimethylocta-2,6-dien-1-ol; 1-ethyl-3-methoxytricyclo[2.2.1.02,6]heptane; 10-isopropyl-2,7-dimethyl-1-oxaspiro[4.5]deca-3,6-diene; 6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-carbaldehyde; (E)-4-(2,2,3,6-tetramethylcyclohexyl)but-3-en-2-one; (Z)-1-(2,6,6-trimethylcyclohex-1-en-1-yl)pent-1-en-3-one; (E)-2,2-dimethyl-3-(3-methylpenta-2,4-dien-1-yl)oxirane; 3-methylcyclopentadecan-1-one; (E)-3,7-dimethylocta-4,6-dien-3-ol; 3-methyl-4-phenylbutan-2-ol; 1-(4-isopropylcyclohexyl)ethan-1-ol; (Z)-hex-3-en-1-yl cyclopropanecarboxylate; (E)-dec-5-enoic acid; 1-phenylethyl propionate; methyl 2-phenylacetate; 4-phenylbutan-2-ol; methyl stearate; methyl (9Z,12Z)-octadeca-9,12-dienoate; 1-hydroxydecan-3-one; 2-methyl-6-oxaspiro[4.5]decan-7-one; (Z)-1,2-dimethoxy-4-(prop-1-en-1-yl)benzene; methyl palmitate; 4-allyl-1,2-dimethoxybenzene; methyl (Z)-3,7-dimethylocta-2,6-dienoate; 1-methyl-2-phenoxybenzene; 2-ethoxy-4-(methoxymethyl)phenol; methyl 2-cyclopentylideneacetate; 1-allyl-4-methoxybenzene; 6-methoxy-2,6-dimethylheptanal; 7-methoxy-3,7-dimethyloctanal; ((1s,4s)-4-isopropylcyclohexyl)methanol; 3-(3-(tert-butyl)phenyl)-2-methylpropanal; (E)-4-(4,8-dimethylnona-3,7-dien-1-yl)pyridine; (E)-trideca-3,12-dienenitrile; 2,2-dimethyl-3-(m-tolyl)propan-1-ol; 8-isopropyl-6-methylbicyclo[2.2.2]oct-5-ene-2-carbaldehyde; 4-(4-hydroxy-4-methylpentyl)cyclohex-3-ene-1-carbaldehyde; (Z)-3-hexen-1-yl-2-cyclopenten-1-one; 3,7-dimethylocta-1,6-dien-3-yl propionate; 3,7-dimethylocta-1,6-dien-3-yl octanoate; 3,7-dimethylocta-1,6-dien-3-yl formate; 3,7-dimethylocta-1,6-dien-3-yl butyrate; 3,7-dimethylocta-1,6-dien-3-yl benzoate; 3,7-dimethylocta-1,6-dien-3-yl 2-aminobenzoate; 3,7-dimethylocta-1,6-dien-3-yl acetate; 3,7-dimethylocta-1,6-dien-3-ol; 3-(4-methylcyclohex-3-en-1-yl)butanal; 3-(4-(tert-butyl)phenyl)-2-methylpropanal; (Z)-hex-3-en-1-yl methyl carbonate; 4-methylquinoline; (E)-1-(1-methoxypropoxy)hex-3-ene; 2-Methyl-5-(1-methylethenyl)-2-cyclohexenone; dodecanal; 2,2-dimethyl-5-phenylhexanenitrile; (E)-6-(pent-3-en-1-yl)tetrahydro-2H-pyran-2-one; 2-hexylcyclopentan-1-one; (Z)-4-(6,6-dimethylcyclohex-2-en-1-yl)-3-methylbut-3-en-2-one; 2,6,9,10-tetramethyl-1-oxaspiro(4.5)deca-3,6-diene; 4-methylpent-1-en-3-ol; isopropyl palmitate; isopropyl dodecanoate; isopropyl 2-methylbutanoate; 4-methylpent-4-en-2-yl isobutyrate; 7-methyloctyl acetate; 7-methyloctan-1-ol; 4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; (Z)-2-methoxy-4-(prop-1-en-1-yl)phenyl acetate; (Z)-2-methoxy-4-(prop-1-en-1-yl)phenol; (1R,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl propionate; (1R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol; 2-(4-isopropylcyclohexa-1,4-dien-1-yl)ethyl formate; isopentyl (E)-undec-6-enoate; isopentyl octanoate; isopentyl dodecanoate; isopentyl isobutyrate; (E)-oxacycloheptadec-10-en-2-one; 8,8-di(1H-indol-1-yl)-2,6-dimethyloctan-2-ol; 2-cyclododecylpropan-1-ol; 3-phenylpropan-1-ol; 3-phenylpropanoic acid; (1,1-dimethoxypropan-2-yl)benzene; 2-phenylpropan-1-ol; hexyl propionate; hexyl butyrate; hexyl 2-methylbutanoate; hexyl furan-2-carboxylate; oxacycloheptadecan-2-one; heptan-1-ol; heptyl acetate; heptanal; 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropyl propionate; 5-(diethoxymethyl)benzo[d][1,3]dioxole; benzo[d][1,3]dioxole-5-carbaldehyde; 3-(benzo[d][1,3]dioxol-5-yl)-2-methylpropanal; (E)-oxacyclohexadec-13-en-2-one; 6-butyl-2,4-dimethyl-3,6-dihydro-2H-pyran; 2-((3S,5R,8S)-3,8-dimethyl-1,2,3,4,5,6,7,8-octahydroazulen-5-yl)propan-2-ol; 1-(2,6,6-trimethylcyclohex-2-en-1-yl)pentan-3-one; (1Z,5Z)-1,5-dimethyl-8-(propan-2-ylidene)cyclodeca-1,5-diene; (E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate; (E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate; (Z)-3,7-dimethylocta-2,6-dienenitrile; (E)-3,7-dimethylocta-2,6-dien-1-yl formate; (E)-3,7-dimethylocta-2,6-dien-1-yl octanoate; (E)-3,7-dimethylocta-2,6-dien-1-yl benzoate; (E)-3,7-dimethylocta-2,6-dienal; N,2-dimethyl-N-phenylbutanamide; 1-isopropyl-4-methylcyclohexa-1,4-diene; (1R,4aR,8aS)-1-isopropyl-7-methyl-4-methylene-1,2,3,4,4a,5,6, 8a-octahydronaphthalene; 5-[(Z)-hex-3-enyl]oxolan-2-one; (4aS,9aR)-3,5,5,9-tetramethyl-2,4a,5,6,7,9a-hexahydro-1H-benzo[7]annulene; (Z)-1-(2,2-dimethyl-6-methylenecyclohexyl)but-2-en-1-one; (1R,4aS,8aS)-1-isopropyl-7-methyl-4-methylene-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 1-(3,3-dimethylcyclohexyl)pent-4-en-1-one; furan-2-ylmethyl octanoate; furan-2-ylmethyl hexanoate; furan-2-ylmethyl heptanoate; ethyl (3aR,4S,7R,7aR)-octahydro-3aH-4,7-methanoindene-3a-carboxylate; 2-(sec-butyl)cyclohexan-1-one; 3-(2-ethylphenyl)-2,2-dimethylpropanal; 2-(tert-butyl)cyclohexyl ethyl carbonate; 3-(2-ethylphenyl)-2,2-dimethylpropanal; (E)-4,8-dimethyldeca-4,9-dienal; 3-(4-ethylphenyl)-2,2-dimethylpropanenitrile; 2-heptylcyclopentan-1-one; 1-ethoxyethoxy Cyclododecane; (Z)-5-methylhept-2-en-4-one; 1,3,3-trimethylbicyclo[2.2.1]heptan-2-ol; oxacyclohexadecan-2-one; (E)-cyclopentadec-4-en-1-one; 1-cyclopentadec-4-en-1-one; 4-allyl-2-methoxyphenyl acetate; 4-allyl-2-methoxyphenol; 1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane; ethyl 3-methyl-3-phenyloxirane-2-carboxylate; 1,4-dioxacycloheptadecane-5,17-dione; 2-ethoxy-4-formylphenyl acetate; ethyl undec-10-enoate; ethyl palmitate; ethyl octanoate; ethyl tetradecanoate; (E)-3,7-dimethylnona-1,6-dien-3-ol; ethyl cinnamate; ethyl 3-phenyloxirane-2-carboxylate; ethyl 2-cyclohexylpropanoate; 6-ethyl-2,10,10-trimethyl-1-oxaspiro[4.5]deca-3,6-diene; (2R,3S,4R)-2,3,4,5-tetrahydroxypentanal; (E)-4-((3 aS,7aS)-octahydro-5H-4,7-methanoinden-5-ylidene)butanal; (2R,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-one; 4-methyl-2-phenyltetrahydro-2H-pyran; oxydibenzene; diphenylmethane; 2-methyl-1-phenylpropan-2-yl butyrate; 2,6-dimethyloct-7-en-2-ol; 3-methyl-2-pentylcyclopent-2-en-1-one; 3,3,5-trimethylcyclohexan-1-one; 2-methoxy-4-propylphenol; chroman-2-one; 2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-one; 2-methyl-5-(prop-1-en-2-yl)cyclohexyl acetate; 2-(4-methylcyclohexyl)propan-2-yl acetate; 4-(2,6,6-trimethylcyclohex-2-en-1-yl)butan-2-one; (oxybis(methylene))dibenzene; dibutyl phthalate; 1,2-diphenylethane; (3R,4R)-1-isopropyl-4-methyl-3-(prop-1-en-2-yl)-4-vinylcyclohex-1-ene; (1 S,8aR)-4,7-dimethyl-1-(propan-2-yl)-1,2,3,5,6,8a-hexahydronaphthalene; (1S,8aS)-1-isopropyl-4,7-dimethyl-1,2,3,5,6,8a-hexahydronaphthalene; 2-pentylcyclopentan-1-one; decyl 2-aminobenzoate; decahydronaphthalen-2-ol; methyl (1s,4s)-1,4-dimethylcyclohexane-1-carboxylate; 3-(4-isopropylphenyl)-2-methylpropanal; cyclotetradecane; cyclopentadecanone; 2-cyclohexylethyl acetate; cyclohexyl 2-hydroxybenzoate; 1,4-dioxacyclohexadecane-5,16-dione; (4-isopropylphenyl)methanol; 2-methoxy-4-methylphenol; (3Z,5Z)-2,6-dimethylocta-1,3,5,7-tetraene; 4-cyclohexyl-2-methylbutan-2-ol; 2-(3-phenylpropyl)pyridine; 3-(4-methylcyclohex-3-en-1-yl)but-3-en-1-yl acetate; 3-(4-methylcyclohex-3-en-1-yl)butan-1-ol; 2-benzyl-2-methylbut-3-enenitrile; 3,7-dimethyloct-6-enenitrile; 3,7-dimethyloct-6-en-1-yl 2-phenylacetate; 3,7-dimethyloct-6-en-1-yl formate; 3,7-dimethyloct-6-en-1-yl benzoate; 3,7-dimethyloct-6-en-1-ol; 3,7-dimethyloct-6-enal; (E)-3,7-dimethylocta-2,6-dienal; (1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptane; (Z)-3-methyl-2-(pent-2-en-1-yl)cyclopent-2-en-1-one; (E)-2-methoxy-4-(prop-1-en-1-yl)phenol; (E)-oxacycloheptadec-11-en-2-one; (Z)-non-6-en-1-ol; (Z)-hex-3-en-1-yl pentanoate; (E)-hex-3-en-1-yl (E)-2-methylbut-2-enoate; (Z)-hex-3-en-1-yl 2-hydroxybenzoate; (Z)-hex-3-en-1-yl propionate; (Z)-hex-3-en-1-yl butyrate; (Z)-hex-3-en-1-yl benzoate; (Z)-hex-3-en-1-ol; (Z)-hex-3-en-1-yl 2-methylbutanoate; (Z)-hex-2-en-1-ol; cinnamonitrile; cinnamyl isobutyrate; cinnamaldehyde; (E)-3-phenylprop-2-en-1-ol; cinnamonitrile; 4-chloro-3,5-dimethylphenol; hexadecan-1-ol; (E)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)hepta-1,6-dien-3-one; 2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butanal; (3aR,5aR,9aR,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; (4Z,8Z)-1,5,9-trimethyl-13-oxabicyclo[10.1.0]trideca-4,8-diene; 5-methyl-1-(2,2,3-trimethylcyclopent-3-en-1-yl)-6-oxabicyclo[3.2.1]octane; 1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-4H-inden-4-one; 5-isopropyl-2-methylphenol; 2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-one; 2-(2-ethoxyethoxy)ethan-1-ol; hexan-1-ol; 2-(2,2,3-trimethylcyclopent-3-en-1-yl)acetonitrile; 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one; 2,2-dimethyl-3-methylenebicyclo[2.2.1]heptane; 2,6-di-tert-butyl-4-methylphenol; butyl stearate; butyl undec-10-enoate; 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)butan-1-ol; (E)-2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)but-2-enal; 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate; (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol; 3,3,6,7-tetramethyloctahydro-2H-chromene; 6,6-dimethylspiro[bicyclo[3.1.1]heptane-2,2′-oxirane]; 3-isopropyl-6-methylenecyclohex-1-ene; 2-ethoxynaphthalene; (R)-3,5,5,9-tetramethyl-2,4a,5,6,7,8-hexahydro-1H-benzo[7]annulene; (1S,4S)-1,4-dimethyl-7-(propan-2-ylidene)-1,2,3,4,5,6,7,8-octahydroazulene; (1R,9S,Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-4-ene; (Z)-4-(2,2,6-trimethyl-7-oxabicyclo[4.1.0]heptan-1-yl)but-3-en-2-one; 4-methoxy-7H-furo[3,2-g]chromen-7-one; 4-phenylbutan-2-one; benzyl 2-hydroxybenzoate; benzyl dodecanoate; benzyl 3-methylbutanoate; benzyl isobutyrate; benzyl cinnamate; benzyl butyrate; phenylmethanol; benzyl benzoate; 1-(3,3-dimethylcyclohexyl)ethyl formate; 4-methoxybenzyl acetate; 4-methoxybenzyl formate; (Z)-1-methoxy-4-(prop-1-en-1-yl)benzene; pentyl benzoate; (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; 2,5,5-trimethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-ol; 2,5,5-trimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-ol; 2-(sec-butyl)-1-vinylcyclohexyl acetate; (1S,4R,5R)-1-isopropyl-4-methylbicyclo[3.1.0]hexan-3-one; 2-(4-methylcyclohex-3-en-1-yl)propan-2-yl propionate; 2-(4-methylcyclohex-3-en-1-yl)propan-2-yl acetate; 1,7-dimethyl-7-(4-methylpent-3-en-1-yl)tricyclo[2.2.1.02,6]heptane; 1-(5,5-dimethylcyclohex-1-en-1-yl)pent-4-en-1-one; (1S,4aS,8aR)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; 4-cyclohexylbutan-2-ol; (R,Z)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)pent-1-en-3-one; (E)-2-methyl-3-phenylacrylaldehyde; (Z)-3-methyl-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-3-en-2-one; (Z)-4-(2,5,6,6-tetramethylcyclohex-2-en-1-yl)but-3-en-2-one; (1Z,4E,8Z)-2,6,6,9-tetramethylcycloundeca-1,4,8-triene; (4aR,8S,9aS)-3,5,5,8-tetramethyl-9-methylene-2,4a,5,6,7,8,9,9a-octahydro-1H-benzo[7]annulene; (1R,4S,4aR,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; (1 S,4aR,8aR)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (R)-2-((R)-4-methylcyclohex-3-en-1-yl)hex-5-en-2-ol; (E)-2-benzylideneheptyl acetate; (1S,4aR,8aS)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; 1-phenylpentan-2-ol; 4-methoxy-2,5-dimethylfuran-3(2H)-one; alpha-4-Dimethyl benzenepropanal; allyl 2-phenoxyacetate; (2-(allyloxy)ethyl)benzene; allyl heptanoate; allyl 3-cyclohexylpropanoate; N-ethyl-N-(m-tolyl)propionamide; 2,6,10-trimethylundec-9-enal; 3-hydroxybutan-2-one; 1-(4-methoxyphenyl)ethan-1-one; (Z)-2-(4-methylbenzylidene)heptanal; (Z)-oxacycloheptadec-8-en-2-one; 7-methoxy-2H-chromen-2-one; 6-methylquinoline; 6,8-dimethylnonan-2-ol; 6,10,14-trimethylpentadecan-2-one; 5-methylheptan-3-one; 4-vinylphenol; 1-phenylpent-4-en-1-one; (E)-3-(4-hydroxy-3-methoxyphenyl)acrylaldehyde; 4-ethyl-2-methoxyphenol; 5-methyl-5-phenylhexan-3-one; 4-(4-methoxyphenyl)butan-2-one; (E)-3-propylideneisobenzofuran-1(3H)-one; (Z)-dodec-2-enal; 3-methyl-5-phenylpentanal; 3-methyl-4-phenyl-1H-pyrazole; 3-methylcyclopentane-1,2-dione; 3-methoxy-5-methylphenol; 3-methoxy-3-methylbutan-1-ol; (E)-hex-3-en-1-ol; 3,7-dimethyl-2-methyleneoct-6-enal; 3,7-dimethyloctan-1-ol; (Z)-undec-2-enenitrile; (E)-undec-2-enal; phenethyl acetate; (Z)-3-(furan-2-yl)-2-phenylacrylaldehyde; phenethyl propionate; 2-pentylcyclopentan-1-ol; (2S,4S)-2-heptyl-2,4-dimethyl-1,3-dioxolane; nonan-2-ol; 2-(sec-butyl)-3-methoxypyrazine; 2-isopropyl-N,2,3-trimethylbutanamide; (E)-2-isopropyl-5-methylhex-2-enal; 2-isopropyl-4-methylthiazole; (E)-2-hexylidenecyclopentan-1-one; (E)-hex-2-en-1-ol; 2-butoxyethan-1-ol; (2E,6E)-nona-2,6-dien-1-ol; 1-isopropyl-4-methyl-7-oxabicyclo[2.2.1]heptane; 1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 1,1,2,3,3-pentamethyl-2,3-dihydro-1H-indene; (Z)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-en-1-one; (Z)-6,10-dimethylundeca-5,9-dien-2-yl acetate; (Z)-hept-3-en-1-yl acetate; (1S,5S)-4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-one; (R)-3,7-dimethylocta-1,6-dien-3-ol; 3,7-dimethyloct-6-enal; (E)-6,10-dimethylundeca-5,9-dien-2-yl acetate; (R)-3,7-dimethyloct-6-enal; (2S,5S,6S)-2,6,10,10-tetramethyl-1-oxaspiro[4.5]decan-6-ol; 3,7-dimethyloct-6-en-1-ol; 3,7-dimethyloct-6-en-1-ol; (1R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene; (S)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-one; (1S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene; methyl 2-methylbutanoate; hexyl (Z)-2-methylbut-2-enoate; 2-(8-isopropyl-6-methylbicyclo[2.2.2]oct-5-en-2-yl)-1,3-dioxolane; 3-(3-isopropylphenyl)butanal; allyl 2-(cyclohexyloxy)acetate; 2-((3S,3aS,5R)-3,8-dimethyl-1,2,3,3a,4,5,6,7-octahydroazulen-5-yl)propan-2-ol; 1,5-dimethylbicyclo[3.2.1]octan-8-one oxime; benzyl 2-phenylacetate; 2-hydroxy-1,2-diphenylethan-1-one; (E)-tridec-2-enal; 1-phenylvinyl acetate; p-tolyl isobutyrate; p-tolyl hexanoate; p-cymene; 5-hexyl-4-methyldihydrofuran-2(3H)-one; 2-cyclohexylidene-2-phenylacetonitrile; 4-(prop-1-en-2-yl)cyclohex-1-ene-1-carbaldehyde; (4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methyl acetate; (4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methanol; (2-(cyclohexyloxy)ethyl)benzene; phenethyl 2-methylbutanoate; phenethyl formate; phenethyl isobutyrate; phenethyl 2-phenylacetate; phenethyl (Z)-2-methylbut-2-enoate; phenyl benzoate; phenethyl benzoate; phenethyl methacrylate; 2-(4-isopropylphenyl)acetaldehyde; 1,2-dimethyl-3-(prop-1-en-2-yl)cyclopentan-1-ol; 1-(4-methoxyphenyl)propan-2-one; (2Z,5Z)-5,6,7-trimethylocta-2,5-dien-4-one; 1-methoxy-4-propylbenzene; 2-(4-(tert-butyl)phenyl)acetaldehyde; 4-(tert-pentyl)cyclohexan-1-ol; p-tolyl 2-phenylacetate; Ethyl 2,4,7-decatrienoate; 2,6,6-trimethylbicyclo[3.1.1]hept-2-ene; 4-(4-hydroxyphenyl)butan-2-one; 2-benzyl-4,4,6-trimethyl-1,3-dioxane; 3,7-dimethyloct-7-en-1-ol; ethyl (2,3,6-trimethylcyclohexyl) carbonate; (Z)-6-ethylideneoctahydro-2H-5,8-methanochromene; 2-((S)-1-((S)-3,3-dimethylcyclohexyl)ethoxy)-2-oxoethyl propionate; methyl 2,2-dimethyl-6-methylenecyclohexane-1-carboxylate; 1-(3,3-dimethylcyclohexyl)ethyl acetate; (S)-3,7-dimethylocta-1,6-dien-3-ol; 1-isopropyl-4-methylenebicyclo[3.1.0]hexane; 5-isopropyl-2-methylbicyclo[3.1.0]hexan-2-ol; (1 S,3R,5S)-1-isopropyl-4-methylenebicyclo[3.1.0]hexan-3-ol; 3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pentan-2-ol; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; propyl (S)-2-(tert-pentyloxy)propanoate; (4aR,8aR)-4a,8-dimethyl-2-(propan-2-ylidene)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropyl cyclopropanecarboxylate; (1R,3R,6R)-2′,2′,3,7,7-pentamethylspiro[bicyclo[4.1.0]heptane-2,5′-[1,3]dioxane]; 1-oxaspiro(4,5)decan-2-one; (Z)-5-methylheptan-3-one oxime; 1-phenylethyl acetate; (1S,4S,4aR,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; (1S,4S,4aR,8aS)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; 3,7-dimethyloctanal; 4-(2,2,6-trimethylcyclohexyl)butan-2-ol; 3-methyl-2-pentylcyclopentan-1-one; 3,7-dimethyloctan-3-ol; 3,7-dimethyloctan-3-yl acetate; 2,6,10,10-tetramethyl-1-oxaspiro[4.5]dec-6-ene; ethyl (1R,6S)-2,2,6-trimethylcyclohexane-1-carboxylate; 2-isopropyl-5-methylphenol; 1-isopropyl-2-methoxy-4-methylbenzene; 1-(2,2,6-trimethylcyclohexyl)hexan-3-ol; (E)-hex-2-en-1-ol; (1R,2S)-2-(tert-butyl)cyclohexan-1-ol; (Z)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-en-1-one; (Z)-oxacycloheptadec-8-en-2-one; (Z)-1-methoxy-4-(prop-1-en-1-yl)benzene; cinnamic acid; (2R,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-one; (E)-3,7-dimethylocta-2,6-dien-1-ol; (Z)-2-methoxy-4-(prop-1-en-1-yl)phenol; 2,2,2-trichloro-1-phenylethyl acetate; triethyl 2-hydroxypropane-1,2,3-tricarboxylate; methyl 2-((1-hydroxy-3-phenylbutyl)amino)benzoate; 1-((2E,5Z,9Z)-2,6,10-trimethylcyclododeca-2,5,9-trien-1-yl)ethan-1-one; 2-mercapto-2-methylpentan-1-ol; 13-methyl oxacyclopentadec-10-en-2-one; undecanal; (E)-4-methyldec-3-en-5-ol; (3R,4aS,5R)-4a,5-dimethyl-3-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,7-octahydronaphthalene; 4-formyl-2-methoxyphenyl acetate; 4-formyl-2-methoxyphenyl isobutyrate; (Z)-2-ethoxy-5-(prop-1-en-1-yl)phenol; 2,2,5-trimethyl-5-pentylcyclopentan-1-one; (Z)-2-methyl-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-enal; 3,4-dimethoxybenzaldehyde; (1R,5R)-4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-one; 1-methoxy-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoindene; 2-(tert-butyl)cyclohexan-1-ol; cis-(4-tert-butylcyclohexyl) acetate; 4-(tert-butyl)cyclohexyl acetate; 2,4-diethoxy-5-methylpyrimidine; 4-methyl-4-phenylpentan-2-yl acetate; 4,8-dimethyl-2-(propan-2-ylidene)-1,2,3,3a,4,5,6,8a-octahydroazulen-6-ol; (Z)-cyclooct-4-en-1-yl methyl carbonate; (Z)-1-((2-methylallyl)oxy)hex-3-ene; 4-(4-hydroxy-3-methoxyphenyl)butan-2-one; (1R,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,7,8,8a-hexahydronaphthalene; 4,5-epoxy-4,11,11-trimethyl-8-methylenebicyclo(7.2.0)undecane; 1,3,4,6,7,8alpha-hexahydro-1,1,5,5-tetramethyl-2H-2,4alpha-methanophtalen-8(5H)-one preferably said malodor reduction materials are selected from the group consisting of: 2-ethylhexyl (Z)-3-(4-methoxyphenyl)acrylate; 2,4-dimethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolane; 1,1-dimethoxynon-2-yne; 2-(p-tolyl)propan-2-ol; 3-methoxy-7,7-dimethyl-10-methylenebicyclo[4.3.1]decane; methoxycyclododecane; 1,1-dimethoxycyclododecane; (Z)-tridec-2-enenitrile; (2-hydroxy-4-methoxyphenyl)(phenyl)methanone; 2,4a,5,8a-tetramethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl formate; 4-methyl-1-oxaspiro[5.5]undecan-4-ol; 7-methyl-2H-benzo[b][1,4]dioxepin-3(4H)-one; 1,8-dioxacycloheptadecan-9-one; 4-(tert-pentyl)cyclohexan-1-one; 2-methoxy-1,1′-biphenyl; 3a,5,6,7,8,8b-hexahydro-2,2,6,6,7,8,8-heptamethyl-4H-indeno(4,5-d)-1,3-dioxole; 7-isopropyl-8,8-dimethyl-6,10-dioxaspiro[4.5]decane; octyl furan-2-carboxylate; octyl acetate; 2-heptyl-4-methyl-1,3-dioxolane; octanal; 1,1-dimethoxyoctane; 7-methyl-3-methyleneocta-1,6-diene; 2-methyl-6-methyleneoct-7-en-2-ol; 2-methyl-6-methyleneoct-7-en-2-yl acetate; tetradecanal; 4-methoxy-6-prop-2-enyl-1,3-benzodioxole; tetradecanenitrile; 2,2,6,8-tetramethyl-1,2,3,4,4a,5,8,8a-octahydronaphthalen-1-ol; (E)-2,6-dimethylocta-5,7-dien-2-ol; (E)-2,7-dimethylocta-1,5,7-trien-3-ol; 2-((1S,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethyl acetate; (4R,4aS,6R)-4,4a-dimethyl-6-(prop-1-en-2-yl)-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one; nonan-1-ol; nonanal; 12-methyl-14-tetradec-9-enolide; N-ethyl-2-isopropyl-5-methylcyclohexane-1-carboxamide; 1-(3-methylbenzofuran-2-yl)ethan-1-one; 2-methoxynaphthalene; (E)-3,7,11-trimethyldodeca-1,6,10-trien-3-ol; (Z)-3,7-dimethylocta-2,6-dien-1-ol; 1-ethyl-3-methoxytricyclo[2.2.1.02,6]heptane; methyl (E)-non-2-enoate; 10-isopropyl-2,7-dimethyl-1-oxaspiro[4.5]deca-3,6-diene; 2-(2-(4-methylcyclohex-3-en-1-yl)propyl)cyclopentan-1-one; 6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-carbaldehyde; (E)-4-(2,2,3,6-tetramethylcyclohexyl)but-3-en-2-one; (4-(4-methylpent-3-en-1-yl)cyclohex-3-en-1-yl)methyl acetate; 2-(tert-butyl)-4,5,6-trimethyl-1,3-phenylene dinitrite; 1,7-dioxacycloheptadecan-8-one; 1-(4-(tert-butyl)-2,6-dimethyl-3,5-dinitrophenyl)ethan-1-one; 1-(tert-butyl)-2-methoxy-4-methyl-3,5-dinitrobenzene; 3-methylcyclopentadecan-1-one; (E)-3-methylcyclopentadec-4-en-1-one; 3-methyl-4-phenylbutan-2-ol; 1-(4-isopropylcyclohexyl)ethan-1-ol; (E)-dec-5-enoic acid; methyl non-2-ynoate; 2-methyldecanal; 6,6-dimethoxy-2,5,5-trimethylhex-2-ene; 4-phenylbutan-2-ol; methyl stearate; 1,1-dimethoxy-2-methylundecane; undecan-2-one; 2-methylundecanal; methyl tetradecanoate; methyl (9Z,12Z)-octadeca-9,12-dienoate; 1-hydroxydecan-3-one; (Z)-1,2-dimethoxy-4-(prop-1-en-1-yl)benzene; methyl palmitate; 4-allyl-1,2-dimethoxybenzene; methyl 2-((1R,2R)-3-oxo-2-((Z)-pent-2-en-1-yl)cyclopentyl)acetate; methyl 2-(3-oxo-2-pentylcyclopentyl)acetate; 1-methyl-2-phenoxybenzene; methyl cinnamate; 1-allyl-4-methoxybenzene; 1-(naphthalen-2-yl)ethan-1-one; methyl oct-2-ynoate; methyl 2,6,6-trimethylcyclohex-2-ene-1-carboxylate; 7-methoxy-3,7-dimethyloctanal; 7-isopropyl-10-methyl-1,5-dioxaspiro[5.5]undecan-3-ol; octahydro-1H-4,7-methanoindene-1-carbaldehyde; 3-(3-(tert-butyl)phenyl)-2-methylpropanal; (E)-4-(4,8-dimethylnona-3,7-dien-1-yl)pyridine; (E)-trideca-3,12-dienenitrile; 2,2-dimethyl-3-(m-tolyl)propan-1-ol; 2,4-dimethyl-4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; 8-isopropyl-6-methylbicyclo[2.2.2]oct-5-ene-2-carbaldehyde; 4-(4-hydroxy-4-methylpentyl)cyclohex-3-ene-1-carbaldehyde; (S)-1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene; (Z)-3-hexen-1-yl-2-cyclopenten-1-one; 3,7-dimethylocta-1,6-dien-3-yl octanoate; 3,7-dimethylocta-1,6-dien-3-yl isobutyrate; 3,7-dimethylocta-1,6-dien-3-yl benzoate; 3,7-dimethylocta-1,6-dien-3-yl 2-aminobenzoate; 2-(5-methyl-5-vinyltetrahydrofuran-2-yl)propan-2-ol; 6-methyl-2-(oxiran-2-yl)hept-5-en-2-ol; (2Z,6E)-3,7-dimethylnona-2,6-dienenitrile; 3-(4-methylcyclohex-3-en-1-yl)butanal; (2,5-dimethyl-1,3-dihydroinden-2-yl)methanol; 3-(4-(tert-butyl)phenyl)-2-methylpropanal; (E)-1-(1-methoxypropoxy)hex-3-ene; (E)-1-(1-ethoxyethoxy)hex-3-ene; (1S,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-ol; dodecan-1-ol; dodecyl acetate; dodecanoic acid; 5-hexyl-5-methyldihydrofuran-2(3H)-one; dodecanal; 3,6-dimethylhexahydrobenzofuran-2(3H)-one; 4-(1-ethoxyvinyl)-3,3,5,5-tetramethylcyclohexan-1-one; ((3S,3aR,6R,8aS)-7,7-dimethyl-8-methyleneoctahydro-1H-3a,6-methanoazulen-3-yl)methanol; 5-(sec-butyl)-2-(2,4-dimethylcyclohex-3-en-1-yl)-5-methyl-1,3-dioxane; (1-methyl-2-((1,2,2-trimethylbicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methanol; 2-propylheptanenitrile; (E)-6-(pent-3-en-1-yl)tetrahydro-2H-pyran-2-one; 2-hexylcyclopentan-1-one; 2-methyl-4-phenyl-1,3-dioxolane; 2,6,9,10-tetramethyl-1-oxaspiro(4.5)deca-3,6-diene; (1R,2S,5R)-5-methyl-2-(prop-1-en-2-yl)cyclohexan-1-ol; isopropyl palmitate; isopropyl tetradecanoate; isopropyl dodecanoate; 4,9-dimethoxy-7H-furo[3,2-g]chromen-7-one; (E)-cyclohexadec-8-en-1-one; (2S,5S)-2-isopropyl-5-methylcyclohexan-1-one; 2-hexylcyclopent-2-en-1-one; (2S,5S)-2-isopropyl-5-methylcyclohexan-1-one; 4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; (Z)-1-(benzyloxy)-2-methoxy-4-(prop-1-en-1-yl)benzene; 1-((2S,3 S)-2,3,8,8-tetramethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-yl)ethan-1-one; 2,5,6-trimethylcyclohex-3-ene-1-carbaldehyde; 6-(sec-butyl)quinoline; 2-(cyclohexyloxy)-1,7,7-trimethylbicyclo[2.2.1]heptane; (1R,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl propionate; (1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate; 4-((2R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)cyclohexan-1-ol; (1R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 2-(4-isopropylcyclohexa-1,4-dien-1-yl)ethyl formate; isopentyl (E)-undec-6-enoate; isopentyl dodecanoate; (E)-oxacycloheptadec-10-en-2-one; (E)-non-2-enenitrile; (E)-8-(1H-indol-1-yl)-2,6-dimethyloct-7-en-2-ol; 8,8-di(1H-indol-1-yl)-2,6-dimethyloctan-2-ol; 4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; 3,7-dimethyloctane-1,7-diol; 2-cyclododecylpropan-1-ol; 3-methyl-5-phenylpentanenitrile; 3-phenylpropan-1-ol; (1,1-dimethoxypropan-2-yl)benzene; 5-ethyl-4-hydroxy-2-methylfuran-3(2H)-one; 2,3-dihydro-3,3-dimethyl-1H-indene-5-propanal; 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)propanal; hexyl octanoate; hexyl hexanoate; (Z)-2-benzylideneoctanal; hexyl benzoate; (Z)-hex-1-en-1-yl (Z)-2-methylbut-2-enoate; (E)-3,7-dimethylocta-2,6-dien-1-yl palmitate; oxacycloheptadecan-2-one; 2-butyl-4,4,6-trimethyl-1,3-dioxane; ethyl (1R,2R,3R,4R)-3-isopropylbicyclo[2.2.1]hept-5-ene-2-carboxylate; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl acetate; 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropyl propionate; 5-(diethoxymethyl)benzo[d][1,3]dioxole; 3-(benzo[d][1,3]dioxol-5-yl)-2-methylpropanal; (E)-oxacyclohexadec-13-en-2-one; 6-butyl-2,4-dimethyl-3,6-dihydro-2H-pyran; 2-((3S,5R,8S)-3,8-dimethyl-1,2,3,4,5,6,7,8-octahydroazulen-5-yl)propan-2-ol; 1-(2,6,6-trimethylcyclohex-2-en-1-yl)pentan-3-one; ethyl 2-ethyl-6,6-dimethylcyclohex-2-ene-1-carboxylate; (1Z,5Z)-1,5-dimethyl-8-(propan-2-ylidene)cyclodeca-1,5-diene; (1E,6E)-8-isopropyl-1-methyl-5-methylenecyclodeca-1,6-diene; (E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate; (E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate; (6E,10E)-3,7,11,15-tetramethylhexadeca-1,6,10,14-tetraen-3-ol; (E)-2-(3,7-dimethylocta-2,6-dien-1-yl)cyclopentan-1-one; 5-heptyldihydrofuran-2(3H)-one; 1-methyl-4-(propan-2-ylidene)cyclohexyl acetate; 1-methyl-4-(propan-2-ylidene)cyclohexan-1-ol; 5-pentyldihydrofuran-2(3H)-one; (1R,4aR,8aS)-1-isopropyl-7-methyl-4-methylene-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 5-[(Z)-hex-3-enyl]oxolan-2-one; (Z)-4-(2,2-dimethyl-6-methylenecyclohexyl)but-3-en-2-one; (4aS,9aR)-3,5,5,9-tetramethyl-2,4a,5,6,7,9a-hexahydro-1H-benzo[7]annulene; (1R,3aR,4R,7R)-1,4-dimethyl-7-(prop-1-en-2-yl)-1,2,3,3a,4,5,6,7-octahydroazulene; 2-((2R,4aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)propan-2-ol; 5-octyldihydrofuran-2(3H)-one; (Z)-1-(2,2-dimethyl-6-methylenecyclohexyl)but-2-en-1-one; 5-hexyldihydrofuran-2(3H)-one; (1R,4aS,8aS)-1-isopropyl-7-methyl-4-methylene-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 1-(3,3-dimethylcyclohexyl)pent-4-en-1-one; 4,6,6,7,8,8-hexamethyl-1,3,4,6,7,8-hexahydrocyclopenta[g]isochromene; furan-2-ylmethyl octanoate; furan-2-ylmethyl hexanoate; furan-2-ylmethyl heptanoate; 2-methyldecanenitrile; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; ethyl (3aR,4S,7R,7aR)-octahydro-3aH-4,7-methanoindene-3a-carboxylate; diethyl cyclohexane-1,4-dicarboxylate; (6-isopropyl-9-methyl-1,4-dioxaspiro[4.5]decan-2-yl)methanol; 2-isobutyl-4-methyltetrahydro-2H-pyran-4-ol; undec-10-enenitrile; (Z)-6-ethylideneoctahydro-2H-5,8-methanochromen-2-one; 3-(2-ethylphenyl)-2,2-dimethylpropanal; (E)-4,8-dimethyldeca-4,9-dienal; (E)-4-((3aR,4R,7R,7aR)-1,3a,4,6,7,7a-hexahydro-5H-4,7-methanoinden-5-ylidene)-3-methylbutan-2-ol; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl acetate; 3-(4-ethylphenyl)-2,2-dimethylpropanenitrile; 2-heptylcyclopentan-1-one; 1-ethoxyethoxy Cyclododecane; 3-cyclohexene-1-carboxylic acid, 2,6,6-trimethyl-, methyl ester; (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl acetate; (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol; oxacyclohexadecan-2-one; (E)-cyclopentadec-4-en-1-one; 1-cyclopentadec-4-en-1-one; 2-methoxy-4-(4-methylenetetrahydro-2H-pyran-2-yl)phenol; 4-allyl-2-methoxyphenyl acetate; 4-allyl-2-methoxyphenol; ethyl 3-methyl-3-phenyloxirane-2-carboxylate; 1,4-dioxacycloheptadecane-5,17-dione; ethyl undec-10-enoate; ethyl palmitate; ethyl nonanoate; ethyl tetradecanoate; (E)-3,7-dimethylnona-1,6-dien-3-ol; ethyl dodecanoate; nonan-3-one; ethyl decanoate; ethyl 6,6-dimethyl-2-methylenecyclohex-3-ene-1-carboxylate; ethyl 3-phenyloxirane-2-carboxylate; 6-ethyl-2,10,10-trimethyl-1-oxaspiro[4.5]deca-3,6-diene; 2-((1R,3 S,4S)-4-methyl-3-(prop-1-en-2-yl)-4-vinylcyclohexyl)propan-2-ol; (2-(1-ethoxyethoxy)ethyl)benzene; (E)-3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pent-4-en-2-ol; (2R,3S,4R)-2,3,4,5-tetrahydroxypentanal; (E)-4-((3aS,7aS)-octahydro-5H-4,7-methanoinden-5-ylidene)butanal; 1,1-dimethoxydodecane; (R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene; 2-(2-hydroxypropoxy)propan-1-ol; 7,9-dimethylspiro[5.5]undecan-3-one; oxydibenzene; diphenylmethane; 2-methyl-1-phenylpropan-2-yl butyrate; 2,6-dimethyloct-7-en-4-one; octahydro-1H-4,7-methanoinden-5-yl acetate; 2-methyl-5-(prop-1-en-2-yl)cyclohexyl acetate; 2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-ol; 3,7-dimethyloct-6-en-3-ol; methyl 2-hexyl-3-oxocyclopentane-1-carboxylate; dibutylsulfane; 1,2-diphenylethane; 6-hexyltetrahydro-2H-pyran-2-one; (3R,4R)-1-isopropyl-4-methyl-3-(prop-1-en-2-yl)-4-vinylcyclohex-1-ene; (3S,3aS,5R)-3,8-dimethyl-5-(prop-1-en-2-yl)-1,2,3,3a,4,5,6,7-octahydroazulene; 6-heptyltetrahydro-2H-pyran-2-one; 6-pentyltetrahydro-2H-pyran-2-one; (1S,8aR)-4,7-dimethyl-1-(propan-2-yl)-1,2,3,5,6,8a-hexahydronaphthalene; (Z)-1-((1R,2S)-2,6,6-trimethylcyclohex-3-en-1-yl)but-2-en-1-one; (1S,8aS)-1-isopropyl-4,7-dimethyl-1,2,3,5,6,8a-hexahydronaphthalene; 3,7,7-trimethylbicyclo[4.1.0]hept-3-ene; dec-9-en-1-ol; decyl propionate; 1,1-diethoxydecane; decahydronaphthalen-2-ol; 1-cyclohexylethyl (E)-but-2-enoate; 3-(4-isopropylphenyl)-2-methylpropanal; cyclotetradecane; cyclopentadecanone; cyclohexyl 2-hydroxybenzoate; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl butyrate; 1,4-dioxacyclohexadecane-5,16-dione; 8,8-dimethyl-1,2,3,4,5,6,7,8-octahydronaphthalene-2-carbaldehyde; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl isobutyrate; (5R,6R)-3,6-dimethyl-5-(prop-1-en-2-yl)-6-vinyl-4,5,6,7-tetrahydrobenzofuran; (4-isopropylphenyl)methanol; 1-(benzofuran-2-yl)ethan-1-one; 2-(3-phenylpropyl)pyridine; dodecanenitrile; (E)-cycloheptadec-9-en-1-one; 3-(4-methylcyclohex-3-en-1-yl)but-3-en-1-yl acetate; 3-(4-methylcyclohex-3-en-1-yl)butan-1-ol; (E)-3-methyl-5-phenylpent-2-enenitrile; (E)-2-(2,6-dimethylhepta-1,5-dien-1-yl)-4-methyl-1,3-dioxolane; (E)-1,1-dimethoxy-3,7-dimethylocta-2,6-diene; (E)-1,1-diethoxy-3,7-dimethylocta-2,6-diene; (E)-3,7-dimethylocta-1,3,6-triene; (1R,4R,6S)-1-methyl-4-(prop-1-en-2-yl)-7-oxabicyclo[4.1.0]heptane; (E)-oxacycloheptadec-11-en-2-one; (Z)-non-6-en-1-ol; (1R,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-ol; (Z)-dec-4-enal; (E)-hex-3-en-1-yl (E)-hex-3-enoate; (Z)-hex-3-en-1-yl 2-hydroxybenzoate; (Z)-hex-3-en-1-yl benzoate; (Z)-hex-3-en-1-yl 2-methylbutanoate; (3Z,6Z)-nona-3,6-dien-1-ol; cinnamyl propionate; cinnamyl isobutyrate; cinnamyl formate; cinnamyl cinnamate; cinnamyl acetate; (E)-3-phenylprop-2-en-1-ol; hexadecan-1-ol; (E)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)hepta-1,6-dien-3-one; 2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butanal; (3aR,5aR,9aR,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; 1,6-dioxacycloheptadecan-7-one; 1-(6-(tert-butyl)-1,1-dimethyl-2,3-dihydro-1H-inden-4-yl)ethan-1-one; (3R,3aR,6S,7S,8aS)-6-methoxy-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-3-yl formate; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl acetate; (4Z,8Z)-1,5,9-trimethyl-13-oxabicyclo[10.1.0]trideca-4,8-diene; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-ol; 5-methyl-1-(2,2,3-trimethylcyclopent-3-en-1-yl)-6-oxabicyclo[3.2.1]octane; 5-methyl-1-(2,2,3-trimethylcyclopent-3-en-1-yl)-6-oxabicyclo[3.2.1]octane; 1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-4H-inden-4-one; (Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-3-en-5-yl acetate; (1S,2S,5R,8S)-4,4,8-trimethyltricyclo[6.3.1.02,5]dodecan-1-ol; 2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-yl acetate; octanenitrile; octan-1-ol; octanoic acid; decanoic acid; decanal; 3-(4-methoxyphenyl)-2-methylpropanal; 1,7,7-trimethylbicyclo[2.2.1]heptane-2,3-dione; 2,2-dimethyl-3-methylenebicyclo[2.2.1]heptane; ethyl 2-methyl-4-oxo-6-pentylcyclohex-2-ene-1-carboxylate; 2,6-di-tert-butyl-4-methylphenol; butyl stearate; 1-butoxy-1-oxopropan-2-yl butyrate; butyl undec-10-enoate; 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)butan-1-ol; 3-(4-(tert-butyl)phenyl)propanal; (1S,2S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate; 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 2-ethoxy-2,6,6-trimethyl-9-methylenebicyclo[3.3.1]nonane; (ethoxymethoxy)cyclododecane; (E)-1-methyl-4-(6-methylhept-5-en-2-ylidene)cyclohex-1-ene; 3,3,6,7-tetramethyloctahydro-2H-chromene; (5R,10R)-6,10-dimethyl-2-(propan-2-ylidene)spiro[4.5]dec-6-en-8-one; 1-methyl-4-(prop-1-en-2-yl)cyclohexyl acetate; 1-methyl-4-(prop-1-en-2-yl)cyclohexan-1-ol; (2Z,6E)-2,6-dimethyl-10-methylenedodeca-2,6,11-trienal; (R)-3-methylene-6-((S)-6-methylhept-5-en-2-yl)cyclohex-1-ene; (4aR,7R,8aS)-4a-methyl-1-methylene-7-(prop-1-en-2-yl)decahydronaphthalene; (Z)-2-methyl-5-((1S,2R,4R)-2-methyl-3-methylenebicyclo[2.2.1]heptan-2-yl)pent-2-en-1-ol; 6,6-dimethyl-2-methylenebicyclo[3.1.1]heptane; 2-ethoxynaphthalene; (1S,4R,7R)-1,4,9,9-tetramethyl-1,2,3,4,5,6,7,8-octahydro-4,7-methanoazulene; (1 aS,5aR,9aR)-1a,5,5,7-tetramethyl-1a,2,3,4,5,5a,8,9-octahydrobenzo[1,7]cyclohepta[1,2-b]oxirene; (R)-3,5,5,9-tetramethyl-2,4a,5,6,7,8-hexahydro-1H-benzo[7]annulene; (1S,4S)-1,4-dimethyl-7-(propan-2-ylidene)-1,2,3,4,5,6,7,8-octahydroazulene; (2,2-dimethoxyethyl)benzene; (E)-7,11-dimethyl-3-methylenedodeca-1,6,10-triene; (1R,2S,6S,7S,8S)-8-isopropyl-1-methyl-3-methylenetricyclo[4.4.0.02,7]decane; (3R,3aS,7S,8aS)-3,8,8-trimethyl-6-methyleneoctahydro-1H-3a,7-methanoazulene; (1R,9S,Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-4-ene; (S)-4-methyl-1-((S)-6-methylhept-5-en-2-yl)cyclohex-3-en-1-ol; (Z)-4-(2,2,6-trimethyl-7-oxabicyclo[4.1.0]heptan-1-yl)but-3-en-2-one; 4-methoxy-7H-furo[3,2-g]chromen-7-one; 2-methyl-4-phenylbutan-2-ol; benzyl dodecanoate; 2-methyl-1-phenylpropan-2-ol; benzyl cinnamate; benzyl benzoate; benzophenone; 7-isopentyl-2H-benzo[b][1,4]dioxepin-3(4H)-one; 2′-isopropyl-1,7,7-trimethylspiro[bicyclo[2.2.1]heptane-2,4′-[1,3]dioxane]/A; 4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbonitrile; methyl (E)-2-((7-hydroxy-3,7-dimethyloctylidene)amino)benzoate; 4-methoxybenzyl 2-phenylacetate; methyl (E)-octa-4,7-dienoate; pentyl (Z)-3-phenylacrylate; (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; (4aR,5R,7aS,9R)-2,2,5,8,8,9a-hexamethyloctahydro-4H-4a,9-methanoazuleno[5,6-d][1,3]dioxole; 2,5,5-trimethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-ol; 2,5,5-trimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-ol; 1-((2-(tert-butyl)cyclohexyl)oxy)butan-2-ol; (3S,5aR,7aS,11aS,11bR)-3,8,8,11a-tetramethyldodecahydro-5H-3,5a-epoxynaphtho[2,1-c]oxepine; 2,2,6,6,7,8,8-heptamethyldecahydro-2H-indeno[4,5-b]furan; 2,2,7,7,8,9,9-heptamethyldecahydroindeno[4,3a-b]furan; 2-(sec-butyl)-1-vinylcyclohexyl acetate; (1S,4R,5R)-1-isopropyl-4-methylbicyclo[3.1.0]hexan-3-one; (4R,4aS)-4,4a-dimethyl-6-(propan-2-ylidene)-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one; 2-(4-methylcyclohex-3-en-1-yl)propan-2-yl propionate; (2Z,6E,9E)-2,6,10-trimethyldodeca-2,6,9,11-tetraenal; (2R,4aR,8aR)-4a,8-dimethyl-2-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 1,7-dimethyl-7-(4-methylpent-3-en-1-yl)tricyclo[2.2.1.02,6]heptane; (E)-5-(2,3-dimethyltricyclo[2.2.1.02,6]heptan-3-yl)-2-methylpent-2-en-1-ol; (1R,3aS,7S,8aR)-1,4,9,9-tetramethyl-2,3,6,7,8,8a-hexahydro-1H-3a,7-methanoazulene; 1-(5,5-dimethylcyclohex-1-en-1-yl)pent-4-en-1-one; (1S,4aS,8aR)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (R,Z)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)pent-1-en-3-one; 1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene; (Z)-4-(2,5,6,6-tetramethylcyclohex-2-en-1-yl)but-3-en-2-one; (1Z,4E,8Z)-2,6,6,9-tetramethylcycloundeca-1,4,8-triene; (4aR,8S,9aS)-3,5,5,8-tetramethyl-9-methylene-2,4a,5,6,7,8,9,9a-octahydro-1H-benzo[7]annulene; (1aR,4R,4aR,7bS)-1,1,4,7-tetramethyl-1a,2,3,4,4a,5,6,7b-octahydro-1H-cyclopropa[e]azulene; 1,4-dimethyl-7-(prop-1-en-2-yl)-1,2,3,4,5,6,7,8-octahydroazulene; (3E,6E)-3,7,11-trimethyldodeca-1,3,6,10-tetraene; 7,7-dimethyl-2-methylenebicyclo[2.2.1]heptane; 2-((2R,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl)propan-2-ol; (R)-1-methyl-4-(6-methylhept-5-en-2-yl)benzene; (3aR,3bR,4S,7R,7aS)-4-isopropyl-7-methyl-3a,3b,4,5,6,7-hexahydro-1H-cyclopenta[1,3]cyclopropa[1,2]benzene; (1aS,2aR,3R,5aS,7R,7aR)-3,6,6,7a-tetramethyloctahydro-2H-2a,7-methanoazuleno[5,6-b]oxirene; (1R,4S,4aR,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; (1S,4aR,8aR)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (R)-2-((R)-4-methylcyclohex-3-en-1-yl)hex-5-en-2-ol; (Z)-1-methyl-4-(6-methylhepta-2,5-dien-2-yl)cyclohex-1-ene; 2,6-dimethyl-6-(4-methylpent-3-en-1-yl)bicyclo[3.1.1]hept-2-ene; (E)-2-benzylideneheptan-1-ol; (E)-2-benzylideneheptyl acetate; (Z)-(2-(diethoxymethyl)hept-1-en-1-yl)benzene; (E)-2-benzylideneheptanal; (1S,4aR,8aS)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (3R,5aS,9aR)-2,2,5a,9-tetramethyl-3,4,5,5a,6,7-hexahydro-2H-3,9a-methanobenzo[b]oxepine; 1-methyl-4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; 1-phenylpentan-2-ol; 3-methyl-1-phenylpentan-3-ol; 2,3,4-trimethoxybenzaldehyde; 2,4,5-trimethoxybenzaldehyde; 2,4,6-trimethoxybenzaldehyde; Trans,Trans-2,4-Nonadienal; 2,6,10-trimethylundecanal; alpha-4-Dimethyl benzenepropanal; allyl 3-cyclohexylpropanoate; allyl 2-(isopentyloxy)acetate; (1aR,4aS,7R,7aR,7bS)-1,1,7-trimethyl-4-methylenedecahydro-1H-cyclopropa[e]azulene; (E)-undec-9-enal; methyl (E)-2-(((3,5-dimethylcyclohex-3-en-1-yl)methylene)amino)benzoate; 2,6,10-trimethylundec-9-enal; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methyl acetate; nonyl acetate; (2-(1-propoxyethoxy)ethyl)benzene; 1-(1-propoxyethoxy)propane; ((1-(2-methoxyethoxy)ethoxy)methyl)benzene; (Z)-2-(4-methylbenzylidene)heptanal; dec-9-enal; (Z)-oxacycloheptadec-8-en-2-one; 7-methoxy-2H-chromen-2-one; (2S,4aR,8aR)-4a,8-dimethyl-2-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 2-((2S,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl)propan-2-ol; 1-(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethan-1-one; 6-isopropylquinoline; 3-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)propanal; 6,10,14-trimethylpentadecan-2-one; 2-methyl-5-(prop-1-en-2-yl)-2-vinyltetrahydrofuran; (E)-cyclohexadec-5-en-1-one; 1-isopropyl-4-methylcyclohex-3-en-1-ol; 1-phenylpent-4-en-1-one; 1-isopropyl-4-methylcyclohex-3-en-1-ol; 3,6-dimethyl-4,5,6,7-tetrahydrobenzofuran; 4-(4-methoxyphenyl)butan-2-one; (1aR,2S,4aS)-2,4a,8,8-tetramethyloctahydrocyclopropa[d]naphthalen-3(1H)-one; (E)-3-propylideneisobenzofuran-1(3H)-one; (Z)-dodec-2-enal; 3-methyl-5-phenylpentanal; (E)-hex-3-en-1-yl 3-methylbutanoate; 3,6-dimethyloctan-3-yl acetate; 3,4,5-trimethoxybenzaldehyde; 3-(4-isopropylphenyl)propanal; (Z)-undec-2-enenitrile; (E)-undec-2-enal; (2E,6E)-nona-2,6-dienal; phenethyl butyrate; (Z)-3-(furan-2-yl)-2-phenylacrylaldehyde; 2-phenoxyethan-1-ol; (Z)-non-2-enal; nonan-2-ol; nonan-2-one; 2-isobutylquinoline; (E)-2-hexylidenecyclopentan-1-one; 2-heptyltetrahydrofuran; (E)-dec-2-enal; (2E,6E)-nona-2,6-dienal; (2E,6E)-nona-2,6-dien-1-ol; 2,6-dimethyloctanal; decan-1-ol; (E)-hept-1-en-1-yl acetate; undec-10-en-1-ol; undec-10-enal; 2-((2R,4aS)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)propan-2-ol; 1-isopropyl-4-methyl-7-thiabicyclo[2.2.1]heptane; (3E,5Z)-undeca-1,3,5-triene; 3,7-dimethyloct-6-en-3-ol; 1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 1,1,2,3,3-pentamethyl-2,3-dihydro-1H-indene; (Z)-6,10-dimethylundeca-5,9-dien-2-yl acetate; (Z)-dodec-3-enal; (S)-5-heptyldihydrofuran-2(3H)-one; (R)-5-heptyldihydrofuran-2(3H)-one; (E)-6,10-dimethylundeca-5,9-dien-2-yl acetate; (Z)-3-methyl-5-phenylpent-2-enenitrile; (2S,5S,6S)-2,6,10,10-tetramethyl-1-oxaspiro[4.5]decan-6-ol; (2E)-3-methyl-5-phenyl-2-pentenenitrile; (1 S,2S,5S)-2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-ol; (2S,5R)-2-isopropyl-5-methylcyclohexan-1-one; (R,E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 2-(8-isopropyl-6-methylbicyclo[2.2.2]oct-5-en-2-yl)-1,3-dioxolane; (E)-4-(2,2-dimethyl-6-methylenecyclohexyl)-3-methylbut-3-en-2-one; 3-(3-isopropylphenyl)butanal; 3-(1-ethoxyethoxy)-3,7-dimethylocta-1,6-diene; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; 2-((3S,3aS,5R)-3,8-dimethyl-1,2,3,3a,4,5,6,7-octahydroazulen-5-yl)propan-2-ol; benzyl 2-phenylacetate; 2-hydroxy-1,2-diphenylethan-1-one; (E)-1,2,4-trimethoxy-5-(prop-1-en-1-yl)benzene; 3-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-2,2-dimethylpropanal; 2-methyl-5-(6-methylhept-5-en-2-yl)bicyclo[3.1.0]hex-2-ene; 1-(1,1,2,3,3,6-hexamethyl-2,3-dihydro-1H-inden-5-yl)ethan-1-one; 2-(m-tolyl)ethan-1-ol; (3E,6E)-nona-3,6-dien-1-ol; (E)-tridec-2-enal; (1R,4S,4aS,6R,8aS)-4,8a,9,9-tetramethyloctahydro-1,6-methanonaphthalen-1(2H)-ol; p-tolyl isobutyrate; p-tolyl hexanoate; 5-hexyl-4-methyldihydrofuran-2(3H)-one; ethyl (2Z,4E)-deca-2,4-dienoate; 2,4-dimethyl-6-phenyl-3,6-dihydro-2H-pyran; 2-cyclohexylidene-2-phenylacetonitrile; 4-(prop-1-en-2-yl)cyclohex-1-ene-1-carbaldehyde; (4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methyl acetate; (4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methanol; (2-isopropoxyethyl)benzene; 2-cyclohexylhepta-1,6-dien-3-one; (2-(cyclohexyloxy)ethyl)benzene; phenethyl 2-methylbutanoate; 2-phenylethan-1-ol; phenethyl 2-phenylacetate; 3-methyl-5-phenylpentan-1-ol; phenyl benzoate; phenethyl benzoate; 2-benzyl-1,3-dioxolane; 2-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)acetaldehyde; 6,6-dimethyl-2-methylenebicyclo[3.1.1]heptan-3-ol; 4-(benzo[d][1,3]dioxol-5-yl)butan-2-one; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl pivalate; (4aR,8aS)-7-methyloctahydro-1,4-methanonaphthalen-6(2H)-one; 4-isopropyl-1-methylcyclohex-3-en-1-ol; (E)-3,3-dimethyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pent-4-en-2-ol; 1-methyl-4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; propane-1,2-diol; p-tolyl 2-phenylacetate; Ethyl 2,4,7-decatrienoate; 2-benzyl-4,4,6-trimethyl-1,3-dioxane; 2,4-dimethyl-4-phenyltetrahydrofuran; (2R,4a′R,8a′R)-3,7′-dimethyl-3′,4′,4a′,5′,8′,8a′-hexahydro-1′H-spiro[oxirane-2,2′-[1,4]methanonaphthalene]; (Z)-6-ethylideneoctahydro-2H-5,8-methanochromene; 2-((S)-1-((S)-3,3-dimethylcyclohexyl)ethoxy)-2-oxoethyl propionate; methyl 2,2-dimethyl-6-methylenecyclohexane-1-carboxylate; 2-methyl-5-phenylpentan-1-ol; 4-methyl-2-phenyl-3,6-dihydro-2H-pyran; (1S,3R,5S)-1-isopropyl-4-methylenebicyclo[3.1.0]hexan-3-ol; 5-allylbenzo[d][1,3]dioxole; 2,2,7,9-tetramethylspiro(5.5)undec-8-en-1-one; 3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pentan-2-ol; (Z)-2-ethyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; (E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; 1-(3-hydroxy-3-methylpent-4-en-1-yl)-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol; (4aR,6aS,10aS,10bR)-3,4a,7,7,10a-pentamethyl-4a,5,6,6a,7,8,9,10,10a, 10b-decahydro-1H-benzo[f]chromene; (4aR,8aR)-4a,8-dimethyl-2-(propan-2-ylidene)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropyl cyclopropanecarboxylate; 3-(4-isobutylphenyl)-2-methylpropanal; (1aR,4aR,7S,7aR,7bR)-1,1,7-trimethyl-4-methylenedecahydro-1H-cyclopropa[e]azulen-7-ol; (1R,3R,6R)-2′,2′,3,7,7-pentamethylspiro[bicyclo[4.1.0]heptane-2,5′-[1,3]dioxane]; 2-methyl-1,5-dioxaspiro[5.5]undecane; 1-(spiro[4.5]dec-7-en-7-yl)pent-4-en-1-one; 2-(4-methylthiazol-5-yl)ethan-1-ol; 2-(heptan-3-yl)-1,3-dioxolane; (Z)-dodec-4-enal; (1 S,4S,4aR,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; (1S,4S,4aR,8aS)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; 3-methyl-2-pentylcyclopentan-1-one; 2,6,10,10-tetramethyl-1-oxaspiro[4.5]dec-6-ene; 2-(2-mercaptopropan-2-yl)-5-methylcyclohexan-1-one; (1aR,4aS)-2,4a,8,8-tetramethyl-1,1a,4,4a,5,6,7,8-octahydrocyclopropa[d]naphthalene; 1-isopropyl-2-methoxy-4-methylbenzene; 1-(2,2,6-trimethylcyclohexyl)hexan-3-ol; (2Z,4E)-nona-2,4-dienal; (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol; (2E,6Z)-nona-2,6-dienal; (Z)-dec-2-enal; (E)-non-2-enal; (3E,6Z)-nona-3,6-dien-1-ol; (E)-dec-4-enal; (Z)-oxacycloheptadec-8-en-2-one; (Z)-3,7-dimethylocta-1,3,6-triene; (Z)-3,7-dimethylocta-1,3,6-triene; (E)-3,7-dimethylocta-2,6-dien-1-ol; methyl 2-((1S,2S)-3-oxo-2-pentylcyclopentyl)acetate; 7-(1,1-Dimethylethyl)-2H-1,5-benzodioxepin-3 (4H)-one; (1R-(1alpha,3alpha,4aalpha))-2,3,4,4a,5,6-hexahydro-2,2-dimethyl-1,3-methanonaphthalen-7(1H)-one; tridecan-1-ol; triethyl 2-hydroxypropane-1,2,3-tricarboxylate; methyl 2-((1-hydroxy-3-phenylbutyl)amino)benzoate; 1-((2E,5Z,9Z)-2,6,10-trimethylcyclododeca-2,5,9-trien-1-yl)ethan-1-one; decahydro-2,6,6,7,8,8-hexamethyl-2h-indeno(4,5-b)furan; 13-methyl oxacyclopentadec-10-en-2-one; undecanal; (E)-4-methyldec-3-en-5-ol; (3R,4aS,5R)-4a,5-dimethyl-3-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,7-octahydronaphthalene; 2-((2R,8R,8aS)-8,8a-dimethyl-1,2,3,4,6,7,8,8a-octahydronaphthalen-2-yl)propan-2-ol; 4-formyl-2-methoxyphenyl isobutyrate; (Z)-2-methyl-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-enal; methyl 2,4-dihydroxy-3,6-dimethylbenzoate; 1-methoxy-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoindene; methyl (Z)-2-((3-(4-(tert-butyl)phenyl)-2-methylpropylidene)amino)benzoate; (Z)-hex-3-en-1-yl isobutyrate; 2,4,6-trimethyl-4-phenyl-1,3-dioxane; 1-((3R,3aR,7R,8aS)-3,6,8,8-tetramethyl-2,3,4,7,8,8a-hexahydro-1H-3a,7-methanoazulen-5-yl)ethan-1-one; methyl (Z)-2-(((2,4-dimethylcyclohex-3-en-1-yl)methylene)amino)benzoate; 4,8-dimethyl-2-(propan-2-ylidene)-1,2,3,3a,4,5,6,8a-octahydroazulen-6-ol; 4,8-dimethyl-2-(propan-2-ylidene)-1,2,3,3a,4,5,6,8a-octahydroazulen-6-yl acetate; decahydro-3H-spiro[furan-2,5′-[4,7]methanoindene]; (2Z,6E)-nona-2,6-dienenitrile; (Z)-cyclooct-4-en-1-yl methyl carbonate; (1aR,4S,4aS,7R,7aS,7bS)-1,1,4,7-tetramethyldecahydro-1H-cyclopropa[e]azulen-4-ol; 3,5,5,6,7,8,8-heptamethyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile; (1 S,2S,3S,5R)-2,6,6-trimethylspiro[bicyclo[3.1.1]heptane-3,1′-cyclohexan]-2′-en-4′-one; 1′,1′,5′,5′-tetramethylhexahydro-2′H,5′H-spiro[[1,3]dioxolane-2,8′-[2,4a]methanonaphthalene]; (2'S,4a'S,8a'S)-1′,1′,5′,5′-tetramethylhexahydro-2′H,5′H-spiro[[1,3]dioxolane-2,8′-[2,4a]methanonaphthalene]; 4-(4-hydroxy-3-methoxyphenyl)butan-2-one; (1R,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,7,8,8a-hexahydronaphthalene; 2,4-dimethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolane; 3a,5,6,7,8,8b-hexahydro-2,2,6,6,7,8,8-heptamethyl-4H-indeno(4,5-d)-1,3-dioxole; 2,4-dimethyl-4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; (1-methyl-2-((1,2,2-trimethylbicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methanol; 2-(cyclohexyloxy)-1,7,7-trimethylbicyclo[2.2.1]heptane; 4-((2R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)cyclohexan-1-ol; 8,8-di(1H-indol-1-yl)-2,6-dimethyloctan-2-ol; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methanol; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; (E)-4-((3aR,4R,7R,7aR)-1,3a,4,6,7,7a-hexahydro-5H-4,7-methanoinden-5-ylidene)-3-methylbutan-2-ol; (3R,3aR,6S,7S,8aS)-6-methoxy-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene; (1R,2S,6S,7S,8S)-8-isopropyl-1-methyl-3-methylenetricyclo[4.4.0.02,7]decane; 2′-isopropyl-1,7,7-trimethylspiro[bicyclo[2.2.1]heptane-2,4′-[1,3]dioxane]; (4aR,5R,7aS,9R)-2,2,5,8,8,9a-hexamethyloctahydro-4H-4a,9-methanoazuleno[5,6-d][1,3]dioxole; (3S,5aR,7aS,11aS,11bR)-3,8,8,11a-tetramethyldodecahydro-5H-3,5a-epoxynaphtho[2,1-c]oxepine; 2,2,6,6,7,8,8-heptamethyldecahydro-2H-indeno[4,5-b]furan; (1 aS,2aR,3R,5aS,7R,7aR)-3,6,6,7a-tetramethyloctahydro-2H-2a,7-methanoazuleno[5,6-b]oxirene; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methyl acetate; 1-(3-hydroxy-3-methylpent-4-en-1-yl)-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol; decahydro-2,6,6,7,8,8-hexamethyl-2h-indeno(4,5-b)furan; 4,5-epoxy-4,11,11-trimethyl-8-methylenebicyclo(7.2.0)undecane; 1,3,4,6,7,8alpha-hexahydro-1,1,5,5-tetramethyl-2H-2,4alpha-methanophtalen-8(5H)-one, more preferably said malodor reduction materials are selected from the group consisting of: 3-methoxy-7,7-dimethyl-10-methylenebicyclo[4.3.1]decane; 2,4a,5,8a-tetramethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl formate; 2,2,6,8-tetramethyl-1,2,3,4,4a,5,8,8a-octahydronaphthalen-1-ol; (4R,4aS,6R)-4,4a-dimethyl-6-(prop-1-en-2-yl)-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one; ((3 S,3aR,6R,8aS)-7,7-dimethyl-8-methyleneoctahydro-1H-3a,6-methanoazulen-3-yl)methanol; 4,9-dimethoxy-7H-furo[3,2-g]chromen-7-one; (E)-cyclohexadec-8-en-1-one; (Z)-1-(benzyloxy)-2-methoxy-4-(prop-1-en-1-yl)benzene; 1-((2S,3S)-2,3,8,8-tetramethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-yl)ethan-1-one; (1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate; 2,3-dihydro-3,3-dimethyl-1H-indene-5-propanal; 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)propanal; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl acetate; 2-((2R,4aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)propan-2-ol; 4,6,6,7,8,8-hexamethyl-1,3,4,6,7,8-hexahydrocyclopenta[g]isochromene; (Z)-6-ethylideneoctahydro-2H-5,8-methanochromen-2-one; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl acetate; octahydro-1H-4,7-methanoinden-5-yl acetate; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl butyrate; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl isobutyrate; (5R,6R)-3,6-dimethyl-5-(prop-1-en-2-yl)-6-vinyl-4,5,6,7-tetrahydrobenzofuran; (E)-cycloheptadec-9-en-1-one; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-3-yl formate; (3R,3 aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl acetate; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-ol; 5-methyl-1-(2,2,3-trimethylcyclopent-3-en-1-yl)-6-oxabicyclo[3.2.1]octane; (Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-3-en-5-yl acetate; (1S,2S,5R,8S)-4,4,8-trimethyltricyclo[6.3.1.02,5]dodecan-1-ol; (1S,2S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate; (Z)-2-methyl-5-((1S,2R,4R)-2-methyl-3-methylenebicyclo[2.2.1]heptan-2-yl)pent-2-en-1-ol; (1 S,4R,7R)-1,4,9,9-tetramethyl-1,2,3,4,5,6,7,8-octahydro-4,7-methanoazulene; (1 aS,5aR,9aR)-1a,5,5,7-tetramethyl-1a,2,3,4,5,5a,8,9-octahydrobenzo[1,7]cyclohepta[1,2-b]oxirene; (2,2-dimethoxyethyl)benzene; (3R,3aS,7S,8aS)-3,8,8-trimethyl-6-methyleneoctahydro-1H-3a,7-methanoazulene; 4-methoxybenzyl 2-phenylacetate; 2,2,7,7,8,9,9-heptamethyldecahydroindeno[4,3a-b]furan; (4R,4aS)-4,4a-dimethyl-6-(propan-2-ylidene)-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one; (E)-5-(2,3-dimethyltricyclo[2.2.1.02,6]heptan-3-yl)-2-methylpent-2-en-1-ol; (1R,3aS,7S,8aR)-1,4,9,9-tetramethyl-2,3,6,7,8,8a-hexahydro-1H-3a,7-methanoazulene; (1aR,4R,4aR,7bS)-1,1,4,7-tetramethyl-1a,2,3,4,4a,5,6,7b-octahydro-1H-cyclopropa[e]azulene; 2-((2R,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl)propan-2-ol; (3aR,3bR,4S,7R,7aS)-4-isopropyl-7-methyl-3a,3b,4,5,6,7-hexahydro-1H-cyclopenta[1,3]cyclopropa[1,2]benzene; (3R,5aS,9aR)-2,2,5a,9-tetramethyl-3,4,5,5a,6,7-hexahydro-2H-3,9a-methanobenzo[b]oxepine; (1aR,4aS,7R,7aR,7bS)-1,1,7-trimethyl-4-methylenedecahydro-1H-cyclopropa[e]azulene; 2-((2S,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl)propan-2-ol; 1-(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethan-1-one; (E)-cyclohexadec-5-en-1-one; (1aR,2S,4aS)-2,4a,8,8-tetramethyloctahydrocyclopropa[d]naphthalen-3(1H)-one; 2-((2R,4aS)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)propan-2-ol; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; 1-(1,1,2,3,3,6-hexamethyl-2,3-dihydro-1H-inden-5-yl)ethan-1-one; (1R,4S,4aS,6R,8aS)-4,8a,9,9-tetramethyloctahydro-1,6-methanonaphthalen-1 (2H)-ol; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl pivalate; (2R,4a′R,8a′R)-3,7′-dimethyl-3′,4′,4a′,5′,8′,8a′-hexahydro-1′H-spiro[oxirane-2,2′-[1,4]methanonaphthalene]; 2,2,7,9-tetramethylspiro(5.5)undec-8-en-1-one; (Z)-2-ethyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; (4aR,6aS,10aS,10bR)-3,4a,7,7,10a-pentamethyl-4a,5,6,6a,7,8,9,10,10a, 10b-decahydro-1H-benzo[f]chromene; (1aR,4aR,7S,7aR,7bR)-1,1,7-trimethyl-4-methylenedecahydro-1H-cyclopropa[e]azulen-7-ol; 1-(spiro[4.5]dec-7-en-7-yl)pent-4-en-1-one; (1aR,4aS)-2,4a,8,8-tetramethyl-1,1a,4,4a,5,6,7,8-octahydrocyclopropa[d]naphthalene; (1R-(1alpha,3alpha,4aalpha))-2,3,4,4a,5,6-hexahydro-2,2-dimethyl-1,3-methanonaphthalen-7(1H)-one; 2-((2R,8R,8aS)-8,8a-dimethyl-1,2,3,4,6,7,8,8a-octahydronaphthalen-2-yl)propan-2-ol; 1-((3R,3aR,7R,8aS)-3,6,8,8-tetramethyl-2,3,4,7,8,8a-hexahydro-1H-3a,7-methanoazulen-5-yl)ethan-1-one; methyl (Z)-2-(((2,4-dimethylcyclohex-3-en-1-yl)methylene)amino)benzoate; 4,8-dimethyl-2-(propan-2-ylidene)-1,2,3,3a,4,5,6,8a-octahydroazulen-6-yl acetate; decahydro-3H-spiro[furan-2,5′-[4,7]methanoindene]; (1aR,4S,4aS,7R,7aS,7bS)-1,1,4,7-tetramethyldecahydro-1H-cyclopropa[e]azulen-4-ol; 3,5,5,6,7,8,8-heptamethyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile; (1S,2S,3S,5R)-2,6,6-trimethylspiro[bicyclo[3.1.1]heptane-3,1′-cyclohexan]-2′-en-4′-one; 1′,1′,5′,5′-tetramethylhexahydro-2′H,5′H-spiro[[1,3]dioxolane-2,8′-[2,4a]methanonaphthalene]; (2'S,4a'S,8a'S)-1′,1′,5′,5′-tetramethylhexahydro-2′H,5′H-spiro[[1,3]dioxolane-2,8′-[2,4a]methanonaphthalene]; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methanol; 4,5-epoxy-4,11,11-trimethyl-8-methylenebicyclo(7.2.0)undecane; 1,3,4,6,7,8alpha-hexahydro-1,1,5,5-tetramethyl-2H-2,4alpha-methanophtalen-8(5H)-one, most preferably said malodor reduction materials are selected from the group consisting of: (E)-cyclohexadec-5-en-1-one; 2,2,7,7,8,9,9-heptamethyldecahydroindeno[4,3a-b]furan; 2,3-dihydro-3,3-dimethyl-1H-indene-5-propanal; 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)propanal; 4,5-epoxy-4,11,11-trimethyl-8-methylenebicyclo(7.2.0)undecane; 1,3,4,6,7,8alpha-hexahydro-1,1,5,5-tetramethyl-2H-2,4alpha-methanophtalen-8(5H)-one and mixtures thereof. 6. A personal care composition according to any preceeding claim, said composition comprising one or more perfume raw materials. 7. A personal care composition according to any preceeding claim wherein, said sum total of malodor reduction materials has an average Log P, based on weight percent of each malodor reduction material in said sum total of malodor reduction materials, of from about 2.5 to about 8, preferably from about 3 to about 8, more preferably from about 3.5 to about 7, most preferably, each of said malodor reduction materials in said sum total of malodor reduction materials and each of said one or more perfume raw materials has a Log P from about 3.5 to about 7. 8. A personal care composition according to any preceding claim wherein, the ratio of said one or more perfume raw materials to said sum total of malodor reduction material being from about 1000:1 to about 1:1, preferably from about 100:1 to about 1:1, more preferably from about 10:1 to about 1:1, most preferably from about 2:1 to about 1:1. 9. A personal care composition according to any preceding claim, wherein less than 10%, preferably less than 5%, more preferably less than 1% of said malodor reduction materials and said one or more perfume raw materials, based on total combined weight of malodor reduction materials and said one or more perfume raw materials comprise an ionone moiety. 10. A personal care composition according to any preceding claim, wherein said malodor reduction materials are not a material selected from the group consisting of geranyl nitrile; helional; nonanal; linalool; (S)-(+)-linalool; (R)-(−)-linalool; nerol; tetrahydrolinalool; 2-phenylethyl acetate; eugenol; ethyl linalool; allyl heptoate; agrumen nitrile; citronitrile; 2,2-dimethyl-3-(m-tolyl)propan-1-ol; 2-methyl-5-phenylpentan-1-ol; dodecanenitrile; 2-heptylcyclopentan-1-one; methyl nonyl acetaldehyde; 3-(2-ethylphenyl)-2,2-dimethylpropanal; (Z)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-en-1-one; (R,E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 4-(tert-butyl)cyclohexyl acetate; 1-cyclohexylethyl (E)-but-2-enoate; allyl 2-(cyclohexyloxy)acetate; alpha terpinyl acetate; beta terpinyl acetate; gamma terpinyl acetate; methyl dodecyl ether; 2,4-dimethyl-4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; cinnamyl isobutyrate; (E)-2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)but-2-enal; gamma methyl ionone; ethyl 2,3,6-trimethyl cyclohexyl carbonate ethyl 2,3,6-trimethyl cyclohexyl carbonate; Citral diethyl acetal; Dimethoxycyclododecane; 1-((2S,3S)-2,3,8,8-tetramethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-yl)ethan-1-one; oxacyclohexadecan-2-one; 4,6,6,7,8,8-hexamethyl-1,3,4,6,7,8-hexahydrocyclopenta[g]isochromene; Ethylene brassylate; Methyl (Z)-2-((3-(4-(tert-butyl)phenyl)-2-methylpropylidene)amino)benzoate; 4,7-Methano-1H-inden-5-ol, 3a,4,5,6,7,7a-hexahydro-, 5-acetate; cedryl methyl ether; vetivert acetate; 1-((3R,3aR,7R,8aS)-3,6,8,8-tetramethyl-2,3,4,7,8,8a-hexahydro-1H-3a,7-methanoazulen-5-yl)ethan-1-one; Benzophenone; Famesol; trans,trans-famesol; 3-(3-isopropylphenyl)butanal; 2,6,10-trimethylundec-9-enal; 3-(4-(tert-butyl)phenyl)propanal; 3-(4-isopropylphenyl)-2-methylpropanal; Citronellal (1); Citronellal (d); (E)-4,8-dimethyldeca-4,9-dienal; Pino Acetaldehyde; 3-(4-(tert-butyl)phenyl)-2-methylpropanal; Cinnamic aldehyde; Citral; Geranial; Methoxy Melonal; o-methoxycinnamaldehyde; (E)-4-((3aS,7aS)-octahydro-5H-4,7-methanoinden-5-ylidene)butanal; Methyl Octyl Acetaldehyde; 3-(4-methoxyphenyl)-2-methylpropanal; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; Iso Cyclocitral; Octanal; 2-Undecenal; 10-Undecenal; Trans-trans-2,6-Nonadienal; Trans-2,cis-6-nondienal; Heliotropin; Hexyl Cinnamic aldehyde; p-methyl-alpha-pentylcinnamaldehyde; Alpha-methyl cinnamaldehyde; 3,4-dimethoxybenzaldehyde; Myrtenal; Perillaldehyde; Maceal; Methyl palmitate; Methyl iso eugenol and mixtures thereof. 11. A personal care composition according to any preceeding claim, said composition comprising a total, based on total personal care composition weight, of from about 0.1% to about 7% of one or more of said malodor reduction materials and from about 3% to 30% of a surfactant, and, optionally, a miscellar phase and/or lamellar phase. 12. A personal care composition according to any preceeding claim said composition comprising a total, based on total personal care composition weight, of from about 0.1% to about 50% of a material selected from structurants, humectants, fatty acids, inorganic salts, antimicrobial agents, antimicrobial actives and mixtures thereof. 13. A personal care composition according to any preceding claim, said composition comprising an adjunct ingredient selected from the group consisting of clay mineral powders, pearl pigments, organic powders, emulsifiers, distributing agents, pharmaceutical active, topical active, preservatives, surfactants and mixtures thereof. 14. A method of controlling malodors comprising: contacting a situs comprising a malodor and/or a situs that will become malodorous with a personal care composition selected from the group consisting of the personal care composition of claims 1 to 13. 15. The method of claim 14 wherein, said situs is a body or head of hair and said contacting step comprises contacting said body or head of hair with a sufficient amount of Applicants' personal care composition to provide said body or hair with a level of malodor reduction material at least 0.0001 mg of malodor reduction material per body or head of hair, preferably from about 0.0001 mg of malodor reduction material per body or head of hair to about 1 mg of malodor reduction material per body or head of hair, more preferably from about 0.001 mg of malodor reduction material per body or head of hair about 0.5 mg of malodor reduction material per body or head of hair, most preferably from about 0.01 of malodor reduction material per body or head of hair to about 0.2 mg of malodor reduction material per body or head of hair.
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The present invention relates to personal care compositions comprising malodor reduction compositions and methods of making and using such personal care compositions. Such personal care compositions comprising the malodor control technologies disclosed herein provide malodor control without leaving an undesireable scent and when perfume is used to scent such compositions, such scent is not unduely altered by the malodor control technology.1. A personal care composition comprising, based on total composition weight,
a) a sum total of from about 0.0001% to about 2%, preferably from about 0.0001% to about 0.75%, more preferably from about 0.001% to about 0.5%, most preferably from about 0.007% to about 0.25% of 1 or more malodor reduction materials, preferably 1 to about 75 malodor reduction materials, more preferably 1 to about 50 malodor reduction materials, more preferably 1 to about 35 malodor reduction materials, most preferably 1 to about 20 malodor reduction materials, each of said malodor reduction materials having a MORV of at least 0.5, preferably from 0.5 to 10, more preferably from 1 to 10, most preferably from 1 to 5, and preferably each of said malodor reduction materials having a Universal MORV, or said sum total of malodor reduction materials having a Blocker Index of less than 3, more preferable less than about 2.5 even more preferably less than about 2 and still more preferably less than about 1 and most preferably 0 and/or a Blocker Index average of 3 to about 0.001; and b) from about 0% to about 12%, preferably from about 0% to about 8%, more preferably from about 0.1% to about 4%, of one or more perfume raw materials having a MORV of less than 0.5, preferably less than 0, more preferably less than −2, most preferably less than −5; c) from about 0.1% to about 99%, preferably from about 1% to about 80%, more preferably from about 5% to about 70%, most preferably from about 10% to about 50% of a solvent, preferably said solvent is selected from, water, glycerin, and mixtures thereof; d) from about 0% to about 50%, preferably from about 0% to about 40%, more preferably from about 0.1% to about 30%, most preferably from about 0.1% to about 15% of a material selected from the group consisting of a structurant, a humectant, a surfactant, an antimicrobial, and mixtures thereof. 2. A personal care composition according to claim 1, wherein said sum total of malodor reduction materials has a Blocker Index of less than 3, more preferable less than about 2.5 even more preferably less than about 2 and still more preferably less than about 1 and most preferably 0 and/or a Blocker Index average of 3 to about 0.001. 3. A personal care composition according to any preceding claim, wherein each of said malodor reduction materials has a MORV of at least 0.5, preferably from 0.5 to 10, more preferably from 1 to 10, most preferably from 1 to 5, and preferably each of said malodor reduction materials having a Universal MORV. 4. A personal care composition according to any preceding claim wherein, said sum total of malodor reduction materials has a Fragrance Fidelity Index average of 3 to about 0.001 Fragrance Fidelity Index, preferably each malodor reduction material in said sum total of malodor reduction materials has a Fragrance Fidelity Index of less than 3, preferably less than 2, more preferably less than 1 and most preferably each malodor reduction material in said sum total of malodor reduction materials has a Fragrance Fidelity Index of 0. 5. A personal care composition according to any preceding claim, wherein said malodor reduction materials are selected from the group consisting of 2-ethylhexyl (Z)-(3-(4-methoxyphenyl)acrylate; 2,4-dimethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolane; 1,1-dimethoxynon-2-yne; 2-(p-tolyl)propan-2-ol; 3-methoxy-7,7-dimethyl-10-methylenebicyclo[4.3.1]decane; methoxycyclododecane; 1,1-dimethoxycyclododecane; (Z)-tridec-2-enenitrile; (2-hydroxy-4-methoxyphenyl)(phenyl)methanone; 2,4a,5,8a-tetramethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl formate; 4-methyl-1-oxaspiro[5.5]undecan-4-ol; 7-methyl-2H-benzo[b][1,4]dioxepin-3(4H)-one; 1,8-dioxacycloheptadecan-9-one; 4-(tert-pentyl)cyclohexan-1-one; 2-methoxy-1,1′-biphenyl; 3a,5,6,7,8,8b-hexahydro-2,2,6,6,7,8,8-heptamethyl-4H-indeno(4,5-d)-1,3-dioxole; 7-isopropyl-8,8-dimethyl-6,10-dioxaspiro[4.5]decane; octyl furan-2-carboxylate; octyl acetate; 2-heptyl-4-methyl-1,3-dioxolane; octanal; 1,1-dimethoxyoctane; 7-methyl-3-methyleneocta-1,6-diene; 2-methyl-6-methyleneoct-7-en-2-ol; 2-methyl-6-methyleneoct-7-en-2-yl acetate; tetradecanal; 4-methoxy-6-prop-2-enyl-1,3-benzodioxole; tetradecanenitrile; 2,2,6,8-tetramethyl-1,2,3,4,4a,5,8,8a-octahydronaphthalen-1-ol; (E)-2,6-dimethylocta-5,7-dien-2-ol; (E)-2,7-dimethylocta-1,5,7-trien-3-ol; 2-((1S,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethyl acetate; (4R,4aS,6R)-4,4a-dimethyl-6-(prop-1-en-2-yl)-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one; nonan-1-ol; nonanal; 12-methyl-14-tetradec-9-enolide; N-ethyl-2-isopropyl-5-methylcyclohexane-1-carboxamide; 1-(3-methylbenzofuran-2-yl)ethan-1-one; 2-methoxynaphthalene; (E)-3,7,11-trimethyldodeca-1,6,10-trien-3-ol; (Z)-3,7-dimethylocta-2,6-dien-1-ol; 1-ethyl-3-methoxytricyclo[2.2.1.02,6]heptane; methyl (E)-non-2-enoate; 10-isopropyl-2,7-dimethyl-1-oxaspiro[4.5]deca-3,6-diene; 2-(2-(4-methylcyclohex-3-en-1-yl)propyl)cyclopentan-1-one; 6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-carbaldehyde; (E)-4-(2,2,3,6-tetramethylcyclohexyl)but-3-en-2-one; (4-(4-methylpent-3-en-1-yl)cyclohex-3-en-1-yl)methyl acetate; 2-(tert-butyl)-4,5,6-trimethyl-1,3-phenylene dinitrite; 1,7-dioxacycloheptadecan-8-one; 1-(4-(tert-butyl)-2,6-dimethyl-3,5-dinitrophenyl)ethan-1-one; 1-(tert-butyl)-2-methoxy-4-methyl-3,5-dinitrobenzene; 3-methylcyclopentadecan-1-one; (E)-3-methylcyclopentadec-4-en-1-one; 3-methyl-4-phenylbutan-2-ol; 1-(4-isopropylcyclohexyl)ethan-1-ol; (E)-dec-5-enoic acid; methyl non-2-ynoate; 2-methyldecanal; 6,6-dimethoxy-2,5,5-trimethylhex-2-ene; 4-phenylbutan-2-ol; methyl stearate; 1,1-dimethoxy-2-methylundecane; undecan-2-one; 2-methylundecanal; methyl tetradecanoate; methyl (9Z,12Z)-octadeca-9,12-dienoate; 1-hydroxydecan-3-one; (Z)-1,2-dimethoxy-4-(prop-1-en-1-yl)benzene; methyl palmitate; 4-allyl-1,2-dimethoxybenzene; methyl 2-((1R,2R)-3-oxo-2-((Z)-pent-2-en-1-yl)cyclopentyl)acetate; methyl 2-(3-oxo-2-pentylcyclopentyl)acetate; 1-methyl-2-phenoxybenzene; methyl cinnamate; 1-allyl-4-methoxybenzene; 1-(naphthalen-2-yl)ethan-1-one; methyl oct-2-ynoate; methyl 2,6,6-trimethylcyclohex-2-ene-1-carboxylate; 7-methoxy-3,7-dimethyloctanal; 7-isopropyl-10-methyl-1,5-dioxaspiro[5.5]undecan-3-ol; octahydro-1H-4,7-methanoindene-1-carbaldehyde; 3-(3-(tert-butyl)phenyl)-2-methylpropanal; (E)-4-(4,8-dimethylnona-3,7-dien-1-yl)pyridine; (E)-trideca-3,12-dienenitrile; 2,2-dimethyl-3-(m-tolyl)propan-1-ol; 2,4-dimethyl-4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; 8-isopropyl-6-methylbicyclo[2.2.2]oct-5-ene-2-carbaldehyde; 4-(4-hydroxy-4-methylpentyl)cyclohex-3-ene-1-carbaldehyde; (S)-1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene; (Z)-3-hexen-1-yl-2-cyclopenten-1-one; 3,7-dimethylocta-1,6-dien-3-yl octanoate; 3,7-dimethylocta-1,6-dien-3-yl isobutyrate; 3,7-dimethylocta-1,6-dien-3-yl benzoate; 3,7-dimethylocta-1,6-dien-3-yl 2-aminobenzoate; 2-(5-methyl-5-vinyltetrahydrofuran-2-yl)propan-2-ol; 6-methyl-2-(oxiran-2-yl)hept-5-en-2-ol; (2Z,6E)-3,7-dimethylnona-2,6-dienenitrile; 3-(4-methylcyclohex-3-en-1-yl)butanal; (2,5-dimethyl-1,3-dihydroinden-2-yl)methanol; 3-(4-(tert-butyl)phenyl)-2-methylpropanal; (E)-1-(1-methoxypropoxy)hex-3-ene; (E)-1-(1-ethoxyethoxy)hex-3-ene; (1S,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-ol; dodecan-1-ol; dodecyl acetate; dodecanoic acid; 5-hexyl-5-methyldihydrofuran-2(3H)-one; dodecanal; 3,6-dimethylhexahydrobenzofuran-2(3H)-one; 4-(1-ethoxyvinyl)-3,3,5,5-tetramethylcyclohexan-1-one; ((3S,3aR,6R,8aS)-7,7-dimethyl-8-methyleneoctahydro-1H-3a,6-methanoazulen-3-yl)methanol; 5-(sec-butyl)-2-(2,4-dimethylcyclohex-3-en-1-yl)-5-methyl-1,3-dioxane; (1-methyl-2-((1,2,2-trimethylbicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methanol; 2-propylheptanenitrile; (E)-6-(pent-3-en-1-yl)tetrahydro-2H-pyran-2-one; 2-hexylcyclopentan-1-one; 2-methyl-4-phenyl-1,3-dioxolane; 2,6,9,10-tetramethyl-1-oxaspiro(4.5)deca-3,6-diene; (1R,2S,5R)-5-methyl-2-(prop-1-en-2-yl)cyclohexan-1-ol; isopropyl palmitate; isopropyl tetradecanoate; isopropyl dodecanoate; 4,9-dimethoxy-7H-furo[3,2-g]chromen-7-one; (E)-cyclohexadec-8-en-1-one; (2S,5S)-2-isopropyl-5-methylcyclohexan-1-one; 2-hexylcyclopent-2-en-1-one; (2S,5 S)-2-isopropyl-5-methylcyclohexan-1-one; 4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; (Z)-1-(benzyloxy)-2-methoxy-4-(prop-1-en-1-yl)benzene; 1-((2S,3S)-2,3,8,8-tetramethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-yl)ethan-1-one; 2,5,6-trimethylcyclohex-3-ene-1-carbaldehyde; 6-(sec-butyl)quinoline; 2-(cyclohexyloxy)-1,7,7-trimethylbicyclo[2.2.1]heptane; (1R,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl propionate; (1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate; 4-((2R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)cyclohexan-1-ol; (1R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 2-(4-isopropylcyclohexa-1,4-dien-1-yl)ethyl formate; isopentyl (E)-undec-6-enoate; isopentyl dodecanoate; (E)-oxacycloheptadec-10-en-2-one; (E)-non-2-enenitrile; (E)-8-(1H-indol-1-yl)-2,6-dimethyloct-7-en-2-ol; 8,8-di(1H-indol-1-yl)-2,6-dimethyloctan-2-ol; 4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; 3,7-dimethyloctane-1,7-diol; 2-cyclododecylpropan-1-ol; 3-methyl-5-phenylpentanenitrile; 3-phenylpropan-1-ol; (1,1-dimethoxypropan-2-yl)benzene; 5-ethyl-4-hydroxy-2-methylfuran-3(2H)-one; 2,3-dihydro-3,3-dimethyl-1H-indene-5-propanal; 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)propanal; hexyl octanoate; hexyl hexanoate; (Z)-2-benzylideneoctanal; hexyl benzoate; (Z)-hex-1-en-1-yl (Z)-2-methylbut-2-enoate; (E)-3,7-dimethylocta-2,6-dien-1-yl palmitate; oxacycloheptadecan-2-one; 2-butyl-4,4,6-trimethyl-1,3-dioxane; ethyl (1R,2R,3R,4R)-3-isopropylbicyclo[2.2.1]hept-5-ene-2-carboxylate; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl acetate; 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropyl propionate; 5-(diethoxymethyl)benzo[d][1,3]dioxole; 3-(benzo[d][1,3]dioxol-5-yl)-2-methylpropanal; (E)-oxacyclohexadec-13-en-2-one; 6-butyl-2,4-dimethyl-3,6-dihydro-2H-pyran; 2-((3S,5R,8S)-3,8-dimethyl-1,2,3,4,5,6,7,8-octahydroazulen-5-yl)propan-2-ol; 1-(2,6,6-trimethylcyclohex-2-en-1-yl)pentan-3-one; ethyl 2-ethyl-6,6-dimethylcyclohex-2-ene-1-carboxylate; (1Z,5Z)-1,5-dimethyl-8-(propan-2-ylidene)cyclodeca-1,5-diene; (1E,6E)-8-isopropyl-1-methyl-5-methylenecyclodeca-1,6-diene; (E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate; (E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate; (6E,10E)-3,7,11,15-tetramethylhexadeca-1,6,10,14-tetraen-3-ol; (E)-2-(3,7-dimethylocta-2,6-dien-1-yl)cyclopentan-1-one; 5-heptyldihydrofuran-2(3H)-one; 1-methyl-4-(propan-2-ylidene)cyclohexyl acetate; 1-methyl-4-(propan-2-ylidene)cyclohexan-1-ol; 5-pentyldihydrofuran-2(3H)-one; (1R,4aR,8aS)-1-isopropyl-7-methyl-4-methylene-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 5-[(Z)-hex-3-enyl]oxolan-2-one; (Z)-4-(2,2-dimethyl-6-methylenecyclohexyl)but-3-en-2-one; (4aS,9aR)-3,5,5,9-tetramethyl-2,4a,5,6,7,9a-hexahydro-1H-benzo[7]annulene; (1R,3aR,4R,7R)-1,4-dimethyl-7-(prop-1-en-2-yl)-1,2,3,3a,4,5,6,7-octahydroazulene; 2-((2R,4aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)propan-2-ol; 5-octyldihydrofuran-2(3H)-one; (Z)-1-(2,2-dimethyl-6-methylenecyclohexyl)but-2-en-1-one; 5-hexyldihydrofuran-2(3H)-one; (1R,4aS,8aS)-1-isopropyl-7-methyl-4-methylene-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 1-(3,3-dimethylcyclohexyl)pent-4-en-1-one; 4,6,6,7,8,8-hexamethyl-1,3,4,6,7,8-hexahydrocyclopenta[g]isochromene; furan-2-ylmethyl octanoate; furan-2-ylmethyl hexanoate; furan-2-ylmethyl heptanoate; 2-methyldecanenitrile; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; ethyl (3aR,4S,7R,7aR)-octahydro-3aH-4,7-methanoindene-3a-carboxylate; diethyl cyclohexane-1,4-dicarboxylate; (6-isopropyl-9-methyl-1,4-dioxaspiro[4.5]decan-2-yl)methanol; 2-isobutyl-4-methyltetrahydro-2H-pyran-4-ol; undec-10-enenitrile; (Z)-6-ethylideneoctahydro-2H-5,8-methanochromen-2-one; 3-(2-ethylphenyl)-2,2-dimethylpropanal; (E)-4,8-dimethyldeca-4,9-dienal; (E)-4-((3aR,4R,7R,7aR)-1,3a,4,6,7,7a-hexahydro-5H-4,7-methanoinden-5-ylidene)-3-methylbutan-2-ol; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl acetate; 3-(4-ethylphenyl)-2,2-dimethylpropanenitrile; 2-heptylcyclopentan-1-one; 1-ethoxyethoxy Cyclododecane; 3-cyclohexene-1-carboxylic acid, 2,6,6-trimethyl-, methyl ester; (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl acetate; (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol; oxacyclohexadecan-2-one; (E)-cyclopentadec-4-en-1-one; 1-cyclopentadec-4-en-1-one; 2-methoxy-4-(4-methylenetetrahydro-2H-pyran-2-yl)phenol; 4-allyl-2-methoxyphenyl acetate; 4-allyl-2-methoxyphenol; ethyl 3-methyl-3-phenyloxirane-2-carboxylate; 1,4-dioxacycloheptadecane-5,17-dione; ethyl undec-10-enoate; ethyl palmitate; ethyl nonanoate; ethyl tetradecanoate; (E)-3,7-dimethylnona-1,6-dien-3-ol; ethyl dodecanoate; nonan-3-one; ethyl decanoate; ethyl 6,6-dimethyl-2-methylenecyclohex-3-ene-1-carboxylate; ethyl 3-phenyloxirane-2-carboxylate; 6-ethyl-2,10,10-trimethyl-1-oxaspiro[4.5]deca-3,6-diene; 2-((1R,3S,4S)-4-methyl-3-(prop-1-en-2-yl)-4-vinylcyclohexyl)propan-2-ol; (2-(1-ethoxyethoxy)ethyl)benzene; (E)-3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pent-4-en-2-ol; (2R,3S,4R)-2,3,4,5-tetrahydroxypentanal; (E)-4-((3aS,7aS)-octahydro-5H-4,7-methanoinden-5-ylidene)butanal; 1,1-dimethoxydodecane; (R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene; 2-(2-hydroxypropoxy)propan-1-ol; 7,9-dimethylspiro[5.5]undecan-3-one; oxydibenzene; diphenylmethane; 2-methyl-1-phenylpropan-2-yl butyrate; 2,6-dimethyloct-7-en-4-one; octahydro-1H-4,7-methanoinden-5-yl acetate; 2-methyl-5-(prop-1-en-2-yl)cyclohexyl acetate; 2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-ol; 3,7-dimethyloct-6-en-3-ol; methyl 2-hexyl-3-oxocyclopentane-1-carboxylate; dibutylsulfane; 1,2-diphenylethane; 6-hexyltetrahydro-2H-pyran-2-one; (3R,4R)-1-isopropyl-4-methyl-3-(prop-1-en-2-yl)-4-vinylcyclohex-1-ene; (3S,3aS,5R)-3,8-dimethyl-5-(prop-1-en-2-yl)-1,2,3,3a,4,5,6,7-octahydroazulene; 6-heptyltetrahydro-2H-pyran-2-one; 6-pentyltetrahydro-2H-pyran-2-one; (1S,8aR)-4,7-dimethyl-1-(propan-2-yl)-1,2,3,5,6,8a-hexahydronaphthalene; (Z)-1-((1R,2S)-2,6,6-trimethylcyclohex-3-en-1-yl)but-2-en-1-one; (1S,8aS)-1-isopropyl-4,7-dimethyl-1,2,3,5,6,8a-hexahydronaphthalene; 3,7,7-trimethylbicyclo[4.1.0]hept-3-ene; dec-9-en-1-ol; decyl propionate; 1,1-diethoxydecane; decahydronaphthalen-2-ol; 1-cyclohexylethyl (E)-but-2-enoate; 3-(4-isopropylphenyl)-2-methylpropanal; cyclotetradecane; cyclopentadecanone; cyclohexyl 2-hydroxybenzoate; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl butyrate; 1,4-dioxacyclohexadecane-5,16-dione; 8,8-dimethyl-1,2,3,4,5,6,7,8-octahydronaphthalene-2-carbaldehyde; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl isobutyrate; (5R,6R)-3,6-dimethyl-5-(prop-1-en-2-yl)-6-vinyl-4,5,6,7-tetrahydrobenzofuran; (4-isopropylphenyl)methanol; 1-(benzofuran-2-yl)ethan-1-one; 2-(3-phenylpropyl)pyridine; dodecanenitrile; (E)-cycloheptadec-9-en-1-one; 3-(4-methylcyclohex-3-en-1-yl)but-3-en-1-yl acetate; 3-(4-methylcyclohex-3-en-1-yl)butan-1-ol; (E)-3-methyl-5-phenylpent-2-enenitrile; (E)-2-(2,6-dimethylhepta-1,5-dien-1-yl)-4-methyl-1,3-dioxolane; (E)-1,1-dimethoxy-3,7-dimethylocta-2,6-diene; (E)-1,1-diethoxy-3,7-dimethylocta-2,6-diene; (E)-3,7-dimethylocta-1,3,6-triene; (1R,4R,6S)-1-methyl-4-(prop-1-en-2-yl)-7-oxabicyclo[4.1.0]heptane; (E)-oxacycloheptadec-11-en-2-one; (Z)-non-6-en-1-ol; (1R,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-ol; (Z)-dec-4-enal; (E)-hex-3-en-1-yl (E)-hex-3-enoate; (Z)-hex-3-en-1-yl 2-hydroxybenzoate; (Z)-hex-3-en-1-yl benzoate; (Z)-hex-3-en-1-yl 2-methylbutanoate; (3Z,6Z)-nona-3,6-dien-1-ol; cinnamyl propionate; cinnamyl isobutyrate; cinnamyl formate; cinnamyl cinnamate; cinnamyl acetate; (E)-3-phenylprop-2-en-1-ol; hexadecan-1-ol; (E)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)hepta-1,6-dien-3-one; 2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butanal; (3aR,5aR,9aR,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; 1,6-dioxacycloheptadecan-7-one; 1-(6-(tert-butyl)-1,1-dimethyl-2,3-dihydro-1H-inden-4-yl)ethan-1-one; (3R,3aR,6S,7S,8aS)-6-methoxy-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-3-yl formate; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl acetate; (4Z,8Z)-1,5,9-trimethyl-13-oxabicyclo[10.1.0]trideca-4,8-diene; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-ol; 5-methyl-1-(2,2,3-trimethylcyclopent-3-en-1-yl)-6-oxabicyclo[3.2.1]octane; 5-methyl-1-(2,2,3-trimethylcyclopent-3-en-1-yl)-6-oxabicyclo[3.2.1]octane; 1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-4H-inden-4-one; (Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-3-en-5-yl acetate; (1S,2S,5R,8S)-4,4,8-trimethyltricyclo[6.3.1.02,5]dodecan-1-ol; 2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-yl acetate; octanenitrile; octan-1-ol; octanoic acid; decanoic acid; decanal; 3-(4-methoxyphenyl)-2-methylpropanal; 1,7,7-trimethylbicyclo[2.2.1]heptane-2,3-dione; 2,2-dimethyl-3-methylenebicyclo[2.2.1]heptane; ethyl 2-methyl-4-oxo-6-pentylcyclohex-2-ene-1-carboxylate; 2,6-di-tert-butyl-4-methylphenol; butyl stearate; 1-butoxy-1-oxopropan-2-yl butyrate; butyl undec-10-enoate; 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)butan-1-ol; 3-(4-(tert-butyl)phenyl)propanal; (1S,2S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate; 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 2-ethoxy-2,6,6-trimethyl-9-methylenebicyclo[3.3.1]nonane; (ethoxymethoxy)cyclododecane; (E)-1-methyl-4-(6-methylhept-5-en-2-ylidene)cyclohex-1-ene; 3,3,6,7-tetramethyloctahydro-2H-chromene; (5R,10R)-6,10-dimethyl-2-(propan-2-ylidene)spiro[4.5]dec-6-en-8-one; 1-methyl-4-(prop-1-en-2-yl)cyclohexyl acetate; 1-methyl-4-(prop-1-en-2-yl)cyclohexan-1-ol; (2Z,6E)-2,6-dimethyl-10-methylenedodeca-2,6,11-trienal; (R)-3-methylene-6-((S)-6-methylhept-5-en-2-yl)cyclohex-1-ene; (4aR,7R,8aS)-4a-methyl-1-methylene-7-(prop-1-en-2-yl)decahydronaphthalene; (Z)-2-methyl-5-((1S,2R,4R)-2-methyl-3-methylenebicyclo[2.2.1]heptan-2-yl)pent-2-en-1-ol; 6,6-dimethyl-2-methylenebicyclo[3.1.1]heptane; 2-ethoxynaphthalene; (1S,4R,7R)-1,4,9,9-tetramethyl-1,2,3,4,5,6,7,8-octahydro-4,7-methanoazulene; (1 aS,5aR,9aR)-1a,5,5,7-tetramethyl-1a,2,3,4,5,5a,8,9-octahydrobenzo[1,7]cyclohepta[1,2-b]oxirene; (R)-3,5,5,9-tetramethyl-2,4a,5,6,7,8-hexahydro-1H-benzo[7]annulene; (1S,4S)-1,4-dimethyl-7-(propan-2-ylidene)-1,2,3,4,5,6,7,8-octahydroazulene; (2,2-dimethoxyethyl)benzene; (E)-7,11-dimethyl-3-methylenedodeca-1,6,10-triene; (1R,2S,6S,7S,8S)-8-isopropyl-1-methyl-3-methylenetricyclo[4.4.0.02,7]decane; (3R,3aS,7S,8aS)-3,8,8-trimethyl-6-methyleneoctahydro-1H-3a,7-methanoazulene; (1R,9S,Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-4-ene; (S)-4-methyl-1-((S)-6-methylhept-5-en-2-yl)cyclohex-3-en-1-ol; (Z)-4-(2,2,6-trimethyl-7-oxabicyclo[4.1.0]heptan-1-yl)but-3-en-2-one; 4-methoxy-7H-furo[3,2-g]chromen-7-one; 2-methyl-4-phenylbutan-2-ol; benzyl dodecanoate; 2-methyl-1-phenylpropan-2-ol; benzyl cinnamate; benzyl benzoate; benzophenone; 7-isopentyl-2H-benzo[b][1,4]dioxepin-3(4H)-one; 2′-isopropyl-1,7,7-trimethylspiro[bicyclo[2.2.1]heptane-2,4′-[1,3]dioxane]/A; 4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbonitrile; methyl (E)-2-((7-hydroxy-3,7-dimethyloctylidene)amino)benzoate; 4-methoxybenzyl 2-phenylacetate; methyl (E)-octa-4,7-dienoate; pentyl (Z)-3-phenylacrylate; (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; (4aR,5R,7aS,9R)-2,2,5,8,8,9a-hexamethyloctahydro-4H-4a,9-methanoazuleno[5,6-d][1,3]dioxole; 2,5,5-trimethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-ol; 2,5,5-trimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-ol; 1-((2-(tert-butyl)cyclohexyl)oxy)butan-2-ol; (3S,5aR,7aS,11aS,11bR)-3,8,8,11a-tetramethyldodecahydro-5H-3,5a-epoxynaphtho[2,1-c]oxepine; 2,2,6,6,7,8,8-heptamethyldecahydro-2H-indeno[4,5-b]furan; 2,2,7,7,8,9,9-heptamethyldecahydroindeno[4,3a-b]furan; 2-(sec-butyl)-1-vinylcyclohexyl acetate; (1S,4R,5R)-1-isopropyl-4-methylbicyclo[3.1.0]hexan-3-one; (4R,4aS)-4,4a-dimethyl-6-(propan-2-ylidene)-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one; 2-(4-methylcyclohex-3-en-1-yl)propan-2-yl propionate; (2Z,6E,9E)-2,6,10-trimethyldodeca-2,6,9,11-tetraenal; (2R,4aR,8aR)-4a,8-dimethyl-2-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 1,7-dimethyl-7-(4-methylpent-3-en-1-yl)tricyclo[2.2.1.02,6]heptane; (E)-5-(2,3-dimethyltricyclo[2.2.1.02,6]heptan-3-yl)-2-methylpent-2-en-1-ol; (1R,3aS,7S,8aR)-1,4,9,9-tetramethyl-2,3,6,7,8,8a-hexahydro-1H-3a,7-methanoazulene; 1-(5,5-dimethylcyclohex-1-en-1-yl)pent-4-en-1-one; (1S,4aS,8aR)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (R,Z)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)pent-1-en-3-one; 1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene; (Z)-4-(2,5,6,6-tetramethylcyclohex-2-en-1-yl)but-3-en-2-one; (1Z,4E,8Z)-2,6,6,9-tetramethylcycloundeca-1,4,8-triene; (4aR,8S,9aS)-3,5,5,8-tetramethyl-9-methylene-2,4a,5,6,7,8,9,9a-octahydro-1H-benzo[7]annulene; (1aR,4R,4aR,7bS)-1,1,4,7-tetramethyl-1a,2,3,4,4a,5,6,7b-octahydro-1H-cyclopropa[e]azulene; 1,4-dimethyl-7-(prop-1-en-2-yl)-1,2,3,4,5,6,7,8-octahydroazulene; (3E,6E)-3,7,11-trimethyldodeca-1,3,6,10-tetraene; 7,7-dimethyl-2-methylenebicyclo[2.2.1]heptane; 2-((2R,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl)propan-2-ol; (R)-1-methyl-4-(6-methylhept-5-en-2-yl)benzene; (3aR,3bR,4S,7R,7aS)-4-isopropyl-7-methyl-3a,3b,4,5,6,7-hexahydro-1H-cyclopenta[1,3]cyclopropa[1,2]benzene; (1aS,2aR,3R,5aS,7R,7aR)-3,6,6,7a-tetramethyloctahydro-2H-2a,7-methanoazuleno[5,6-b]oxirene; (1R,4S,4aR,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; (1S,4aR,8aR)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (R)-2-((R)-4-methylcyclohex-3-en-1-yl)hex-5-en-2-ol; (Z)-1-methyl-4-(6-methylhepta-2,5-dien-2-yl)cyclohex-1-ene; 2,6-dimethyl-6-(4-methylpent-3-en-1-yl)bicyclo[3.1.1]hept-2-ene; (E)-2-benzylideneheptan-1-ol; (E)-2-benzylideneheptyl acetate; (Z)-(2-(diethoxymethyl)hept-1-en-1-yl)benzene; (E)-2-benzylideneheptanal; (1S,4aR,8aS)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (3R,5aS,9aR)-2,2,5a,9-tetramethyl-3,4,5,5a,6,7-hexahydro-2H-3,9a-methanobenzo[b]oxepine; 1-methyl-4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; 1-phenylpentan-2-ol; 3-methyl-1-phenylpentan-3-ol; 2,3,4-trimethoxybenzaldehyde; 2,4,5-trimethoxybenzaldehyde; 2,4,6-trimethoxybenzaldehyde; Trans,Trans-2,4-Nonadienal; 2,6,10-trimethylundecanal; alpha-4-Dimethyl benzenepropanal; allyl 3-cyclohexylpropanoate; allyl 2-(isopentyloxy)acetate; (1aR,4aS,7R,7aR,7bS)-1,1,7-trimethyl-4-methylenedecahydro-1H-cyclopropa[e]azulene; (E)-undec-9-enal; methyl (E)-2-(((3,5-dimethylcyclohex-3-en-1-yl)methylene)amino)benzoate; 2,6,10-trimethylundec-9-enal; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methyl acetate; nonyl acetate; (2-(1-propoxyethoxy)ethyl)benzene; 1-(1-propoxyethoxy)propane; ((1-(2-methoxyethoxy)ethoxy)methyl)benzene; (Z)-2-(4-methylbenzylidene)heptanal; dec-9-enal; (Z)-oxacycloheptadec-8-en-2-one; 7-methoxy-2H-chromen-2-one; (2S,4aR,8aR)-4a,8-dimethyl-2-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 2-((2S,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl)propan-2-ol; 1-(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethan-1-one; 6-isopropylquinoline; 3-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)propanal; 6,10,14-trimethylpentadecan-2-one; 2-methyl-5-(prop-1-en-2-yl)-2-vinyltetrahydrofuran; (E)-cyclohexadec-5-en-1-one; 1-isopropyl-4-methylcyclohex-3-en-1-ol; 1-phenylpent-4-en-1-one; 1-isopropyl-4-methylcyclohex-3-en-1-ol; 3,6-dimethyl-4,5,6,7-tetrahydrobenzofuran; 4-(4-methoxyphenyl)butan-2-one; (1aR,2S,4aS)-2,4a,8,8-tetramethyloctahydrocyclopropa[d]naphthalen-3(1H)-one; (E)-3-propylideneisobenzofuran-1(3H)-one; (Z)-dodec-2-enal; 3-methyl-5-phenylpentanal; (E)-hex-3-en-1-yl 3-methylbutanoate; 3,6-dimethyloctan-3-yl acetate; 3,4,5-trimethoxybenzaldehyde; 3-(4-isopropylphenyl)propanal; (Z)-undec-2-enenitrile; (E)-undec-2-enal; (2E,6E)-nona-2,6-dienal; phenethyl butyrate; (Z)-3-(furan-2-yl)-2-phenylacrylaldehyde; 2-phenoxyethan-1-ol; (Z)-non-2-enal; nonan-2-ol; nonan-2-one; 2-isobutylquinoline; (E)-2-hexylidenecyclopentan-1-one; 2-heptyltetrahydrofuran; (E)-dec-2-enal; (2E,6E)-nona-2,6-dienal; (2E,6E)-nona-2,6-dien-1-ol; 2,6-dimethyloctanal; decan-1-ol; (E)-hept-1-en-1-yl acetate; undec-10-en-1-ol; undec-10-enal; 2-((2R,4aS)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)propan-2-ol; 1-isopropyl-4-methyl-7-thiabicyclo[2.2.1]heptane; (3E,5Z)-undeca-1,3,5-triene; 3,7-dimethyloct-6-en-3-ol; 1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 1,1,2,3,3-pentamethyl-2,3-dihydro-1H-indene; (Z)-6,10-dimethylundeca-5,9-dien-2-yl acetate; (Z)-dodec-3-enal; (S)-5-heptyldihydrofuran-2(3H)-one; (R)-5-heptyldihydrofuran-2(3H)-one; (E)-6,10-dimethylundeca-5,9-dien-2-yl acetate; (Z)-3-methyl-5-phenylpent-2-enenitrile; (2S,5S,6S)-2,6,10,10-tetramethyl-1-oxaspiro[4.5]decan-6-ol; (2E)-3-methyl-5-phenyl-2-pentenenitrile; (1 S,2S,5S)-2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-ol; (2S,5R)-2-isopropyl-5-methylcyclohexan-1-one; (R,E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 2-(8-isopropyl-6-methylbicyclo[2.2.2]oct-5-en-2-yl)-1,3-dioxolane; (E)-4-(2,2-dimethyl-6-methylenecyclohexyl)-3-methylbut-3-en-2-one; 3-(3-isopropylphenyl)butanal; 3-(1-ethoxyethoxy)-3,7-dimethylocta-1,6-diene; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; 2-((3S,3aS,5R)-3,8-dimethyl-1,2,3,3a,4,5,6,7-octahydroazulen-5-yl)propan-2-ol; benzyl 2-phenylacetate; 2-hydroxy-1,2-diphenylethan-1-one; (E)-1,2,4-trimethoxy-5-(prop-1-en-1-yl)benzene; 3-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-2,2-dimethylpropanal; 2-methyl-5-(6-methylhept-5-en-2-yl)bicyclo[3.1.0]hex-2-ene; 1-(1,1,2,3,3,6-hexamethyl-2,3-dihydro-1H-inden-5-yl)ethan-1-one; 2-(m-tolyl)ethan-1-ol; (3E,6E)-nona-3,6-dien-1-ol; (E)-tridec-2-enal; (1R,4S,4aS,6R,8aS)-4,8a,9,9-tetramethyloctahydro-1,6-methanonaphthalen-1(2H)-ol; p-tolyl isobutyrate; p-tolyl hexanoate; 5-hexyl-4-methyldihydrofuran-2(3H)-one; ethyl (2Z,4E)-deca-2,4-dienoate; 2,4-dimethyl-6-phenyl-3,6-dihydro-2H-pyran; 2-cyclohexylidene-2-phenylacetonitrile; 4-(prop-1-en-2-yl)cyclohex-1-ene-1-carbaldehyde; (4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methyl acetate; (4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methanol; (2-isopropoxyethyl)benzene; 2-cyclohexylhepta-1,6-dien-3-one; (2-(cyclohexyloxy)ethyl)benzene; phenethyl 2-methylbutanoate; 2-phenylethan-1-ol; phenethyl 2-phenylacetate; 3-methyl-5-phenylpentan-1-ol; phenyl benzoate; phenethyl benzoate; 2-benzyl-1,3-dioxolane; 2-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)acetaldehyde; 6,6-dimethyl-2-methylenebicyclo[3.1.1]heptan-3-ol; 4-(benzo[d][1,3]dioxol-5-yl)butan-2-one; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl pivalate; (4aR,8aS)-7-methyloctahydro-1,4-methanonaphthalen-6(2H)-one; 4-isopropyl-1-methylcyclohex-3-en-1-ol; (E)-3,3-dimethyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pent-4-en-2-ol; 1-methyl-4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; propane-1,2-diol; p-tolyl 2-phenylacetate; Ethyl 2,4,7-decatrienoate; 2-benzyl-4,4,6-trimethyl-1,3-dioxane; 2,4-dimethyl-4-phenyltetrahydrofuran; (2R,4a′R,8a′R)-3,7′-dimethyl-3′,4′,4a′,5′,8′,8a′-hexahydro-1′H-spiro[oxirane-2,2′-[1,4]methanonaphthalene]; (Z)-6-ethylideneoctahydro-2H-5,8-methanochromene; 2-((S)-1-((S)-3,3-dimethylcyclohexyl)ethoxy)-2-oxoethyl propionate; methyl 2,2-dimethyl-6-methylenecyclohexane-1-carboxylate; 2-methyl-5-phenylpentan-1-ol; 4-methyl-2-phenyl-3,6-dihydro-2H-pyran; (1S,3R,5S)-1-isopropyl-4-methylenebicyclo[3.1.0]hexan-3-ol; 5-allylbenzo[d][1,3]dioxole; 2,2,7,9-tetramethylspiro(5.5)undec-8-en-1-one; 3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pentan-2-ol; (Z)-2-ethyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; (E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; 1-(3-hydroxy-3-methylpent-4-en-1-yl)-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol; (4aR,6aS,10aS,10bR)-3,4a,7,7,10a-pentamethyl-4a,5,6,6a,7,8,9,10,10a, 10b-decahydro-1H-benzo[f]chromene; (4aR,8aR)-4a,8-dimethyl-2-(propan-2-ylidene)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropyl cyclopropanecarboxylate; 3-(4-isobutylphenyl)-2-methylpropanal; (1aR,4aR,7S,7aR,7bR)-1,1,7-trimethyl-4-methylenedecahydro-1H-cyclopropa[e]azulen-7-ol; (1R,3R,6R)-2′,2′,3,7,7-pentamethylspiro[bicyclo[4.1.0]heptane-2,5′-[1,3]dioxane]; 2-methyl-1,5-dioxaspiro[5.5]undecane; 1-(spiro[4.5]dec-7-en-7-yl)pent-4-en-1-one; 2-(4-methylthiazol-5-yl)ethan-1-ol; 2-(heptan-3-yl)-1,3-dioxolane; (Z)-dodec-4-enal; (1 S,4S,4aR,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; (1S,4S,4aR,8aS)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; 3-methyl-2-pentylcyclopentan-1-one; 2,6,10,10-tetramethyl-1-oxaspiro[4.5]dec-6-ene; 2-(2-mercaptopropan-2-yl)-5-methylcyclohexan-1-one; (1aR,4aS)-2,4a,8,8-tetramethyl-1,1a,4,4a,5,6,7,8-octahydrocyclopropa[d]naphthalene; 1-isopropyl-2-methoxy-4-methylbenzene; 1-(2,2,6-trimethylcyclohexyl)hexan-3-ol; (2Z,4E)-nona-2,4-dienal; (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol; (2E,6Z)-nona-2,6-dienal; (Z)-dec-2-enal; (E)-non-2-enal; (3E,6Z)-nona-3,6-dien-1-ol; (E)-dec-4-enal; (Z)-oxacycloheptadec-8-en-2-one; (Z)-3,7-dimethylocta-1,3,6-triene; (Z)-3,7-dimethylocta-1,3,6-triene; (E)-3,7-dimethylocta-2,6-dien-1-ol; methyl 2-((1S,2S)-3-oxo-2-pentylcyclopentyl)acetate; 7-(1,1-Dimethylethyl)-2H-1,5-benzodioxepin-3 (4H)-one; (1R-(1alpha,3alpha,4aalpha))-2,3,4,4a,5,6-hexahydro-2,2-dimethyl-1,3-methanonaphthalen-7(1H)-one; tridecan-1-ol; triethyl 2-hydroxypropane-1,2,3-tricarboxylate; methyl 2-((1-hydroxy-3-phenylbutyl)amino)benzoate; 1-((2E,5Z,9Z)-2,6,10-trimethylcyclododeca-2,5,9-trien-1-yl)ethan-1-one; decahydro-2,6,6,7,8,8-hexamethyl-2h-indeno(4,5-b)furan; 13-methyl oxacyclopentadec-10-en-2-one; undecanal; (E)-4-methyldec-3-en-5-ol; (3R,4aS,5R)-4a,5-dimethyl-3-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,7-octahydronaphthalene; 2-((2R,8R,8aS)-8,8a-dimethyl-1,2,3,4,6,7,8,8a-octahydronaphthalen-2-yl)propan-2-ol; 4-formyl-2-methoxyphenyl isobutyrate; (Z)-2-methyl-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-enal; methyl 2,4-dihydroxy-3,6-dimethylbenzoate; 1-methoxy-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoindene; methyl (Z)-2-((3-(4-(tert-butyl)phenyl)-2-methylpropylidene)amino)benzoate; (Z)-hex-3-en-1-yl isobutyrate; 2,4,6-trimethyl-4-phenyl-1,3-dioxane; 1-((3R,3aR,7R,8aS)-3,6,8,8-tetramethyl-2,3,4,7,8,8a-hexahydro-1H-3a,7-methanoazulen-5-yl)ethan-1-one; methyl (Z)-2-(((2,4-dimethylcyclohex-3-en-1-yl)methylene)amino)benzoate; 4,8-dimethyl-2-(propan-2-ylidene)-1,2,3,3a,4,5,6,8a-octahydroazulen-6-ol; 4,8-dimethyl-2-(propan-2-ylidene)-1,2,3,3a,4,5,6,8a-octahydroazulen-6-yl acetate; decahydro-3H-spiro[furan-2,5′-[4,7]methanoindene]; (2Z,6E)-nona-2,6-dienenitrile; (Z)-cyclooct-4-en-1-yl methyl carbonate; (1aR,4S,4aS,7R,7aS,7bS)-1,1,4,7-tetramethyldecahydro-1H-cyclopropa[e]azulen-4-ol; 3,5,5,6,7,8,8-heptamethyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile; (1S,2S,3S,5R)-2,6,6-trimethylspiro[bicyclo[3.1.1]heptane-3,1′-cyclohexan]-2′-en-4′-one; 1′,1′,5′,5′-tetramethylhexahydro-2′H,5′H-spiro[[1,3]dioxolane-2,8′-[2,4a]methanonaphthalene]; (2'S,4a'S,8a'S)-1′,1′,5′,5′-tetramethylhexahydro-2′H,5′H-spiro[[1,3]dioxolane-2,8′-[2,4a]methanonaphthalene]; 4-(4-hydroxy-3-methoxyphenyl)butan-2-one; (1R,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,7,8,8a-hexahydronaphthalene; 2,4-dimethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolane; 3a,5,6,7,8,8b-hexahydro-2,2,6,6,7,8,8-heptamethyl-4H-indeno(4,5-d)-1,3-dioxole; 2,4-dimethyl-4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; (1-methyl-2-((1,2,2-trimethylbicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methanol; 2-(cyclohexyloxy)-1,7,7-trimethylbicyclo[2.2.1]heptane; 4-((2R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)cyclohexan-1-ol; 8,8-di(1H-indol-1-yl)-2,6-dimethyloctan-2-ol; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methanol; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; (E)-4-((3aR,4R,7R,7aR)-1,3a,4,6,7,7a-hexahydro-5H-4,7-methanoinden-5-ylidene)-3-methylbutan-2-ol; (3R,3aR,6S,7S,8aS)-6-methoxy-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene; (1R,2S,6S,7S,8S)-8-isopropyl-1-methyl-3-methylenetricyclo[4.4.0.02,7]decane; 2′-isopropyl-1,7,7-trimethylspiro[bicyclo[2.2.1]heptane-2,4′-[1,3]dioxane]; (4aR,5R,7aS,9R)-2,2,5,8,8,9a-hexamethyloctahydro-4H-4a,9-methanoazuleno[5,6-d][1,3]dioxole; (3S,5aR,7aS,11aS,11bR)-3,8,8,11a-tetramethyldodecahydro-5H-3,5a-epoxynaphtho[2,1-c]oxepine; 2,2,6,6,7,8,8-heptamethyldecahydro-2H-indeno[4,5-b]furan; (1 aS,2aR,3R,5aS,7R,7aR)-3,6,6,7a-tetramethyloctahydro-2H-2a,7-methanoazuleno[5,6-b]oxirene; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methyl acetate; 1-(3-hydroxy-3-methylpent-4-en-1-yl)-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol; decahydro-2,6,6,7,8,8-hexamethyl-2h-indeno(4,5-b)furan; 2-ethylhexyl (Z)-3-(4-methoxyphenyl)acrylate; methoxycyclododecane; 1-ethoxy-4-(tert-pentyl)cyclohexane; (2-hydroxy-4-methoxyphenyl)(phenyl)methanone; (3Z)-1-(2-buten-1-yloxy)-3-hexene; 4-(2-methoxypropan-2-yl)-1-methylcyclohex-1-ene; 4-(tert-pentyl)cyclohexan-1-one; 3-methoxy-3,7-dimethylocta-1,6-diene; 7-isopropyl-8,8-dimethyl-6,10-dioxaspiro[4.5]decane; (E)-3-(2-methoxyphenyl)acrylaldehyde; 3,7-dimethyloctanal; 1,1-dimethoxyoctane; 2-methyl-6-methyleneoct-7-en-2-ol; 4-methoxy-6-prop-2-enyl-1,3-benzodioxole; tetradecanenitrile; (E)-2,7-dimethylocta-1,5,7-trien-3-ol; 3,3-Dimethyl-5(2,2,3-Trimethyl-3-Cyclopenten-1yl)-4-Penten-2-ol; hexyl 2-hydroxybenzoate; hexyl (Z)-but-2-enoate; (Z)-3,7-dimethylocta-2,6-dien-1-yl formate; (Z)-3,7-dimethylocta-2,6-dien-1-ol; 1-ethyl-3-methoxytricyclo[2.2.1.02,6]heptane; 10-isopropyl-2,7-dimethyl-1-oxaspiro[4.5]deca-3,6-diene; 6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-carbaldehyde; (E)-4-(2,2,3,6-tetramethylcyclohexyl)but-3-en-2-one; (Z)-1-(2,6,6-trimethylcyclohex-1-en-1-yl)pent-1-en-3-one; (E)-2,2-dimethyl-3-(3-methylpenta-2,4-dien-1-yl)oxirane; 3-methylcyclopentadecan-1-one; (E)-3,7-dimethylocta-4,6-dien-3-ol; 3-methyl-4-phenylbutan-2-ol; 1-(4-isopropylcyclohexyl)ethan-1-ol; (Z)-hex-3-en-1-yl cyclopropanecarboxylate; (E)-dec-5-enoic acid; 1-phenylethyl propionate; methyl 2-phenylacetate; 4-phenylbutan-2-ol; methyl stearate; methyl (9Z,12Z)-octadeca-9,12-dienoate; 1-hydroxydecan-3-one; 2-methyl-6-oxaspiro[4.5]decan-7-one; (Z)-1,2-dimethoxy-4-(prop-1-en-1-yl)benzene; methyl palmitate; 4-allyl-1,2-dimethoxybenzene; methyl (Z)-3,7-dimethylocta-2,6-dienoate; 1-methyl-2-phenoxybenzene; 2-ethoxy-4-(methoxymethyl)phenol; methyl 2-cyclopentylideneacetate; 1-allyl-4-methoxybenzene; 6-methoxy-2,6-dimethylheptanal; 7-methoxy-3,7-dimethyloctanal; ((1s,4s)-4-isopropylcyclohexyl)methanol; 3-(3-(tert-butyl)phenyl)-2-methylpropanal; (E)-4-(4,8-dimethylnona-3,7-dien-1-yl)pyridine; (E)-trideca-3,12-dienenitrile; 2,2-dimethyl-3-(m-tolyl)propan-1-ol; 8-isopropyl-6-methylbicyclo[2.2.2]oct-5-ene-2-carbaldehyde; 4-(4-hydroxy-4-methylpentyl)cyclohex-3-ene-1-carbaldehyde; (Z)-3-hexen-1-yl-2-cyclopenten-1-one; 3,7-dimethylocta-1,6-dien-3-yl propionate; 3,7-dimethylocta-1,6-dien-3-yl octanoate; 3,7-dimethylocta-1,6-dien-3-yl formate; 3,7-dimethylocta-1,6-dien-3-yl butyrate; 3,7-dimethylocta-1,6-dien-3-yl benzoate; 3,7-dimethylocta-1,6-dien-3-yl 2-aminobenzoate; 3,7-dimethylocta-1,6-dien-3-yl acetate; 3,7-dimethylocta-1,6-dien-3-ol; 3-(4-methylcyclohex-3-en-1-yl)butanal; 3-(4-(tert-butyl)phenyl)-2-methylpropanal; (Z)-hex-3-en-1-yl methyl carbonate; 4-methylquinoline; (E)-1-(1-methoxypropoxy)hex-3-ene; 2-Methyl-5-(1-methylethenyl)-2-cyclohexenone; dodecanal; 2,2-dimethyl-5-phenylhexanenitrile; (E)-6-(pent-3-en-1-yl)tetrahydro-2H-pyran-2-one; 2-hexylcyclopentan-1-one; (Z)-4-(6,6-dimethylcyclohex-2-en-1-yl)-3-methylbut-3-en-2-one; 2,6,9,10-tetramethyl-1-oxaspiro(4.5)deca-3,6-diene; 4-methylpent-1-en-3-ol; isopropyl palmitate; isopropyl dodecanoate; isopropyl 2-methylbutanoate; 4-methylpent-4-en-2-yl isobutyrate; 7-methyloctyl acetate; 7-methyloctan-1-ol; 4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; (Z)-2-methoxy-4-(prop-1-en-1-yl)phenyl acetate; (Z)-2-methoxy-4-(prop-1-en-1-yl)phenol; (1R,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl propionate; (1R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol; 2-(4-isopropylcyclohexa-1,4-dien-1-yl)ethyl formate; isopentyl (E)-undec-6-enoate; isopentyl octanoate; isopentyl dodecanoate; isopentyl isobutyrate; (E)-oxacycloheptadec-10-en-2-one; 8,8-di(1H-indol-1-yl)-2,6-dimethyloctan-2-ol; 2-cyclododecylpropan-1-ol; 3-phenylpropan-1-ol; 3-phenylpropanoic acid; (1,1-dimethoxypropan-2-yl)benzene; 2-phenylpropan-1-ol; hexyl propionate; hexyl butyrate; hexyl 2-methylbutanoate; hexyl furan-2-carboxylate; oxacycloheptadecan-2-one; heptan-1-ol; heptyl acetate; heptanal; 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropyl propionate; 5-(diethoxymethyl)benzo[d][1,3]dioxole; benzo[d][1,3]dioxole-5-carbaldehyde; 3-(benzo[d][1,3]dioxol-5-yl)-2-methylpropanal; (E)-oxacyclohexadec-13-en-2-one; 6-butyl-2,4-dimethyl-3,6-dihydro-2H-pyran; 2-((3S,5R,8S)-3,8-dimethyl-1,2,3,4,5,6,7,8-octahydroazulen-5-yl)propan-2-ol; 1-(2,6,6-trimethylcyclohex-2-en-1-yl)pentan-3-one; (1Z,5Z)-1,5-dimethyl-8-(propan-2-ylidene)cyclodeca-1,5-diene; (E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate; (E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate; (Z)-3,7-dimethylocta-2,6-dienenitrile; (E)-3,7-dimethylocta-2,6-dien-1-yl formate; (E)-3,7-dimethylocta-2,6-dien-1-yl octanoate; (E)-3,7-dimethylocta-2,6-dien-1-yl benzoate; (E)-3,7-dimethylocta-2,6-dienal; N,2-dimethyl-N-phenylbutanamide; 1-isopropyl-4-methylcyclohexa-1,4-diene; (1R,4aR,8aS)-1-isopropyl-7-methyl-4-methylene-1,2,3,4,4a,5,6, 8a-octahydronaphthalene; 5-[(Z)-hex-3-enyl]oxolan-2-one; (4aS,9aR)-3,5,5,9-tetramethyl-2,4a,5,6,7,9a-hexahydro-1H-benzo[7]annulene; (Z)-1-(2,2-dimethyl-6-methylenecyclohexyl)but-2-en-1-one; (1R,4aS,8aS)-1-isopropyl-7-methyl-4-methylene-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 1-(3,3-dimethylcyclohexyl)pent-4-en-1-one; furan-2-ylmethyl octanoate; furan-2-ylmethyl hexanoate; furan-2-ylmethyl heptanoate; ethyl (3aR,4S,7R,7aR)-octahydro-3aH-4,7-methanoindene-3a-carboxylate; 2-(sec-butyl)cyclohexan-1-one; 3-(2-ethylphenyl)-2,2-dimethylpropanal; 2-(tert-butyl)cyclohexyl ethyl carbonate; 3-(2-ethylphenyl)-2,2-dimethylpropanal; (E)-4,8-dimethyldeca-4,9-dienal; 3-(4-ethylphenyl)-2,2-dimethylpropanenitrile; 2-heptylcyclopentan-1-one; 1-ethoxyethoxy Cyclododecane; (Z)-5-methylhept-2-en-4-one; 1,3,3-trimethylbicyclo[2.2.1]heptan-2-ol; oxacyclohexadecan-2-one; (E)-cyclopentadec-4-en-1-one; 1-cyclopentadec-4-en-1-one; 4-allyl-2-methoxyphenyl acetate; 4-allyl-2-methoxyphenol; 1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane; ethyl 3-methyl-3-phenyloxirane-2-carboxylate; 1,4-dioxacycloheptadecane-5,17-dione; 2-ethoxy-4-formylphenyl acetate; ethyl undec-10-enoate; ethyl palmitate; ethyl octanoate; ethyl tetradecanoate; (E)-3,7-dimethylnona-1,6-dien-3-ol; ethyl cinnamate; ethyl 3-phenyloxirane-2-carboxylate; ethyl 2-cyclohexylpropanoate; 6-ethyl-2,10,10-trimethyl-1-oxaspiro[4.5]deca-3,6-diene; (2R,3S,4R)-2,3,4,5-tetrahydroxypentanal; (E)-4-((3 aS,7aS)-octahydro-5H-4,7-methanoinden-5-ylidene)butanal; (2R,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-one; 4-methyl-2-phenyltetrahydro-2H-pyran; oxydibenzene; diphenylmethane; 2-methyl-1-phenylpropan-2-yl butyrate; 2,6-dimethyloct-7-en-2-ol; 3-methyl-2-pentylcyclopent-2-en-1-one; 3,3,5-trimethylcyclohexan-1-one; 2-methoxy-4-propylphenol; chroman-2-one; 2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-one; 2-methyl-5-(prop-1-en-2-yl)cyclohexyl acetate; 2-(4-methylcyclohexyl)propan-2-yl acetate; 4-(2,6,6-trimethylcyclohex-2-en-1-yl)butan-2-one; (oxybis(methylene))dibenzene; dibutyl phthalate; 1,2-diphenylethane; (3R,4R)-1-isopropyl-4-methyl-3-(prop-1-en-2-yl)-4-vinylcyclohex-1-ene; (1 S,8aR)-4,7-dimethyl-1-(propan-2-yl)-1,2,3,5,6,8a-hexahydronaphthalene; (1S,8aS)-1-isopropyl-4,7-dimethyl-1,2,3,5,6,8a-hexahydronaphthalene; 2-pentylcyclopentan-1-one; decyl 2-aminobenzoate; decahydronaphthalen-2-ol; methyl (1s,4s)-1,4-dimethylcyclohexane-1-carboxylate; 3-(4-isopropylphenyl)-2-methylpropanal; cyclotetradecane; cyclopentadecanone; 2-cyclohexylethyl acetate; cyclohexyl 2-hydroxybenzoate; 1,4-dioxacyclohexadecane-5,16-dione; (4-isopropylphenyl)methanol; 2-methoxy-4-methylphenol; (3Z,5Z)-2,6-dimethylocta-1,3,5,7-tetraene; 4-cyclohexyl-2-methylbutan-2-ol; 2-(3-phenylpropyl)pyridine; 3-(4-methylcyclohex-3-en-1-yl)but-3-en-1-yl acetate; 3-(4-methylcyclohex-3-en-1-yl)butan-1-ol; 2-benzyl-2-methylbut-3-enenitrile; 3,7-dimethyloct-6-enenitrile; 3,7-dimethyloct-6-en-1-yl 2-phenylacetate; 3,7-dimethyloct-6-en-1-yl formate; 3,7-dimethyloct-6-en-1-yl benzoate; 3,7-dimethyloct-6-en-1-ol; 3,7-dimethyloct-6-enal; (E)-3,7-dimethylocta-2,6-dienal; (1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptane; (Z)-3-methyl-2-(pent-2-en-1-yl)cyclopent-2-en-1-one; (E)-2-methoxy-4-(prop-1-en-1-yl)phenol; (E)-oxacycloheptadec-11-en-2-one; (Z)-non-6-en-1-ol; (Z)-hex-3-en-1-yl pentanoate; (E)-hex-3-en-1-yl (E)-2-methylbut-2-enoate; (Z)-hex-3-en-1-yl 2-hydroxybenzoate; (Z)-hex-3-en-1-yl propionate; (Z)-hex-3-en-1-yl butyrate; (Z)-hex-3-en-1-yl benzoate; (Z)-hex-3-en-1-ol; (Z)-hex-3-en-1-yl 2-methylbutanoate; (Z)-hex-2-en-1-ol; cinnamonitrile; cinnamyl isobutyrate; cinnamaldehyde; (E)-3-phenylprop-2-en-1-ol; cinnamonitrile; 4-chloro-3,5-dimethylphenol; hexadecan-1-ol; (E)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)hepta-1,6-dien-3-one; 2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butanal; (3aR,5aR,9aR,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; (4Z,8Z)-1,5,9-trimethyl-13-oxabicyclo[10.1.0]trideca-4,8-diene; 5-methyl-1-(2,2,3-trimethylcyclopent-3-en-1-yl)-6-oxabicyclo[3.2.1]octane; 1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-4H-inden-4-one; 5-isopropyl-2-methylphenol; 2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-one; 2-(2-ethoxyethoxy)ethan-1-ol; hexan-1-ol; 2-(2,2,3-trimethylcyclopent-3-en-1-yl)acetonitrile; 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one; 2,2-dimethyl-3-methylenebicyclo[2.2.1]heptane; 2,6-di-tert-butyl-4-methylphenol; butyl stearate; butyl undec-10-enoate; 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)butan-1-ol; (E)-2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)but-2-enal; 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate; (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol; 3,3,6,7-tetramethyloctahydro-2H-chromene; 6,6-dimethylspiro[bicyclo[3.1.1]heptane-2,2′-oxirane]; 3-isopropyl-6-methylenecyclohex-1-ene; 2-ethoxynaphthalene; (R)-3,5,5,9-tetramethyl-2,4a,5,6,7,8-hexahydro-1H-benzo[7]annulene; (1S,4S)-1,4-dimethyl-7-(propan-2-ylidene)-1,2,3,4,5,6,7,8-octahydroazulene; (1R,9S,Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-4-ene; (Z)-4-(2,2,6-trimethyl-7-oxabicyclo[4.1.0]heptan-1-yl)but-3-en-2-one; 4-methoxy-7H-furo[3,2-g]chromen-7-one; 4-phenylbutan-2-one; benzyl 2-hydroxybenzoate; benzyl dodecanoate; benzyl 3-methylbutanoate; benzyl isobutyrate; benzyl cinnamate; benzyl butyrate; phenylmethanol; benzyl benzoate; 1-(3,3-dimethylcyclohexyl)ethyl formate; 4-methoxybenzyl acetate; 4-methoxybenzyl formate; (Z)-1-methoxy-4-(prop-1-en-1-yl)benzene; pentyl benzoate; (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; 2,5,5-trimethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-ol; 2,5,5-trimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-ol; 2-(sec-butyl)-1-vinylcyclohexyl acetate; (1S,4R,5R)-1-isopropyl-4-methylbicyclo[3.1.0]hexan-3-one; 2-(4-methylcyclohex-3-en-1-yl)propan-2-yl propionate; 2-(4-methylcyclohex-3-en-1-yl)propan-2-yl acetate; 1,7-dimethyl-7-(4-methylpent-3-en-1-yl)tricyclo[2.2.1.02,6]heptane; 1-(5,5-dimethylcyclohex-1-en-1-yl)pent-4-en-1-one; (1S,4aS,8aR)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; 4-cyclohexylbutan-2-ol; (R,Z)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)pent-1-en-3-one; (E)-2-methyl-3-phenylacrylaldehyde; (Z)-3-methyl-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-3-en-2-one; (Z)-4-(2,5,6,6-tetramethylcyclohex-2-en-1-yl)but-3-en-2-one; (1Z,4E,8Z)-2,6,6,9-tetramethylcycloundeca-1,4,8-triene; (4aR,8S,9aS)-3,5,5,8-tetramethyl-9-methylene-2,4a,5,6,7,8,9,9a-octahydro-1H-benzo[7]annulene; (1R,4S,4aR,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; (1 S,4aR,8aR)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (R)-2-((R)-4-methylcyclohex-3-en-1-yl)hex-5-en-2-ol; (E)-2-benzylideneheptyl acetate; (1S,4aR,8aS)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; 1-phenylpentan-2-ol; 4-methoxy-2,5-dimethylfuran-3(2H)-one; alpha-4-Dimethyl benzenepropanal; allyl 2-phenoxyacetate; (2-(allyloxy)ethyl)benzene; allyl heptanoate; allyl 3-cyclohexylpropanoate; N-ethyl-N-(m-tolyl)propionamide; 2,6,10-trimethylundec-9-enal; 3-hydroxybutan-2-one; 1-(4-methoxyphenyl)ethan-1-one; (Z)-2-(4-methylbenzylidene)heptanal; (Z)-oxacycloheptadec-8-en-2-one; 7-methoxy-2H-chromen-2-one; 6-methylquinoline; 6,8-dimethylnonan-2-ol; 6,10,14-trimethylpentadecan-2-one; 5-methylheptan-3-one; 4-vinylphenol; 1-phenylpent-4-en-1-one; (E)-3-(4-hydroxy-3-methoxyphenyl)acrylaldehyde; 4-ethyl-2-methoxyphenol; 5-methyl-5-phenylhexan-3-one; 4-(4-methoxyphenyl)butan-2-one; (E)-3-propylideneisobenzofuran-1(3H)-one; (Z)-dodec-2-enal; 3-methyl-5-phenylpentanal; 3-methyl-4-phenyl-1H-pyrazole; 3-methylcyclopentane-1,2-dione; 3-methoxy-5-methylphenol; 3-methoxy-3-methylbutan-1-ol; (E)-hex-3-en-1-ol; 3,7-dimethyl-2-methyleneoct-6-enal; 3,7-dimethyloctan-1-ol; (Z)-undec-2-enenitrile; (E)-undec-2-enal; phenethyl acetate; (Z)-3-(furan-2-yl)-2-phenylacrylaldehyde; phenethyl propionate; 2-pentylcyclopentan-1-ol; (2S,4S)-2-heptyl-2,4-dimethyl-1,3-dioxolane; nonan-2-ol; 2-(sec-butyl)-3-methoxypyrazine; 2-isopropyl-N,2,3-trimethylbutanamide; (E)-2-isopropyl-5-methylhex-2-enal; 2-isopropyl-4-methylthiazole; (E)-2-hexylidenecyclopentan-1-one; (E)-hex-2-en-1-ol; 2-butoxyethan-1-ol; (2E,6E)-nona-2,6-dien-1-ol; 1-isopropyl-4-methyl-7-oxabicyclo[2.2.1]heptane; 1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 1,1,2,3,3-pentamethyl-2,3-dihydro-1H-indene; (Z)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-en-1-one; (Z)-6,10-dimethylundeca-5,9-dien-2-yl acetate; (Z)-hept-3-en-1-yl acetate; (1S,5S)-4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-one; (R)-3,7-dimethylocta-1,6-dien-3-ol; 3,7-dimethyloct-6-enal; (E)-6,10-dimethylundeca-5,9-dien-2-yl acetate; (R)-3,7-dimethyloct-6-enal; (2S,5S,6S)-2,6,10,10-tetramethyl-1-oxaspiro[4.5]decan-6-ol; 3,7-dimethyloct-6-en-1-ol; 3,7-dimethyloct-6-en-1-ol; (1R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene; (S)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-one; (1S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene; methyl 2-methylbutanoate; hexyl (Z)-2-methylbut-2-enoate; 2-(8-isopropyl-6-methylbicyclo[2.2.2]oct-5-en-2-yl)-1,3-dioxolane; 3-(3-isopropylphenyl)butanal; allyl 2-(cyclohexyloxy)acetate; 2-((3S,3aS,5R)-3,8-dimethyl-1,2,3,3a,4,5,6,7-octahydroazulen-5-yl)propan-2-ol; 1,5-dimethylbicyclo[3.2.1]octan-8-one oxime; benzyl 2-phenylacetate; 2-hydroxy-1,2-diphenylethan-1-one; (E)-tridec-2-enal; 1-phenylvinyl acetate; p-tolyl isobutyrate; p-tolyl hexanoate; p-cymene; 5-hexyl-4-methyldihydrofuran-2(3H)-one; 2-cyclohexylidene-2-phenylacetonitrile; 4-(prop-1-en-2-yl)cyclohex-1-ene-1-carbaldehyde; (4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methyl acetate; (4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methanol; (2-(cyclohexyloxy)ethyl)benzene; phenethyl 2-methylbutanoate; phenethyl formate; phenethyl isobutyrate; phenethyl 2-phenylacetate; phenethyl (Z)-2-methylbut-2-enoate; phenyl benzoate; phenethyl benzoate; phenethyl methacrylate; 2-(4-isopropylphenyl)acetaldehyde; 1,2-dimethyl-3-(prop-1-en-2-yl)cyclopentan-1-ol; 1-(4-methoxyphenyl)propan-2-one; (2Z,5Z)-5,6,7-trimethylocta-2,5-dien-4-one; 1-methoxy-4-propylbenzene; 2-(4-(tert-butyl)phenyl)acetaldehyde; 4-(tert-pentyl)cyclohexan-1-ol; p-tolyl 2-phenylacetate; Ethyl 2,4,7-decatrienoate; 2,6,6-trimethylbicyclo[3.1.1]hept-2-ene; 4-(4-hydroxyphenyl)butan-2-one; 2-benzyl-4,4,6-trimethyl-1,3-dioxane; 3,7-dimethyloct-7-en-1-ol; ethyl (2,3,6-trimethylcyclohexyl) carbonate; (Z)-6-ethylideneoctahydro-2H-5,8-methanochromene; 2-((S)-1-((S)-3,3-dimethylcyclohexyl)ethoxy)-2-oxoethyl propionate; methyl 2,2-dimethyl-6-methylenecyclohexane-1-carboxylate; 1-(3,3-dimethylcyclohexyl)ethyl acetate; (S)-3,7-dimethylocta-1,6-dien-3-ol; 1-isopropyl-4-methylenebicyclo[3.1.0]hexane; 5-isopropyl-2-methylbicyclo[3.1.0]hexan-2-ol; (1 S,3R,5S)-1-isopropyl-4-methylenebicyclo[3.1.0]hexan-3-ol; 3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pentan-2-ol; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; propyl (S)-2-(tert-pentyloxy)propanoate; (4aR,8aR)-4a,8-dimethyl-2-(propan-2-ylidene)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropyl cyclopropanecarboxylate; (1R,3R,6R)-2′,2′,3,7,7-pentamethylspiro[bicyclo[4.1.0]heptane-2,5′-[1,3]dioxane]; 1-oxaspiro(4,5)decan-2-one; (Z)-5-methylheptan-3-one oxime; 1-phenylethyl acetate; (1S,4S,4aR,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; (1S,4S,4aR,8aS)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; 3,7-dimethyloctanal; 4-(2,2,6-trimethylcyclohexyl)butan-2-ol; 3-methyl-2-pentylcyclopentan-1-one; 3,7-dimethyloctan-3-ol; 3,7-dimethyloctan-3-yl acetate; 2,6,10,10-tetramethyl-1-oxaspiro[4.5]dec-6-ene; ethyl (1R,6S)-2,2,6-trimethylcyclohexane-1-carboxylate; 2-isopropyl-5-methylphenol; 1-isopropyl-2-methoxy-4-methylbenzene; 1-(2,2,6-trimethylcyclohexyl)hexan-3-ol; (E)-hex-2-en-1-ol; (1R,2S)-2-(tert-butyl)cyclohexan-1-ol; (Z)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-en-1-one; (Z)-oxacycloheptadec-8-en-2-one; (Z)-1-methoxy-4-(prop-1-en-1-yl)benzene; cinnamic acid; (2R,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-one; (E)-3,7-dimethylocta-2,6-dien-1-ol; (Z)-2-methoxy-4-(prop-1-en-1-yl)phenol; 2,2,2-trichloro-1-phenylethyl acetate; triethyl 2-hydroxypropane-1,2,3-tricarboxylate; methyl 2-((1-hydroxy-3-phenylbutyl)amino)benzoate; 1-((2E,5Z,9Z)-2,6,10-trimethylcyclododeca-2,5,9-trien-1-yl)ethan-1-one; 2-mercapto-2-methylpentan-1-ol; 13-methyl oxacyclopentadec-10-en-2-one; undecanal; (E)-4-methyldec-3-en-5-ol; (3R,4aS,5R)-4a,5-dimethyl-3-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,7-octahydronaphthalene; 4-formyl-2-methoxyphenyl acetate; 4-formyl-2-methoxyphenyl isobutyrate; (Z)-2-ethoxy-5-(prop-1-en-1-yl)phenol; 2,2,5-trimethyl-5-pentylcyclopentan-1-one; (Z)-2-methyl-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-enal; 3,4-dimethoxybenzaldehyde; (1R,5R)-4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-one; 1-methoxy-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoindene; 2-(tert-butyl)cyclohexan-1-ol; cis-(4-tert-butylcyclohexyl) acetate; 4-(tert-butyl)cyclohexyl acetate; 2,4-diethoxy-5-methylpyrimidine; 4-methyl-4-phenylpentan-2-yl acetate; 4,8-dimethyl-2-(propan-2-ylidene)-1,2,3,3a,4,5,6,8a-octahydroazulen-6-ol; (Z)-cyclooct-4-en-1-yl methyl carbonate; (Z)-1-((2-methylallyl)oxy)hex-3-ene; 4-(4-hydroxy-3-methoxyphenyl)butan-2-one; (1R,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,7,8,8a-hexahydronaphthalene; 4,5-epoxy-4,11,11-trimethyl-8-methylenebicyclo(7.2.0)undecane; 1,3,4,6,7,8alpha-hexahydro-1,1,5,5-tetramethyl-2H-2,4alpha-methanophtalen-8(5H)-one preferably said malodor reduction materials are selected from the group consisting of: 2-ethylhexyl (Z)-3-(4-methoxyphenyl)acrylate; 2,4-dimethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolane; 1,1-dimethoxynon-2-yne; 2-(p-tolyl)propan-2-ol; 3-methoxy-7,7-dimethyl-10-methylenebicyclo[4.3.1]decane; methoxycyclododecane; 1,1-dimethoxycyclododecane; (Z)-tridec-2-enenitrile; (2-hydroxy-4-methoxyphenyl)(phenyl)methanone; 2,4a,5,8a-tetramethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl formate; 4-methyl-1-oxaspiro[5.5]undecan-4-ol; 7-methyl-2H-benzo[b][1,4]dioxepin-3(4H)-one; 1,8-dioxacycloheptadecan-9-one; 4-(tert-pentyl)cyclohexan-1-one; 2-methoxy-1,1′-biphenyl; 3a,5,6,7,8,8b-hexahydro-2,2,6,6,7,8,8-heptamethyl-4H-indeno(4,5-d)-1,3-dioxole; 7-isopropyl-8,8-dimethyl-6,10-dioxaspiro[4.5]decane; octyl furan-2-carboxylate; octyl acetate; 2-heptyl-4-methyl-1,3-dioxolane; octanal; 1,1-dimethoxyoctane; 7-methyl-3-methyleneocta-1,6-diene; 2-methyl-6-methyleneoct-7-en-2-ol; 2-methyl-6-methyleneoct-7-en-2-yl acetate; tetradecanal; 4-methoxy-6-prop-2-enyl-1,3-benzodioxole; tetradecanenitrile; 2,2,6,8-tetramethyl-1,2,3,4,4a,5,8,8a-octahydronaphthalen-1-ol; (E)-2,6-dimethylocta-5,7-dien-2-ol; (E)-2,7-dimethylocta-1,5,7-trien-3-ol; 2-((1S,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethyl acetate; (4R,4aS,6R)-4,4a-dimethyl-6-(prop-1-en-2-yl)-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one; nonan-1-ol; nonanal; 12-methyl-14-tetradec-9-enolide; N-ethyl-2-isopropyl-5-methylcyclohexane-1-carboxamide; 1-(3-methylbenzofuran-2-yl)ethan-1-one; 2-methoxynaphthalene; (E)-3,7,11-trimethyldodeca-1,6,10-trien-3-ol; (Z)-3,7-dimethylocta-2,6-dien-1-ol; 1-ethyl-3-methoxytricyclo[2.2.1.02,6]heptane; methyl (E)-non-2-enoate; 10-isopropyl-2,7-dimethyl-1-oxaspiro[4.5]deca-3,6-diene; 2-(2-(4-methylcyclohex-3-en-1-yl)propyl)cyclopentan-1-one; 6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-carbaldehyde; (E)-4-(2,2,3,6-tetramethylcyclohexyl)but-3-en-2-one; (4-(4-methylpent-3-en-1-yl)cyclohex-3-en-1-yl)methyl acetate; 2-(tert-butyl)-4,5,6-trimethyl-1,3-phenylene dinitrite; 1,7-dioxacycloheptadecan-8-one; 1-(4-(tert-butyl)-2,6-dimethyl-3,5-dinitrophenyl)ethan-1-one; 1-(tert-butyl)-2-methoxy-4-methyl-3,5-dinitrobenzene; 3-methylcyclopentadecan-1-one; (E)-3-methylcyclopentadec-4-en-1-one; 3-methyl-4-phenylbutan-2-ol; 1-(4-isopropylcyclohexyl)ethan-1-ol; (E)-dec-5-enoic acid; methyl non-2-ynoate; 2-methyldecanal; 6,6-dimethoxy-2,5,5-trimethylhex-2-ene; 4-phenylbutan-2-ol; methyl stearate; 1,1-dimethoxy-2-methylundecane; undecan-2-one; 2-methylundecanal; methyl tetradecanoate; methyl (9Z,12Z)-octadeca-9,12-dienoate; 1-hydroxydecan-3-one; (Z)-1,2-dimethoxy-4-(prop-1-en-1-yl)benzene; methyl palmitate; 4-allyl-1,2-dimethoxybenzene; methyl 2-((1R,2R)-3-oxo-2-((Z)-pent-2-en-1-yl)cyclopentyl)acetate; methyl 2-(3-oxo-2-pentylcyclopentyl)acetate; 1-methyl-2-phenoxybenzene; methyl cinnamate; 1-allyl-4-methoxybenzene; 1-(naphthalen-2-yl)ethan-1-one; methyl oct-2-ynoate; methyl 2,6,6-trimethylcyclohex-2-ene-1-carboxylate; 7-methoxy-3,7-dimethyloctanal; 7-isopropyl-10-methyl-1,5-dioxaspiro[5.5]undecan-3-ol; octahydro-1H-4,7-methanoindene-1-carbaldehyde; 3-(3-(tert-butyl)phenyl)-2-methylpropanal; (E)-4-(4,8-dimethylnona-3,7-dien-1-yl)pyridine; (E)-trideca-3,12-dienenitrile; 2,2-dimethyl-3-(m-tolyl)propan-1-ol; 2,4-dimethyl-4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; 8-isopropyl-6-methylbicyclo[2.2.2]oct-5-ene-2-carbaldehyde; 4-(4-hydroxy-4-methylpentyl)cyclohex-3-ene-1-carbaldehyde; (S)-1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene; (Z)-3-hexen-1-yl-2-cyclopenten-1-one; 3,7-dimethylocta-1,6-dien-3-yl octanoate; 3,7-dimethylocta-1,6-dien-3-yl isobutyrate; 3,7-dimethylocta-1,6-dien-3-yl benzoate; 3,7-dimethylocta-1,6-dien-3-yl 2-aminobenzoate; 2-(5-methyl-5-vinyltetrahydrofuran-2-yl)propan-2-ol; 6-methyl-2-(oxiran-2-yl)hept-5-en-2-ol; (2Z,6E)-3,7-dimethylnona-2,6-dienenitrile; 3-(4-methylcyclohex-3-en-1-yl)butanal; (2,5-dimethyl-1,3-dihydroinden-2-yl)methanol; 3-(4-(tert-butyl)phenyl)-2-methylpropanal; (E)-1-(1-methoxypropoxy)hex-3-ene; (E)-1-(1-ethoxyethoxy)hex-3-ene; (1S,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-ol; dodecan-1-ol; dodecyl acetate; dodecanoic acid; 5-hexyl-5-methyldihydrofuran-2(3H)-one; dodecanal; 3,6-dimethylhexahydrobenzofuran-2(3H)-one; 4-(1-ethoxyvinyl)-3,3,5,5-tetramethylcyclohexan-1-one; ((3S,3aR,6R,8aS)-7,7-dimethyl-8-methyleneoctahydro-1H-3a,6-methanoazulen-3-yl)methanol; 5-(sec-butyl)-2-(2,4-dimethylcyclohex-3-en-1-yl)-5-methyl-1,3-dioxane; (1-methyl-2-((1,2,2-trimethylbicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methanol; 2-propylheptanenitrile; (E)-6-(pent-3-en-1-yl)tetrahydro-2H-pyran-2-one; 2-hexylcyclopentan-1-one; 2-methyl-4-phenyl-1,3-dioxolane; 2,6,9,10-tetramethyl-1-oxaspiro(4.5)deca-3,6-diene; (1R,2S,5R)-5-methyl-2-(prop-1-en-2-yl)cyclohexan-1-ol; isopropyl palmitate; isopropyl tetradecanoate; isopropyl dodecanoate; 4,9-dimethoxy-7H-furo[3,2-g]chromen-7-one; (E)-cyclohexadec-8-en-1-one; (2S,5S)-2-isopropyl-5-methylcyclohexan-1-one; 2-hexylcyclopent-2-en-1-one; (2S,5S)-2-isopropyl-5-methylcyclohexan-1-one; 4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; (Z)-1-(benzyloxy)-2-methoxy-4-(prop-1-en-1-yl)benzene; 1-((2S,3 S)-2,3,8,8-tetramethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-yl)ethan-1-one; 2,5,6-trimethylcyclohex-3-ene-1-carbaldehyde; 6-(sec-butyl)quinoline; 2-(cyclohexyloxy)-1,7,7-trimethylbicyclo[2.2.1]heptane; (1R,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl propionate; (1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate; 4-((2R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)cyclohexan-1-ol; (1R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 2-(4-isopropylcyclohexa-1,4-dien-1-yl)ethyl formate; isopentyl (E)-undec-6-enoate; isopentyl dodecanoate; (E)-oxacycloheptadec-10-en-2-one; (E)-non-2-enenitrile; (E)-8-(1H-indol-1-yl)-2,6-dimethyloct-7-en-2-ol; 8,8-di(1H-indol-1-yl)-2,6-dimethyloctan-2-ol; 4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; 3,7-dimethyloctane-1,7-diol; 2-cyclododecylpropan-1-ol; 3-methyl-5-phenylpentanenitrile; 3-phenylpropan-1-ol; (1,1-dimethoxypropan-2-yl)benzene; 5-ethyl-4-hydroxy-2-methylfuran-3(2H)-one; 2,3-dihydro-3,3-dimethyl-1H-indene-5-propanal; 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)propanal; hexyl octanoate; hexyl hexanoate; (Z)-2-benzylideneoctanal; hexyl benzoate; (Z)-hex-1-en-1-yl (Z)-2-methylbut-2-enoate; (E)-3,7-dimethylocta-2,6-dien-1-yl palmitate; oxacycloheptadecan-2-one; 2-butyl-4,4,6-trimethyl-1,3-dioxane; ethyl (1R,2R,3R,4R)-3-isopropylbicyclo[2.2.1]hept-5-ene-2-carboxylate; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl acetate; 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropyl propionate; 5-(diethoxymethyl)benzo[d][1,3]dioxole; 3-(benzo[d][1,3]dioxol-5-yl)-2-methylpropanal; (E)-oxacyclohexadec-13-en-2-one; 6-butyl-2,4-dimethyl-3,6-dihydro-2H-pyran; 2-((3S,5R,8S)-3,8-dimethyl-1,2,3,4,5,6,7,8-octahydroazulen-5-yl)propan-2-ol; 1-(2,6,6-trimethylcyclohex-2-en-1-yl)pentan-3-one; ethyl 2-ethyl-6,6-dimethylcyclohex-2-ene-1-carboxylate; (1Z,5Z)-1,5-dimethyl-8-(propan-2-ylidene)cyclodeca-1,5-diene; (1E,6E)-8-isopropyl-1-methyl-5-methylenecyclodeca-1,6-diene; (E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate; (E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate; (6E,10E)-3,7,11,15-tetramethylhexadeca-1,6,10,14-tetraen-3-ol; (E)-2-(3,7-dimethylocta-2,6-dien-1-yl)cyclopentan-1-one; 5-heptyldihydrofuran-2(3H)-one; 1-methyl-4-(propan-2-ylidene)cyclohexyl acetate; 1-methyl-4-(propan-2-ylidene)cyclohexan-1-ol; 5-pentyldihydrofuran-2(3H)-one; (1R,4aR,8aS)-1-isopropyl-7-methyl-4-methylene-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 5-[(Z)-hex-3-enyl]oxolan-2-one; (Z)-4-(2,2-dimethyl-6-methylenecyclohexyl)but-3-en-2-one; (4aS,9aR)-3,5,5,9-tetramethyl-2,4a,5,6,7,9a-hexahydro-1H-benzo[7]annulene; (1R,3aR,4R,7R)-1,4-dimethyl-7-(prop-1-en-2-yl)-1,2,3,3a,4,5,6,7-octahydroazulene; 2-((2R,4aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)propan-2-ol; 5-octyldihydrofuran-2(3H)-one; (Z)-1-(2,2-dimethyl-6-methylenecyclohexyl)but-2-en-1-one; 5-hexyldihydrofuran-2(3H)-one; (1R,4aS,8aS)-1-isopropyl-7-methyl-4-methylene-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 1-(3,3-dimethylcyclohexyl)pent-4-en-1-one; 4,6,6,7,8,8-hexamethyl-1,3,4,6,7,8-hexahydrocyclopenta[g]isochromene; furan-2-ylmethyl octanoate; furan-2-ylmethyl hexanoate; furan-2-ylmethyl heptanoate; 2-methyldecanenitrile; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; ethyl (3aR,4S,7R,7aR)-octahydro-3aH-4,7-methanoindene-3a-carboxylate; diethyl cyclohexane-1,4-dicarboxylate; (6-isopropyl-9-methyl-1,4-dioxaspiro[4.5]decan-2-yl)methanol; 2-isobutyl-4-methyltetrahydro-2H-pyran-4-ol; undec-10-enenitrile; (Z)-6-ethylideneoctahydro-2H-5,8-methanochromen-2-one; 3-(2-ethylphenyl)-2,2-dimethylpropanal; (E)-4,8-dimethyldeca-4,9-dienal; (E)-4-((3aR,4R,7R,7aR)-1,3a,4,6,7,7a-hexahydro-5H-4,7-methanoinden-5-ylidene)-3-methylbutan-2-ol; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl acetate; 3-(4-ethylphenyl)-2,2-dimethylpropanenitrile; 2-heptylcyclopentan-1-one; 1-ethoxyethoxy Cyclododecane; 3-cyclohexene-1-carboxylic acid, 2,6,6-trimethyl-, methyl ester; (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl acetate; (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol; oxacyclohexadecan-2-one; (E)-cyclopentadec-4-en-1-one; 1-cyclopentadec-4-en-1-one; 2-methoxy-4-(4-methylenetetrahydro-2H-pyran-2-yl)phenol; 4-allyl-2-methoxyphenyl acetate; 4-allyl-2-methoxyphenol; ethyl 3-methyl-3-phenyloxirane-2-carboxylate; 1,4-dioxacycloheptadecane-5,17-dione; ethyl undec-10-enoate; ethyl palmitate; ethyl nonanoate; ethyl tetradecanoate; (E)-3,7-dimethylnona-1,6-dien-3-ol; ethyl dodecanoate; nonan-3-one; ethyl decanoate; ethyl 6,6-dimethyl-2-methylenecyclohex-3-ene-1-carboxylate; ethyl 3-phenyloxirane-2-carboxylate; 6-ethyl-2,10,10-trimethyl-1-oxaspiro[4.5]deca-3,6-diene; 2-((1R,3 S,4S)-4-methyl-3-(prop-1-en-2-yl)-4-vinylcyclohexyl)propan-2-ol; (2-(1-ethoxyethoxy)ethyl)benzene; (E)-3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pent-4-en-2-ol; (2R,3S,4R)-2,3,4,5-tetrahydroxypentanal; (E)-4-((3aS,7aS)-octahydro-5H-4,7-methanoinden-5-ylidene)butanal; 1,1-dimethoxydodecane; (R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene; 2-(2-hydroxypropoxy)propan-1-ol; 7,9-dimethylspiro[5.5]undecan-3-one; oxydibenzene; diphenylmethane; 2-methyl-1-phenylpropan-2-yl butyrate; 2,6-dimethyloct-7-en-4-one; octahydro-1H-4,7-methanoinden-5-yl acetate; 2-methyl-5-(prop-1-en-2-yl)cyclohexyl acetate; 2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-ol; 3,7-dimethyloct-6-en-3-ol; methyl 2-hexyl-3-oxocyclopentane-1-carboxylate; dibutylsulfane; 1,2-diphenylethane; 6-hexyltetrahydro-2H-pyran-2-one; (3R,4R)-1-isopropyl-4-methyl-3-(prop-1-en-2-yl)-4-vinylcyclohex-1-ene; (3S,3aS,5R)-3,8-dimethyl-5-(prop-1-en-2-yl)-1,2,3,3a,4,5,6,7-octahydroazulene; 6-heptyltetrahydro-2H-pyran-2-one; 6-pentyltetrahydro-2H-pyran-2-one; (1S,8aR)-4,7-dimethyl-1-(propan-2-yl)-1,2,3,5,6,8a-hexahydronaphthalene; (Z)-1-((1R,2S)-2,6,6-trimethylcyclohex-3-en-1-yl)but-2-en-1-one; (1S,8aS)-1-isopropyl-4,7-dimethyl-1,2,3,5,6,8a-hexahydronaphthalene; 3,7,7-trimethylbicyclo[4.1.0]hept-3-ene; dec-9-en-1-ol; decyl propionate; 1,1-diethoxydecane; decahydronaphthalen-2-ol; 1-cyclohexylethyl (E)-but-2-enoate; 3-(4-isopropylphenyl)-2-methylpropanal; cyclotetradecane; cyclopentadecanone; cyclohexyl 2-hydroxybenzoate; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl butyrate; 1,4-dioxacyclohexadecane-5,16-dione; 8,8-dimethyl-1,2,3,4,5,6,7,8-octahydronaphthalene-2-carbaldehyde; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl isobutyrate; (5R,6R)-3,6-dimethyl-5-(prop-1-en-2-yl)-6-vinyl-4,5,6,7-tetrahydrobenzofuran; (4-isopropylphenyl)methanol; 1-(benzofuran-2-yl)ethan-1-one; 2-(3-phenylpropyl)pyridine; dodecanenitrile; (E)-cycloheptadec-9-en-1-one; 3-(4-methylcyclohex-3-en-1-yl)but-3-en-1-yl acetate; 3-(4-methylcyclohex-3-en-1-yl)butan-1-ol; (E)-3-methyl-5-phenylpent-2-enenitrile; (E)-2-(2,6-dimethylhepta-1,5-dien-1-yl)-4-methyl-1,3-dioxolane; (E)-1,1-dimethoxy-3,7-dimethylocta-2,6-diene; (E)-1,1-diethoxy-3,7-dimethylocta-2,6-diene; (E)-3,7-dimethylocta-1,3,6-triene; (1R,4R,6S)-1-methyl-4-(prop-1-en-2-yl)-7-oxabicyclo[4.1.0]heptane; (E)-oxacycloheptadec-11-en-2-one; (Z)-non-6-en-1-ol; (1R,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-ol; (Z)-dec-4-enal; (E)-hex-3-en-1-yl (E)-hex-3-enoate; (Z)-hex-3-en-1-yl 2-hydroxybenzoate; (Z)-hex-3-en-1-yl benzoate; (Z)-hex-3-en-1-yl 2-methylbutanoate; (3Z,6Z)-nona-3,6-dien-1-ol; cinnamyl propionate; cinnamyl isobutyrate; cinnamyl formate; cinnamyl cinnamate; cinnamyl acetate; (E)-3-phenylprop-2-en-1-ol; hexadecan-1-ol; (E)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)hepta-1,6-dien-3-one; 2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butanal; (3aR,5aR,9aR,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; 1,6-dioxacycloheptadecan-7-one; 1-(6-(tert-butyl)-1,1-dimethyl-2,3-dihydro-1H-inden-4-yl)ethan-1-one; (3R,3aR,6S,7S,8aS)-6-methoxy-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-3-yl formate; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl acetate; (4Z,8Z)-1,5,9-trimethyl-13-oxabicyclo[10.1.0]trideca-4,8-diene; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-ol; 5-methyl-1-(2,2,3-trimethylcyclopent-3-en-1-yl)-6-oxabicyclo[3.2.1]octane; 5-methyl-1-(2,2,3-trimethylcyclopent-3-en-1-yl)-6-oxabicyclo[3.2.1]octane; 1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-4H-inden-4-one; (Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-3-en-5-yl acetate; (1S,2S,5R,8S)-4,4,8-trimethyltricyclo[6.3.1.02,5]dodecan-1-ol; 2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-yl acetate; octanenitrile; octan-1-ol; octanoic acid; decanoic acid; decanal; 3-(4-methoxyphenyl)-2-methylpropanal; 1,7,7-trimethylbicyclo[2.2.1]heptane-2,3-dione; 2,2-dimethyl-3-methylenebicyclo[2.2.1]heptane; ethyl 2-methyl-4-oxo-6-pentylcyclohex-2-ene-1-carboxylate; 2,6-di-tert-butyl-4-methylphenol; butyl stearate; 1-butoxy-1-oxopropan-2-yl butyrate; butyl undec-10-enoate; 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)butan-1-ol; 3-(4-(tert-butyl)phenyl)propanal; (1S,2S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate; 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 2-ethoxy-2,6,6-trimethyl-9-methylenebicyclo[3.3.1]nonane; (ethoxymethoxy)cyclododecane; (E)-1-methyl-4-(6-methylhept-5-en-2-ylidene)cyclohex-1-ene; 3,3,6,7-tetramethyloctahydro-2H-chromene; (5R,10R)-6,10-dimethyl-2-(propan-2-ylidene)spiro[4.5]dec-6-en-8-one; 1-methyl-4-(prop-1-en-2-yl)cyclohexyl acetate; 1-methyl-4-(prop-1-en-2-yl)cyclohexan-1-ol; (2Z,6E)-2,6-dimethyl-10-methylenedodeca-2,6,11-trienal; (R)-3-methylene-6-((S)-6-methylhept-5-en-2-yl)cyclohex-1-ene; (4aR,7R,8aS)-4a-methyl-1-methylene-7-(prop-1-en-2-yl)decahydronaphthalene; (Z)-2-methyl-5-((1S,2R,4R)-2-methyl-3-methylenebicyclo[2.2.1]heptan-2-yl)pent-2-en-1-ol; 6,6-dimethyl-2-methylenebicyclo[3.1.1]heptane; 2-ethoxynaphthalene; (1S,4R,7R)-1,4,9,9-tetramethyl-1,2,3,4,5,6,7,8-octahydro-4,7-methanoazulene; (1 aS,5aR,9aR)-1a,5,5,7-tetramethyl-1a,2,3,4,5,5a,8,9-octahydrobenzo[1,7]cyclohepta[1,2-b]oxirene; (R)-3,5,5,9-tetramethyl-2,4a,5,6,7,8-hexahydro-1H-benzo[7]annulene; (1S,4S)-1,4-dimethyl-7-(propan-2-ylidene)-1,2,3,4,5,6,7,8-octahydroazulene; (2,2-dimethoxyethyl)benzene; (E)-7,11-dimethyl-3-methylenedodeca-1,6,10-triene; (1R,2S,6S,7S,8S)-8-isopropyl-1-methyl-3-methylenetricyclo[4.4.0.02,7]decane; (3R,3aS,7S,8aS)-3,8,8-trimethyl-6-methyleneoctahydro-1H-3a,7-methanoazulene; (1R,9S,Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-4-ene; (S)-4-methyl-1-((S)-6-methylhept-5-en-2-yl)cyclohex-3-en-1-ol; (Z)-4-(2,2,6-trimethyl-7-oxabicyclo[4.1.0]heptan-1-yl)but-3-en-2-one; 4-methoxy-7H-furo[3,2-g]chromen-7-one; 2-methyl-4-phenylbutan-2-ol; benzyl dodecanoate; 2-methyl-1-phenylpropan-2-ol; benzyl cinnamate; benzyl benzoate; benzophenone; 7-isopentyl-2H-benzo[b][1,4]dioxepin-3(4H)-one; 2′-isopropyl-1,7,7-trimethylspiro[bicyclo[2.2.1]heptane-2,4′-[1,3]dioxane]/A; 4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbonitrile; methyl (E)-2-((7-hydroxy-3,7-dimethyloctylidene)amino)benzoate; 4-methoxybenzyl 2-phenylacetate; methyl (E)-octa-4,7-dienoate; pentyl (Z)-3-phenylacrylate; (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; (4aR,5R,7aS,9R)-2,2,5,8,8,9a-hexamethyloctahydro-4H-4a,9-methanoazuleno[5,6-d][1,3]dioxole; 2,5,5-trimethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-ol; 2,5,5-trimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-ol; 1-((2-(tert-butyl)cyclohexyl)oxy)butan-2-ol; (3S,5aR,7aS,11aS,11bR)-3,8,8,11a-tetramethyldodecahydro-5H-3,5a-epoxynaphtho[2,1-c]oxepine; 2,2,6,6,7,8,8-heptamethyldecahydro-2H-indeno[4,5-b]furan; 2,2,7,7,8,9,9-heptamethyldecahydroindeno[4,3a-b]furan; 2-(sec-butyl)-1-vinylcyclohexyl acetate; (1S,4R,5R)-1-isopropyl-4-methylbicyclo[3.1.0]hexan-3-one; (4R,4aS)-4,4a-dimethyl-6-(propan-2-ylidene)-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one; 2-(4-methylcyclohex-3-en-1-yl)propan-2-yl propionate; (2Z,6E,9E)-2,6,10-trimethyldodeca-2,6,9,11-tetraenal; (2R,4aR,8aR)-4a,8-dimethyl-2-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 1,7-dimethyl-7-(4-methylpent-3-en-1-yl)tricyclo[2.2.1.02,6]heptane; (E)-5-(2,3-dimethyltricyclo[2.2.1.02,6]heptan-3-yl)-2-methylpent-2-en-1-ol; (1R,3aS,7S,8aR)-1,4,9,9-tetramethyl-2,3,6,7,8,8a-hexahydro-1H-3a,7-methanoazulene; 1-(5,5-dimethylcyclohex-1-en-1-yl)pent-4-en-1-one; (1S,4aS,8aR)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (R,Z)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)pent-1-en-3-one; 1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene; (Z)-4-(2,5,6,6-tetramethylcyclohex-2-en-1-yl)but-3-en-2-one; (1Z,4E,8Z)-2,6,6,9-tetramethylcycloundeca-1,4,8-triene; (4aR,8S,9aS)-3,5,5,8-tetramethyl-9-methylene-2,4a,5,6,7,8,9,9a-octahydro-1H-benzo[7]annulene; (1aR,4R,4aR,7bS)-1,1,4,7-tetramethyl-1a,2,3,4,4a,5,6,7b-octahydro-1H-cyclopropa[e]azulene; 1,4-dimethyl-7-(prop-1-en-2-yl)-1,2,3,4,5,6,7,8-octahydroazulene; (3E,6E)-3,7,11-trimethyldodeca-1,3,6,10-tetraene; 7,7-dimethyl-2-methylenebicyclo[2.2.1]heptane; 2-((2R,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl)propan-2-ol; (R)-1-methyl-4-(6-methylhept-5-en-2-yl)benzene; (3aR,3bR,4S,7R,7aS)-4-isopropyl-7-methyl-3a,3b,4,5,6,7-hexahydro-1H-cyclopenta[1,3]cyclopropa[1,2]benzene; (1aS,2aR,3R,5aS,7R,7aR)-3,6,6,7a-tetramethyloctahydro-2H-2a,7-methanoazuleno[5,6-b]oxirene; (1R,4S,4aR,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; (1S,4aR,8aR)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (R)-2-((R)-4-methylcyclohex-3-en-1-yl)hex-5-en-2-ol; (Z)-1-methyl-4-(6-methylhepta-2,5-dien-2-yl)cyclohex-1-ene; 2,6-dimethyl-6-(4-methylpent-3-en-1-yl)bicyclo[3.1.1]hept-2-ene; (E)-2-benzylideneheptan-1-ol; (E)-2-benzylideneheptyl acetate; (Z)-(2-(diethoxymethyl)hept-1-en-1-yl)benzene; (E)-2-benzylideneheptanal; (1S,4aR,8aS)-1-isopropyl-4,7-dimethyl-1,2,4a,5,6,8a-hexahydronaphthalene; (3R,5aS,9aR)-2,2,5a,9-tetramethyl-3,4,5,5a,6,7-hexahydro-2H-3,9a-methanobenzo[b]oxepine; 1-methyl-4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; 1-phenylpentan-2-ol; 3-methyl-1-phenylpentan-3-ol; 2,3,4-trimethoxybenzaldehyde; 2,4,5-trimethoxybenzaldehyde; 2,4,6-trimethoxybenzaldehyde; Trans,Trans-2,4-Nonadienal; 2,6,10-trimethylundecanal; alpha-4-Dimethyl benzenepropanal; allyl 3-cyclohexylpropanoate; allyl 2-(isopentyloxy)acetate; (1aR,4aS,7R,7aR,7bS)-1,1,7-trimethyl-4-methylenedecahydro-1H-cyclopropa[e]azulene; (E)-undec-9-enal; methyl (E)-2-(((3,5-dimethylcyclohex-3-en-1-yl)methylene)amino)benzoate; 2,6,10-trimethylundec-9-enal; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methyl acetate; nonyl acetate; (2-(1-propoxyethoxy)ethyl)benzene; 1-(1-propoxyethoxy)propane; ((1-(2-methoxyethoxy)ethoxy)methyl)benzene; (Z)-2-(4-methylbenzylidene)heptanal; dec-9-enal; (Z)-oxacycloheptadec-8-en-2-one; 7-methoxy-2H-chromen-2-one; (2S,4aR,8aR)-4a,8-dimethyl-2-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 2-((2S,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl)propan-2-ol; 1-(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethan-1-one; 6-isopropylquinoline; 3-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)propanal; 6,10,14-trimethylpentadecan-2-one; 2-methyl-5-(prop-1-en-2-yl)-2-vinyltetrahydrofuran; (E)-cyclohexadec-5-en-1-one; 1-isopropyl-4-methylcyclohex-3-en-1-ol; 1-phenylpent-4-en-1-one; 1-isopropyl-4-methylcyclohex-3-en-1-ol; 3,6-dimethyl-4,5,6,7-tetrahydrobenzofuran; 4-(4-methoxyphenyl)butan-2-one; (1aR,2S,4aS)-2,4a,8,8-tetramethyloctahydrocyclopropa[d]naphthalen-3(1H)-one; (E)-3-propylideneisobenzofuran-1(3H)-one; (Z)-dodec-2-enal; 3-methyl-5-phenylpentanal; (E)-hex-3-en-1-yl 3-methylbutanoate; 3,6-dimethyloctan-3-yl acetate; 3,4,5-trimethoxybenzaldehyde; 3-(4-isopropylphenyl)propanal; (Z)-undec-2-enenitrile; (E)-undec-2-enal; (2E,6E)-nona-2,6-dienal; phenethyl butyrate; (Z)-3-(furan-2-yl)-2-phenylacrylaldehyde; 2-phenoxyethan-1-ol; (Z)-non-2-enal; nonan-2-ol; nonan-2-one; 2-isobutylquinoline; (E)-2-hexylidenecyclopentan-1-one; 2-heptyltetrahydrofuran; (E)-dec-2-enal; (2E,6E)-nona-2,6-dienal; (2E,6E)-nona-2,6-dien-1-ol; 2,6-dimethyloctanal; decan-1-ol; (E)-hept-1-en-1-yl acetate; undec-10-en-1-ol; undec-10-enal; 2-((2R,4aS)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)propan-2-ol; 1-isopropyl-4-methyl-7-thiabicyclo[2.2.1]heptane; (3E,5Z)-undeca-1,3,5-triene; 3,7-dimethyloct-6-en-3-ol; 1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl acetate; 1,1,2,3,3-pentamethyl-2,3-dihydro-1H-indene; (Z)-6,10-dimethylundeca-5,9-dien-2-yl acetate; (Z)-dodec-3-enal; (S)-5-heptyldihydrofuran-2(3H)-one; (R)-5-heptyldihydrofuran-2(3H)-one; (E)-6,10-dimethylundeca-5,9-dien-2-yl acetate; (Z)-3-methyl-5-phenylpent-2-enenitrile; (2S,5S,6S)-2,6,10,10-tetramethyl-1-oxaspiro[4.5]decan-6-ol; (2E)-3-methyl-5-phenyl-2-pentenenitrile; (1 S,2S,5S)-2-methyl-5-(prop-1-en-2-yl)cyclohexan-1-ol; (2S,5R)-2-isopropyl-5-methylcyclohexan-1-one; (R,E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 2-(8-isopropyl-6-methylbicyclo[2.2.2]oct-5-en-2-yl)-1,3-dioxolane; (E)-4-(2,2-dimethyl-6-methylenecyclohexyl)-3-methylbut-3-en-2-one; 3-(3-isopropylphenyl)butanal; 3-(1-ethoxyethoxy)-3,7-dimethylocta-1,6-diene; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; 2-((3S,3aS,5R)-3,8-dimethyl-1,2,3,3a,4,5,6,7-octahydroazulen-5-yl)propan-2-ol; benzyl 2-phenylacetate; 2-hydroxy-1,2-diphenylethan-1-one; (E)-1,2,4-trimethoxy-5-(prop-1-en-1-yl)benzene; 3-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-2,2-dimethylpropanal; 2-methyl-5-(6-methylhept-5-en-2-yl)bicyclo[3.1.0]hex-2-ene; 1-(1,1,2,3,3,6-hexamethyl-2,3-dihydro-1H-inden-5-yl)ethan-1-one; 2-(m-tolyl)ethan-1-ol; (3E,6E)-nona-3,6-dien-1-ol; (E)-tridec-2-enal; (1R,4S,4aS,6R,8aS)-4,8a,9,9-tetramethyloctahydro-1,6-methanonaphthalen-1(2H)-ol; p-tolyl isobutyrate; p-tolyl hexanoate; 5-hexyl-4-methyldihydrofuran-2(3H)-one; ethyl (2Z,4E)-deca-2,4-dienoate; 2,4-dimethyl-6-phenyl-3,6-dihydro-2H-pyran; 2-cyclohexylidene-2-phenylacetonitrile; 4-(prop-1-en-2-yl)cyclohex-1-ene-1-carbaldehyde; (4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methyl acetate; (4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methanol; (2-isopropoxyethyl)benzene; 2-cyclohexylhepta-1,6-dien-3-one; (2-(cyclohexyloxy)ethyl)benzene; phenethyl 2-methylbutanoate; 2-phenylethan-1-ol; phenethyl 2-phenylacetate; 3-methyl-5-phenylpentan-1-ol; phenyl benzoate; phenethyl benzoate; 2-benzyl-1,3-dioxolane; 2-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)acetaldehyde; 6,6-dimethyl-2-methylenebicyclo[3.1.1]heptan-3-ol; 4-(benzo[d][1,3]dioxol-5-yl)butan-2-one; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl pivalate; (4aR,8aS)-7-methyloctahydro-1,4-methanonaphthalen-6(2H)-one; 4-isopropyl-1-methylcyclohex-3-en-1-ol; (E)-3,3-dimethyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pent-4-en-2-ol; 1-methyl-4-(4-methylpent-3-en-1-yl)cyclohex-3-ene-1-carbaldehyde; propane-1,2-diol; p-tolyl 2-phenylacetate; Ethyl 2,4,7-decatrienoate; 2-benzyl-4,4,6-trimethyl-1,3-dioxane; 2,4-dimethyl-4-phenyltetrahydrofuran; (2R,4a′R,8a′R)-3,7′-dimethyl-3′,4′,4a′,5′,8′,8a′-hexahydro-1′H-spiro[oxirane-2,2′-[1,4]methanonaphthalene]; (Z)-6-ethylideneoctahydro-2H-5,8-methanochromene; 2-((S)-1-((S)-3,3-dimethylcyclohexyl)ethoxy)-2-oxoethyl propionate; methyl 2,2-dimethyl-6-methylenecyclohexane-1-carboxylate; 2-methyl-5-phenylpentan-1-ol; 4-methyl-2-phenyl-3,6-dihydro-2H-pyran; (1S,3R,5S)-1-isopropyl-4-methylenebicyclo[3.1.0]hexan-3-ol; 5-allylbenzo[d][1,3]dioxole; 2,2,7,9-tetramethylspiro(5.5)undec-8-en-1-one; 3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pentan-2-ol; (Z)-2-ethyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; (E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; 1-(3-hydroxy-3-methylpent-4-en-1-yl)-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol; (4aR,6aS,10aS,10bR)-3,4a,7,7,10a-pentamethyl-4a,5,6,6a,7,8,9,10,10a, 10b-decahydro-1H-benzo[f]chromene; (4aR,8aR)-4a,8-dimethyl-2-(propan-2-ylidene)-1,2,3,4,4a,5,6,8a-octahydronaphthalene; 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropyl cyclopropanecarboxylate; 3-(4-isobutylphenyl)-2-methylpropanal; (1aR,4aR,7S,7aR,7bR)-1,1,7-trimethyl-4-methylenedecahydro-1H-cyclopropa[e]azulen-7-ol; (1R,3R,6R)-2′,2′,3,7,7-pentamethylspiro[bicyclo[4.1.0]heptane-2,5′-[1,3]dioxane]; 2-methyl-1,5-dioxaspiro[5.5]undecane; 1-(spiro[4.5]dec-7-en-7-yl)pent-4-en-1-one; 2-(4-methylthiazol-5-yl)ethan-1-ol; 2-(heptan-3-yl)-1,3-dioxolane; (Z)-dodec-4-enal; (1 S,4S,4aR,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; (1S,4S,4aR,8aS)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol; 3-methyl-2-pentylcyclopentan-1-one; 2,6,10,10-tetramethyl-1-oxaspiro[4.5]dec-6-ene; 2-(2-mercaptopropan-2-yl)-5-methylcyclohexan-1-one; (1aR,4aS)-2,4a,8,8-tetramethyl-1,1a,4,4a,5,6,7,8-octahydrocyclopropa[d]naphthalene; 1-isopropyl-2-methoxy-4-methylbenzene; 1-(2,2,6-trimethylcyclohexyl)hexan-3-ol; (2Z,4E)-nona-2,4-dienal; (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol; (2E,6Z)-nona-2,6-dienal; (Z)-dec-2-enal; (E)-non-2-enal; (3E,6Z)-nona-3,6-dien-1-ol; (E)-dec-4-enal; (Z)-oxacycloheptadec-8-en-2-one; (Z)-3,7-dimethylocta-1,3,6-triene; (Z)-3,7-dimethylocta-1,3,6-triene; (E)-3,7-dimethylocta-2,6-dien-1-ol; methyl 2-((1S,2S)-3-oxo-2-pentylcyclopentyl)acetate; 7-(1,1-Dimethylethyl)-2H-1,5-benzodioxepin-3 (4H)-one; (1R-(1alpha,3alpha,4aalpha))-2,3,4,4a,5,6-hexahydro-2,2-dimethyl-1,3-methanonaphthalen-7(1H)-one; tridecan-1-ol; triethyl 2-hydroxypropane-1,2,3-tricarboxylate; methyl 2-((1-hydroxy-3-phenylbutyl)amino)benzoate; 1-((2E,5Z,9Z)-2,6,10-trimethylcyclododeca-2,5,9-trien-1-yl)ethan-1-one; decahydro-2,6,6,7,8,8-hexamethyl-2h-indeno(4,5-b)furan; 13-methyl oxacyclopentadec-10-en-2-one; undecanal; (E)-4-methyldec-3-en-5-ol; (3R,4aS,5R)-4a,5-dimethyl-3-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,7-octahydronaphthalene; 2-((2R,8R,8aS)-8,8a-dimethyl-1,2,3,4,6,7,8,8a-octahydronaphthalen-2-yl)propan-2-ol; 4-formyl-2-methoxyphenyl isobutyrate; (Z)-2-methyl-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-enal; methyl 2,4-dihydroxy-3,6-dimethylbenzoate; 1-methoxy-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoindene; methyl (Z)-2-((3-(4-(tert-butyl)phenyl)-2-methylpropylidene)amino)benzoate; (Z)-hex-3-en-1-yl isobutyrate; 2,4,6-trimethyl-4-phenyl-1,3-dioxane; 1-((3R,3aR,7R,8aS)-3,6,8,8-tetramethyl-2,3,4,7,8,8a-hexahydro-1H-3a,7-methanoazulen-5-yl)ethan-1-one; methyl (Z)-2-(((2,4-dimethylcyclohex-3-en-1-yl)methylene)amino)benzoate; 4,8-dimethyl-2-(propan-2-ylidene)-1,2,3,3a,4,5,6,8a-octahydroazulen-6-ol; 4,8-dimethyl-2-(propan-2-ylidene)-1,2,3,3a,4,5,6,8a-octahydroazulen-6-yl acetate; decahydro-3H-spiro[furan-2,5′-[4,7]methanoindene]; (2Z,6E)-nona-2,6-dienenitrile; (Z)-cyclooct-4-en-1-yl methyl carbonate; (1aR,4S,4aS,7R,7aS,7bS)-1,1,4,7-tetramethyldecahydro-1H-cyclopropa[e]azulen-4-ol; 3,5,5,6,7,8,8-heptamethyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile; (1 S,2S,3S,5R)-2,6,6-trimethylspiro[bicyclo[3.1.1]heptane-3,1′-cyclohexan]-2′-en-4′-one; 1′,1′,5′,5′-tetramethylhexahydro-2′H,5′H-spiro[[1,3]dioxolane-2,8′-[2,4a]methanonaphthalene]; (2'S,4a'S,8a'S)-1′,1′,5′,5′-tetramethylhexahydro-2′H,5′H-spiro[[1,3]dioxolane-2,8′-[2,4a]methanonaphthalene]; 4-(4-hydroxy-3-methoxyphenyl)butan-2-one; (1R,8aR)-4-isopropyl-1,6-dimethyl-1,2,3,7,8,8a-hexahydronaphthalene; 2,4-dimethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolane; 3a,5,6,7,8,8b-hexahydro-2,2,6,6,7,8,8-heptamethyl-4H-indeno(4,5-d)-1,3-dioxole; 2,4-dimethyl-4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; (1-methyl-2-((1,2,2-trimethylbicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methanol; 2-(cyclohexyloxy)-1,7,7-trimethylbicyclo[2.2.1]heptane; 4-((2R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)cyclohexan-1-ol; 8,8-di(1H-indol-1-yl)-2,6-dimethyloctan-2-ol; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methanol; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; (E)-4-((3aR,4R,7R,7aR)-1,3a,4,6,7,7a-hexahydro-5H-4,7-methanoinden-5-ylidene)-3-methylbutan-2-ol; (3R,3aR,6S,7S,8aS)-6-methoxy-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene; (1R,2S,6S,7S,8S)-8-isopropyl-1-methyl-3-methylenetricyclo[4.4.0.02,7]decane; 2′-isopropyl-1,7,7-trimethylspiro[bicyclo[2.2.1]heptane-2,4′-[1,3]dioxane]; (4aR,5R,7aS,9R)-2,2,5,8,8,9a-hexamethyloctahydro-4H-4a,9-methanoazuleno[5,6-d][1,3]dioxole; (3S,5aR,7aS,11aS,11bR)-3,8,8,11a-tetramethyldodecahydro-5H-3,5a-epoxynaphtho[2,1-c]oxepine; 2,2,6,6,7,8,8-heptamethyldecahydro-2H-indeno[4,5-b]furan; (1 aS,2aR,3R,5aS,7R,7aR)-3,6,6,7a-tetramethyloctahydro-2H-2a,7-methanoazuleno[5,6-b]oxirene; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methyl acetate; 1-(3-hydroxy-3-methylpent-4-en-1-yl)-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol; decahydro-2,6,6,7,8,8-hexamethyl-2h-indeno(4,5-b)furan; 4,5-epoxy-4,11,11-trimethyl-8-methylenebicyclo(7.2.0)undecane; 1,3,4,6,7,8alpha-hexahydro-1,1,5,5-tetramethyl-2H-2,4alpha-methanophtalen-8(5H)-one, more preferably said malodor reduction materials are selected from the group consisting of: 3-methoxy-7,7-dimethyl-10-methylenebicyclo[4.3.1]decane; 2,4a,5,8a-tetramethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl formate; 2,2,6,8-tetramethyl-1,2,3,4,4a,5,8,8a-octahydronaphthalen-1-ol; (4R,4aS,6R)-4,4a-dimethyl-6-(prop-1-en-2-yl)-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one; ((3 S,3aR,6R,8aS)-7,7-dimethyl-8-methyleneoctahydro-1H-3a,6-methanoazulen-3-yl)methanol; 4,9-dimethoxy-7H-furo[3,2-g]chromen-7-one; (E)-cyclohexadec-8-en-1-one; (Z)-1-(benzyloxy)-2-methoxy-4-(prop-1-en-1-yl)benzene; 1-((2S,3S)-2,3,8,8-tetramethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-yl)ethan-1-one; (1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate; 2,3-dihydro-3,3-dimethyl-1H-indene-5-propanal; 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)propanal; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl acetate; 2-((2R,4aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)propan-2-ol; 4,6,6,7,8,8-hexamethyl-1,3,4,6,7,8-hexahydrocyclopenta[g]isochromene; (Z)-6-ethylideneoctahydro-2H-5,8-methanochromen-2-one; 8,8-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl acetate; octahydro-1H-4,7-methanoinden-5-yl acetate; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl butyrate; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl isobutyrate; (5R,6R)-3,6-dimethyl-5-(prop-1-en-2-yl)-6-vinyl-4,5,6,7-tetrahydrobenzofuran; (E)-cycloheptadec-9-en-1-one; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-3-yl formate; (3R,3 aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl acetate; (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-ol; 5-methyl-1-(2,2,3-trimethylcyclopent-3-en-1-yl)-6-oxabicyclo[3.2.1]octane; (Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-3-en-5-yl acetate; (1S,2S,5R,8S)-4,4,8-trimethyltricyclo[6.3.1.02,5]dodecan-1-ol; (1S,2S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl isobutyrate; (Z)-2-methyl-5-((1S,2R,4R)-2-methyl-3-methylenebicyclo[2.2.1]heptan-2-yl)pent-2-en-1-ol; (1 S,4R,7R)-1,4,9,9-tetramethyl-1,2,3,4,5,6,7,8-octahydro-4,7-methanoazulene; (1 aS,5aR,9aR)-1a,5,5,7-tetramethyl-1a,2,3,4,5,5a,8,9-octahydrobenzo[1,7]cyclohepta[1,2-b]oxirene; (2,2-dimethoxyethyl)benzene; (3R,3aS,7S,8aS)-3,8,8-trimethyl-6-methyleneoctahydro-1H-3a,7-methanoazulene; 4-methoxybenzyl 2-phenylacetate; 2,2,7,7,8,9,9-heptamethyldecahydroindeno[4,3a-b]furan; (4R,4aS)-4,4a-dimethyl-6-(propan-2-ylidene)-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one; (E)-5-(2,3-dimethyltricyclo[2.2.1.02,6]heptan-3-yl)-2-methylpent-2-en-1-ol; (1R,3aS,7S,8aR)-1,4,9,9-tetramethyl-2,3,6,7,8,8a-hexahydro-1H-3a,7-methanoazulene; (1aR,4R,4aR,7bS)-1,1,4,7-tetramethyl-1a,2,3,4,4a,5,6,7b-octahydro-1H-cyclopropa[e]azulene; 2-((2R,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl)propan-2-ol; (3aR,3bR,4S,7R,7aS)-4-isopropyl-7-methyl-3a,3b,4,5,6,7-hexahydro-1H-cyclopenta[1,3]cyclopropa[1,2]benzene; (3R,5aS,9aR)-2,2,5a,9-tetramethyl-3,4,5,5a,6,7-hexahydro-2H-3,9a-methanobenzo[b]oxepine; (1aR,4aS,7R,7aR,7bS)-1,1,7-trimethyl-4-methylenedecahydro-1H-cyclopropa[e]azulene; 2-((2S,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl)propan-2-ol; 1-(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethan-1-one; (E)-cyclohexadec-5-en-1-one; (1aR,2S,4aS)-2,4a,8,8-tetramethyloctahydrocyclopropa[d]naphthalen-3(1H)-one; 2-((2R,4aS)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)propan-2-ol; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl propionate; 1-(1,1,2,3,3,6-hexamethyl-2,3-dihydro-1H-inden-5-yl)ethan-1-one; (1R,4S,4aS,6R,8aS)-4,8a,9,9-tetramethyloctahydro-1,6-methanonaphthalen-1 (2H)-ol; 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl pivalate; (2R,4a′R,8a′R)-3,7′-dimethyl-3′,4′,4a′,5′,8′,8a′-hexahydro-1′H-spiro[oxirane-2,2′-[1,4]methanonaphthalene]; 2,2,7,9-tetramethylspiro(5.5)undec-8-en-1-one; (Z)-2-ethyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; (4aR,6aS,10aS,10bR)-3,4a,7,7,10a-pentamethyl-4a,5,6,6a,7,8,9,10,10a, 10b-decahydro-1H-benzo[f]chromene; (1aR,4aR,7S,7aR,7bR)-1,1,7-trimethyl-4-methylenedecahydro-1H-cyclopropa[e]azulen-7-ol; 1-(spiro[4.5]dec-7-en-7-yl)pent-4-en-1-one; (1aR,4aS)-2,4a,8,8-tetramethyl-1,1a,4,4a,5,6,7,8-octahydrocyclopropa[d]naphthalene; (1R-(1alpha,3alpha,4aalpha))-2,3,4,4a,5,6-hexahydro-2,2-dimethyl-1,3-methanonaphthalen-7(1H)-one; 2-((2R,8R,8aS)-8,8a-dimethyl-1,2,3,4,6,7,8,8a-octahydronaphthalen-2-yl)propan-2-ol; 1-((3R,3aR,7R,8aS)-3,6,8,8-tetramethyl-2,3,4,7,8,8a-hexahydro-1H-3a,7-methanoazulen-5-yl)ethan-1-one; methyl (Z)-2-(((2,4-dimethylcyclohex-3-en-1-yl)methylene)amino)benzoate; 4,8-dimethyl-2-(propan-2-ylidene)-1,2,3,3a,4,5,6,8a-octahydroazulen-6-yl acetate; decahydro-3H-spiro[furan-2,5′-[4,7]methanoindene]; (1aR,4S,4aS,7R,7aS,7bS)-1,1,4,7-tetramethyldecahydro-1H-cyclopropa[e]azulen-4-ol; 3,5,5,6,7,8,8-heptamethyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile; (1S,2S,3S,5R)-2,6,6-trimethylspiro[bicyclo[3.1.1]heptane-3,1′-cyclohexan]-2′-en-4′-one; 1′,1′,5′,5′-tetramethylhexahydro-2′H,5′H-spiro[[1,3]dioxolane-2,8′-[2,4a]methanonaphthalene]; (2'S,4a'S,8a'S)-1′,1′,5′,5′-tetramethylhexahydro-2′H,5′H-spiro[[1,3]dioxolane-2,8′-[2,4a]methanonaphthalene]; (7,7,8,8-tetramethyloctahydro-2,3b-methanocyclopenta[1,3]cyclopropa[1,2]benzen-4-yl)methanol; 4,5-epoxy-4,11,11-trimethyl-8-methylenebicyclo(7.2.0)undecane; 1,3,4,6,7,8alpha-hexahydro-1,1,5,5-tetramethyl-2H-2,4alpha-methanophtalen-8(5H)-one, most preferably said malodor reduction materials are selected from the group consisting of: (E)-cyclohexadec-5-en-1-one; 2,2,7,7,8,9,9-heptamethyldecahydroindeno[4,3a-b]furan; 2,3-dihydro-3,3-dimethyl-1H-indene-5-propanal; 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)propanal; 4,5-epoxy-4,11,11-trimethyl-8-methylenebicyclo(7.2.0)undecane; 1,3,4,6,7,8alpha-hexahydro-1,1,5,5-tetramethyl-2H-2,4alpha-methanophtalen-8(5H)-one and mixtures thereof. 6. A personal care composition according to any preceeding claim, said composition comprising one or more perfume raw materials. 7. A personal care composition according to any preceeding claim wherein, said sum total of malodor reduction materials has an average Log P, based on weight percent of each malodor reduction material in said sum total of malodor reduction materials, of from about 2.5 to about 8, preferably from about 3 to about 8, more preferably from about 3.5 to about 7, most preferably, each of said malodor reduction materials in said sum total of malodor reduction materials and each of said one or more perfume raw materials has a Log P from about 3.5 to about 7. 8. A personal care composition according to any preceding claim wherein, the ratio of said one or more perfume raw materials to said sum total of malodor reduction material being from about 1000:1 to about 1:1, preferably from about 100:1 to about 1:1, more preferably from about 10:1 to about 1:1, most preferably from about 2:1 to about 1:1. 9. A personal care composition according to any preceding claim, wherein less than 10%, preferably less than 5%, more preferably less than 1% of said malodor reduction materials and said one or more perfume raw materials, based on total combined weight of malodor reduction materials and said one or more perfume raw materials comprise an ionone moiety. 10. A personal care composition according to any preceding claim, wherein said malodor reduction materials are not a material selected from the group consisting of geranyl nitrile; helional; nonanal; linalool; (S)-(+)-linalool; (R)-(−)-linalool; nerol; tetrahydrolinalool; 2-phenylethyl acetate; eugenol; ethyl linalool; allyl heptoate; agrumen nitrile; citronitrile; 2,2-dimethyl-3-(m-tolyl)propan-1-ol; 2-methyl-5-phenylpentan-1-ol; dodecanenitrile; 2-heptylcyclopentan-1-one; methyl nonyl acetaldehyde; 3-(2-ethylphenyl)-2,2-dimethylpropanal; (Z)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-en-1-one; (R,E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 4-(tert-butyl)cyclohexyl acetate; 1-cyclohexylethyl (E)-but-2-enoate; allyl 2-(cyclohexyloxy)acetate; alpha terpinyl acetate; beta terpinyl acetate; gamma terpinyl acetate; methyl dodecyl ether; 2,4-dimethyl-4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine; cinnamyl isobutyrate; (E)-2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)but-2-enal; gamma methyl ionone; ethyl 2,3,6-trimethyl cyclohexyl carbonate ethyl 2,3,6-trimethyl cyclohexyl carbonate; Citral diethyl acetal; Dimethoxycyclododecane; 1-((2S,3S)-2,3,8,8-tetramethyl-1,2,3,4,5,6,7,8-octahydronaphthalen-2-yl)ethan-1-one; oxacyclohexadecan-2-one; 4,6,6,7,8,8-hexamethyl-1,3,4,6,7,8-hexahydrocyclopenta[g]isochromene; Ethylene brassylate; Methyl (Z)-2-((3-(4-(tert-butyl)phenyl)-2-methylpropylidene)amino)benzoate; 4,7-Methano-1H-inden-5-ol, 3a,4,5,6,7,7a-hexahydro-, 5-acetate; cedryl methyl ether; vetivert acetate; 1-((3R,3aR,7R,8aS)-3,6,8,8-tetramethyl-2,3,4,7,8,8a-hexahydro-1H-3a,7-methanoazulen-5-yl)ethan-1-one; Benzophenone; Famesol; trans,trans-famesol; 3-(3-isopropylphenyl)butanal; 2,6,10-trimethylundec-9-enal; 3-(4-(tert-butyl)phenyl)propanal; 3-(4-isopropylphenyl)-2-methylpropanal; Citronellal (1); Citronellal (d); (E)-4,8-dimethyldeca-4,9-dienal; Pino Acetaldehyde; 3-(4-(tert-butyl)phenyl)-2-methylpropanal; Cinnamic aldehyde; Citral; Geranial; Methoxy Melonal; o-methoxycinnamaldehyde; (E)-4-((3aS,7aS)-octahydro-5H-4,7-methanoinden-5-ylidene)butanal; Methyl Octyl Acetaldehyde; 3-(4-methoxyphenyl)-2-methylpropanal; 5-methoxyoctahydro-1H-4,7-methanoindene-2-carbaldehyde; Iso Cyclocitral; Octanal; 2-Undecenal; 10-Undecenal; Trans-trans-2,6-Nonadienal; Trans-2,cis-6-nondienal; Heliotropin; Hexyl Cinnamic aldehyde; p-methyl-alpha-pentylcinnamaldehyde; Alpha-methyl cinnamaldehyde; 3,4-dimethoxybenzaldehyde; Myrtenal; Perillaldehyde; Maceal; Methyl palmitate; Methyl iso eugenol and mixtures thereof. 11. A personal care composition according to any preceeding claim, said composition comprising a total, based on total personal care composition weight, of from about 0.1% to about 7% of one or more of said malodor reduction materials and from about 3% to 30% of a surfactant, and, optionally, a miscellar phase and/or lamellar phase. 12. A personal care composition according to any preceeding claim said composition comprising a total, based on total personal care composition weight, of from about 0.1% to about 50% of a material selected from structurants, humectants, fatty acids, inorganic salts, antimicrobial agents, antimicrobial actives and mixtures thereof. 13. A personal care composition according to any preceding claim, said composition comprising an adjunct ingredient selected from the group consisting of clay mineral powders, pearl pigments, organic powders, emulsifiers, distributing agents, pharmaceutical active, topical active, preservatives, surfactants and mixtures thereof. 14. A method of controlling malodors comprising: contacting a situs comprising a malodor and/or a situs that will become malodorous with a personal care composition selected from the group consisting of the personal care composition of claims 1 to 13. 15. The method of claim 14 wherein, said situs is a body or head of hair and said contacting step comprises contacting said body or head of hair with a sufficient amount of Applicants' personal care composition to provide said body or hair with a level of malodor reduction material at least 0.0001 mg of malodor reduction material per body or head of hair, preferably from about 0.0001 mg of malodor reduction material per body or head of hair to about 1 mg of malodor reduction material per body or head of hair, more preferably from about 0.001 mg of malodor reduction material per body or head of hair about 0.5 mg of malodor reduction material per body or head of hair, most preferably from about 0.01 of malodor reduction material per body or head of hair to about 0.2 mg of malodor reduction material per body or head of hair.
| 1,600 |
947 | 12,663,848 | 1,626 |
Disclosed is a method for protecting an animal from a parasitic invertebrate pest comprising treating an animal orally or by injection with a pesticidally effective amount of a compound of Formula 1,
wherein
R 1 is halogen, C 1 -C 3 haloalkyl or C 1 -C 3 haloalkoxy; R 2 is H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or cyano; R 3 is H, halogen, C 1 -C 3 haloalkyl or C 1 -C 3 haloalkoxy; R 4 is halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 haloalkoxy; R 5 is H, CH 3 , C 2 -C 4 alkylcarbonyl, C 2 -C 4 haloalkylcarbonyl, C 2 -C 5 alkoxycarbonyl or CH 2 O(C 1 -C 3 alkyl); R 6 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl or C 3 -C 6 halocycloalkyl, each group substituted with one R 7 ; or R 6 is (CH 2 ) m Q; and Q, R 7 , R 8a and R 8b are as defined in the disclosure.
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1. A method for protecting an animal from a parasitic invertebrate pest comprising orally or parenterally administering to the animal a pesticidally effective amount of a compound of Formula 1, an N-oxide or a salt thereof
wherein
R1 is halogen, C1-C3 haloalkyl or C1-C3 haloalkoxy;
R2 is H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or cyano;
R3 is H, halogen, C1-C3 haloalkyl or C1-C3 haloalkoxy;
R4 is halogen, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 haloalkoxy;
R5 is H, CH3, C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl, C2-C5 alkoxycarbonyl or CH2O(C1-C3 alkyl);
R6 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl or C3-C6 halocycloalkyl, each group substituted with one R7; or R6 is (CH2)mQ;
Q is a 4- to 6-membered saturated ring containing carbon atoms and one O or S(O)n as ring members and optionally substituted with 1 or 2 R8a and one R8b;
R7 is OR9, S(O)nR10 or C(O)NR11R12; or R7 is pyridine or thiazole, each optionally substituted with 1 or 2 R15;
each R8a is independently halogen, cyano or C1-C2 alkyl;
R8b is OR9, S(O)nR10 or C(O)NR11R12;
R9 is H, CHO, C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl or C2-C5 alkoxycarbonyl; or R9 is C1-C4 alkyl or C1-C4 haloalkyl, each optionally substituted with one R13; or R9 is pyridine or thiazole, each optionally substituted with 1 or 2 R15;
R10 is C1-C4 alkyl or C1-C4 haloalkyl, each optionally substituted with one R13; or R10 is pyridine or thiazole, each optionally substituted with 1 or 2 R15;
R11 is H, CHO, C1-C4 alkyl, C1-C4 haloalkyl, CH2O(C1-C3 alkyl), C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl or C2-C5 alkoxycarbonyl;
R12 is C1-C4 alkyl, C1-C4 haloalkyl or C3-C6 cycloalkyl, each optionally substituted with one R13; or R12 is H, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl or OR14;
R13 is cyano, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, OH, OR14 or S(O)nR16; or R13 is pyridine or thiazole, each optionally substituted with 1 or 2 R15;
R14 is C1-C4 alkyl or C1-C4 haloalkyl;
each R15 is independently halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 haloalkoxy;
R16 is C1-C4 alkyl or C1-C4 haloalkyl;
m is 0 or 1; and
n is 0, 1 or 2. 2. The method of claim 1 wherein
R4 is C1 or CH3; R5 is H; R6 is C1-C6 alkyl substituted with one R7; and R7 is OR9, S(O)nR10 or C(O)NR11R12. 3. The method of claim 2 wherein
R1 is Cl, Br, CF3, OCF3 or OCH2CF3; R2 is H; and R3 is H, F, Cl, Br or CF3. 4. The method of claim 3 wherein
R4 is CH3; and R7 is C(O)NR11R12. 5. The method of claim 4 wherein
R1 is CF3; and R3 is Cl, Br or CF3. 6. The method of claim 4 wherein
R11 is H; and R12 is C1-C4 alkyl or C1-C4 haloalkyl. 7. The method of claim 4 wherein
R11 is H; and R12 is cyclopropyl or cyclopropylmethyl. 8. The method of claim 1 wherein the pesticidally effective amount of a compound of Formula 1 is administered orally. 9. The method of claim 1 wherein the pesticidally effective amount of a compound of Formula 1 is administered parenterally. 10. The method of claim 9 wherein the pesticidally effective amount of a compound of Formula 1 is administered by injection. 11. The method of claim 1 wherein the animal to be protected is a mammal. 12. The method of claim 11 wherein the mammal to be protected is livestock. 13. The method of claim 11 wherein the mammal to be protected is a canine. 14. The method of claim 11 wherein the mammal to be protected is a feline. 15. The method of claim 1 wherein the parasitic invertebrate pest is an ectoparasite. 16. The method of claim 1 wherein the parasitic invertebrate pest is an arthropod. 17. The method of claim 1 wherein the parasitic invertebrate pest is a fly, mosquito, mite, tick, louse, flea, true bug or maggot. 18. The method of claim 17 wherein the animal to be protected is a cat or dog and the parasitic invertebrate pest is a flea, tick or mite.
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Disclosed is a method for protecting an animal from a parasitic invertebrate pest comprising treating an animal orally or by injection with a pesticidally effective amount of a compound of Formula 1,
wherein
R 1 is halogen, C 1 -C 3 haloalkyl or C 1 -C 3 haloalkoxy; R 2 is H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or cyano; R 3 is H, halogen, C 1 -C 3 haloalkyl or C 1 -C 3 haloalkoxy; R 4 is halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 haloalkoxy; R 5 is H, CH 3 , C 2 -C 4 alkylcarbonyl, C 2 -C 4 haloalkylcarbonyl, C 2 -C 5 alkoxycarbonyl or CH 2 O(C 1 -C 3 alkyl); R 6 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl or C 3 -C 6 halocycloalkyl, each group substituted with one R 7 ; or R 6 is (CH 2 ) m Q; and Q, R 7 , R 8a and R 8b are as defined in the disclosure.1. A method for protecting an animal from a parasitic invertebrate pest comprising orally or parenterally administering to the animal a pesticidally effective amount of a compound of Formula 1, an N-oxide or a salt thereof
wherein
R1 is halogen, C1-C3 haloalkyl or C1-C3 haloalkoxy;
R2 is H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or cyano;
R3 is H, halogen, C1-C3 haloalkyl or C1-C3 haloalkoxy;
R4 is halogen, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 haloalkoxy;
R5 is H, CH3, C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl, C2-C5 alkoxycarbonyl or CH2O(C1-C3 alkyl);
R6 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl or C3-C6 halocycloalkyl, each group substituted with one R7; or R6 is (CH2)mQ;
Q is a 4- to 6-membered saturated ring containing carbon atoms and one O or S(O)n as ring members and optionally substituted with 1 or 2 R8a and one R8b;
R7 is OR9, S(O)nR10 or C(O)NR11R12; or R7 is pyridine or thiazole, each optionally substituted with 1 or 2 R15;
each R8a is independently halogen, cyano or C1-C2 alkyl;
R8b is OR9, S(O)nR10 or C(O)NR11R12;
R9 is H, CHO, C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl or C2-C5 alkoxycarbonyl; or R9 is C1-C4 alkyl or C1-C4 haloalkyl, each optionally substituted with one R13; or R9 is pyridine or thiazole, each optionally substituted with 1 or 2 R15;
R10 is C1-C4 alkyl or C1-C4 haloalkyl, each optionally substituted with one R13; or R10 is pyridine or thiazole, each optionally substituted with 1 or 2 R15;
R11 is H, CHO, C1-C4 alkyl, C1-C4 haloalkyl, CH2O(C1-C3 alkyl), C2-C4 alkylcarbonyl, C2-C4 haloalkylcarbonyl or C2-C5 alkoxycarbonyl;
R12 is C1-C4 alkyl, C1-C4 haloalkyl or C3-C6 cycloalkyl, each optionally substituted with one R13; or R12 is H, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl or OR14;
R13 is cyano, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, OH, OR14 or S(O)nR16; or R13 is pyridine or thiazole, each optionally substituted with 1 or 2 R15;
R14 is C1-C4 alkyl or C1-C4 haloalkyl;
each R15 is independently halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 haloalkoxy;
R16 is C1-C4 alkyl or C1-C4 haloalkyl;
m is 0 or 1; and
n is 0, 1 or 2. 2. The method of claim 1 wherein
R4 is C1 or CH3; R5 is H; R6 is C1-C6 alkyl substituted with one R7; and R7 is OR9, S(O)nR10 or C(O)NR11R12. 3. The method of claim 2 wherein
R1 is Cl, Br, CF3, OCF3 or OCH2CF3; R2 is H; and R3 is H, F, Cl, Br or CF3. 4. The method of claim 3 wherein
R4 is CH3; and R7 is C(O)NR11R12. 5. The method of claim 4 wherein
R1 is CF3; and R3 is Cl, Br or CF3. 6. The method of claim 4 wherein
R11 is H; and R12 is C1-C4 alkyl or C1-C4 haloalkyl. 7. The method of claim 4 wherein
R11 is H; and R12 is cyclopropyl or cyclopropylmethyl. 8. The method of claim 1 wherein the pesticidally effective amount of a compound of Formula 1 is administered orally. 9. The method of claim 1 wherein the pesticidally effective amount of a compound of Formula 1 is administered parenterally. 10. The method of claim 9 wherein the pesticidally effective amount of a compound of Formula 1 is administered by injection. 11. The method of claim 1 wherein the animal to be protected is a mammal. 12. The method of claim 11 wherein the mammal to be protected is livestock. 13. The method of claim 11 wherein the mammal to be protected is a canine. 14. The method of claim 11 wherein the mammal to be protected is a feline. 15. The method of claim 1 wherein the parasitic invertebrate pest is an ectoparasite. 16. The method of claim 1 wherein the parasitic invertebrate pest is an arthropod. 17. The method of claim 1 wherein the parasitic invertebrate pest is a fly, mosquito, mite, tick, louse, flea, true bug or maggot. 18. The method of claim 17 wherein the animal to be protected is a cat or dog and the parasitic invertebrate pest is a flea, tick or mite.
| 1,600 |
948 | 16,149,759 | 1,611 |
Core-shell capsules comprising a fragrance-containing core and a shell formed around said core, wherein the shell is formed of polycarboxylic acid having a molecular weight of 1,000 to 10,000,000 Daltons
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1. (canceled) 2. (canceled) 3. (canceled) 4. (canceled) 5. (canceled) 6. (canceled) 7. (canceled) 8. (canceled) 9. (canceled) 10. (canceled) 11. (canceled) 12. (canceled) 13. (canceled) 14. A method of encapsulation of a beneficial agent, comprising the steps of:
a) dispersing oil droplets comprising said beneficial agent in an external phase comprising an aqueous medium having a pH of less than about 6 to form a dispersed phase; and b) causing the formation around the dispersed phase of a sequential series of as least two layers, wherein the first layer is a poly(methacrylic acid) polymer having a molecular weight of from 1,000 to 10,000,000 Daltons, and the second layer is a poly(pyrrolidone) polymer, and wherein additional layers are layers alternating layers of a poly(methacrylic acid) polymer and a poly(pyrrolidone) polymer. 15. The method according to claim 14, wherein the beneficial agent is a fragrance composition. 16. The method of claim 14, wherein the aqueous medium has a pH of less from about 2 to about 6. 17. The method of claim 16, wherein the aqueous medium has a pH of less from about 2 to 4. 18. The method of claim 14 wherein the aqueous medium further comprises stabiliser and/or a buffer. 19. A consumer product composition having a pH of less than 6, selected from laundry cleaners and softeners, personal care and hair care products including shampoo, conditioners, combing creams, leave on conditioners, styling cream, soaps, body creams; deodorants and anti-perspirants; household applications, fine fragrance and oral care products, comprising core-shell capsules formed from the method of claim 14. 20. A method of stabilising core-shell capsules formed by the method of claim 14, the method comprising the step of storing them in a suitable medium at a pH of less than about 6. 21. The method of claim 14, wherein any carboxylic acid monomer contained in the capsules is present in an amount of 10 ppm or less. 22. The method of claim 21, wherein any carboxylic acid monomer contained in the capsules is present in an amount of 1 ppm or less.
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Core-shell capsules comprising a fragrance-containing core and a shell formed around said core, wherein the shell is formed of polycarboxylic acid having a molecular weight of 1,000 to 10,000,000 Daltons1. (canceled) 2. (canceled) 3. (canceled) 4. (canceled) 5. (canceled) 6. (canceled) 7. (canceled) 8. (canceled) 9. (canceled) 10. (canceled) 11. (canceled) 12. (canceled) 13. (canceled) 14. A method of encapsulation of a beneficial agent, comprising the steps of:
a) dispersing oil droplets comprising said beneficial agent in an external phase comprising an aqueous medium having a pH of less than about 6 to form a dispersed phase; and b) causing the formation around the dispersed phase of a sequential series of as least two layers, wherein the first layer is a poly(methacrylic acid) polymer having a molecular weight of from 1,000 to 10,000,000 Daltons, and the second layer is a poly(pyrrolidone) polymer, and wherein additional layers are layers alternating layers of a poly(methacrylic acid) polymer and a poly(pyrrolidone) polymer. 15. The method according to claim 14, wherein the beneficial agent is a fragrance composition. 16. The method of claim 14, wherein the aqueous medium has a pH of less from about 2 to about 6. 17. The method of claim 16, wherein the aqueous medium has a pH of less from about 2 to 4. 18. The method of claim 14 wherein the aqueous medium further comprises stabiliser and/or a buffer. 19. A consumer product composition having a pH of less than 6, selected from laundry cleaners and softeners, personal care and hair care products including shampoo, conditioners, combing creams, leave on conditioners, styling cream, soaps, body creams; deodorants and anti-perspirants; household applications, fine fragrance and oral care products, comprising core-shell capsules formed from the method of claim 14. 20. A method of stabilising core-shell capsules formed by the method of claim 14, the method comprising the step of storing them in a suitable medium at a pH of less than about 6. 21. The method of claim 14, wherein any carboxylic acid monomer contained in the capsules is present in an amount of 10 ppm or less. 22. The method of claim 21, wherein any carboxylic acid monomer contained in the capsules is present in an amount of 1 ppm or less.
| 1,600 |
949 | 15,568,244 | 1,632 |
Described herein are vectors, such as adeno-associated virus (AAV) vectors, and recombinant AAV expressing Smad7. The disclosed AAV vectors and rAAV can be used for therapeutic applications in the treatment and amelioration of muscle wasting, cardiac and/or skeletal muscle wasting associated with cancer cachexia.
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1. A composition comprising a Smad7 gene or cDNA in a recombinant adeno-assisted virus (rAAV) construct, wherein the rAAV construct provides expression of the Smad7 gene or cDNA in muscle cells. 2. The composition of claim 1, wherein the rAAV construct is serotype 6 (rAAV6), serotype 8 (rAAV8), or serotype 9 (rAAV9). 3. The composition of claim 1, wherein the Smad7 gene or cDNA is of human, mouse, equine, bovine, ovine, canine, or porcine origin. 4. The composition of claim 1, wherein the Smad7 gene or cDNA expressed is a constitutively active mutant. 5. The composition of claim 1, wherein the rAAV construct comprises a tissue-specific promoter or enhancer that directs expression of the Smad7 gene or cDNA in muscle cells. 6. The composition of claim 5, wherein the rAAV construct provides expression of the Smad7 gene or cDNA in cardiac muscle cells, skeletal muscle cells, or both. 7. The composition of claim 1, wherein the rAAV construct comprises a tissue-specific silencer that limits expression of the Smad7 gene or cDNA to muscle cells or to heart cells. 8. A method of enhancing muscle mass and/or strength in a subject, comprising administering to the subject a therapeutically effective amount of the composition of claim 1. 9. The method of claim 8, wherein the subject is not diagnosed with a muscle-wasting disorder or disease. 10. A method of treating muscle wasting in a subject diagnosed with a cancer cachexia, comprising selecting a subject with cancer cachexia and administering to the subject a therapeutically effective amount of the composition of claim 1. 11. A method of treating muscle wasting to increase muscle strength and/or muscle volume using the composition of claim 1. 12. A method of inhibiting or preventing muscle wasting in a subject, comprising administering to the subject a therapeutically effective amount of the composition of claim 1. 13. The method of claim 12, wherein the muscle wasting is caused by a chronic disorder. 14. The method of claim 13, wherein the chronic disorder comprises cancer, aging (sarcopenia), muscular dystrophy, myopathies, kidney disease, chronic obstructive pulmonary disorder, chronic infection, AIDS, disuse atrophy, neuromuscular injury, neuropathies, obesity, cardiovascular disease, or a combination of two or more thereof. 15. The method of claim 12, wherein muscle wasting is caused by microgravity stress. 16. The method of claim 12, wherein the muscle wasting comprises wasting of cardiac muscle, skeletal muscle, or both. 17. The method of claim 8, comprising delivering the composition via intramuscular or intravenous injections. 18. The method of claim 8, wherein administering the rAAV comprises administration of a single dose of rAAV. 19. The method of claim 8, wherein administering the rAAV comprises administration of multiple doses of rAAV.
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Described herein are vectors, such as adeno-associated virus (AAV) vectors, and recombinant AAV expressing Smad7. The disclosed AAV vectors and rAAV can be used for therapeutic applications in the treatment and amelioration of muscle wasting, cardiac and/or skeletal muscle wasting associated with cancer cachexia.1. A composition comprising a Smad7 gene or cDNA in a recombinant adeno-assisted virus (rAAV) construct, wherein the rAAV construct provides expression of the Smad7 gene or cDNA in muscle cells. 2. The composition of claim 1, wherein the rAAV construct is serotype 6 (rAAV6), serotype 8 (rAAV8), or serotype 9 (rAAV9). 3. The composition of claim 1, wherein the Smad7 gene or cDNA is of human, mouse, equine, bovine, ovine, canine, or porcine origin. 4. The composition of claim 1, wherein the Smad7 gene or cDNA expressed is a constitutively active mutant. 5. The composition of claim 1, wherein the rAAV construct comprises a tissue-specific promoter or enhancer that directs expression of the Smad7 gene or cDNA in muscle cells. 6. The composition of claim 5, wherein the rAAV construct provides expression of the Smad7 gene or cDNA in cardiac muscle cells, skeletal muscle cells, or both. 7. The composition of claim 1, wherein the rAAV construct comprises a tissue-specific silencer that limits expression of the Smad7 gene or cDNA to muscle cells or to heart cells. 8. A method of enhancing muscle mass and/or strength in a subject, comprising administering to the subject a therapeutically effective amount of the composition of claim 1. 9. The method of claim 8, wherein the subject is not diagnosed with a muscle-wasting disorder or disease. 10. A method of treating muscle wasting in a subject diagnosed with a cancer cachexia, comprising selecting a subject with cancer cachexia and administering to the subject a therapeutically effective amount of the composition of claim 1. 11. A method of treating muscle wasting to increase muscle strength and/or muscle volume using the composition of claim 1. 12. A method of inhibiting or preventing muscle wasting in a subject, comprising administering to the subject a therapeutically effective amount of the composition of claim 1. 13. The method of claim 12, wherein the muscle wasting is caused by a chronic disorder. 14. The method of claim 13, wherein the chronic disorder comprises cancer, aging (sarcopenia), muscular dystrophy, myopathies, kidney disease, chronic obstructive pulmonary disorder, chronic infection, AIDS, disuse atrophy, neuromuscular injury, neuropathies, obesity, cardiovascular disease, or a combination of two or more thereof. 15. The method of claim 12, wherein muscle wasting is caused by microgravity stress. 16. The method of claim 12, wherein the muscle wasting comprises wasting of cardiac muscle, skeletal muscle, or both. 17. The method of claim 8, comprising delivering the composition via intramuscular or intravenous injections. 18. The method of claim 8, wherein administering the rAAV comprises administration of a single dose of rAAV. 19. The method of claim 8, wherein administering the rAAV comprises administration of multiple doses of rAAV.
| 1,600 |
950 | 15,948,359 | 1,628 |
in which R1, R2, R3, R4, R5, R6, X, and a are defined herein, or a pharmaceutically acceptable salt thereof. Also disclosed are a pharmaceutical composition comprising a compound or salt thereof of Formula (I) and a method of treating a disease which benefits from the modulation of the vitamin D receptor, such as a bone disorder, cardiovascular disease, a cardiovascular complication associated with renal disease, endothelial dysfunction, hyperparathyroidism, hypocalcemia, an immune disorder, left ventricular hypertrophy, a proliferative disease, proteinuria, renal disease, and thrombosis.
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1. A compound of Formula (I)
wherein
R1 is ═CH2; or
R1 and the carbon to which it is bonded together form a cyclopropyl group;
R4 and R5 are the same or different and each is selected from the group consisting of H, C1-12 alkyl, hydroxyl, C1-12 alkoxy, and halo;
wherein said C1-C12 alkyl and said C1-C12 alkoxy are optionally and independently substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aroyl, halo, monohaloalkyl, dihaloalkyl, trihaloalkyl, monohaloalkoxy, dihaloalkoxy, trihaloalkoxy, hydroxy, alkoxy, alkoxycarbonyl, cycloalkyloxy, heterocyclooxy, oxo, alkanoyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocyclyl, aryloxy, alkanoyloxy, amino, monoalkylamino, dialkylamino, trialkylamino, arylamino, arylalkylamino, cycloalkylamino, heterocycloamino, alkanoylamino, aroylamino, aralkanoylamino, mercapto, alkylthio, arylthio, arylalkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, arylalkylthiono, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfamato NH2SO2O—, alkylsulfamato, sulfonamido —SO2NH2, alkyl sulfonamido, nitro, cyano, carboxy, carbamyl NH2CO—, monosubstituted carbamyl selected from alkyl-NH—CO, aryl-NH—CO and arylalkyl-NH—CO and disubstituted carbamyl selected from dialkyl-NCO, diaryl-N—CO and alkyl-aryl-N—CO;
R6 is C1-12 alkyl or aryl;
wherein said C1-C12 alkyl is optionally and independently substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aroyl, halo, monohaloalkyl, dihaloalkyl, trihaloalkyl, monohaloalkoxy, dihaloalkoxy, trihaloalkoxy, hydroxy, alkoxy, alkoxycarbonyl, cycloalkyloxy, heterocyclooxy, oxo, alkanoyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocyclyl, aryloxy, alkanoyloxy, amino, monoalkylamino, dialkylamino, trialkylamino, arylamino, arylalkylamino, cycloalkylamino, heterocycloamino, alkanoylamino, aroylamino, aralkanoylamino, mercapto, alkylthio, arylthio, arylalkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, arylalkylthiono, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfamato NH2SO2O—, alkylsulfamato, sulfonamido —SO2NH2, alkyl sulfonamido, nitro, cyano, carboxy, carbamyl NH2CO—, monosubstituted carbamyl selected from alkyl-NH—CO, aryl-NH—CO and arylalkyl-NH—CO, and disubstituted carbamyl selected from dialkyl-N—CO, diaryl-N—CO and alkyl-aryl-N—CO; and
wherein said aryl is optionally independently substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aroyl, halo, monohaloalkyl, dihaloalkyl or trihaloalkyl, monohaloalkoxy, dihaloalkoxy or trihaloalkoxy, hydroxy, alkoxy, alkoxycarbonyl, cycloalkyloxy, heterocyclooxy, oxo, alkanoyl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocyclyl, aryloxy, alkanoyloxy, amino, monoalkylamino, dialkylamino or trialkylamino, arylamino, arylalkylamino, cycloalkylamino, heterocycloamino, alkanoylamino, aroylamino, aralkanoylamino, mercapto, alkylthio, arylthio, arylalkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, arylalkylthiono, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfamato NH2SO2O—, alkylsulfamato, sulfonamido —SO2NH2, alkyl sulfonamido, nitro, cyano, carboxy, carbamyl NH2CO—, and monosubstituted carbamyl selected from alkyl-NH—CO, aryl-NH—CO and arylalkyl-NHCO, and disubstituted carbamyl selected from dialkyl-N—CO, diaryl-N—CO and alkylaryl-N—CO;
X is oxygen or sulfur; and
a is 0-5;
provided that when a is 1-5, then R6 is optionally substituted aryl, the optional substituents of aryl being as defined above;
and when a is 0, R is optionally substituted C1-12 alkyl, the optional substituents of C1-12 alkyl being as defined above;
or a pharmaceutically acceptable salt thereof. 2. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein X is oxygen. 3. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein X is sulfur. 4. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein R1 is ═CH2. 5. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein R1 is cyclopropyl. 6. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein R4 and R5 are each H. 7. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein a is 0 and R6 is selected from one or more of (i) optionally substituted C1-12 alkyl; and (ii) C1-12 alkyl or hydroxy C1-12 alkyl, the optional substituents as defined above. 8. The compound or a pharmaceutically acceptable salt thereof of claim 7, wherein R6 is isopentyl, 3-hydroxy-3-methylbutyl, 2,3-dimethylbutyl, 2,3-dimethyl-3-hydroxybutyl, 3-ethylpentyl, 3-ethyl-3-hydroxypentyl, 4-ethylhexyl, or 4-ethyl-4-hydroxyhexyl. 9. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein a is 1 to 5 and R6 is selected from one or more of (i) optionally substituted aryl; and (ii) aryl substituted with a C1-12 alkyl or a C1-12 hydroxyalkyl, the optional substituents as defined above. 10. The compound or a pharmaceutically acceptable salt thereof of claim 9, wherein R6 is aryl substituted with isopropyl or 2-hydroxypropan-2-yl. 11. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein a is 1. 12. The compound or a pharmaceutically acceptable salt thereof of claim 1 wherein the compound is selected from the group consisting of
(1R, 3R)-5-((E)-2-((3αS, 7αS)-1-((R)-1-((S)-3-hydroxy-2,3-dimethylbutoxy)ethyl)-7α-methyldihydro-1H-inden-4(2H, 5H, 6H, 7H, 7αH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Vida-5);
(4R,8R)-6-((E)-2-((1S,7S)-1-((R)-1-(3-ethyl-3-hydroxypentyloxy)ethyl)-7α-methyldihydro-1H-inden-4(2H, 5H,6H, 7H, 7αH)-ylidene)ethylidene)spiro[2.5]octane-4,8-diol (Vida-10);
(4R, 8R)-6-((E)-2-((1S, 7αS)-1-((R)-1-(4-ethyl-4-hydroxyhexyloxy)ethyl)-7α-methyldihydro-1H-inden-4(2H,5H,6H, 7H, 7αH)-ylidene)ethylidene)spiro[2.5]octane-4,8-diol (Vida-20);
(1R, 3R)-5-((E)-2-((1S, 3αS, 7αS)-1-((R)-1-(3-ethyl-3-hydroxypentyloxy)ethyl)-7α-methyldihydro-1H-inden-4(2H, 5H, 6H, 7H, 7αH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Vida-11);
(1R, 3R)-5-((E)-2-((1S, 7αS)-1-((R)-1-(4-ethyl-4-hydroxyhexyloxy)ethyl)-7α-methyldihydro-1H-inden-4(2H, 5H, 6H, 7H, 7a/H)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Vida-21);
(4R,8R)-6-((E)-2-((1S, 7αS)-1-((R)-1-(3-hydroxy-3-methylbutoxy)ethyl)-7α-methyldihydro-1H-inden-4(2H,5H,6H, 7H, 7αH)-ylidene)ethylidene)spiro[2.5]octane-4,8-diol (Vida-1);
(4R,8R)-6-((E)-2-((3αS, 7αS)-1-((R)-1-((S)-3-hydroxy-2,3-dimethylbutoxy)ethyl)-7α-methyldihydro-1H-inden-4(2H, 5H, 6H, 7H, 7αH)-lidene)ethylidene)spiro[2.5]octane-4,8-diol (Vida-4);
(4R,8R)-6-((E)-2-(1-((R)-1-(3-(2-hydroxypropan-2-yl)phenoxy)propan-2-yl)-7α-methydihydro-1H-inden-4(2H,5H, 6H,7H,7αH)-ylidene)ethylidene)spiro[2.5]octane-4,8-diol (Vida-57);
(4R, 8R)-6-((E)-2-(1-((R)-1-(3-(2-hydroxypropan-2-yl)phenylthio)propan-2-yl)-7α-methyldihydro-1H-inden-4(2H, 5H, 6H, 7H, 7αH)-ylidene)ethylidene)spiro[2.5]octane-4,8-diol (Vida-58);
(1R,3R)-5-((E)-2-(1-((R)-1-(3-(2-hydroxypropan-2-yl)phenoxy)propan-2-yl)-7α-methyldihydro-1H-inden-4(2H, 5H, 6H, 7H, 7αH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Vida-37);
(1R,3R)-5-((E)-2-(1-((R)-1-(3-(2-hydroxypropan-2-yl)phenythio)propan-2-yl)-7α-methyldihydro-1H-inden-4(2H,5H, 6H, 7H, 7αH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Vida-43);
(4R, 8R)-6-((E)-2-((1S, 7αS)-1-((R)-1-(3-methylbutoxy)ethyl)-7α-methyldihydro-1H-inden-4(2H,5H,6H, 7H, 7αH)-ylidene)ethylidene)spiro[2.5]octane-4,8-diol (Vida-81);
(4R, 8R)-6-((E)-2-((3αS, 7αS)-1-((R)-1-((S)-2,3-dimethylbutoxy)ethyl)-7α-methyldihydro-1H-inden-4(2H,5H,6H, 7H, 7αH)-ylidene)ethylidene)spiro[2.5]octane-4,8-diol (Vida-84);
(1R,3R)-5-((E)-2-((3αS, 7αS)-1-((R)-1-((S)-2,3-dimethylbutoxy)ethyl)-7α-methyldihydro-1H-inden-4(2H, 5H, 6H, 7H, 7αH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Vida-85);
(4R, 8R)-6-((E)-2-((1S, 7αS)-1-((R)-1-(3-ethyl-pentyloxy)ethyl)-7α-methyldihydro-1H-inden-4(2H,5H,6H, 7H, 7αH)-ylidene)ethylidene)spiro[2.5]octane-4,8-diol (Vida-90);
(1R, 3R)-5-((E)-2-((1S, 3αS, 7αS)-1-((R)-1-(3-ethyl-pentyloxy)ethyl)-7α-methyldihydro-1H-inden-4(2H,5H,6H, 7H, 7αH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Vida-91);
(4R, 8R)-6-((E)-2-((1S, 7αS)-1-((R)-1-(4-ethyl-hexyloxy)ethyl)-7α-methyldihydro-1H-inden-4(2H,5H,6H, 7H, 7αH)-ylidene)ethylidene)spiro[2.5]octane-4,8-diol (Vida-100);
(1R,3R)-5-((E)-2-((1S, 7αS)-1-((R)-1-(4-ethyl-hexyloxy)ethyl)-7α-methyldihydro-1H-inden-4(2H, 5H, 6H, 7H, 7αH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Vida-101);
(1R,3R)-5-((E)-2-(1-((R)-1-(3-isopropylphenoxy)propan-2-yl)-7α-methyldihydro-1H-inden-4(2H,5H,6H, 7H, 7αH)-ylidene)ethylidene)-2-methylenecyclohexane-,3-diol (Vida-117);
(1R, 3R)-5-((E)-2-(1-((R)-1-(3-isopropylphenylthio)propan-2-yl)-7α-methyldihydro-1-H-inden-4(2H,5H,6H, 7H, 7αH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Vida-123) (4R, 8R)-6-((E)-2-(1-((R)-1-(3-isopropylphenoxy)propan-2-yl)-7α-methyldihydro-1H-inden-4(2H,5H,6H, 7H, 7αH)-ylidene)ethylidene)spiro[2.5]octane-4,8-diol (Vida-137); and
(4R,8R)-6-((E)-2-(1-((R)-1-(3-isopropylphenylthio)propan-2-yl)-7α-methyldihydro-1H-inden-4(2H,5H,6H, 7H, 7αH)-ylidene)ethylidene)spiro[2.5]octane-4,8-diol (Vida-138). 13. A pharmaceutical composition comprising (i) a compound or a pharmaceutically acceptable salt thereof of claim 1 and (ii) a pharmaceutically acceptable carrier. 14. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 for use in a method of treating a disease which benefits from a modulation of the vitamin D receptor. 15. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 for use in a method of medical treatment for a disease which is selected from the group consisting of hypocalcemia, cancer, psoriasis, hyperparathyroidism, osteoporosis, secondary hyperparathyroidism, proteinuria/renal disease progression, endothelial dysfunction, left ventricular hypertrophy, aging, metabolic syndrome, insulin resistance, obesity, viral infection, bacterial infection, musculoskeletal disorders, high blood pressure, hypertriglyceridemia, immune disorders, multiple sclerosis, myelodysplastic syndrome, proximal myopathy, seasonal affective disorder, senile warts, skin pigmentation disorders, and thrombosis. 16. A pharmaceutical composition comprising (i) a compound or a pharmaceutically acceptable salt thereof of claim 12 and (ii) a pharmaceutically acceptable carrier. 17. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 12 for use in a method of treating a disease which benefits from a modulation of the vitamin D receptor. 18. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 12 for use in a method of medical treatment for a disease which is selected from the group consisting of hypocalcemia, cancer, psoriasis, hyperparathyroidism, osteoporosis, secondary hyperparathyroidism, proteinuria/renal disease progression, endothelial dysfunction, left ventricular hypertrophy, aging, metabolic syndrome, insulin resistance, obesity, viral infection, bacterial infection, musculoskeletal disorders, high blood pressure, hypertriglyceridemia, immune disorders, multiple sclerosis, myelodysplastic syndrome, proximal myopathy, seasonal affective disorder, senile warts, skin pigmentation disorders, and thrombosis.
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in which R1, R2, R3, R4, R5, R6, X, and a are defined herein, or a pharmaceutically acceptable salt thereof. Also disclosed are a pharmaceutical composition comprising a compound or salt thereof of Formula (I) and a method of treating a disease which benefits from the modulation of the vitamin D receptor, such as a bone disorder, cardiovascular disease, a cardiovascular complication associated with renal disease, endothelial dysfunction, hyperparathyroidism, hypocalcemia, an immune disorder, left ventricular hypertrophy, a proliferative disease, proteinuria, renal disease, and thrombosis.1. A compound of Formula (I)
wherein
R1 is ═CH2; or
R1 and the carbon to which it is bonded together form a cyclopropyl group;
R4 and R5 are the same or different and each is selected from the group consisting of H, C1-12 alkyl, hydroxyl, C1-12 alkoxy, and halo;
wherein said C1-C12 alkyl and said C1-C12 alkoxy are optionally and independently substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aroyl, halo, monohaloalkyl, dihaloalkyl, trihaloalkyl, monohaloalkoxy, dihaloalkoxy, trihaloalkoxy, hydroxy, alkoxy, alkoxycarbonyl, cycloalkyloxy, heterocyclooxy, oxo, alkanoyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocyclyl, aryloxy, alkanoyloxy, amino, monoalkylamino, dialkylamino, trialkylamino, arylamino, arylalkylamino, cycloalkylamino, heterocycloamino, alkanoylamino, aroylamino, aralkanoylamino, mercapto, alkylthio, arylthio, arylalkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, arylalkylthiono, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfamato NH2SO2O—, alkylsulfamato, sulfonamido —SO2NH2, alkyl sulfonamido, nitro, cyano, carboxy, carbamyl NH2CO—, monosubstituted carbamyl selected from alkyl-NH—CO, aryl-NH—CO and arylalkyl-NH—CO and disubstituted carbamyl selected from dialkyl-NCO, diaryl-N—CO and alkyl-aryl-N—CO;
R6 is C1-12 alkyl or aryl;
wherein said C1-C12 alkyl is optionally and independently substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aroyl, halo, monohaloalkyl, dihaloalkyl, trihaloalkyl, monohaloalkoxy, dihaloalkoxy, trihaloalkoxy, hydroxy, alkoxy, alkoxycarbonyl, cycloalkyloxy, heterocyclooxy, oxo, alkanoyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocyclyl, aryloxy, alkanoyloxy, amino, monoalkylamino, dialkylamino, trialkylamino, arylamino, arylalkylamino, cycloalkylamino, heterocycloamino, alkanoylamino, aroylamino, aralkanoylamino, mercapto, alkylthio, arylthio, arylalkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, arylalkylthiono, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfamato NH2SO2O—, alkylsulfamato, sulfonamido —SO2NH2, alkyl sulfonamido, nitro, cyano, carboxy, carbamyl NH2CO—, monosubstituted carbamyl selected from alkyl-NH—CO, aryl-NH—CO and arylalkyl-NH—CO, and disubstituted carbamyl selected from dialkyl-N—CO, diaryl-N—CO and alkyl-aryl-N—CO; and
wherein said aryl is optionally independently substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aroyl, halo, monohaloalkyl, dihaloalkyl or trihaloalkyl, monohaloalkoxy, dihaloalkoxy or trihaloalkoxy, hydroxy, alkoxy, alkoxycarbonyl, cycloalkyloxy, heterocyclooxy, oxo, alkanoyl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocyclyl, aryloxy, alkanoyloxy, amino, monoalkylamino, dialkylamino or trialkylamino, arylamino, arylalkylamino, cycloalkylamino, heterocycloamino, alkanoylamino, aroylamino, aralkanoylamino, mercapto, alkylthio, arylthio, arylalkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, arylalkylthiono, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfamato NH2SO2O—, alkylsulfamato, sulfonamido —SO2NH2, alkyl sulfonamido, nitro, cyano, carboxy, carbamyl NH2CO—, and monosubstituted carbamyl selected from alkyl-NH—CO, aryl-NH—CO and arylalkyl-NHCO, and disubstituted carbamyl selected from dialkyl-N—CO, diaryl-N—CO and alkylaryl-N—CO;
X is oxygen or sulfur; and
a is 0-5;
provided that when a is 1-5, then R6 is optionally substituted aryl, the optional substituents of aryl being as defined above;
and when a is 0, R is optionally substituted C1-12 alkyl, the optional substituents of C1-12 alkyl being as defined above;
or a pharmaceutically acceptable salt thereof. 2. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein X is oxygen. 3. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein X is sulfur. 4. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein R1 is ═CH2. 5. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein R1 is cyclopropyl. 6. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein R4 and R5 are each H. 7. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein a is 0 and R6 is selected from one or more of (i) optionally substituted C1-12 alkyl; and (ii) C1-12 alkyl or hydroxy C1-12 alkyl, the optional substituents as defined above. 8. The compound or a pharmaceutically acceptable salt thereof of claim 7, wherein R6 is isopentyl, 3-hydroxy-3-methylbutyl, 2,3-dimethylbutyl, 2,3-dimethyl-3-hydroxybutyl, 3-ethylpentyl, 3-ethyl-3-hydroxypentyl, 4-ethylhexyl, or 4-ethyl-4-hydroxyhexyl. 9. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein a is 1 to 5 and R6 is selected from one or more of (i) optionally substituted aryl; and (ii) aryl substituted with a C1-12 alkyl or a C1-12 hydroxyalkyl, the optional substituents as defined above. 10. The compound or a pharmaceutically acceptable salt thereof of claim 9, wherein R6 is aryl substituted with isopropyl or 2-hydroxypropan-2-yl. 11. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein a is 1. 12. The compound or a pharmaceutically acceptable salt thereof of claim 1 wherein the compound is selected from the group consisting of
(1R, 3R)-5-((E)-2-((3αS, 7αS)-1-((R)-1-((S)-3-hydroxy-2,3-dimethylbutoxy)ethyl)-7α-methyldihydro-1H-inden-4(2H, 5H, 6H, 7H, 7αH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Vida-5);
(4R,8R)-6-((E)-2-((1S,7S)-1-((R)-1-(3-ethyl-3-hydroxypentyloxy)ethyl)-7α-methyldihydro-1H-inden-4(2H, 5H,6H, 7H, 7αH)-ylidene)ethylidene)spiro[2.5]octane-4,8-diol (Vida-10);
(4R, 8R)-6-((E)-2-((1S, 7αS)-1-((R)-1-(4-ethyl-4-hydroxyhexyloxy)ethyl)-7α-methyldihydro-1H-inden-4(2H,5H,6H, 7H, 7αH)-ylidene)ethylidene)spiro[2.5]octane-4,8-diol (Vida-20);
(1R, 3R)-5-((E)-2-((1S, 3αS, 7αS)-1-((R)-1-(3-ethyl-3-hydroxypentyloxy)ethyl)-7α-methyldihydro-1H-inden-4(2H, 5H, 6H, 7H, 7αH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Vida-11);
(1R, 3R)-5-((E)-2-((1S, 7αS)-1-((R)-1-(4-ethyl-4-hydroxyhexyloxy)ethyl)-7α-methyldihydro-1H-inden-4(2H, 5H, 6H, 7H, 7a/H)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Vida-21);
(4R,8R)-6-((E)-2-((1S, 7αS)-1-((R)-1-(3-hydroxy-3-methylbutoxy)ethyl)-7α-methyldihydro-1H-inden-4(2H,5H,6H, 7H, 7αH)-ylidene)ethylidene)spiro[2.5]octane-4,8-diol (Vida-1);
(4R,8R)-6-((E)-2-((3αS, 7αS)-1-((R)-1-((S)-3-hydroxy-2,3-dimethylbutoxy)ethyl)-7α-methyldihydro-1H-inden-4(2H, 5H, 6H, 7H, 7αH)-lidene)ethylidene)spiro[2.5]octane-4,8-diol (Vida-4);
(4R,8R)-6-((E)-2-(1-((R)-1-(3-(2-hydroxypropan-2-yl)phenoxy)propan-2-yl)-7α-methydihydro-1H-inden-4(2H,5H, 6H,7H,7αH)-ylidene)ethylidene)spiro[2.5]octane-4,8-diol (Vida-57);
(4R, 8R)-6-((E)-2-(1-((R)-1-(3-(2-hydroxypropan-2-yl)phenylthio)propan-2-yl)-7α-methyldihydro-1H-inden-4(2H, 5H, 6H, 7H, 7αH)-ylidene)ethylidene)spiro[2.5]octane-4,8-diol (Vida-58);
(1R,3R)-5-((E)-2-(1-((R)-1-(3-(2-hydroxypropan-2-yl)phenoxy)propan-2-yl)-7α-methyldihydro-1H-inden-4(2H, 5H, 6H, 7H, 7αH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Vida-37);
(1R,3R)-5-((E)-2-(1-((R)-1-(3-(2-hydroxypropan-2-yl)phenythio)propan-2-yl)-7α-methyldihydro-1H-inden-4(2H,5H, 6H, 7H, 7αH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Vida-43);
(4R, 8R)-6-((E)-2-((1S, 7αS)-1-((R)-1-(3-methylbutoxy)ethyl)-7α-methyldihydro-1H-inden-4(2H,5H,6H, 7H, 7αH)-ylidene)ethylidene)spiro[2.5]octane-4,8-diol (Vida-81);
(4R, 8R)-6-((E)-2-((3αS, 7αS)-1-((R)-1-((S)-2,3-dimethylbutoxy)ethyl)-7α-methyldihydro-1H-inden-4(2H,5H,6H, 7H, 7αH)-ylidene)ethylidene)spiro[2.5]octane-4,8-diol (Vida-84);
(1R,3R)-5-((E)-2-((3αS, 7αS)-1-((R)-1-((S)-2,3-dimethylbutoxy)ethyl)-7α-methyldihydro-1H-inden-4(2H, 5H, 6H, 7H, 7αH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Vida-85);
(4R, 8R)-6-((E)-2-((1S, 7αS)-1-((R)-1-(3-ethyl-pentyloxy)ethyl)-7α-methyldihydro-1H-inden-4(2H,5H,6H, 7H, 7αH)-ylidene)ethylidene)spiro[2.5]octane-4,8-diol (Vida-90);
(1R, 3R)-5-((E)-2-((1S, 3αS, 7αS)-1-((R)-1-(3-ethyl-pentyloxy)ethyl)-7α-methyldihydro-1H-inden-4(2H,5H,6H, 7H, 7αH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Vida-91);
(4R, 8R)-6-((E)-2-((1S, 7αS)-1-((R)-1-(4-ethyl-hexyloxy)ethyl)-7α-methyldihydro-1H-inden-4(2H,5H,6H, 7H, 7αH)-ylidene)ethylidene)spiro[2.5]octane-4,8-diol (Vida-100);
(1R,3R)-5-((E)-2-((1S, 7αS)-1-((R)-1-(4-ethyl-hexyloxy)ethyl)-7α-methyldihydro-1H-inden-4(2H, 5H, 6H, 7H, 7αH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Vida-101);
(1R,3R)-5-((E)-2-(1-((R)-1-(3-isopropylphenoxy)propan-2-yl)-7α-methyldihydro-1H-inden-4(2H,5H,6H, 7H, 7αH)-ylidene)ethylidene)-2-methylenecyclohexane-,3-diol (Vida-117);
(1R, 3R)-5-((E)-2-(1-((R)-1-(3-isopropylphenylthio)propan-2-yl)-7α-methyldihydro-1-H-inden-4(2H,5H,6H, 7H, 7αH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Vida-123) (4R, 8R)-6-((E)-2-(1-((R)-1-(3-isopropylphenoxy)propan-2-yl)-7α-methyldihydro-1H-inden-4(2H,5H,6H, 7H, 7αH)-ylidene)ethylidene)spiro[2.5]octane-4,8-diol (Vida-137); and
(4R,8R)-6-((E)-2-(1-((R)-1-(3-isopropylphenylthio)propan-2-yl)-7α-methyldihydro-1H-inden-4(2H,5H,6H, 7H, 7αH)-ylidene)ethylidene)spiro[2.5]octane-4,8-diol (Vida-138). 13. A pharmaceutical composition comprising (i) a compound or a pharmaceutically acceptable salt thereof of claim 1 and (ii) a pharmaceutically acceptable carrier. 14. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 for use in a method of treating a disease which benefits from a modulation of the vitamin D receptor. 15. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 for use in a method of medical treatment for a disease which is selected from the group consisting of hypocalcemia, cancer, psoriasis, hyperparathyroidism, osteoporosis, secondary hyperparathyroidism, proteinuria/renal disease progression, endothelial dysfunction, left ventricular hypertrophy, aging, metabolic syndrome, insulin resistance, obesity, viral infection, bacterial infection, musculoskeletal disorders, high blood pressure, hypertriglyceridemia, immune disorders, multiple sclerosis, myelodysplastic syndrome, proximal myopathy, seasonal affective disorder, senile warts, skin pigmentation disorders, and thrombosis. 16. A pharmaceutical composition comprising (i) a compound or a pharmaceutically acceptable salt thereof of claim 12 and (ii) a pharmaceutically acceptable carrier. 17. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 12 for use in a method of treating a disease which benefits from a modulation of the vitamin D receptor. 18. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 12 for use in a method of medical treatment for a disease which is selected from the group consisting of hypocalcemia, cancer, psoriasis, hyperparathyroidism, osteoporosis, secondary hyperparathyroidism, proteinuria/renal disease progression, endothelial dysfunction, left ventricular hypertrophy, aging, metabolic syndrome, insulin resistance, obesity, viral infection, bacterial infection, musculoskeletal disorders, high blood pressure, hypertriglyceridemia, immune disorders, multiple sclerosis, myelodysplastic syndrome, proximal myopathy, seasonal affective disorder, senile warts, skin pigmentation disorders, and thrombosis.
| 1,600 |
951 | 15,596,529 | 1,658 |
Hydrogel compositions and methods of using hydrogel compositions are disclosed. Advantageously, the hydrogel compositions offer the ability to promote cellular expansion and/or cellular differentiation of various cells.
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1. A hydrogel composition comprising an 8-arm, 20 kDa polyethylene glycol functionalized with norbornene, a crosslinking peptide, and a cell adhesion peptide. 2. The hydrogel composition of claim 1 comprising at least 1 mM cell adhesion peptide selected from the group consisting of CRGDS (SEQ ID NO: 2), Acetylated-GCYGRGDSPG (SEQ ID NO:31), cyclic RGD (SEQ ID NO:35), CRGD-(G)13-PHSRN (SEQ ID NO:29), CPHSRN-(SG)5-RGD (SEQ ID NO:30) and IKVAV (SEQ ID NO:38). 3. The hydrogel composition of claim 2 comprising a shear modulus range of from about 2 kPa to about 12 kPa. 4. The hydrogel composition of claim 2 comprising a shear modulus of from about 1.8 kPa to about 33 kPa. 5. The hydrogel composition of claim 1 comprising a concentration of polyethylene glycol of from about 36 mg/mL to about 160 mg/mL. 6. The hydrogel composition of claim 1 comprising a concentration of polyethylene glycol of from about 36 mg/mL to about 70 mg/mL. 7. The hydrogel composition of claim 1 comprising at least 0.25 mM of cell adhesion peptide selected from the group consisting of CRGDS (SEQ ID NO: 2), Acetylated-GCYGRGDSPG (SEQ ID NO:31), cyclic RGD (SEQ ID NO:35), CRGD-(G)13-PHSRN (SEQ ID NO:29), CPHSRN-(SG)5-RGD (SEQ ID NO:30) and IKVAV (SEQ ID NO:38). 8. The hydrogel composition of claim 7 comprising a shear modulus of from about 3 kPa to about 16 kPa. 9. The hydrogel composition of claim 1 further comprising an immobilized low molecular weight heparin. 10. The hydrogel composition of claim 1, wherein the crosslinking peptide is selected from the group consisting of KCGGPQGIWGQGCK (SEQ ID NO:27), KCGGPQGIAGQGCK (SEQ ID NO:28) and combinations thereof. 11. The hydrogel composition of claim 1 comprising an extent of crosslinking, wherein the extent of crosslinking is from about 35% to about 75%. 12. A hydrogel composition comprising a polyethylene glycol functionalized with norbornene, a crosslinking peptide, and at least 1 mM cell adhesion peptide selected from the group consisting of CRGDS (SEQ ID NO: 2), Acetylated-GCYGRGDSPG (SEQ ID NO:31), cyclic RGD (SEQ ID NO:35), CRGD-(G)13-PHSRN (SEQ ID NO:29), CPHSRN-(SG)5-RGD (SEQ ID NO:30) and IKVAV (SEQ ID NO:38), wherein the hydrogel composition comprises a shear modulus in the range of about 1.8 kPa to about 33 kPa. 13. The hydrogel composition of claim 12, wherein the shear modulus is in the range of about 2 kPa to about 12 kPa. 14. The hydrogel composition of claim 12 comprising at least 0.25 mM of cell adhesion peptide selected from the group consisting of CRGDS (SEQ ID NO: 2), Acetylated-GCYGRGDSPG (SEQ ID NO:31), cyclic RGD (SEQ ID NO:35), CRGD-(G)13-PHSRN (SEQ ID NO:29), CPHSRN-(SG)5-RGD (SEQ ID NO:30) and IKVAV (SEQ ID NO:38). 15. The hydrogel composition of claim 14, wherein the shear modulus is in the range of from about 3 kPa to about 16 kPa. 16. The hydrogel composition of claim 12, wherein the crosslinking peptide is selected from the group consisting of KCGGPQGIWGQGCK (SEQ ID NO:27), KCGGPQGIAGQGCK (SEQ ID NO:28) and combinations thereof. 17. A hydrogel composition comprising a polyethylene glycol functionalized with norbornene, a crosslinking peptide, and at least 1 mM cell adhesion peptide selected from the group consisting of CRGDS (SEQ ID NO: 2), Acetylated-GCYGRGDSPG (SEQ ID NO:31), cyclic RGD (SEQ ID NO:35), CRGD-(G)13-PHSRN (SEQ ID NO:29), CPHSRN-(SG)5-RGD (SEQ ID NO:30) and IKVAV (SEQ ID NO:38), wherein the hydrogel composition comprises a concentration of polyethylene glycol of from about 36 mg/mL to about 160 mg/mL. 18. The hydrogel composition of claim 17, wherein the concentration of polyethylene glycol is in the range of from about 36 mg/mL to about 70 mg/mL. 19. The hydrogel composition of claim 17 comprising at least 0.25 mM of cell adhesion peptide selected from the group consisting of CRGDS (SEQ ID NO: 2), Acetylated-GCYGRGDSPG (SEQ ID NO:31), cyclic RGD (SEQ ID NO:35), CRGD-(G)13-PHSRN (SEQ ID NO:29), CPHSRN-(SG)5-RGD (SEQ ID NO:30) and IKVAV (SEQ ID NO:38). 20. The hydrogel composition of claim 17, wherein the crosslinking peptide is selected from the group consisting of KCGGPQGIWGQGCK (SEQ ID NO:27), KCGGPQGIAGQGCK (SEQ ID NO:28) and combinations thereof.
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Hydrogel compositions and methods of using hydrogel compositions are disclosed. Advantageously, the hydrogel compositions offer the ability to promote cellular expansion and/or cellular differentiation of various cells.1. A hydrogel composition comprising an 8-arm, 20 kDa polyethylene glycol functionalized with norbornene, a crosslinking peptide, and a cell adhesion peptide. 2. The hydrogel composition of claim 1 comprising at least 1 mM cell adhesion peptide selected from the group consisting of CRGDS (SEQ ID NO: 2), Acetylated-GCYGRGDSPG (SEQ ID NO:31), cyclic RGD (SEQ ID NO:35), CRGD-(G)13-PHSRN (SEQ ID NO:29), CPHSRN-(SG)5-RGD (SEQ ID NO:30) and IKVAV (SEQ ID NO:38). 3. The hydrogel composition of claim 2 comprising a shear modulus range of from about 2 kPa to about 12 kPa. 4. The hydrogel composition of claim 2 comprising a shear modulus of from about 1.8 kPa to about 33 kPa. 5. The hydrogel composition of claim 1 comprising a concentration of polyethylene glycol of from about 36 mg/mL to about 160 mg/mL. 6. The hydrogel composition of claim 1 comprising a concentration of polyethylene glycol of from about 36 mg/mL to about 70 mg/mL. 7. The hydrogel composition of claim 1 comprising at least 0.25 mM of cell adhesion peptide selected from the group consisting of CRGDS (SEQ ID NO: 2), Acetylated-GCYGRGDSPG (SEQ ID NO:31), cyclic RGD (SEQ ID NO:35), CRGD-(G)13-PHSRN (SEQ ID NO:29), CPHSRN-(SG)5-RGD (SEQ ID NO:30) and IKVAV (SEQ ID NO:38). 8. The hydrogel composition of claim 7 comprising a shear modulus of from about 3 kPa to about 16 kPa. 9. The hydrogel composition of claim 1 further comprising an immobilized low molecular weight heparin. 10. The hydrogel composition of claim 1, wherein the crosslinking peptide is selected from the group consisting of KCGGPQGIWGQGCK (SEQ ID NO:27), KCGGPQGIAGQGCK (SEQ ID NO:28) and combinations thereof. 11. The hydrogel composition of claim 1 comprising an extent of crosslinking, wherein the extent of crosslinking is from about 35% to about 75%. 12. A hydrogel composition comprising a polyethylene glycol functionalized with norbornene, a crosslinking peptide, and at least 1 mM cell adhesion peptide selected from the group consisting of CRGDS (SEQ ID NO: 2), Acetylated-GCYGRGDSPG (SEQ ID NO:31), cyclic RGD (SEQ ID NO:35), CRGD-(G)13-PHSRN (SEQ ID NO:29), CPHSRN-(SG)5-RGD (SEQ ID NO:30) and IKVAV (SEQ ID NO:38), wherein the hydrogel composition comprises a shear modulus in the range of about 1.8 kPa to about 33 kPa. 13. The hydrogel composition of claim 12, wherein the shear modulus is in the range of about 2 kPa to about 12 kPa. 14. The hydrogel composition of claim 12 comprising at least 0.25 mM of cell adhesion peptide selected from the group consisting of CRGDS (SEQ ID NO: 2), Acetylated-GCYGRGDSPG (SEQ ID NO:31), cyclic RGD (SEQ ID NO:35), CRGD-(G)13-PHSRN (SEQ ID NO:29), CPHSRN-(SG)5-RGD (SEQ ID NO:30) and IKVAV (SEQ ID NO:38). 15. The hydrogel composition of claim 14, wherein the shear modulus is in the range of from about 3 kPa to about 16 kPa. 16. The hydrogel composition of claim 12, wherein the crosslinking peptide is selected from the group consisting of KCGGPQGIWGQGCK (SEQ ID NO:27), KCGGPQGIAGQGCK (SEQ ID NO:28) and combinations thereof. 17. A hydrogel composition comprising a polyethylene glycol functionalized with norbornene, a crosslinking peptide, and at least 1 mM cell adhesion peptide selected from the group consisting of CRGDS (SEQ ID NO: 2), Acetylated-GCYGRGDSPG (SEQ ID NO:31), cyclic RGD (SEQ ID NO:35), CRGD-(G)13-PHSRN (SEQ ID NO:29), CPHSRN-(SG)5-RGD (SEQ ID NO:30) and IKVAV (SEQ ID NO:38), wherein the hydrogel composition comprises a concentration of polyethylene glycol of from about 36 mg/mL to about 160 mg/mL. 18. The hydrogel composition of claim 17, wherein the concentration of polyethylene glycol is in the range of from about 36 mg/mL to about 70 mg/mL. 19. The hydrogel composition of claim 17 comprising at least 0.25 mM of cell adhesion peptide selected from the group consisting of CRGDS (SEQ ID NO: 2), Acetylated-GCYGRGDSPG (SEQ ID NO:31), cyclic RGD (SEQ ID NO:35), CRGD-(G)13-PHSRN (SEQ ID NO:29), CPHSRN-(SG)5-RGD (SEQ ID NO:30) and IKVAV (SEQ ID NO:38). 20. The hydrogel composition of claim 17, wherein the crosslinking peptide is selected from the group consisting of KCGGPQGIWGQGCK (SEQ ID NO:27), KCGGPQGIAGQGCK (SEQ ID NO:28) and combinations thereof.
| 1,600 |
952 | 12,850,269 | 1,653 |
The claimed subject matter comprises a device to collect and preserve cells comprising of: (1) a collection container comprised of a tube having an open end and a closed end, a closure in the open end of the tube, a vacuum drawn to a predetermined level inside the container; and (2) compounds including an anticoagulant agent and a fixative agent, wherein the compounds are in a sufficient amount to preserve said cells” original morphology and antigenic sites without significant dilution of said cells, and thereby allowing said cells to be directly analyzed by a flow cytometer without further treatment. The claimed subject matter further comprises of a method of making a collection device for cells comprising of: (1) providing a tube having an open end and a closed end; (2) preloading compounds including: an anticoagulant agent, and a fixative agent into the tube, wherein the compounds are in a sufficient amount to preserve the cells” original morphology and antigenic sites without significant dilution of the cells, and thereby allowing the cells to be directly analyzed by a flow cytometer without further treatment; (3) inserting a closure into the open end of the tube; and (4) drawing a vacuum inside the tube to a predetermined level to form the collection device.
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1. A method of preserving biological specimens for disease diagnosis comprising:
providing a tube having an open end and a closed end; preloading compounds including: a fixative agent into said tube, said fixative agent capable of stabilizing abnormal cells such as cancer cells; placing a biological specimen containing cancer cells into the tube; wherein said compounds prevent significant in vitro cell clumping and dilution of said cells at room temperature. 2-27. (canceled) 28. The method of claim 1, wherein the fixative agent is a formaldehyde donor capable of releasing free formaldehyde. 29. The method of claim 1, wherein the fixative agent is imidazolidinyl urea. 30. The method of claim 1, wherein the preloaded compounds include polyethylene glycol. 31. The method of claim 1, wherein the preloaded compounds include an anti-coagulating agent. 32. The method of claim 31, wherein the anti-coagulating agent is a chelating agent. 33. The method of claim 32, wherein the anti-coagulating agent is ethylenediamine tetraacetic acid (EDTA). 34. The method of claim 31, wherein the fixative agent and anti-coagulating agent are combined prior to contact with the biological specimen. 35. The method of claim 34, wherein the anti-coagulating agent is a chelating agent. 36. The method of claim 35, wherein the anti-coagulating agent is ethylenediamine tetraacetic acid (EDTA). 37. The method of claim 31, wherein the anti-coagulating agents and fixative agents are present in volumes of about 0.5% to about 2% of the total volume of the biological specimen and compounds combined. 38. A method for preserving blood samples suspected to contain cancer cells comprising:
a. obtaining a biological specimen that contains cells; b. contacting the biological specimen with a fixative agent capable of stabilizing cancer cells; c. mixing the fixative agent and biological specimen where the mixing prevents in vitro formation of cell clumps and in vitro cell dilution during storage at room temperature. 39. The method of claim 38, wherein the fixative agent is a formaldehyde donor capable of releasing free formaldehyde. 40. The method of claim 38, wherein the fixative agent is imidazolidinyl urea. 41. The method of claim 38, wherein the preloaded compounds include polyethylene glycol. 42. The method of claim 41, wherein the preloaded compounds include an anti-coagulating agent. 43. The method of claim 42, wherein the anti-coagulating agent is a chelating agent. 44. The method of claim 43, wherein the anti-coagulating agent is ethylenediamine tetraacetic acid (EDTA). 45. The method of claim 42, wherein the fixative agent and anti-coagulating agent are combined prior to contact with the biological specimen. 46. The method of claim 45, wherein the anti-coagulating agent is a chelating agent. 47. The method of claim 46, wherein the anti-coagulating agent is ethylenediamine tetraacetic acid (EDTA). 48. The method of claim 42, wherein the anti-coagulating agents and fixative agents are present in volumes of about 0.5% to about 2% of the total volume of the biological specimen and compounds combined.
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The claimed subject matter comprises a device to collect and preserve cells comprising of: (1) a collection container comprised of a tube having an open end and a closed end, a closure in the open end of the tube, a vacuum drawn to a predetermined level inside the container; and (2) compounds including an anticoagulant agent and a fixative agent, wherein the compounds are in a sufficient amount to preserve said cells” original morphology and antigenic sites without significant dilution of said cells, and thereby allowing said cells to be directly analyzed by a flow cytometer without further treatment. The claimed subject matter further comprises of a method of making a collection device for cells comprising of: (1) providing a tube having an open end and a closed end; (2) preloading compounds including: an anticoagulant agent, and a fixative agent into the tube, wherein the compounds are in a sufficient amount to preserve the cells” original morphology and antigenic sites without significant dilution of the cells, and thereby allowing the cells to be directly analyzed by a flow cytometer without further treatment; (3) inserting a closure into the open end of the tube; and (4) drawing a vacuum inside the tube to a predetermined level to form the collection device.1. A method of preserving biological specimens for disease diagnosis comprising:
providing a tube having an open end and a closed end; preloading compounds including: a fixative agent into said tube, said fixative agent capable of stabilizing abnormal cells such as cancer cells; placing a biological specimen containing cancer cells into the tube; wherein said compounds prevent significant in vitro cell clumping and dilution of said cells at room temperature. 2-27. (canceled) 28. The method of claim 1, wherein the fixative agent is a formaldehyde donor capable of releasing free formaldehyde. 29. The method of claim 1, wherein the fixative agent is imidazolidinyl urea. 30. The method of claim 1, wherein the preloaded compounds include polyethylene glycol. 31. The method of claim 1, wherein the preloaded compounds include an anti-coagulating agent. 32. The method of claim 31, wherein the anti-coagulating agent is a chelating agent. 33. The method of claim 32, wherein the anti-coagulating agent is ethylenediamine tetraacetic acid (EDTA). 34. The method of claim 31, wherein the fixative agent and anti-coagulating agent are combined prior to contact with the biological specimen. 35. The method of claim 34, wherein the anti-coagulating agent is a chelating agent. 36. The method of claim 35, wherein the anti-coagulating agent is ethylenediamine tetraacetic acid (EDTA). 37. The method of claim 31, wherein the anti-coagulating agents and fixative agents are present in volumes of about 0.5% to about 2% of the total volume of the biological specimen and compounds combined. 38. A method for preserving blood samples suspected to contain cancer cells comprising:
a. obtaining a biological specimen that contains cells; b. contacting the biological specimen with a fixative agent capable of stabilizing cancer cells; c. mixing the fixative agent and biological specimen where the mixing prevents in vitro formation of cell clumps and in vitro cell dilution during storage at room temperature. 39. The method of claim 38, wherein the fixative agent is a formaldehyde donor capable of releasing free formaldehyde. 40. The method of claim 38, wherein the fixative agent is imidazolidinyl urea. 41. The method of claim 38, wherein the preloaded compounds include polyethylene glycol. 42. The method of claim 41, wherein the preloaded compounds include an anti-coagulating agent. 43. The method of claim 42, wherein the anti-coagulating agent is a chelating agent. 44. The method of claim 43, wherein the anti-coagulating agent is ethylenediamine tetraacetic acid (EDTA). 45. The method of claim 42, wherein the fixative agent and anti-coagulating agent are combined prior to contact with the biological specimen. 46. The method of claim 45, wherein the anti-coagulating agent is a chelating agent. 47. The method of claim 46, wherein the anti-coagulating agent is ethylenediamine tetraacetic acid (EDTA). 48. The method of claim 42, wherein the anti-coagulating agents and fixative agents are present in volumes of about 0.5% to about 2% of the total volume of the biological specimen and compounds combined.
| 1,600 |
953 | 14,994,913 | 1,648 |
The present invention relates to a pharmaceutical composition comprising a modified mRNA that is stabilised by sequence modifications and optimised for translation. The pharmaceutical composition according to the invention is particularly well suited for use as an inoculating agent, as well as a therapeutic agent for tissue regeneration. In addition, a process is described for determining sequence modifications that promote stabilisation and translational efficiency of modified mRNA of the invention.
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1. A method for stimulating an anti-influenza immune response in a subject comprising administering an effective amount of a pharmaceutical composition comprising a mRNA that encodes an influenza virus antigen to the subject. 2. The method of claim 1, wherein the influenza virus antigen is an influenza virus surface antigen. 3. The method of claim 1, wherein the pharmaceutical composition is administered by injection. 4. The method of claim 1, wherein the pharmaceutical composition is administered intravenously, intradermally, subcutaneously, intramuscularly, topically or orally 5. The method of claim 4, wherein the pharmaceutical composition is administered intradermally. 6. The method of claim 1, wherein the mRNA that encodes the influenza virus antigen comprises an increased G/C content relative to a wild type RNA encoding the influenza virus antigen. 7. The method of claim 1, wherein the mRNA encoding the influenza virus antigen comprises a sequence wherein at least one codon of a wild-type sequence recognized by a rare cellular tRNA is replaced with a codon recognized by an abundant cellular tRNA, and wherein said rare cellular tRNA and said abundant cellular tRNA recognize the same amino acid. 8. The method of claim 1, wherein the mRNA encoding the influenza virus antigen comprises at least one nucleotide position replaced with a nucleotide analogue selected from the group consisting of phosphorus amidates, phosphorus thioates, peptide nucleotides, methylphosphonates, 7-deazaguanosine, 5-methylcytosine and inosine. 9. The method of claim 1, wherein the mRNA further encodes a secretory leader. 10. The method of claim 1, wherein the mRNA is dissolved in the aqueous carrier. 11. The method of claim 10, wherein the aqueous carrier is water for injection (WFI), a buffered solution or a salt solution. 12. The method of claim 11, wherein the salt solution comprises sodium chloride or potassium chloride solution. 13. The method of claim 1, wherein the pharmaceutical composition comprises a component selected from the group consisting of human serum albumin, a polycationic protein, polysorbate 80, a sugar and an amino acid. 14. The method of claim 13, wherein pharmaceutical composition comprises a polycationic protein. 15. The method of claim 14, wherein the polycationic protein comprises protamine. 16. The method of claim 15, wherein the mRNA is in complex with protamine. 17. The method of claim 1, wherein the pharmaceutical composition further comprises an adjuvant. 18. The method of claim 1, further comprising administering the composition to the subject two or more times. 19. The method of claim 1, further comprising administering a cytokine to the subject. 20. The method of claim 19, wherein the cytokine comprises GM-CSF. 21. The method of claim 1, wherein the composition is administered intradermally and wherein the mRNA is provided in complex with protamine and encodes an influenza virus surface antigen.
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The present invention relates to a pharmaceutical composition comprising a modified mRNA that is stabilised by sequence modifications and optimised for translation. The pharmaceutical composition according to the invention is particularly well suited for use as an inoculating agent, as well as a therapeutic agent for tissue regeneration. In addition, a process is described for determining sequence modifications that promote stabilisation and translational efficiency of modified mRNA of the invention.1. A method for stimulating an anti-influenza immune response in a subject comprising administering an effective amount of a pharmaceutical composition comprising a mRNA that encodes an influenza virus antigen to the subject. 2. The method of claim 1, wherein the influenza virus antigen is an influenza virus surface antigen. 3. The method of claim 1, wherein the pharmaceutical composition is administered by injection. 4. The method of claim 1, wherein the pharmaceutical composition is administered intravenously, intradermally, subcutaneously, intramuscularly, topically or orally 5. The method of claim 4, wherein the pharmaceutical composition is administered intradermally. 6. The method of claim 1, wherein the mRNA that encodes the influenza virus antigen comprises an increased G/C content relative to a wild type RNA encoding the influenza virus antigen. 7. The method of claim 1, wherein the mRNA encoding the influenza virus antigen comprises a sequence wherein at least one codon of a wild-type sequence recognized by a rare cellular tRNA is replaced with a codon recognized by an abundant cellular tRNA, and wherein said rare cellular tRNA and said abundant cellular tRNA recognize the same amino acid. 8. The method of claim 1, wherein the mRNA encoding the influenza virus antigen comprises at least one nucleotide position replaced with a nucleotide analogue selected from the group consisting of phosphorus amidates, phosphorus thioates, peptide nucleotides, methylphosphonates, 7-deazaguanosine, 5-methylcytosine and inosine. 9. The method of claim 1, wherein the mRNA further encodes a secretory leader. 10. The method of claim 1, wherein the mRNA is dissolved in the aqueous carrier. 11. The method of claim 10, wherein the aqueous carrier is water for injection (WFI), a buffered solution or a salt solution. 12. The method of claim 11, wherein the salt solution comprises sodium chloride or potassium chloride solution. 13. The method of claim 1, wherein the pharmaceutical composition comprises a component selected from the group consisting of human serum albumin, a polycationic protein, polysorbate 80, a sugar and an amino acid. 14. The method of claim 13, wherein pharmaceutical composition comprises a polycationic protein. 15. The method of claim 14, wherein the polycationic protein comprises protamine. 16. The method of claim 15, wherein the mRNA is in complex with protamine. 17. The method of claim 1, wherein the pharmaceutical composition further comprises an adjuvant. 18. The method of claim 1, further comprising administering the composition to the subject two or more times. 19. The method of claim 1, further comprising administering a cytokine to the subject. 20. The method of claim 19, wherein the cytokine comprises GM-CSF. 21. The method of claim 1, wherein the composition is administered intradermally and wherein the mRNA is provided in complex with protamine and encodes an influenza virus surface antigen.
| 1,600 |
954 | 15,744,322 | 1,643 |
The present invention provides a method for treating a tumor comprising administering an effective amount of an antibody which specifically binds to human CC chemokine receptor 4, human epidermal growth factor receptor 2, human CD20, or epidermal growth factor receptor, and an indoleamine 2,3-dioxygenase inhibitor to a human in need thereof, and the like.
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1-210. (canceled) 211. A method for treating a tumor comprising administering an effective amount of
(i) (a) an antibody which specifically binds to human CC chemokine receptor 4, human epidermal growth factor receptor 2, human CD20, or epidermal growth factor receptor, or (b) an antibody which specifically binds to human folate receptor 1, human IL-3Rα or human TIM-3, and (ii) an indoleamine 2,3-dioxygenase inhibitor to a human in need thereof. 212. The method according to claim 211, wherein the indoleamine 2,3-dioxygenase inhibitor is Compound (I) represented by formula (I)
wherein
R6 and R7 may be the same or different, and each represents a hydrogen atom, or optionally substituted lower alkyl,
R8, R9, R10, and R11 may be the same or different, and each represents a hydrogen atom, halogen, cyano, or lower alkyl,
R1 represents lower alkyl which may be substituted with lower alkoxy, and
R3 represents an optionally substituted aromatic heterocyclic group,
or a pharmaceutically acceptable salt thereof,
or Compound (II) represented by formula (II)
wherein
R22 represents halogen, cyano, trifluoromethyl, or lower alkyl,
R23 represents a hydrogen atom, or halogen, and
n represents 1 or 2,
or a pharmaceutically acceptable salt thereof. 213. The method according to claim 211, wherein the antibody is (a) an antibody which specifically binds to human CC chemokine receptor 4, human epidermal growth factor receptor 2, human CD20, or epidermal growth factor receptor, wherein the antibody which specifically binds to human CC chemokine receptor 4, human epidermal growth factor receptor 2, human CD20, or epidermal growth factor receptor is mogamulizumab, trastuzumab, rituximab or cetuximab, respectively. 214. The method according to claim 211, wherein the antibody and the indoleamine 2,3-dioxygenase inhibitor are administered simultaneously or sequentially. 215. The method according to claim 211, wherein the antibody and the indoleamine 2,3-dioxygenase inhibitor are administered separately at intervals. 216. The method according to 211, wherein the tumor is (a) a tumor which expresses human CC chemokine receptor 4, human epidermal growth factor receptor 2, human CD20, or epidermal growth factor receptor, or (b) a tumor associated with human folate receptor 1, human IL-3Rα or human TIM-3. 217. The method according to claim 216, wherein the tumor is (a) a tumor which expresses human CC chemokine receptor 4, human epidermal growth factor receptor 2, human CD20, or epidermal growth factor receptor, wherein the tumor which expresses human CC chemokine receptor 4 is T cell lymphoma. 218. The method according to claim 216, wherein the tumor is (a) a tumor which expresses human CC chemokine receptor 4, human epidermal growth factor receptor 2, human CD20, or epidermal growth factor receptor, wherein the tumor which expresses human CC chemokine receptor 4 is peripheral T cell lymphoma, cutaneous T cell lymphoma or adult T cell leukemic lymphoma. 219. The method according to claim 216, wherein the tumor is (a) a tumor which expresses human CC chemokine receptor 4, human epidermal growth factor receptor 2, human CD20, or epidermal growth factor receptor, wherein the tumor which expresses human epidermal growth factor receptor 2 is breast cancer, gastric cancer, ovarian cancer, osteosarcoma, or endometrial cancer. 220. The method according to claim 216, wherein the tumor is (a) a tumor which expresses human CC chemokine receptor 4, human epidermal growth factor receptor 2, human CD20, or epidermal growth factor receptor, wherein the tumor which expresses human CD20 is chronic leukemia, or non-Hodgkin's lymphoma. 221. The method according to claim 216, wherein the tumor is (a) a tumor which expresses human CC chemokine receptor 4, human epidermal growth factor receptor 2, human CD20, or epidermal growth factor receptor, wherein the tumor which expresses epidermal growth factor receptor is colon cancer, head and neck cancer, gastric cancer, or hepatic cancer. 222. The method according to claim 211, wherein the antibody is (b) an antibody which specifically binds to human folate receptor 1, human IL-3Rα or human TIM-3, wherein the antibody which specifically binds to human folate receptor 1 is a monoclonal antibody. 223. The method according to claim 211, wherein the antibody is (b) an antibody which specifically binds to human folate receptor 1, human IL-3Rα or human TIM-3, wherein the antibody which specifically binds to human folate receptor 1 is a monoclonal antibody that is selected from the following (a1)-(c1):
(a1) a monoclonal antibody in which CDRs 1-3 of H chain of the antibody comprise the amino acid sequences represented by SEQ ID NOs. 1, 2, and 3, respectively and CDRs 1-3 of L chain of the antibody comprise the amino acid sequences represented by SEQ ID NOs. 4, 5, and 6, respectively;
(b1) a monoclonal antibody in which CDRs 1-3 of H chain of the antibody comprise the amino acid sequences represented by SEQ ID NOs. 1, 2, and 3, respectively and CDRs 1-3 of L chain of the antibody comprise the amino acid sequences represented by SEQ ID NOs. 4, 5, and 6, respectively, and cysteine in the amino acid sequence represented by SEQ ID NO. 3 (CDR3 of antibody H chain) is substituted with threonine, methionine, isoleucine, valine, phenylalanine, or glutamine; and
(c1) a monoclonal antibody in which H chain of the antibody comprises the amino acid sequence represented by SEQ ID NO. 7, and L chain of the antibody comprises the amino acid sequence represented by SEQ ID NO. 8. 224. The method according to claim 211, wherein the antibody is (b) an antibody which specifically binds to human folate receptor 1, human IL-3Rα or human TIM-3, wherein the antibody which specifically binds to human IL-3Rα is an antibody to a human IL-3Rα chain, which does not inhibit IL-3 signaling and binds to B domain of the human IL-3Rα chain but does not bind to C domain of the human IL-3Rα chain. 225. The method according to claim 224, wherein the antibody to a human IL-3Rα chain comprises amino acid sequences of CDRs of heavy chain and CDRs of light chain selected from the group consisting of the following (a2) to (e2);
(a2) CDR 1 to 3 of heavy chain are the amino acid sequences of SEQ ID NOs:9 to 11, respectively, and CDR 1 to 3 of light chain are the amino acid sequences of SEQ ID NOs:24 to 26, respectively,
(b2) CDR 1 to 3 of heavy chain are the amino acid sequences of SEQ ID NOs: 12 to 14, respectively, and CDR 1 to 3 of light chain are the amino acid sequences of SEQ ID NOs:27 to 29, respectively,
(c2) CDR 1 to 3 of heavy chain are the amino acid sequences of SEQ ID NOs:15 to 17, respectively, and CDR 1 to 3 of light chain are the amino acid sequences of SEQ ID NOs:30 to 32, respectively,
(d2) CDR 1 to 3 of heavy chain are the amino acid sequences of SEQ ID NOs: 18 to 20, respectively, and CDR 1 to 3 of light chain are the amino acid sequences of SEQ ID NOs:33 to 35, respectively, and
(e2) CDR 1 to 3 of heavy chain are the amino acid sequences of SEQ ID NOs:21 to 23, respectively, and CDR 1 to 3 of light chain are the amino acid sequences of SEQ ID NOs:36 to 38, respectively. 226. The method according to claim 224, wherein the antibody to a human IL-3Rα chain comprises amino acid sequences of CDRs of heavy chain and CDRs of light chain consisting of the following (e2);
(e2) CDR 1 to 3 of heavy chain are the amino acid sequences of SEQ ID NOs:21 to 23, respectively, and CDR 1 to 3 of light chain are the amino acid sequences of SEQ ID NOs:36 to 38, respectively. 227. The method according to claim 211, wherein the antibody is (b) an antibody which specifically binds to human folate receptor 1, human IL-3Rα or human TIM-3, wherein the antibody which specifically binds to human TIM-3 is a monoclonal antibody, which binds to an extracellular region of human TIM-3. 228. The method according to claim 227, wherein the monoclonal antibody is one selected from the group consisting of following (i) to (iii):
(i) a monoclonal antibody which comprises an H chain of an antibody which comprises CDRs 1 to 3 comprising the amino acid sequences represented by SEQ ID NOs:39 to 41, respectively, and comprises an L chain of an antibody which comprises CDRs1 to 3 comprising the amino acid sequences represented by SEQ ID NOs:42 to 44, respectively, (ii) a monoclonal antibody which comprises an H chain of an antibody which comprises CDRs 1 to 3 comprising the amino acid sequences represented by SEQ ID NOs:45 to 47, respectively, and comprises an L chain of an antibody which comprises CDRs 1 to 3 comprising the amino acid sequences represented by SEQ ID NOs:48 to 50, respectively, and (iii) a monoclonal antibody which comprises an H chain of an antibody which comprises CDRs 1 to 3 comprising the amino acid sequences represented by SEQ ID NOs:51 to 53, respectively, and comprises an L chain of an antibody which comprises CDRs 1 to 3 comprising the amino acid sequences represented by SEQ ID NOs:54 to 56, respectively. 229. The method according to claim 227, wherein the monoclonal antibody is one selected from the group consisting of following (a3) and (b3):
(a3) a monoclonal antibody which comprises VH of an antibody comprising the amino acid sequence represented by SEQ ID NO:57 and comprises VL of an antibody comprising the amino acid sequence represented by SEQ ID NO:58, and (b3) a monoclonal antibody which comprises VH of an antibody comprising the amino acid sequence represented by SEQ ID NO:59 and comprises VL of an antibody comprising the amino acid sequence represented by SEQ ID NO:60. 230. The method according to claim 216, wherein the tumor is (b) a tumor associated with human folate receptor 1, human IL-3Rα or human TIM-3, wherein the tumor associated with human folate receptor 1 is blood cancer, breast cancer, uterine cancer, colorectal cancer, esophageal cancer, stomach cancer, ovarian cancer, lung cancer, renal cancer, rectal cancer, thyroid cancer, uterine cervix cancer, small intestinal cancer, prostate cancer, mesothelioma or pancreatic cancer. 231. The method according to claim 216, wherein the tumor is (b) a tumor associated with human folate receptor 1, human IL-3Rα or human TIM-3, wherein the tumor associated with human IL-3Rα is acute myeloid leukemia (AML), acute lymphocytic leukemia, atypical leukemia, chronic lymphocytic leukemia, adult T cell leukemia, NK/T cell lymphoma, granular lymphocytosis (LGL leukemia), polycythemia vera, essential thrombocythemia, hypereosinophilic syndrome, Hodgkin lymphoma, non-Hodgkin lymphoma, follicular lymphoma, MALT lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma or Castleman disease. 232. The method according to claim 216, wherein the tumor is (b) a tumor associated with human folate receptor 1, human IL-3Rα or human TIM-3, wherein the tumor associated with human TIM-3 is blood cancer, breast cancer, uterine cancer, colorectal cancer, esophageal cancer, gastric cancer, ovarian cancer, lung cancer, renal cancer, rectal cancer, thyroid cancer, uterine cervix cancer, small intestinal cancer, prostate cancer or pancreatic cancer. 233. A method for suppressing decreasing antibody dependent cellular cytotoxicity activity of (a) an antibody which specifically binds to human CC chemokine receptor 4, human epidermal growth factor receptor 2, human CD20, or epidermal growth factor receptor or (b) an antibody which specifically binds to human folate receptor 1, human IL-3Rα or human TIM-3 comprising administering an indoleamine 2,3-dioxygenase inhibitor. 234. The method according to claim 233, wherein the indoleamine 2,3-dioxygenase inhibitor is Compound (I) represented by formula (I)
wherein
R6 and R7 may be the same or different, and each represents a hydrogen atom, or optionally substituted lower alkyl,
R8, R9, R10, and R11 may be the same or different, and each represents a hydrogen atom, halogen, cyano, or lower alkyl,
R1 represents lower alkyl which may be substituted with lower alkoxy, and
R3 represents an optionally substituted aromatic heterocyclic group,
or a pharmaceutically acceptable salt thereof,
or Compound (II) represented by formula (II)
wherein
R21 represents amino or methyl,
R22 represents halogen, cyano, trifluoromethyl, or lower alkyl,
R23 represents a hydrogen atom, or halogen, and
n represents 1 or 2,
or a pharmaceutically acceptable salt thereof. 235. A combination of an indoleamine 2,3-dioxygenase inhibitor and (a) an antibody which specifically binds to human CC chemokine receptor 4, human epidermal growth factor receptor 2, human CD20, or epidermal growth factor receptor, or (b) an antibody which specifically binds to human folate receptor 1, human IL-3Rα or human TIM-3, for use in the treatment of a tumor. 236. The combination of an indoleamine 2,3-dioxygenase inhibitor and an antibody according to claim 235, wherein the combination is a pharmaceutical composition for use in administering an effective amount of an antibody and an indoleamine 2,3-dioxygenase inhibitor.
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The present invention provides a method for treating a tumor comprising administering an effective amount of an antibody which specifically binds to human CC chemokine receptor 4, human epidermal growth factor receptor 2, human CD20, or epidermal growth factor receptor, and an indoleamine 2,3-dioxygenase inhibitor to a human in need thereof, and the like.1-210. (canceled) 211. A method for treating a tumor comprising administering an effective amount of
(i) (a) an antibody which specifically binds to human CC chemokine receptor 4, human epidermal growth factor receptor 2, human CD20, or epidermal growth factor receptor, or (b) an antibody which specifically binds to human folate receptor 1, human IL-3Rα or human TIM-3, and (ii) an indoleamine 2,3-dioxygenase inhibitor to a human in need thereof. 212. The method according to claim 211, wherein the indoleamine 2,3-dioxygenase inhibitor is Compound (I) represented by formula (I)
wherein
R6 and R7 may be the same or different, and each represents a hydrogen atom, or optionally substituted lower alkyl,
R8, R9, R10, and R11 may be the same or different, and each represents a hydrogen atom, halogen, cyano, or lower alkyl,
R1 represents lower alkyl which may be substituted with lower alkoxy, and
R3 represents an optionally substituted aromatic heterocyclic group,
or a pharmaceutically acceptable salt thereof,
or Compound (II) represented by formula (II)
wherein
R22 represents halogen, cyano, trifluoromethyl, or lower alkyl,
R23 represents a hydrogen atom, or halogen, and
n represents 1 or 2,
or a pharmaceutically acceptable salt thereof. 213. The method according to claim 211, wherein the antibody is (a) an antibody which specifically binds to human CC chemokine receptor 4, human epidermal growth factor receptor 2, human CD20, or epidermal growth factor receptor, wherein the antibody which specifically binds to human CC chemokine receptor 4, human epidermal growth factor receptor 2, human CD20, or epidermal growth factor receptor is mogamulizumab, trastuzumab, rituximab or cetuximab, respectively. 214. The method according to claim 211, wherein the antibody and the indoleamine 2,3-dioxygenase inhibitor are administered simultaneously or sequentially. 215. The method according to claim 211, wherein the antibody and the indoleamine 2,3-dioxygenase inhibitor are administered separately at intervals. 216. The method according to 211, wherein the tumor is (a) a tumor which expresses human CC chemokine receptor 4, human epidermal growth factor receptor 2, human CD20, or epidermal growth factor receptor, or (b) a tumor associated with human folate receptor 1, human IL-3Rα or human TIM-3. 217. The method according to claim 216, wherein the tumor is (a) a tumor which expresses human CC chemokine receptor 4, human epidermal growth factor receptor 2, human CD20, or epidermal growth factor receptor, wherein the tumor which expresses human CC chemokine receptor 4 is T cell lymphoma. 218. The method according to claim 216, wherein the tumor is (a) a tumor which expresses human CC chemokine receptor 4, human epidermal growth factor receptor 2, human CD20, or epidermal growth factor receptor, wherein the tumor which expresses human CC chemokine receptor 4 is peripheral T cell lymphoma, cutaneous T cell lymphoma or adult T cell leukemic lymphoma. 219. The method according to claim 216, wherein the tumor is (a) a tumor which expresses human CC chemokine receptor 4, human epidermal growth factor receptor 2, human CD20, or epidermal growth factor receptor, wherein the tumor which expresses human epidermal growth factor receptor 2 is breast cancer, gastric cancer, ovarian cancer, osteosarcoma, or endometrial cancer. 220. The method according to claim 216, wherein the tumor is (a) a tumor which expresses human CC chemokine receptor 4, human epidermal growth factor receptor 2, human CD20, or epidermal growth factor receptor, wherein the tumor which expresses human CD20 is chronic leukemia, or non-Hodgkin's lymphoma. 221. The method according to claim 216, wherein the tumor is (a) a tumor which expresses human CC chemokine receptor 4, human epidermal growth factor receptor 2, human CD20, or epidermal growth factor receptor, wherein the tumor which expresses epidermal growth factor receptor is colon cancer, head and neck cancer, gastric cancer, or hepatic cancer. 222. The method according to claim 211, wherein the antibody is (b) an antibody which specifically binds to human folate receptor 1, human IL-3Rα or human TIM-3, wherein the antibody which specifically binds to human folate receptor 1 is a monoclonal antibody. 223. The method according to claim 211, wherein the antibody is (b) an antibody which specifically binds to human folate receptor 1, human IL-3Rα or human TIM-3, wherein the antibody which specifically binds to human folate receptor 1 is a monoclonal antibody that is selected from the following (a1)-(c1):
(a1) a monoclonal antibody in which CDRs 1-3 of H chain of the antibody comprise the amino acid sequences represented by SEQ ID NOs. 1, 2, and 3, respectively and CDRs 1-3 of L chain of the antibody comprise the amino acid sequences represented by SEQ ID NOs. 4, 5, and 6, respectively;
(b1) a monoclonal antibody in which CDRs 1-3 of H chain of the antibody comprise the amino acid sequences represented by SEQ ID NOs. 1, 2, and 3, respectively and CDRs 1-3 of L chain of the antibody comprise the amino acid sequences represented by SEQ ID NOs. 4, 5, and 6, respectively, and cysteine in the amino acid sequence represented by SEQ ID NO. 3 (CDR3 of antibody H chain) is substituted with threonine, methionine, isoleucine, valine, phenylalanine, or glutamine; and
(c1) a monoclonal antibody in which H chain of the antibody comprises the amino acid sequence represented by SEQ ID NO. 7, and L chain of the antibody comprises the amino acid sequence represented by SEQ ID NO. 8. 224. The method according to claim 211, wherein the antibody is (b) an antibody which specifically binds to human folate receptor 1, human IL-3Rα or human TIM-3, wherein the antibody which specifically binds to human IL-3Rα is an antibody to a human IL-3Rα chain, which does not inhibit IL-3 signaling and binds to B domain of the human IL-3Rα chain but does not bind to C domain of the human IL-3Rα chain. 225. The method according to claim 224, wherein the antibody to a human IL-3Rα chain comprises amino acid sequences of CDRs of heavy chain and CDRs of light chain selected from the group consisting of the following (a2) to (e2);
(a2) CDR 1 to 3 of heavy chain are the amino acid sequences of SEQ ID NOs:9 to 11, respectively, and CDR 1 to 3 of light chain are the amino acid sequences of SEQ ID NOs:24 to 26, respectively,
(b2) CDR 1 to 3 of heavy chain are the amino acid sequences of SEQ ID NOs: 12 to 14, respectively, and CDR 1 to 3 of light chain are the amino acid sequences of SEQ ID NOs:27 to 29, respectively,
(c2) CDR 1 to 3 of heavy chain are the amino acid sequences of SEQ ID NOs:15 to 17, respectively, and CDR 1 to 3 of light chain are the amino acid sequences of SEQ ID NOs:30 to 32, respectively,
(d2) CDR 1 to 3 of heavy chain are the amino acid sequences of SEQ ID NOs: 18 to 20, respectively, and CDR 1 to 3 of light chain are the amino acid sequences of SEQ ID NOs:33 to 35, respectively, and
(e2) CDR 1 to 3 of heavy chain are the amino acid sequences of SEQ ID NOs:21 to 23, respectively, and CDR 1 to 3 of light chain are the amino acid sequences of SEQ ID NOs:36 to 38, respectively. 226. The method according to claim 224, wherein the antibody to a human IL-3Rα chain comprises amino acid sequences of CDRs of heavy chain and CDRs of light chain consisting of the following (e2);
(e2) CDR 1 to 3 of heavy chain are the amino acid sequences of SEQ ID NOs:21 to 23, respectively, and CDR 1 to 3 of light chain are the amino acid sequences of SEQ ID NOs:36 to 38, respectively. 227. The method according to claim 211, wherein the antibody is (b) an antibody which specifically binds to human folate receptor 1, human IL-3Rα or human TIM-3, wherein the antibody which specifically binds to human TIM-3 is a monoclonal antibody, which binds to an extracellular region of human TIM-3. 228. The method according to claim 227, wherein the monoclonal antibody is one selected from the group consisting of following (i) to (iii):
(i) a monoclonal antibody which comprises an H chain of an antibody which comprises CDRs 1 to 3 comprising the amino acid sequences represented by SEQ ID NOs:39 to 41, respectively, and comprises an L chain of an antibody which comprises CDRs1 to 3 comprising the amino acid sequences represented by SEQ ID NOs:42 to 44, respectively, (ii) a monoclonal antibody which comprises an H chain of an antibody which comprises CDRs 1 to 3 comprising the amino acid sequences represented by SEQ ID NOs:45 to 47, respectively, and comprises an L chain of an antibody which comprises CDRs 1 to 3 comprising the amino acid sequences represented by SEQ ID NOs:48 to 50, respectively, and (iii) a monoclonal antibody which comprises an H chain of an antibody which comprises CDRs 1 to 3 comprising the amino acid sequences represented by SEQ ID NOs:51 to 53, respectively, and comprises an L chain of an antibody which comprises CDRs 1 to 3 comprising the amino acid sequences represented by SEQ ID NOs:54 to 56, respectively. 229. The method according to claim 227, wherein the monoclonal antibody is one selected from the group consisting of following (a3) and (b3):
(a3) a monoclonal antibody which comprises VH of an antibody comprising the amino acid sequence represented by SEQ ID NO:57 and comprises VL of an antibody comprising the amino acid sequence represented by SEQ ID NO:58, and (b3) a monoclonal antibody which comprises VH of an antibody comprising the amino acid sequence represented by SEQ ID NO:59 and comprises VL of an antibody comprising the amino acid sequence represented by SEQ ID NO:60. 230. The method according to claim 216, wherein the tumor is (b) a tumor associated with human folate receptor 1, human IL-3Rα or human TIM-3, wherein the tumor associated with human folate receptor 1 is blood cancer, breast cancer, uterine cancer, colorectal cancer, esophageal cancer, stomach cancer, ovarian cancer, lung cancer, renal cancer, rectal cancer, thyroid cancer, uterine cervix cancer, small intestinal cancer, prostate cancer, mesothelioma or pancreatic cancer. 231. The method according to claim 216, wherein the tumor is (b) a tumor associated with human folate receptor 1, human IL-3Rα or human TIM-3, wherein the tumor associated with human IL-3Rα is acute myeloid leukemia (AML), acute lymphocytic leukemia, atypical leukemia, chronic lymphocytic leukemia, adult T cell leukemia, NK/T cell lymphoma, granular lymphocytosis (LGL leukemia), polycythemia vera, essential thrombocythemia, hypereosinophilic syndrome, Hodgkin lymphoma, non-Hodgkin lymphoma, follicular lymphoma, MALT lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma or Castleman disease. 232. The method according to claim 216, wherein the tumor is (b) a tumor associated with human folate receptor 1, human IL-3Rα or human TIM-3, wherein the tumor associated with human TIM-3 is blood cancer, breast cancer, uterine cancer, colorectal cancer, esophageal cancer, gastric cancer, ovarian cancer, lung cancer, renal cancer, rectal cancer, thyroid cancer, uterine cervix cancer, small intestinal cancer, prostate cancer or pancreatic cancer. 233. A method for suppressing decreasing antibody dependent cellular cytotoxicity activity of (a) an antibody which specifically binds to human CC chemokine receptor 4, human epidermal growth factor receptor 2, human CD20, or epidermal growth factor receptor or (b) an antibody which specifically binds to human folate receptor 1, human IL-3Rα or human TIM-3 comprising administering an indoleamine 2,3-dioxygenase inhibitor. 234. The method according to claim 233, wherein the indoleamine 2,3-dioxygenase inhibitor is Compound (I) represented by formula (I)
wherein
R6 and R7 may be the same or different, and each represents a hydrogen atom, or optionally substituted lower alkyl,
R8, R9, R10, and R11 may be the same or different, and each represents a hydrogen atom, halogen, cyano, or lower alkyl,
R1 represents lower alkyl which may be substituted with lower alkoxy, and
R3 represents an optionally substituted aromatic heterocyclic group,
or a pharmaceutically acceptable salt thereof,
or Compound (II) represented by formula (II)
wherein
R21 represents amino or methyl,
R22 represents halogen, cyano, trifluoromethyl, or lower alkyl,
R23 represents a hydrogen atom, or halogen, and
n represents 1 or 2,
or a pharmaceutically acceptable salt thereof. 235. A combination of an indoleamine 2,3-dioxygenase inhibitor and (a) an antibody which specifically binds to human CC chemokine receptor 4, human epidermal growth factor receptor 2, human CD20, or epidermal growth factor receptor, or (b) an antibody which specifically binds to human folate receptor 1, human IL-3Rα or human TIM-3, for use in the treatment of a tumor. 236. The combination of an indoleamine 2,3-dioxygenase inhibitor and an antibody according to claim 235, wherein the combination is a pharmaceutical composition for use in administering an effective amount of an antibody and an indoleamine 2,3-dioxygenase inhibitor.
| 1,600 |
955 | 14,897,794 | 1,617 |
The present invention encompasses methods of improving reproductive and respiratory health.
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1. A method for improving the per cycle pregnancy rate for maiden or barren equine mares and/or reducing the post-breeding inflammatory response of an equine mare, the method comprising administering a composition comprising Composition A at a daily dose of between 4-7 g per 110 lbs of body weight at least 10 days before coitus, and continuing to dose daily till at least 2 days post-coitus. 2.-5. (canceled) 6. The method of claim 1, wherein Composition A comprises flaxseed meal, algal DHA, vitamin E, and vitamin D3. 7. The method of claim 6, wherein Composition A further comprises sorbitol, ascorbic acid, alfalfa meal, sodium saccharin, propionic acid and artificial flavor. 8. The method of claim 1, wherein Composition A comprises total omega-3 fatty acids of 7,200 mg per 60 g dose. 9. The method of claim 8, wherein Composition A further comprises 2,000 mg of DHA per 60 g dose. 10. The method of claim 9, wherein Composition A further comprises 6000 IU of Vitamin D3, and 1000 IU of Vitamin E per 60 grams of total composition. 11. A method for reducing chronic respiratory disease in an equid, the method comprising administering 2-4 g of Composition B per 110 lbs body weight for at least two weeks. 12. The method of claim 11, wherein the equid is further restricted to a low dust diet. 13. (canceled) 14. The method of claim 11, wherein the chronic respiratory disease is recurrent airway obstruction (RAO) or inflammatory airway disease (IAD). 15. (canceled) 16. The method of claim 11, wherein Composition B comprises a mushroom blend and DHA. 17. The method of claim 16, wherein Composition B further comprises mixed tocopherols and ascorbic acid. 18. The method of claim 16, wherein Composition B comprises between about 4500 g and 5500 g methylsulfonylmethane per 30 g dose. 19.-20. (canceled) 21. The method of claim 30, wherein the method increases DHA availability to foals. 22.-29. (canceled) 30. A method for improving behavior and cognitive development in nursing foals and/or improving reproductive function in postpartum mares, the method comprising administering to a pregnant mare a composition comprising Composition A at a daily dose of between 4-7 g per 110 lbs of body weight at least 30 days before expected foaling, and continuing to dose daily through at least 30 days lactation. 31. The method of claim 30, wherein behavior and cognitive development is improved by increasing engagement in social affiliative, increasing nursing, and increasing lying down. 32. The method of claim 30, wherein Composition A is administered at least 90 days before expected foaling. 33. The method of claim 30, wherein Composition A is administered through at least 70 days lactation. 34. The method of claim 30, wherein Composition A comprises flaxseed meal, algal DHA, vitamin E, and vitamin D3. 35. (canceled) 36. The method of claim 30, wherein Composition A comprises total omega-3 fatty acids of 7,200 mg per 60 g dose. 37. The method of claim 36, wherein Composition A further comprises 2,000 mg of DHA per 60 g dose. 38.-55. (canceled)
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The present invention encompasses methods of improving reproductive and respiratory health.1. A method for improving the per cycle pregnancy rate for maiden or barren equine mares and/or reducing the post-breeding inflammatory response of an equine mare, the method comprising administering a composition comprising Composition A at a daily dose of between 4-7 g per 110 lbs of body weight at least 10 days before coitus, and continuing to dose daily till at least 2 days post-coitus. 2.-5. (canceled) 6. The method of claim 1, wherein Composition A comprises flaxseed meal, algal DHA, vitamin E, and vitamin D3. 7. The method of claim 6, wherein Composition A further comprises sorbitol, ascorbic acid, alfalfa meal, sodium saccharin, propionic acid and artificial flavor. 8. The method of claim 1, wherein Composition A comprises total omega-3 fatty acids of 7,200 mg per 60 g dose. 9. The method of claim 8, wherein Composition A further comprises 2,000 mg of DHA per 60 g dose. 10. The method of claim 9, wherein Composition A further comprises 6000 IU of Vitamin D3, and 1000 IU of Vitamin E per 60 grams of total composition. 11. A method for reducing chronic respiratory disease in an equid, the method comprising administering 2-4 g of Composition B per 110 lbs body weight for at least two weeks. 12. The method of claim 11, wherein the equid is further restricted to a low dust diet. 13. (canceled) 14. The method of claim 11, wherein the chronic respiratory disease is recurrent airway obstruction (RAO) or inflammatory airway disease (IAD). 15. (canceled) 16. The method of claim 11, wherein Composition B comprises a mushroom blend and DHA. 17. The method of claim 16, wherein Composition B further comprises mixed tocopherols and ascorbic acid. 18. The method of claim 16, wherein Composition B comprises between about 4500 g and 5500 g methylsulfonylmethane per 30 g dose. 19.-20. (canceled) 21. The method of claim 30, wherein the method increases DHA availability to foals. 22.-29. (canceled) 30. A method for improving behavior and cognitive development in nursing foals and/or improving reproductive function in postpartum mares, the method comprising administering to a pregnant mare a composition comprising Composition A at a daily dose of between 4-7 g per 110 lbs of body weight at least 30 days before expected foaling, and continuing to dose daily through at least 30 days lactation. 31. The method of claim 30, wherein behavior and cognitive development is improved by increasing engagement in social affiliative, increasing nursing, and increasing lying down. 32. The method of claim 30, wherein Composition A is administered at least 90 days before expected foaling. 33. The method of claim 30, wherein Composition A is administered through at least 70 days lactation. 34. The method of claim 30, wherein Composition A comprises flaxseed meal, algal DHA, vitamin E, and vitamin D3. 35. (canceled) 36. The method of claim 30, wherein Composition A comprises total omega-3 fatty acids of 7,200 mg per 60 g dose. 37. The method of claim 36, wherein Composition A further comprises 2,000 mg of DHA per 60 g dose. 38.-55. (canceled)
| 1,600 |
956 | 14,894,426 | 1,633 |
The present invention relates to methods for developing engineered T-cells for immunotherapy and more specifically to methods for modifying T-cells by inactivating at immune checkpoint genes, preferably at least two selected from different pathways, to increase T-cell immune activity. This method involves the use of specific rare cutting endonucleases, in particular TALE-nucleases (TAL effector endonuclease) and polynucleotides encoding such polypeptides, to precisely target a selection of key genes in T-cells, which are available from donors or from culture of primary cells. The invention opens the way to highly efficient adoptive immunotherapy strategies for treating cancer and viral infections.
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1) A method of preparing T-cell(s) for immunotherapy comprising:
(a) modifying T-cell(s) by inactivating at least two genes encoding immune checkpoint proteins; and (b) expanding said cell(s). 2) The method of claim 1 comprising:
(a) modifying T-cell(s) by introducing into said T-cell(s) at least one rare-cutting endonuclease able to inactivate by DNA cleavage at least two genes encoding immune checkpoint proteins; and
(b) expanding said T-cell(s). 3) The method according to claim 1, wherein said genes encoding immune checkpoint proteins are selected from the group consisting of: CTLA4, PPP2CA, PPP2CB, PTPN6, PTPN22, PDCD1, CD223, HAVCR2, BTLA, CD160, TIGIT, CD96, CRTAM, LAIR1, SIGLEC7, SIGLEC9, CD244, TNFRSF10B, TNFRSF10A, CASP8, CASP10, CASP3, CASP6, CASP7, FADD, FAS, TGFBRII, TGFRBRI, SMAD2, SMAD3, SMAD4, SMAD10, SKI, SKIL, TGIF1, IL10RA, IL10RB, HMOX2, IL6R, IL6ST, EIF2AK4, CSK, PAG1, SIT, FOXP3, PRDM1, BATF, GUCY1A2, GUCY1A3, GUCY1B2, and GUCY1B3. 4) The method according to claim 1, wherein said modified T-cell(s) are expanded in a patient's blood. 5) The method according to claim 1, wherein said modified T-cell(s) are expanded in vitro. 6) The method according to claim 1, wherein said genes are PD1 and CTLA-4. 7) The method according to claim 1, wherein said at least one rare-cutting endonuclease is encoded by mRNA. 8) The method of claim 7 that comprises introducing one or more rare-cutting endonuclease(s) into said cell in step (a) by way of RNA electroporation. 9) The method according to claim 2, wherein said at least one rare-cutting endonuclease is a TALE-nuclease. 10) The method according to claim 9, wherein said at least one TALE-nuclease is directed against one of the gene target sequences of PD1 selected from SEQ ID NO: 77 and SEQ ID NO: 78. 11) The method according to claim 9, wherein said at least one TALE-nucleases is directed against one of the gene target sequences of CTLA-4 selected from SEQ ID NO: 74 and SEQ ID NO: 76. 12) The method according to claim 1, further comprising introducing into said T-cell(s) a chimeric antigen receptor (CAR). 13) The method of claim 12 wherein said chimeric antigen receptor is a multi-chain chimeric antigen receptor. 14) The method according to claim 1, wherein said T-cell(s) in step a) are derived from inflammatory T-lymphocytes, cytotoxic T-lymphocytes, regulatory T-lymphocytes or helper T-lymphocytes. 15) The method according to claim 1, wherein said T-cell(s) in step a) are derived from CD4+T-lymphocytes and/or CD8+T-lymphocytes. 16) An isolated T-cell or cell line obtainable by the method of claim 1, or a subculture thereof. 17) The isolated T-cell according to claim 16, further comprising an exogenous polynucleotide sequence encoding a Chimeric Antigen Receptor. 18) The isolated T-cell of claim 17, wherein said Chimeric Antigen Receptor is a multi-chain Chimeric Antigen Receptor. 19-21) (canceled) 22) A pharmaceutical composition comprising at least one isolated T-cell according to claim 17. 23) A method for treating a patient comprising:
(a) preparing a population of modified T-cells by the method according to claim 1, and (b) administrating said modified T-cells to said patient. 24) The method according to claim 23, wherein said patient is diagnosed with cancer, a viral infection, or an autoimmune disorder. 25) A TALE-nuclease directed against one of the selected target sequences of the PD1 gene selected from: SEQ ID NO: 77 to SEQ ID NO: 78. 26) A TALE-nuclease directed against one of the selected target sequences of the CTLA-4 gene selected from: SEQ ID NO: 74 to SEQ ID NO: 76. 27) A TALE-nuclease which comprises the amino acid sequence selected from the group consisting of: SEQ ID NO: 79 to SEQ ID NO: 88.
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The present invention relates to methods for developing engineered T-cells for immunotherapy and more specifically to methods for modifying T-cells by inactivating at immune checkpoint genes, preferably at least two selected from different pathways, to increase T-cell immune activity. This method involves the use of specific rare cutting endonucleases, in particular TALE-nucleases (TAL effector endonuclease) and polynucleotides encoding such polypeptides, to precisely target a selection of key genes in T-cells, which are available from donors or from culture of primary cells. The invention opens the way to highly efficient adoptive immunotherapy strategies for treating cancer and viral infections.1) A method of preparing T-cell(s) for immunotherapy comprising:
(a) modifying T-cell(s) by inactivating at least two genes encoding immune checkpoint proteins; and (b) expanding said cell(s). 2) The method of claim 1 comprising:
(a) modifying T-cell(s) by introducing into said T-cell(s) at least one rare-cutting endonuclease able to inactivate by DNA cleavage at least two genes encoding immune checkpoint proteins; and
(b) expanding said T-cell(s). 3) The method according to claim 1, wherein said genes encoding immune checkpoint proteins are selected from the group consisting of: CTLA4, PPP2CA, PPP2CB, PTPN6, PTPN22, PDCD1, CD223, HAVCR2, BTLA, CD160, TIGIT, CD96, CRTAM, LAIR1, SIGLEC7, SIGLEC9, CD244, TNFRSF10B, TNFRSF10A, CASP8, CASP10, CASP3, CASP6, CASP7, FADD, FAS, TGFBRII, TGFRBRI, SMAD2, SMAD3, SMAD4, SMAD10, SKI, SKIL, TGIF1, IL10RA, IL10RB, HMOX2, IL6R, IL6ST, EIF2AK4, CSK, PAG1, SIT, FOXP3, PRDM1, BATF, GUCY1A2, GUCY1A3, GUCY1B2, and GUCY1B3. 4) The method according to claim 1, wherein said modified T-cell(s) are expanded in a patient's blood. 5) The method according to claim 1, wherein said modified T-cell(s) are expanded in vitro. 6) The method according to claim 1, wherein said genes are PD1 and CTLA-4. 7) The method according to claim 1, wherein said at least one rare-cutting endonuclease is encoded by mRNA. 8) The method of claim 7 that comprises introducing one or more rare-cutting endonuclease(s) into said cell in step (a) by way of RNA electroporation. 9) The method according to claim 2, wherein said at least one rare-cutting endonuclease is a TALE-nuclease. 10) The method according to claim 9, wherein said at least one TALE-nuclease is directed against one of the gene target sequences of PD1 selected from SEQ ID NO: 77 and SEQ ID NO: 78. 11) The method according to claim 9, wherein said at least one TALE-nucleases is directed against one of the gene target sequences of CTLA-4 selected from SEQ ID NO: 74 and SEQ ID NO: 76. 12) The method according to claim 1, further comprising introducing into said T-cell(s) a chimeric antigen receptor (CAR). 13) The method of claim 12 wherein said chimeric antigen receptor is a multi-chain chimeric antigen receptor. 14) The method according to claim 1, wherein said T-cell(s) in step a) are derived from inflammatory T-lymphocytes, cytotoxic T-lymphocytes, regulatory T-lymphocytes or helper T-lymphocytes. 15) The method according to claim 1, wherein said T-cell(s) in step a) are derived from CD4+T-lymphocytes and/or CD8+T-lymphocytes. 16) An isolated T-cell or cell line obtainable by the method of claim 1, or a subculture thereof. 17) The isolated T-cell according to claim 16, further comprising an exogenous polynucleotide sequence encoding a Chimeric Antigen Receptor. 18) The isolated T-cell of claim 17, wherein said Chimeric Antigen Receptor is a multi-chain Chimeric Antigen Receptor. 19-21) (canceled) 22) A pharmaceutical composition comprising at least one isolated T-cell according to claim 17. 23) A method for treating a patient comprising:
(a) preparing a population of modified T-cells by the method according to claim 1, and (b) administrating said modified T-cells to said patient. 24) The method according to claim 23, wherein said patient is diagnosed with cancer, a viral infection, or an autoimmune disorder. 25) A TALE-nuclease directed against one of the selected target sequences of the PD1 gene selected from: SEQ ID NO: 77 to SEQ ID NO: 78. 26) A TALE-nuclease directed against one of the selected target sequences of the CTLA-4 gene selected from: SEQ ID NO: 74 to SEQ ID NO: 76. 27) A TALE-nuclease which comprises the amino acid sequence selected from the group consisting of: SEQ ID NO: 79 to SEQ ID NO: 88.
| 1,600 |
957 | 14,414,368 | 1,627 |
The present invention encompasses methods of treating a subject who has been diagnosed as having a tic disorder or a movement disorder. The tic disorder can be Tourette's Syndrome, and the methods can include the steps of: (a) identifying a subject in need of treatment; and (b) administering to the subject a therapeutically effective amount of a composition comprising a D1/D5 receptor antagonist, a D1/D5 receptor partial agonist, or a mixture thereof. For example, the D1/D5 receptor antagonist can be ecopipam or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, structural analog, metabolite, or polymorph thereof.
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1. (canceled) 2. A method of treating a subject diagnosed as having a tic disorder, the method comprising:
(a) identifying a subject in need of treatment; and (b) administering to the subject a therapeutically effective amount of a composition comprising a D1/D5 receptor antagonist, a D1/D5 receptor partial agonist, or a mixture thereof. 3. The method of claim 2, wherein the subject is a human. 4. The method of claim 3, wherein the subject is not older than 17 years. 5. The method of claim 2, wherein the subject is considered to be free from attention-deficit-hyperactivity disorder, depression, and obsessive-compulsive disorder. 6. The method of claim 2, wherein the tic disorder is Tourette's Syndrome. 7. The method of claim 2, wherein the tic disorder is a pediatric autoimmune disorder associated with streptococcal infection (PANDAS), a transient tic disorder, a chronic tic disorder, or a Tic Disorder Not Otherwise Specified (NOS). 8. The method of claim 2, wherein the subject exhibits a motor tic, a vocal tic, or a combination thereof. 9. The method of claim 8, wherein the motor tic is a complex motor tic. 10. The method of claim 8, wherein the vocal tic is a complex vocal tic. 11. The method of claim 2, wherein the D1/D5 receptor antagonist comprises ecopipam or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, structural analog or polymorph thereof. 12. The method of claim 11, wherein the D1/D5 receptor antagonist comprises ecopipam or a pharmaceutically acceptable salt thereof. 13. The method of claim 12, wherein the D1/D5 receptor antagonist is formulated for oral delivery. 14. The method of claim 13, wherein the D1/D5 receptor antagonist is administered at a dose of about 0.01 mg/kg to about 500 mg/kg. 15. The method of claim 14, wherein the D1/D5 receptor antagonist is administered at a dose of about 0.01 mg/kg to about 50 mg/kg; about 0.01 mg/kg to about 5 mg/kg; or about 0.1 mg/kg to about 5 mg/kg. 16. The method of claim 14, wherein the D1/D5 receptor antagonist is administered at a dose of 50-100 mg/day. 17. The method of claim 11, wherein administering the composition is repeated once daily. 18. The method of claim 2, further comprising a step of administering a second treatment for treating the tic disorder. 19. The method of claim 18, wherein the second treatment is a behavioral, surgical, or pharmaceutical therapy. 20. The method of claim 2, further comprising a step of administering to the subject a therapeutically effective amount of a second composition for the treatment of attention-deficit-hyperactivity disorder, depression, or obsessive-compulsive disorder.
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The present invention encompasses methods of treating a subject who has been diagnosed as having a tic disorder or a movement disorder. The tic disorder can be Tourette's Syndrome, and the methods can include the steps of: (a) identifying a subject in need of treatment; and (b) administering to the subject a therapeutically effective amount of a composition comprising a D1/D5 receptor antagonist, a D1/D5 receptor partial agonist, or a mixture thereof. For example, the D1/D5 receptor antagonist can be ecopipam or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, structural analog, metabolite, or polymorph thereof.1. (canceled) 2. A method of treating a subject diagnosed as having a tic disorder, the method comprising:
(a) identifying a subject in need of treatment; and (b) administering to the subject a therapeutically effective amount of a composition comprising a D1/D5 receptor antagonist, a D1/D5 receptor partial agonist, or a mixture thereof. 3. The method of claim 2, wherein the subject is a human. 4. The method of claim 3, wherein the subject is not older than 17 years. 5. The method of claim 2, wherein the subject is considered to be free from attention-deficit-hyperactivity disorder, depression, and obsessive-compulsive disorder. 6. The method of claim 2, wherein the tic disorder is Tourette's Syndrome. 7. The method of claim 2, wherein the tic disorder is a pediatric autoimmune disorder associated with streptococcal infection (PANDAS), a transient tic disorder, a chronic tic disorder, or a Tic Disorder Not Otherwise Specified (NOS). 8. The method of claim 2, wherein the subject exhibits a motor tic, a vocal tic, or a combination thereof. 9. The method of claim 8, wherein the motor tic is a complex motor tic. 10. The method of claim 8, wherein the vocal tic is a complex vocal tic. 11. The method of claim 2, wherein the D1/D5 receptor antagonist comprises ecopipam or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, structural analog or polymorph thereof. 12. The method of claim 11, wherein the D1/D5 receptor antagonist comprises ecopipam or a pharmaceutically acceptable salt thereof. 13. The method of claim 12, wherein the D1/D5 receptor antagonist is formulated for oral delivery. 14. The method of claim 13, wherein the D1/D5 receptor antagonist is administered at a dose of about 0.01 mg/kg to about 500 mg/kg. 15. The method of claim 14, wherein the D1/D5 receptor antagonist is administered at a dose of about 0.01 mg/kg to about 50 mg/kg; about 0.01 mg/kg to about 5 mg/kg; or about 0.1 mg/kg to about 5 mg/kg. 16. The method of claim 14, wherein the D1/D5 receptor antagonist is administered at a dose of 50-100 mg/day. 17. The method of claim 11, wherein administering the composition is repeated once daily. 18. The method of claim 2, further comprising a step of administering a second treatment for treating the tic disorder. 19. The method of claim 18, wherein the second treatment is a behavioral, surgical, or pharmaceutical therapy. 20. The method of claim 2, further comprising a step of administering to the subject a therapeutically effective amount of a second composition for the treatment of attention-deficit-hyperactivity disorder, depression, or obsessive-compulsive disorder.
| 1,600 |
958 | 15,726,555 | 1,615 |
The present disclosure provides a method of positioning an implant in a patient. The method includes inserting a deflated biodegradable balloon into a joint of the patient, wherein the biodegradable balloon is wedged between at least one of bone and soft tissue in the joint of the patient. The biodegradable balloon is inflated by injecting a warmed sterile liquid from a syringe through an inlet valve and the inflated biodegradable balloon is at least one of sized and shaped to fit within the surgical field. The expanded biodegradable balloon is a joint spacer, changing the spatial relationship between the bones and soft tissue in the joint of the patient.
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1. A method of positioning an implant in a patient, the method comprising:
endoscopically inserting a deflated biodegradable balloon into the shoulder joint of the patient, wherein the biodegradable balloon is wedged between at least one of bone and soft tissue in the shoulder joint of the patient; and inflating the biodegradable balloon by injecting a warmed sterile liquid from a syringe through an inlet valve, wherein the inflated biodegradable balloon is at least one of sized and shaped to fit within the surgical field, and wherein the expanded biodegradable balloon is a joint spacer, changing the spatial relationship between the at least one of bones and soft tissue in the shoulder joint of the patient. 2. The method of claim 1, wherein the balloon is at least partially comprised of polylactic acid. 3. The method of claim 1, wherein the balloon is comprised of at least one biodegradable co-polymer. 4. The method of claim 1, wherein the balloon is a temporary spacer. 5. The method of claim 1, wherein the implant reduces adhesions in the shoulder joint. 6. The method of claim 1, wherein the balloon is drug eluting. 7. A surgical system for a patient, the surgical system comprised of:
a balloon comprised of at least one biodegradable polymer, wherein the biodegradable balloon is endoscopically inserted while in a deflated state, and wherein the deflated biodegradable balloon is wedged between at least one of bone and soft tissue in the shoulder joint of a patient; an inlet valve attached to the biodegradable balloon; a syringe, removably coupled to the inlet valve; and warmed sterile liquid, wherein the warmed sterile liquid is injected through the inlet valve and into the biodegradable balloon with the syringe, wherein the inflated biodegradable balloon is at least one of sized and shaped to fit within the surgical field, and wherein the expanded biodegradable balloon is a joint spacer, changing the spatial relationship between the at least one of bones and soft tissue in the shoulder joint of the patient. 8. The system of claim 1, wherein the balloon is at least partially comprised of polylactic acid. 9. The system of claim 1, wherein the balloon is comprised of at least one biodegradable co-polymer. 10. The system of claim 1, wherein the balloon is a temporary spacer. 11. The system of claim 1, wherein the balloon reduces adhesions in the shoulder joint. 12. The system of claim 1, wherein the balloon is drug eluting. 13. A method of positioning an implant in a patient, the method comprising:
inserting a deflated biodegradable balloon into a joint of the patient, wherein the biodegradable balloon is wedged between at least one of bone and soft tissue in the joint of the patient; and inflating the biodegradable balloon by injecting a warmed sterile liquid from a syringe through an inlet valve, wherein the inflated biodegradable balloon is at least one of sized and shaped to fit within the surgical field, and wherein the expanded biodegradable balloon is a joint spacer, changing the spatial relationship between the at least one of bones and soft tissue in the joint of the patient. 14. The method of claim 13, wherein the deflated biodegradable balloon is inserted into the joint of the patient in at least one of an endoscopic and open procedure. 15. The method of claim 13, wherein the joint of the patient is at least one of a spine, knee, foot, ankle, hip, shoulder, elbow, wrist, and hand. 16. The method of claim 13, wherein the balloon is at least partially comprised of polylactic acid. 17. The method of claim 13, wherein the balloon is comprised of at least one biodegradable co-polymer. 18. The method of claim 13, wherein the balloon is a temporary spacer. 19. The method of claim 13, wherein the implant reduces adhesions in the shoulder joint. 20. The method of claim 13, wherein the balloon is drug eluting.
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The present disclosure provides a method of positioning an implant in a patient. The method includes inserting a deflated biodegradable balloon into a joint of the patient, wherein the biodegradable balloon is wedged between at least one of bone and soft tissue in the joint of the patient. The biodegradable balloon is inflated by injecting a warmed sterile liquid from a syringe through an inlet valve and the inflated biodegradable balloon is at least one of sized and shaped to fit within the surgical field. The expanded biodegradable balloon is a joint spacer, changing the spatial relationship between the bones and soft tissue in the joint of the patient.1. A method of positioning an implant in a patient, the method comprising:
endoscopically inserting a deflated biodegradable balloon into the shoulder joint of the patient, wherein the biodegradable balloon is wedged between at least one of bone and soft tissue in the shoulder joint of the patient; and inflating the biodegradable balloon by injecting a warmed sterile liquid from a syringe through an inlet valve, wherein the inflated biodegradable balloon is at least one of sized and shaped to fit within the surgical field, and wherein the expanded biodegradable balloon is a joint spacer, changing the spatial relationship between the at least one of bones and soft tissue in the shoulder joint of the patient. 2. The method of claim 1, wherein the balloon is at least partially comprised of polylactic acid. 3. The method of claim 1, wherein the balloon is comprised of at least one biodegradable co-polymer. 4. The method of claim 1, wherein the balloon is a temporary spacer. 5. The method of claim 1, wherein the implant reduces adhesions in the shoulder joint. 6. The method of claim 1, wherein the balloon is drug eluting. 7. A surgical system for a patient, the surgical system comprised of:
a balloon comprised of at least one biodegradable polymer, wherein the biodegradable balloon is endoscopically inserted while in a deflated state, and wherein the deflated biodegradable balloon is wedged between at least one of bone and soft tissue in the shoulder joint of a patient; an inlet valve attached to the biodegradable balloon; a syringe, removably coupled to the inlet valve; and warmed sterile liquid, wherein the warmed sterile liquid is injected through the inlet valve and into the biodegradable balloon with the syringe, wherein the inflated biodegradable balloon is at least one of sized and shaped to fit within the surgical field, and wherein the expanded biodegradable balloon is a joint spacer, changing the spatial relationship between the at least one of bones and soft tissue in the shoulder joint of the patient. 8. The system of claim 1, wherein the balloon is at least partially comprised of polylactic acid. 9. The system of claim 1, wherein the balloon is comprised of at least one biodegradable co-polymer. 10. The system of claim 1, wherein the balloon is a temporary spacer. 11. The system of claim 1, wherein the balloon reduces adhesions in the shoulder joint. 12. The system of claim 1, wherein the balloon is drug eluting. 13. A method of positioning an implant in a patient, the method comprising:
inserting a deflated biodegradable balloon into a joint of the patient, wherein the biodegradable balloon is wedged between at least one of bone and soft tissue in the joint of the patient; and inflating the biodegradable balloon by injecting a warmed sterile liquid from a syringe through an inlet valve, wherein the inflated biodegradable balloon is at least one of sized and shaped to fit within the surgical field, and wherein the expanded biodegradable balloon is a joint spacer, changing the spatial relationship between the at least one of bones and soft tissue in the joint of the patient. 14. The method of claim 13, wherein the deflated biodegradable balloon is inserted into the joint of the patient in at least one of an endoscopic and open procedure. 15. The method of claim 13, wherein the joint of the patient is at least one of a spine, knee, foot, ankle, hip, shoulder, elbow, wrist, and hand. 16. The method of claim 13, wherein the balloon is at least partially comprised of polylactic acid. 17. The method of claim 13, wherein the balloon is comprised of at least one biodegradable co-polymer. 18. The method of claim 13, wherein the balloon is a temporary spacer. 19. The method of claim 13, wherein the implant reduces adhesions in the shoulder joint. 20. The method of claim 13, wherein the balloon is drug eluting.
| 1,600 |
959 | 12,935,077 | 1,653 |
The invention relates to the treatment of chronic stroke, traumatic brain injury, and neurodegenerative disorders using umbilical cord blood cells.
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1. A method for treating chronic stroke comprising
intraparenchymally administering, to a brain of a human subject who has experienced a stroke, an isolated umbilical cord blood cell population enriched in CD34+, CD133+, or CD34+/CD133+ cells, wherein the isolated umbilical cord blood cell population is administered more than 7 days after the stroke. 2. The method of claim 1, wherein the isolated umbilical cord blood cell population is enriched in CD34+ umbilical cord blood cells. 3. The method of claim 1, wherein the isolated umbilical cord blood cell population is enriched in CD133+ umbilical cord blood cells. 4. The method of claim 1, wherein the isolated umbilical cord blood cell population is enriched in both CD34+/CD133+ umbilical cord blood cells. 5. The method of claim 1, wherein the isolated umbilical cord blood cell population comprises mononuclear cells that are at least 75% CD34+. 6. The method of claim 1, wherein the isolated umbilical cord blood cell population comprises mononuclear cells that are at least 90% CD34+. 7. The method of claim 1, wherein the isolated umbilical cord blood cell population comprises mononuclear cells that are at least 75% CD133+. 8. The method of claim 1, wherein the isolated umbilical cord blood cell population comprises mononuclear cells that are at least 90% CD133+. 9. The method of claim 1, wherein the isolated umbilical cord blood cell population comprises mononuclear cells that are at least 75% CD34+/CD133+. 10. The method of claim 1, wherein the isolated umbilical cord blood cell population comprises mononuclear cells that are at least 90% CD34+/CD133+. 11. The method of claim 1, wherein the subject is at least 60 years of age. 12. The method of claim 1, wherein at least 2×106 cells are administered to the subject. 13. The method of claim 1, wherein at least 5×106 cells are administered to the subject. 14. The method of claim 1, wherein at least 8×106 cells are administered to the subject. 15. The method of claim 1, wherein the isolated umbilical cord blood cell population is administered more than 1 month after the stroke. 16. The method of claim 1, wherein the isolated umbilical cord blood cell population is administered more than 6 months after the stroke. 17. The method of claim 1, wherein the isolated umbilical cord blood cell population is administered more than 1 year after the stroke. 18. The method of claim 1, wherein the isolated umbilical cord blood cell population is administered to three sites along a damaged cortical spinal tract. 19. The method of claim 1, wherein the isolated umbilical cord blood cell population is derived from a single cord blood unit. 20. The method of claim 1, wherein the isolated umbilical cord blood cell population is derived from multiple cord blood units. 21. The method of claim 1, wherein the isolated umbilical cord blood cell population shares less than 4 out of 6 histocompatibility markers with the subject. 22. The method of claim 1, wherein the isolated umbilical cord blood cell population shares at least 4 out of 6 histocompatibility markers with the subject. 23. A method for treating brain tissue damage comprising
intraparenchymally administering to a brain of a human subject who has experienced brain tissue damage an isolated umbilical cord blood cell population enriched in CD34+, CD133+, or CD34+/CD133+ umbilical cord blood cells. 24-45. (canceled) 46. A method for treating brain tissue damage comprising
intraparenchymally administering to a brain of a human subject having brain tissue damage resulting from traumatic brain injury an isolated umbilical cord blood cell population enriched in CD34+, CD133+, or CD34+/CD133+ umbilical cord blood cells, wherein the cells are administered more than one month after the occurrence of the traumatic brain injury.
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The invention relates to the treatment of chronic stroke, traumatic brain injury, and neurodegenerative disorders using umbilical cord blood cells.1. A method for treating chronic stroke comprising
intraparenchymally administering, to a brain of a human subject who has experienced a stroke, an isolated umbilical cord blood cell population enriched in CD34+, CD133+, or CD34+/CD133+ cells, wherein the isolated umbilical cord blood cell population is administered more than 7 days after the stroke. 2. The method of claim 1, wherein the isolated umbilical cord blood cell population is enriched in CD34+ umbilical cord blood cells. 3. The method of claim 1, wherein the isolated umbilical cord blood cell population is enriched in CD133+ umbilical cord blood cells. 4. The method of claim 1, wherein the isolated umbilical cord blood cell population is enriched in both CD34+/CD133+ umbilical cord blood cells. 5. The method of claim 1, wherein the isolated umbilical cord blood cell population comprises mononuclear cells that are at least 75% CD34+. 6. The method of claim 1, wherein the isolated umbilical cord blood cell population comprises mononuclear cells that are at least 90% CD34+. 7. The method of claim 1, wherein the isolated umbilical cord blood cell population comprises mononuclear cells that are at least 75% CD133+. 8. The method of claim 1, wherein the isolated umbilical cord blood cell population comprises mononuclear cells that are at least 90% CD133+. 9. The method of claim 1, wherein the isolated umbilical cord blood cell population comprises mononuclear cells that are at least 75% CD34+/CD133+. 10. The method of claim 1, wherein the isolated umbilical cord blood cell population comprises mononuclear cells that are at least 90% CD34+/CD133+. 11. The method of claim 1, wherein the subject is at least 60 years of age. 12. The method of claim 1, wherein at least 2×106 cells are administered to the subject. 13. The method of claim 1, wherein at least 5×106 cells are administered to the subject. 14. The method of claim 1, wherein at least 8×106 cells are administered to the subject. 15. The method of claim 1, wherein the isolated umbilical cord blood cell population is administered more than 1 month after the stroke. 16. The method of claim 1, wherein the isolated umbilical cord blood cell population is administered more than 6 months after the stroke. 17. The method of claim 1, wherein the isolated umbilical cord blood cell population is administered more than 1 year after the stroke. 18. The method of claim 1, wherein the isolated umbilical cord blood cell population is administered to three sites along a damaged cortical spinal tract. 19. The method of claim 1, wherein the isolated umbilical cord blood cell population is derived from a single cord blood unit. 20. The method of claim 1, wherein the isolated umbilical cord blood cell population is derived from multiple cord blood units. 21. The method of claim 1, wherein the isolated umbilical cord blood cell population shares less than 4 out of 6 histocompatibility markers with the subject. 22. The method of claim 1, wherein the isolated umbilical cord blood cell population shares at least 4 out of 6 histocompatibility markers with the subject. 23. A method for treating brain tissue damage comprising
intraparenchymally administering to a brain of a human subject who has experienced brain tissue damage an isolated umbilical cord blood cell population enriched in CD34+, CD133+, or CD34+/CD133+ umbilical cord blood cells. 24-45. (canceled) 46. A method for treating brain tissue damage comprising
intraparenchymally administering to a brain of a human subject having brain tissue damage resulting from traumatic brain injury an isolated umbilical cord blood cell population enriched in CD34+, CD133+, or CD34+/CD133+ umbilical cord blood cells, wherein the cells are administered more than one month after the occurrence of the traumatic brain injury.
| 1,600 |
960 | 14,889,686 | 1,633 |
The present invention relates to methods for developing engineered T-cells for immunotherapy that are non-alloreactive. The present invention relates to methods for modifying T-cells by inactivating both genes encoding T-cell receptor and an immune checkpoint gene to unleash the potential of the immune response. This method involves the use of specific rare cutting endonucleases, in particular TALE-nucleases (TAL effector endonuclease) and polynucleotides encoding such polypeptides, to precisely target a selection of key genes in T-cells, which are available from donors or from culture of primary cells. The invention opens the way to standard and affordable adoptive immunotherapy strategies for treating cancer and viral infections.
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1) A method of preparing T-cell(s) for immunotherapy comprising:
(a) modifying T-cell(s) by inactivating at least:
a first gene encoding a immune checkpoint protein, and
a second gene encoding a component of the T-cell receptor (TCR); and
(b) expanding said T-cell(s). 2) The method of claim 1 comprising modifying T-cells by:
(a) introducing into said T-cell at least one rare-cutting endonuclease able to selectively inactivate by DNA cleavage respectively:
said gene encoding a immune checkpoint protein, and
at least one gene encoding one component of the T-cell receptor (TCR); and
(b) expanding said T-cells. 3) The method according to claim 1, wherein said immune checkpoint gene is selected from the group consisting of: PD1, CTLA-4, LAG3, Tim3, BTLA, BY55, TIGIT, B7H5, LAIR1, SIGLEC10, and 2B4. 4) The method according to claim 1, wherein said modified T-cells are expanded in a patient's blood. 5) The method according to claim 1, wherein said modified T-cells are expanded in vivo. 6) The method according to claim 1, wherein said immune checkpoint gene is PD1 or CTLA-4. 7) The method according to claim 1, wherein the at least first and second inactivated genes are selected from the group consisting of PD1 and TCR alpha, PD1 and TCR beta, CTLA-4 and TCR alpha, CTLA-4 and TCR beta, LAG3 and TCR alpha, LAG3 and TCR beta, Tim3 and TCR alpha, Tim3 and TCR beta, BTLA and TCR alpha, BTLA and TCR beta, BY55 and TCR alpha, BY55 and TCR beta, TIGIT and TCR alpha, TIGIT and TCR beta, B7H5 and TCR alpha, B7H5 and TCR beta, LAIR1 and TCR alpha, LAIR1 and TCR beta, SIGLEC10 and TCR alpha, SIGLEC10 and TCR beta, 2B4 and TCR alpha, and 2B4 and TCR beta. 8) The method according to claim 2, wherein said at least one rare-cutting endonuclease is encoded by mRNA. 9) The method according to claim 2 that comprises introducing one or more rare-cutting endonuclease(s) into said T-cell in step (a) by way of RNA electroporation. 10) The method according to claim 2, wherein said at least one rare-cutting endonuclease is a TALE-nuclease. 11) The method according to claim 10, wherein at least one TALE-nuclease is directed against one of the gene target sequences of TCRalpha selected from SEQ ID NO: 37 or SEQ ID NO: 57 to SEQ ID NO: 60. 12) The method according to claim 10, wherein at least one TALE-nuclease is directed against one of the gene target sequences of TCRbeta selected from the group consisting of SEQ ID NO: 38 and SEQ ID NO: 39. 13) The method according to claim 10, wherein at least one TALE-nuclease is directed against one of the gene target sequences of PD1 selected from the group consisting of SEQ ID NO: 77 and SEQ ID NO: 78. 14) The method according to claim 10, wherein at least one TALE-nuclease is directed against one of the gene target sequences of CTLA-4 selected from the group consisting of SEQ ID NO: 74 and SEQ ID NO: 76. 15) The method according to claim 1, further comprising introducing into said T-cell(s) a chimeric antigen receptor (CAR). 16) The method according to claim 1, wherein said T-cell(s) in step a) are derived from inflammatory T-lymphocytes, cytotoxic T-lymphocytes, regulatory T-lymphocytes or helper T-lymphocytes. 17) The method according to claim 1, wherein said T-cell(s) in step a) are derived from CD4+ T-lymphocytes and/or CD8+ T-lymphocytes. 18) An isolated T-cell or cell line obtainable by the method of claim 1, or a subculture thereof. 19) An isolated T-cell, in which at least two genes have been inactivated which genes are selected from the group consisting of: PD1 and TCR alpha, PD1 and TCR beta, CTLA-4 and TCR alpha, CTLA-4 and TCR beta, LAG3 and TCR alpha, LAG3 and TCR beta, Tim3 and TCR alpha, Tim3 and TCR beta, BTLA and TCR alpha, BTLA and TCR beta, BY55 and TCR alpha, BY55 and TCR beta, TIGIT and TCR alpha, TIGIT and TCR beta, B7H5 and TCR alpha, B7H5 and TCR beta, LAIR1 and TCR alpha, LAIR1 and TCR beta, SIGLEC10 and TCR alpha, SIGLEC10 and TCR beta, 2B4 and TCR alpha, and 2B4 and TCR beta. 20) The isolated T-cell according to claim 19, further comprising an exogenous polynucleotide sequence encoding a Chimeric Antigen Receptor. 21) The isolated T-cell of claim 20 wherein said Chimeric Antigen Receptor is a multi-chain Chimeric Antigen Receptor. 22) The isolated T-cell of claim 19, further comprising an exogenous nucleic acid comprising at least a fragment of pTalpha transgene to support CD3 surface expression. 23) The isolated T-cell of claim 19 for use as a medicament. 24) The isolated T-cell of claim 19 for treating a cancer or a viral infection. 25) The isolated T-cell of claim 19 for treating lymphoma. 26) A pharmaceutical composition comprising at least one isolated T-cell of claim 19. 27) A method for treating a patient comprising:
(a) preparing a population of modified T-cells according to the method of claim 1; and (b) administrating said modified T-cells to said patient. 28) The method according to claim 27, wherein said patient is diagnosed with cancer, a viral infection, an autoimmune disorder or Graft versus Host Disease (GvHD).
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The present invention relates to methods for developing engineered T-cells for immunotherapy that are non-alloreactive. The present invention relates to methods for modifying T-cells by inactivating both genes encoding T-cell receptor and an immune checkpoint gene to unleash the potential of the immune response. This method involves the use of specific rare cutting endonucleases, in particular TALE-nucleases (TAL effector endonuclease) and polynucleotides encoding such polypeptides, to precisely target a selection of key genes in T-cells, which are available from donors or from culture of primary cells. The invention opens the way to standard and affordable adoptive immunotherapy strategies for treating cancer and viral infections.1) A method of preparing T-cell(s) for immunotherapy comprising:
(a) modifying T-cell(s) by inactivating at least:
a first gene encoding a immune checkpoint protein, and
a second gene encoding a component of the T-cell receptor (TCR); and
(b) expanding said T-cell(s). 2) The method of claim 1 comprising modifying T-cells by:
(a) introducing into said T-cell at least one rare-cutting endonuclease able to selectively inactivate by DNA cleavage respectively:
said gene encoding a immune checkpoint protein, and
at least one gene encoding one component of the T-cell receptor (TCR); and
(b) expanding said T-cells. 3) The method according to claim 1, wherein said immune checkpoint gene is selected from the group consisting of: PD1, CTLA-4, LAG3, Tim3, BTLA, BY55, TIGIT, B7H5, LAIR1, SIGLEC10, and 2B4. 4) The method according to claim 1, wherein said modified T-cells are expanded in a patient's blood. 5) The method according to claim 1, wherein said modified T-cells are expanded in vivo. 6) The method according to claim 1, wherein said immune checkpoint gene is PD1 or CTLA-4. 7) The method according to claim 1, wherein the at least first and second inactivated genes are selected from the group consisting of PD1 and TCR alpha, PD1 and TCR beta, CTLA-4 and TCR alpha, CTLA-4 and TCR beta, LAG3 and TCR alpha, LAG3 and TCR beta, Tim3 and TCR alpha, Tim3 and TCR beta, BTLA and TCR alpha, BTLA and TCR beta, BY55 and TCR alpha, BY55 and TCR beta, TIGIT and TCR alpha, TIGIT and TCR beta, B7H5 and TCR alpha, B7H5 and TCR beta, LAIR1 and TCR alpha, LAIR1 and TCR beta, SIGLEC10 and TCR alpha, SIGLEC10 and TCR beta, 2B4 and TCR alpha, and 2B4 and TCR beta. 8) The method according to claim 2, wherein said at least one rare-cutting endonuclease is encoded by mRNA. 9) The method according to claim 2 that comprises introducing one or more rare-cutting endonuclease(s) into said T-cell in step (a) by way of RNA electroporation. 10) The method according to claim 2, wherein said at least one rare-cutting endonuclease is a TALE-nuclease. 11) The method according to claim 10, wherein at least one TALE-nuclease is directed against one of the gene target sequences of TCRalpha selected from SEQ ID NO: 37 or SEQ ID NO: 57 to SEQ ID NO: 60. 12) The method according to claim 10, wherein at least one TALE-nuclease is directed against one of the gene target sequences of TCRbeta selected from the group consisting of SEQ ID NO: 38 and SEQ ID NO: 39. 13) The method according to claim 10, wherein at least one TALE-nuclease is directed against one of the gene target sequences of PD1 selected from the group consisting of SEQ ID NO: 77 and SEQ ID NO: 78. 14) The method according to claim 10, wherein at least one TALE-nuclease is directed against one of the gene target sequences of CTLA-4 selected from the group consisting of SEQ ID NO: 74 and SEQ ID NO: 76. 15) The method according to claim 1, further comprising introducing into said T-cell(s) a chimeric antigen receptor (CAR). 16) The method according to claim 1, wherein said T-cell(s) in step a) are derived from inflammatory T-lymphocytes, cytotoxic T-lymphocytes, regulatory T-lymphocytes or helper T-lymphocytes. 17) The method according to claim 1, wherein said T-cell(s) in step a) are derived from CD4+ T-lymphocytes and/or CD8+ T-lymphocytes. 18) An isolated T-cell or cell line obtainable by the method of claim 1, or a subculture thereof. 19) An isolated T-cell, in which at least two genes have been inactivated which genes are selected from the group consisting of: PD1 and TCR alpha, PD1 and TCR beta, CTLA-4 and TCR alpha, CTLA-4 and TCR beta, LAG3 and TCR alpha, LAG3 and TCR beta, Tim3 and TCR alpha, Tim3 and TCR beta, BTLA and TCR alpha, BTLA and TCR beta, BY55 and TCR alpha, BY55 and TCR beta, TIGIT and TCR alpha, TIGIT and TCR beta, B7H5 and TCR alpha, B7H5 and TCR beta, LAIR1 and TCR alpha, LAIR1 and TCR beta, SIGLEC10 and TCR alpha, SIGLEC10 and TCR beta, 2B4 and TCR alpha, and 2B4 and TCR beta. 20) The isolated T-cell according to claim 19, further comprising an exogenous polynucleotide sequence encoding a Chimeric Antigen Receptor. 21) The isolated T-cell of claim 20 wherein said Chimeric Antigen Receptor is a multi-chain Chimeric Antigen Receptor. 22) The isolated T-cell of claim 19, further comprising an exogenous nucleic acid comprising at least a fragment of pTalpha transgene to support CD3 surface expression. 23) The isolated T-cell of claim 19 for use as a medicament. 24) The isolated T-cell of claim 19 for treating a cancer or a viral infection. 25) The isolated T-cell of claim 19 for treating lymphoma. 26) A pharmaceutical composition comprising at least one isolated T-cell of claim 19. 27) A method for treating a patient comprising:
(a) preparing a population of modified T-cells according to the method of claim 1; and (b) administrating said modified T-cells to said patient. 28) The method according to claim 27, wherein said patient is diagnosed with cancer, a viral infection, an autoimmune disorder or Graft versus Host Disease (GvHD).
| 1,600 |
961 | 15,514,833 | 1,654 |
The invention relates to a method for peptide synthesis, wherein said method comprises the steps of reacting a first amino acid or a first peptide with an α-amine protected second amino acid in a solvent selected from the group consisting of water, alcohol, and a mixture of water and alcohol, and removing the α-amine protecting group with a deprotecting solution. The invention further relates to protective agents, their use and an apparatus for carrying out a method for solid phase synthesis of peptides.
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1. A method of forming protecting groups on functional groups during water based peptide synthesis, the method comprising using a protective agent,
wherein the protective agent comprises a) a backbone structure, b) at least one water-solubility enhancing functional group and c) at least one reactive group, wherein the backbone structure comprises a moiety selected from the group consisting of 9-methylfluorene, t-butane and/or mono-, di or triphenylmethane, wherein the water-solubility enhancing functional group is selected from the group consisting of SO3 −, PO3 2−, N(CH3)2, N(CH3)3 +, CN, OSO3 − ester, OPO3 2− ester and combinations thereof, and wherein the water-solubility enhancing functional group and the reactive group are attached to the backbone structure via at least one covalent bond, for protecting a functional group in a chemical reaction, wherein the agent is used for forming protecting groups on functional groups during water based peptide synthesis. 2. The method according to claim 1, wherein the agent is used for forming protecting groups on functional groups on a peptide and/or amino acid during water based peptide synthesis. 3. The method according to claim 2, wherein the functional group to be protected is selected from amine, alcohol, thiol and carboxyl groups. 4. The method according to claim 3, wherein the reactive group is selected from the group consisting of oxycarbonyl halogenide, oxycarbonyl Oxyma ester, oxycarbonyl O-succinimide, oxycarbonyl anhydride, halogenide, hydroxide and thiol groups. 5. The method according to claim 4, wherein the water solubility-enhancing functional group is SO3 −. 6. The method according to claim 5, wherein the functional group to be protected is present on an amino acid, peptide or protein and the chemical reaction is peptide or protein synthesis in a solvent selected form water, alcohol or a mixture of water and alcohol. 7. Protective agent suitable for forming protecting groups on functional groups on a peptide and/or amino acid during water based peptide synthesis,
wherein the protective agent comprises a) a backbone structure, b) at least one two water-solubility enhancing functional group and c) at least one reactive group, wherein the backbone structure comprises a moiety selected from the group consisting of 9-methylfluorene, t-butane and/or mono-, di or triphenylmethane, wherein the water-solubility enhancing functional group is selected from the group consisting of SO3 −, PO3 2−, N(CH3)2, N(CH3)3 +, CN, OSO3 − ester, OPO3 2− ester and combinations thereof, and wherein the water-solubility enhancing functional group and the reactive group are attached to the backbone structure via at least one covalent bond. 8. (canceled) 9. A method for peptide synthesis, wherein said method comprises the steps of reacting a first amino acid or a first peptide with an α-amine protected second amino acid or second peptide in a solvent selected from the group consisting of water, alcohol, and a mixture of water and alcohol, and removing the α-amine protecting group with a deprotecting solution, characterized in that the α-amine protecting group is formed by reaction of a protective agent with a functional group on an amino acid or peptide, wherein the protective agent is suitable for forming protecting groups on functional groups during water based peptide synthesis,
wherein the protective agent comprises
a) a backbone structure,
b) at least one water-solubility enhancing functional group and
c) at least one reactive group,
wherein the backbone structure comprises a moiety selected from the group consisting of 9-methylfluorene, t-butane and/or mono-, di or triphenylmethane,
wherein the water-solubility enhancing functional group is selected from the group consisting of SO3 −, PO3 2−, N(CH3)2, N(CH3)3 +, CN, OSO3 − ester, OPO3 2− ester and combinations thereof, and
wherein the water-solubility enhancing functional group and the reactive group are attached to the backbone structure via at least one covalent bond. 10. The method according to claim 9, characterized in that the C-terminus of said first amino acid or first peptide is anchored to an insoluble support and that the method further comprises the step of cleaving the resulting peptide or protein from the polymeric support with a cleaving composition. 11. The method according to claim 10, characterized in that any reactive side chain functional group of said first amino acid or first peptide and said second amino acid or second peptide is protected with a side chain protecting group comprising at least one water solubility enhancing functional group and that the method further comprises the step of removing the side chain protecting groups. 12. The method according to claim 11, wherein the α-amine protecting group comprises a fluorescent structure and the method further comprises the step of monitoring the degree of formation of peptide bonds and/or monitoring the degree of removal of the α-amine protecting group by measuring fluorescence that is generated by the α-amine protecting groups coupled to the first amino acid or first peptide. 13. An apparatus for carrying out a method for solid phase synthesis of peptides or proteins according to claim 12, said apparatus comprising a reaction vessel for receiving an insoluble support material and a fluorimeter arranged for monitoring the changes in fluorescence intensity that is generated by a protecting group coupled to the insoluble support material. 14. Modified amino acid, peptide, protein or salt thereof comprising a protecting group formed by reaction of protective agent with a functional group of the amino acid, peptide or protein, wherein the functional group is selected from α-amino, side chain amino, thiol, carboxyl and hydroxy, wherein the protective agent comprises
a) a backbone structure,
b) at least one water-solubility enhancing functional group and
c) at least one reactive group,
wherein the backbone structure comprises a moiety selected from the group consisting of 9-methylfluorene, t-butane and/or mono-, di or triphenylmethane,
wherein the water-solubility enhancing functional group is selected from the group consisting of SO3 −, PO3 2−, N(CH3)2, N(CH3)3 +, CN, OSO3 − ester, OPO3 2− ester and combinations thereof, and
wherein the water-solubility enhancing functional group and the reactive group are attached to the backbone structure via at least one covalent bond. 15. A method of peptide synthesis, wherein a capping agent is used for capping of free amines after a coupling step in order to prevent the formation of side products, the capping agent comprising
a) a backbone structure, b) at least one water-solubility enhancing functional group and c) at least one reactive group, wherein the backbone structure comprises a moiety selected from the group selected from short chain alkyl, preferably C1 to C8 alkyl, cyclic alkyl chains or aromatic compounds, more preferably C1 to C4 alkyl or benzyl, wherein the water-solubility enhancing functional group is selected from the group consisting of SO3 −, PO3 2−, N(CH3)2, N(CH3)3 +, CN, OSO3 − ester, OPO3 2− ester and combinations thereof, and wherein the water-solubility enhancing functional group and the reactive group are attached to the backbone structure via at least one covalent bond. 16. (canceled) 17. (canceled) 18. The method according to claim 6, wherein the protective agent has the following formula
wherein R2 and R7 are SO3 − and R1, R3 to R6 and R8 are hydrogen, or R3 and R6 are SO3 − and R1, R2, R4, R5, R7 and R8 are hydrogen, and
wherein R99 is selected from the group consisting of oxycarbonyl halogenide, oxycarbonyl O-succinimide, oxycarbonyl Oxyma ester, oxycarbonyl anhydride, halogenide, oxymethyl halogenide, hydroxide and thiol groups, wherein R99 is preferably selected from oxycarbonyl halogenide, oxycarbonyl Oxyma ester and oxycarbonyl O-succinimide. 19. Protective agent according to claim 7, having the following formula
wherein R2 and R7 are SO3 − and R1, R3 to R6 and R8 are hydrogen, or R3 and R6 are SO3 − and R1, R2, R4, R5, R7 and R8 are hydrogen, and
wherein R99 is selected from the group consisting of oxycarbonyl halogenide, oxycarbonyl O-succinimide, oxycarbonyl Oxyma ester, oxycarbonyl anhydride, halogenide, oxymethyl halogenide, hydroxide and thiol groups, wherein R99 is preferably selected from oxycarbonyl halogenide, oxycarbonyl Oxyma ester and oxycarbonyl O-succinimide. 20. The method according to claim 15, wherein after the completion of the reaction the reaction mixture is passed through an affinity column in order to purify the reaction mixture.
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The invention relates to a method for peptide synthesis, wherein said method comprises the steps of reacting a first amino acid or a first peptide with an α-amine protected second amino acid in a solvent selected from the group consisting of water, alcohol, and a mixture of water and alcohol, and removing the α-amine protecting group with a deprotecting solution. The invention further relates to protective agents, their use and an apparatus for carrying out a method for solid phase synthesis of peptides.1. A method of forming protecting groups on functional groups during water based peptide synthesis, the method comprising using a protective agent,
wherein the protective agent comprises a) a backbone structure, b) at least one water-solubility enhancing functional group and c) at least one reactive group, wherein the backbone structure comprises a moiety selected from the group consisting of 9-methylfluorene, t-butane and/or mono-, di or triphenylmethane, wherein the water-solubility enhancing functional group is selected from the group consisting of SO3 −, PO3 2−, N(CH3)2, N(CH3)3 +, CN, OSO3 − ester, OPO3 2− ester and combinations thereof, and wherein the water-solubility enhancing functional group and the reactive group are attached to the backbone structure via at least one covalent bond, for protecting a functional group in a chemical reaction, wherein the agent is used for forming protecting groups on functional groups during water based peptide synthesis. 2. The method according to claim 1, wherein the agent is used for forming protecting groups on functional groups on a peptide and/or amino acid during water based peptide synthesis. 3. The method according to claim 2, wherein the functional group to be protected is selected from amine, alcohol, thiol and carboxyl groups. 4. The method according to claim 3, wherein the reactive group is selected from the group consisting of oxycarbonyl halogenide, oxycarbonyl Oxyma ester, oxycarbonyl O-succinimide, oxycarbonyl anhydride, halogenide, hydroxide and thiol groups. 5. The method according to claim 4, wherein the water solubility-enhancing functional group is SO3 −. 6. The method according to claim 5, wherein the functional group to be protected is present on an amino acid, peptide or protein and the chemical reaction is peptide or protein synthesis in a solvent selected form water, alcohol or a mixture of water and alcohol. 7. Protective agent suitable for forming protecting groups on functional groups on a peptide and/or amino acid during water based peptide synthesis,
wherein the protective agent comprises a) a backbone structure, b) at least one two water-solubility enhancing functional group and c) at least one reactive group, wherein the backbone structure comprises a moiety selected from the group consisting of 9-methylfluorene, t-butane and/or mono-, di or triphenylmethane, wherein the water-solubility enhancing functional group is selected from the group consisting of SO3 −, PO3 2−, N(CH3)2, N(CH3)3 +, CN, OSO3 − ester, OPO3 2− ester and combinations thereof, and wherein the water-solubility enhancing functional group and the reactive group are attached to the backbone structure via at least one covalent bond. 8. (canceled) 9. A method for peptide synthesis, wherein said method comprises the steps of reacting a first amino acid or a first peptide with an α-amine protected second amino acid or second peptide in a solvent selected from the group consisting of water, alcohol, and a mixture of water and alcohol, and removing the α-amine protecting group with a deprotecting solution, characterized in that the α-amine protecting group is formed by reaction of a protective agent with a functional group on an amino acid or peptide, wherein the protective agent is suitable for forming protecting groups on functional groups during water based peptide synthesis,
wherein the protective agent comprises
a) a backbone structure,
b) at least one water-solubility enhancing functional group and
c) at least one reactive group,
wherein the backbone structure comprises a moiety selected from the group consisting of 9-methylfluorene, t-butane and/or mono-, di or triphenylmethane,
wherein the water-solubility enhancing functional group is selected from the group consisting of SO3 −, PO3 2−, N(CH3)2, N(CH3)3 +, CN, OSO3 − ester, OPO3 2− ester and combinations thereof, and
wherein the water-solubility enhancing functional group and the reactive group are attached to the backbone structure via at least one covalent bond. 10. The method according to claim 9, characterized in that the C-terminus of said first amino acid or first peptide is anchored to an insoluble support and that the method further comprises the step of cleaving the resulting peptide or protein from the polymeric support with a cleaving composition. 11. The method according to claim 10, characterized in that any reactive side chain functional group of said first amino acid or first peptide and said second amino acid or second peptide is protected with a side chain protecting group comprising at least one water solubility enhancing functional group and that the method further comprises the step of removing the side chain protecting groups. 12. The method according to claim 11, wherein the α-amine protecting group comprises a fluorescent structure and the method further comprises the step of monitoring the degree of formation of peptide bonds and/or monitoring the degree of removal of the α-amine protecting group by measuring fluorescence that is generated by the α-amine protecting groups coupled to the first amino acid or first peptide. 13. An apparatus for carrying out a method for solid phase synthesis of peptides or proteins according to claim 12, said apparatus comprising a reaction vessel for receiving an insoluble support material and a fluorimeter arranged for monitoring the changes in fluorescence intensity that is generated by a protecting group coupled to the insoluble support material. 14. Modified amino acid, peptide, protein or salt thereof comprising a protecting group formed by reaction of protective agent with a functional group of the amino acid, peptide or protein, wherein the functional group is selected from α-amino, side chain amino, thiol, carboxyl and hydroxy, wherein the protective agent comprises
a) a backbone structure,
b) at least one water-solubility enhancing functional group and
c) at least one reactive group,
wherein the backbone structure comprises a moiety selected from the group consisting of 9-methylfluorene, t-butane and/or mono-, di or triphenylmethane,
wherein the water-solubility enhancing functional group is selected from the group consisting of SO3 −, PO3 2−, N(CH3)2, N(CH3)3 +, CN, OSO3 − ester, OPO3 2− ester and combinations thereof, and
wherein the water-solubility enhancing functional group and the reactive group are attached to the backbone structure via at least one covalent bond. 15. A method of peptide synthesis, wherein a capping agent is used for capping of free amines after a coupling step in order to prevent the formation of side products, the capping agent comprising
a) a backbone structure, b) at least one water-solubility enhancing functional group and c) at least one reactive group, wherein the backbone structure comprises a moiety selected from the group selected from short chain alkyl, preferably C1 to C8 alkyl, cyclic alkyl chains or aromatic compounds, more preferably C1 to C4 alkyl or benzyl, wherein the water-solubility enhancing functional group is selected from the group consisting of SO3 −, PO3 2−, N(CH3)2, N(CH3)3 +, CN, OSO3 − ester, OPO3 2− ester and combinations thereof, and wherein the water-solubility enhancing functional group and the reactive group are attached to the backbone structure via at least one covalent bond. 16. (canceled) 17. (canceled) 18. The method according to claim 6, wherein the protective agent has the following formula
wherein R2 and R7 are SO3 − and R1, R3 to R6 and R8 are hydrogen, or R3 and R6 are SO3 − and R1, R2, R4, R5, R7 and R8 are hydrogen, and
wherein R99 is selected from the group consisting of oxycarbonyl halogenide, oxycarbonyl O-succinimide, oxycarbonyl Oxyma ester, oxycarbonyl anhydride, halogenide, oxymethyl halogenide, hydroxide and thiol groups, wherein R99 is preferably selected from oxycarbonyl halogenide, oxycarbonyl Oxyma ester and oxycarbonyl O-succinimide. 19. Protective agent according to claim 7, having the following formula
wherein R2 and R7 are SO3 − and R1, R3 to R6 and R8 are hydrogen, or R3 and R6 are SO3 − and R1, R2, R4, R5, R7 and R8 are hydrogen, and
wherein R99 is selected from the group consisting of oxycarbonyl halogenide, oxycarbonyl O-succinimide, oxycarbonyl Oxyma ester, oxycarbonyl anhydride, halogenide, oxymethyl halogenide, hydroxide and thiol groups, wherein R99 is preferably selected from oxycarbonyl halogenide, oxycarbonyl Oxyma ester and oxycarbonyl O-succinimide. 20. The method according to claim 15, wherein after the completion of the reaction the reaction mixture is passed through an affinity column in order to purify the reaction mixture.
| 1,600 |
962 | 15,523,850 | 1,627 |
The present invention relates to a method of controlling abiotic stress on warm-season turfgrass using an effective amount of acibenzolar-s-methyl.
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1. A method for controlling or suppressing abiotic stress in warm-season turfgrass, comprising applying to the turfgrass or to the locus of the turfgrass, a turf quality improving amount of acibenzolar-S-methyl at a rate between about 32 and 96 g/ha. 2. The method of claim 1, wherein the warm season turfgrass is Bermudagrass. 3. The method of claim 1, wherein the warm-season turfgrass is Zoysiagrass. 4. The method of claim 1, using a composition comprising acibenzolar-S-methyl. 5. The method of claim 4, wherein the composition further comprises adjuvants, solvents, carrier, surfactants or extenders. 6. The method according to claim 5, wherein the composition comprises from 0.01 to 90% by weight of the acibenzolar-S-methyl, from 10 to 99.99% of a carrier and from 0 to 20% of a surfactant. 7. The method of claim 1, wherein acibenzolar-S-methyl is applied at the rate of from 32 to 64 g/ha. 8. The method of claim 1, wherein acibenzolar-S-methyl is applied between about two and 18 times, at intervals of from 5 to 21 days during the turf growing season. 9. The method of claim 1, wherein acibenzolar-S-methyl is applied between about three and four times, at intervals of from 14 to 21 days during the turf growing season. 10. The method of claim 1, wherein the method for controlling or suppressing abiotic stress in warm-season turfgrass provides a greater improvement over the same method on cool-season grasses. 11. The method according to claim 1, wherein the abiotic stress relates to drought conditions. 12. The method according to claim 1, wherein the method further comprising applying trinexapac-ethyl to said warm-season turfgrass.
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The present invention relates to a method of controlling abiotic stress on warm-season turfgrass using an effective amount of acibenzolar-s-methyl.1. A method for controlling or suppressing abiotic stress in warm-season turfgrass, comprising applying to the turfgrass or to the locus of the turfgrass, a turf quality improving amount of acibenzolar-S-methyl at a rate between about 32 and 96 g/ha. 2. The method of claim 1, wherein the warm season turfgrass is Bermudagrass. 3. The method of claim 1, wherein the warm-season turfgrass is Zoysiagrass. 4. The method of claim 1, using a composition comprising acibenzolar-S-methyl. 5. The method of claim 4, wherein the composition further comprises adjuvants, solvents, carrier, surfactants or extenders. 6. The method according to claim 5, wherein the composition comprises from 0.01 to 90% by weight of the acibenzolar-S-methyl, from 10 to 99.99% of a carrier and from 0 to 20% of a surfactant. 7. The method of claim 1, wherein acibenzolar-S-methyl is applied at the rate of from 32 to 64 g/ha. 8. The method of claim 1, wherein acibenzolar-S-methyl is applied between about two and 18 times, at intervals of from 5 to 21 days during the turf growing season. 9. The method of claim 1, wherein acibenzolar-S-methyl is applied between about three and four times, at intervals of from 14 to 21 days during the turf growing season. 10. The method of claim 1, wherein the method for controlling or suppressing abiotic stress in warm-season turfgrass provides a greater improvement over the same method on cool-season grasses. 11. The method according to claim 1, wherein the abiotic stress relates to drought conditions. 12. The method according to claim 1, wherein the method further comprising applying trinexapac-ethyl to said warm-season turfgrass.
| 1,600 |
963 | 15,757,424 | 1,612 |
The present invention concerns a composition under the form of aqueous gel for caring for and/or making up keratin materials comprising, in a physiologically acceptable medium, a) one aqueous phase; and b) at least one hydrophilic gelling agent, and c) at least microcapsules comprising:—an inner core comprising at least a dispersion of at least one reflective agent, in particular bismuth oxychloride, in at least one oil, and—at least one outer shell formed of a wall-forming polymeric material surrounding the said core, the said outer shell comprising i) at least one wall-forming polymer, and ii) optionally at least one plasticizer and/or at least one opaque substance and/:or at least one fatty acid salt. The present invention concerns also a cosmetic process for caring for and/or making up keratinic materials, comprising application on said keratinic materials in particular on the skin of a composition as above defined.
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1. A composition, in the form of aqueous gel, comprising, in a physiologically acceptable medium;
a) one aqueous phase; b) at least one hydrophilic gelling agent; and c) at least microcapsules comprising:
an inner core comprising at least a dispersion of at least one reflective agent in at least one oil, and
at least one outer shell formed of a wall-forming polymeric material surrounding the core, the outer shell comprising
i) at least one wall-forming polymer, and
ii) optionally at least one plasticizer, at least one opaque substance, and/or at least one fatty acid salt. 2. The composition according to claim 1, wherein the reflective agent is bismuth oxychloride. 3. The composition according to claim 1, wherein the oil of the dispersion is polar. 4. The composition according to claim 1, wherein an amount of reflective agent ranges from 50% to 90% by weight of the total weight of the dispersion. 5. The composition according to claim 1, wherein a weight ratio of the reflective agent particles to the oil(s) ranges from 1.5/1 to 5/1. 6. The composition according to claim 1, wherein the oily dispersion of reflective agent is a dispersion of bismuth oxychloride in ethylhexyl hydroxystearate. 7. The composition according to claim 1, wherein the wall-forming polymer forming the outer shell(s) is selected from the group consisting of a polyacrylate, a polymethacrylate, a cellulose ether or ester, and any combination thereof. 8. The composition according to claim 7, wherein the wall-forming polymer is selected from the group consisting of poly(methyl methacrylate (PMMA), poly(methyl methacrylate)-co-(methacrylic acid) (PMMA MA), an acrylate/ammonium methacrylate copolymer, and cellulose acetate. 9. The composition according to claim 1, wherein the opaque substance is selected from the group consisting of TiO2, zinc oxide, alumina, boron nitride, talc, mica and any combination thereof. 10. The composition according to claim 1, wherein the fatty acid salt is magnesium stearate. 11. The composition according to claim 1, wherein the microcapsules comprise:
the inner core constituted by the oily dispersion of reflective agent, in an amount within a range of from 20% to 90% %, by weight relative to the total weight of the microcapsule; the wall-forming polymer(s) of the outer shell is within a range of from 5% to 30%, by weight relative to the total microcapsule weight; and optionally, the amount of opaque substance(s) in the outer shell is within a range of from 1% to 50% by weight, relative to the total weight of the microcapsule and/or optionally the fatty acid salt in an amount within a range of from 0.05% 5%, by weight, relative to the total weight of the microcapsule; and/or optionally the plasticizer(s) is within a range of from 0.5% to about 30% by weight, relative to the total weight of the microcapsule. 12. The composition according to claim 1, wherein the microcapsules are single-layer microcapsules. 13. The composition according to claim 1, wherein the microcapsules are single-layer microcapsules comprising the inner core constituted by bismuth oxychloride dispersed in 2-ethylhexyl hydroxystearate in an amount from 60 to 80% by weight, the outer shell comprises magnesium stearate in an amount within a range of from 1.0% to 2.0% by weight, TiO2 in an amount within a range of from 1% to 20% by weight, and, as a wall-forming polymer, PMMA, in an amount within a range of from 5% to 20% by weight, relative to the total weight of the microcapsule. 14. The composition according to claim 1, wherein the microcapsules are single-layer microcapsules comprising the inner core constituted by bismuth oxychloride dispersed in 2-ethylhexyl hydroxystearate in an amount from 60 to 80% by weight, the outer shell does not comprise magnesium stearate, and comprises
TiO2 in an amount within a range of 10% to 50% by weight, and, as a wall-forming polymer, ethyl cellulose, in an amount within a range of 1% to 10% by weight relative to the total weight of the microcapsule. 15. The composition according to claim 1, wherein the microcapsules are single-layer microcapsules comprising the inner core constituted by bismuth oxychloride dispersed in 2-ethylhexyl hydroxystearate in an amount from 60 to 80% by weight, the outer shell comprises magnesium stearate in an amount within a range of from 1.0% to 2.0% by weight, TiO2 in an amount within a range of 1% to 20% by weight, and, as a wall-forming polymer, poly(ethyl acrylate-co-methyl methacrylate-co-trimethyl ammonium ethyl methacrylate chloride, in an amount within a range of 5% to 20% by weight, relative to the total weight of the microcapsule. 16. The composition according to claim 1, wherein the microcapsules are single-layer microcapsules comprising the inner core constituted by bismuth oxychloride dispersed in 2-ethylhexyl hydroxystearate in an amount of from 60 to 80% by weight, the outer shell comprises magnesium stearate in an amount within a range of from 1.0% to 2.0% by weight, TiO2 in an amount within a range of 1% to 20% by weight, and, as a wall-forming polymer, PMMA/MA, in an amount within a range of 5% to 20% by weight, relative to the total weight of the microcapsule. 17. The composition according to claim 1, wherein the microcapsules are single-layer microcapsules comprising the inner core constituted by bismuth oxychloride dispersed in 2-ethylhexyl hydroxystearate in an amount of from 60 to 80% by weight, the outer shell does not comprise magnesium stearate nor TiO2, and comprises a plasticizer, in an amount within a range of 1% to 20% by weight, and, as a wall-forming material, poly(ethyl acrylate-co-methyl methacrylate-co-trimethyl ammonium ethyl methacrylate chloride, in an amount within a range of 5% to 20% by weight relative to the total weight of the microcapsule. 18. The composition according to claim 1, wherein the hydrophilic gelling agent is chosen from synthetic polymeric gelling agents, natural or polymeric gelling agents of natural origin, mixed silicates and pyrogenic silicas, and mixtures thereof. 19. The composition according to claim 1, comprising which contains at least one coloring agent. 20. The composition according to claim 1, comprising at least one mono-alcohol comprising from 2 to 8 carbon atoms. 21. The composition according to claim 1, comprising at least one filler. 22. The composition according to claim 1, comprising at least one non-emulsifying organopolysiloxane elastomer. 23. A cosmetic process for caring for and/or making up keratinic materials, the process comprising applying the composition according to claim 1 on the keratinic materials.
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The present invention concerns a composition under the form of aqueous gel for caring for and/or making up keratin materials comprising, in a physiologically acceptable medium, a) one aqueous phase; and b) at least one hydrophilic gelling agent, and c) at least microcapsules comprising:—an inner core comprising at least a dispersion of at least one reflective agent, in particular bismuth oxychloride, in at least one oil, and—at least one outer shell formed of a wall-forming polymeric material surrounding the said core, the said outer shell comprising i) at least one wall-forming polymer, and ii) optionally at least one plasticizer and/or at least one opaque substance and/:or at least one fatty acid salt. The present invention concerns also a cosmetic process for caring for and/or making up keratinic materials, comprising application on said keratinic materials in particular on the skin of a composition as above defined.1. A composition, in the form of aqueous gel, comprising, in a physiologically acceptable medium;
a) one aqueous phase; b) at least one hydrophilic gelling agent; and c) at least microcapsules comprising:
an inner core comprising at least a dispersion of at least one reflective agent in at least one oil, and
at least one outer shell formed of a wall-forming polymeric material surrounding the core, the outer shell comprising
i) at least one wall-forming polymer, and
ii) optionally at least one plasticizer, at least one opaque substance, and/or at least one fatty acid salt. 2. The composition according to claim 1, wherein the reflective agent is bismuth oxychloride. 3. The composition according to claim 1, wherein the oil of the dispersion is polar. 4. The composition according to claim 1, wherein an amount of reflective agent ranges from 50% to 90% by weight of the total weight of the dispersion. 5. The composition according to claim 1, wherein a weight ratio of the reflective agent particles to the oil(s) ranges from 1.5/1 to 5/1. 6. The composition according to claim 1, wherein the oily dispersion of reflective agent is a dispersion of bismuth oxychloride in ethylhexyl hydroxystearate. 7. The composition according to claim 1, wherein the wall-forming polymer forming the outer shell(s) is selected from the group consisting of a polyacrylate, a polymethacrylate, a cellulose ether or ester, and any combination thereof. 8. The composition according to claim 7, wherein the wall-forming polymer is selected from the group consisting of poly(methyl methacrylate (PMMA), poly(methyl methacrylate)-co-(methacrylic acid) (PMMA MA), an acrylate/ammonium methacrylate copolymer, and cellulose acetate. 9. The composition according to claim 1, wherein the opaque substance is selected from the group consisting of TiO2, zinc oxide, alumina, boron nitride, talc, mica and any combination thereof. 10. The composition according to claim 1, wherein the fatty acid salt is magnesium stearate. 11. The composition according to claim 1, wherein the microcapsules comprise:
the inner core constituted by the oily dispersion of reflective agent, in an amount within a range of from 20% to 90% %, by weight relative to the total weight of the microcapsule; the wall-forming polymer(s) of the outer shell is within a range of from 5% to 30%, by weight relative to the total microcapsule weight; and optionally, the amount of opaque substance(s) in the outer shell is within a range of from 1% to 50% by weight, relative to the total weight of the microcapsule and/or optionally the fatty acid salt in an amount within a range of from 0.05% 5%, by weight, relative to the total weight of the microcapsule; and/or optionally the plasticizer(s) is within a range of from 0.5% to about 30% by weight, relative to the total weight of the microcapsule. 12. The composition according to claim 1, wherein the microcapsules are single-layer microcapsules. 13. The composition according to claim 1, wherein the microcapsules are single-layer microcapsules comprising the inner core constituted by bismuth oxychloride dispersed in 2-ethylhexyl hydroxystearate in an amount from 60 to 80% by weight, the outer shell comprises magnesium stearate in an amount within a range of from 1.0% to 2.0% by weight, TiO2 in an amount within a range of from 1% to 20% by weight, and, as a wall-forming polymer, PMMA, in an amount within a range of from 5% to 20% by weight, relative to the total weight of the microcapsule. 14. The composition according to claim 1, wherein the microcapsules are single-layer microcapsules comprising the inner core constituted by bismuth oxychloride dispersed in 2-ethylhexyl hydroxystearate in an amount from 60 to 80% by weight, the outer shell does not comprise magnesium stearate, and comprises
TiO2 in an amount within a range of 10% to 50% by weight, and, as a wall-forming polymer, ethyl cellulose, in an amount within a range of 1% to 10% by weight relative to the total weight of the microcapsule. 15. The composition according to claim 1, wherein the microcapsules are single-layer microcapsules comprising the inner core constituted by bismuth oxychloride dispersed in 2-ethylhexyl hydroxystearate in an amount from 60 to 80% by weight, the outer shell comprises magnesium stearate in an amount within a range of from 1.0% to 2.0% by weight, TiO2 in an amount within a range of 1% to 20% by weight, and, as a wall-forming polymer, poly(ethyl acrylate-co-methyl methacrylate-co-trimethyl ammonium ethyl methacrylate chloride, in an amount within a range of 5% to 20% by weight, relative to the total weight of the microcapsule. 16. The composition according to claim 1, wherein the microcapsules are single-layer microcapsules comprising the inner core constituted by bismuth oxychloride dispersed in 2-ethylhexyl hydroxystearate in an amount of from 60 to 80% by weight, the outer shell comprises magnesium stearate in an amount within a range of from 1.0% to 2.0% by weight, TiO2 in an amount within a range of 1% to 20% by weight, and, as a wall-forming polymer, PMMA/MA, in an amount within a range of 5% to 20% by weight, relative to the total weight of the microcapsule. 17. The composition according to claim 1, wherein the microcapsules are single-layer microcapsules comprising the inner core constituted by bismuth oxychloride dispersed in 2-ethylhexyl hydroxystearate in an amount of from 60 to 80% by weight, the outer shell does not comprise magnesium stearate nor TiO2, and comprises a plasticizer, in an amount within a range of 1% to 20% by weight, and, as a wall-forming material, poly(ethyl acrylate-co-methyl methacrylate-co-trimethyl ammonium ethyl methacrylate chloride, in an amount within a range of 5% to 20% by weight relative to the total weight of the microcapsule. 18. The composition according to claim 1, wherein the hydrophilic gelling agent is chosen from synthetic polymeric gelling agents, natural or polymeric gelling agents of natural origin, mixed silicates and pyrogenic silicas, and mixtures thereof. 19. The composition according to claim 1, comprising which contains at least one coloring agent. 20. The composition according to claim 1, comprising at least one mono-alcohol comprising from 2 to 8 carbon atoms. 21. The composition according to claim 1, comprising at least one filler. 22. The composition according to claim 1, comprising at least one non-emulsifying organopolysiloxane elastomer. 23. A cosmetic process for caring for and/or making up keratinic materials, the process comprising applying the composition according to claim 1 on the keratinic materials.
| 1,600 |
964 | 15,023,858 | 1,642 |
Provided herein are antibodies and antigen binding fragments thereof that bind the extracellular domain of the HER3 receptor and inhibit various HER3 receptor related functions via ligand-dependent and/or ligand-independent mechanisms. Also provided are compositions with increased half-life, as well as compositions and methods for diagnosing and treating diseases associated with HER3 mediated signal transduction.
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1. A method of resensitizing a tumor or tumor cell in a subject to a HER targeted therapy, comprising administering to the subject a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5GE
X6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFDI
[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 2. The method of claim 1 further comprising administering to the subject a therapeutically effective amount of a HER targeted therapy. 3. The method of claim 1, wherein the cancer is characterized as expressing heregulin. 4. The method of claim 1, wherein the HER targeted therapy is an anti-EGFR antibody, anti-HER2 antibody, anti-HER3 antibody or anti-HER4 antibody or a small molecule inhibiting the activity of EGFR, HER2, HER3 or HER4. 5. The method of claim 4, wherein the HER targeted therapy is an anti-EGFR antibody. 6. The method of claim 1, wherein the cancer was previous treated with the HER targeted therapy and had acquired resistance to the HER targeted therapy. 7. The method of claim 1, wherein the tumor is a lung cancer tumor. 8. The method of claim 1, wherein the tumor or tumor cell had acquired resistance to the HER targeted therapy following treatment with the HER targeted therapy. 9. The method of claim 1, wherein the antibody or antigen binding fragment thereof is administered after surgical removal of a tumor of the cancer. 10. The method of claim 2, wherein the HER targeted therapy and the antibody or antigen binding fragment thereof are administered after surgical removal of a tumor of the cancer. 11. The method of claim 2, further comprising administering an anti-cancer agent. 12. The method of claim 11, wherein the anticancer agent is an antimetabolite, alkylating agent, topoisomerase inhibitor, or microtubule targeting agent. 13. The method of claim 2, wherein the antibody or antigen binding fragment thereof is administered for a first period of time and a second period of time, wherein there is a period of rest between the first period of time and the second period of time, wherein the antibody or antigen binding fragment thereof is not administered to the subject during the period of rest. 14. The method of claim 13, wherein the HER targeted therapy is administered during the first period of time and the second period of time, and wherein the HER targeted therapy is not administered to the subject during the period of rest. 15. The method of claim 13, wherein the period of rest is 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, or 26 weeks. 16. A method of resensitizing a HER2 amplified tumor or tumor cell in a subject to a HER2 targeted therapy, comprising administering to the subject a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5GE
X6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFDI
[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 17. The method of claim 16 further comprising administering to the subject a therapeutically effective amount of a HER2 targeted therapy. 18. The method of claim 16, wherein the cancer is characterized as expressing heregulin. 19. The method of claim 16, wherein the HER2 targeted therapy is neratinib, lapatinib, afatinib, trastuzumab, or pertuzumab. 20. The method of claim 16, wherein the cancer is breast cancer. 21. The method of claim 16, wherein the cancer was previous treated with the HER2 targeted therapy and had acquired resistance to the HER2 targeted therapy. 22. The method of claim 17, wherein the tumor is a breast cancer tumor. 23. The method of claim 16, wherein the tumor or tumor cell had acquired resistance to the HER2 targeted therapy following treatment with the HER2 targeted therapy. 24. The method claim 17, wherein the HER2 targeted therapy is administered concurrently with the antibody or antigen binding fragment thereof. 25. The method claim 17, wherein the HER2 targeted therapy and the antibody or antigen binding fragment thereof are administered sequentially. 26. The method of claim 16, wherein the antibody or antigen binding fragment thereof is administered after surgical removal of a tumor of the cancer. 27. The method of claim 17, wherein the HER2 targeted therapy and the antibody or antigen binding fragment thereof are administered after surgical removal of a tumor of the cancer. 28. The method of claim 16, further comprising administering an anti-cancer agent. 29. The method of claim 28, wherein the anticancer agent is an antimetabolite, alkylating agent, topoisomerase inhibitor, or microtubule targeting agent. 30. The method of claim 16, wherein the antibody or antigen binding fragment thereof is administered for a first period of time and a second period of time, wherein there is a period of rest between the first period of time and the second period of time, wherein the antibody or antigen binding fragment thereof is not administered to the subject during the period of rest. 31. The method of claim 30, wherein the HER2 targeted therapy is administered during the first period of time and the second period of time, and wherein the trastuzumab is not administered to the subject during the period of rest. 32. The method of claim 31, wherein the period of rest is 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, or 26 weeks. 33. The method of any one of claim 32, comprising measuring the expression level of HER2. 34. The method of claim 33, comprising measuring the expression level of HER2, and starting the period of rest when the expression level of HER2 has decreased relative to the expression level of HER2 during the first period of time. 35. The method of claim 33, comprising starting the second period of time when the expression level of HER2 has increased relative to the expression level of HER2 during the period of rest. 36. The method of claim 34, wherein the expression level of HER2 has decreased by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%. 37. The method of claim 35, wherein the expression level of HER2 has increased by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%. 38. The method of claim 17, further comprising administering to the subject a therapeutically effective amount of pertuzumab. 39. A method of resensitizing a tumor in a subject to trastuzumab, comprising administering to a subject diagnosed as having a cancer resistant to treatment with trastuzumab a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5
GEX6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFDI
[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 40. The method of claim 39 further comprising administering to the subject a therapeutically effective amount of trastuzumab. 41. The method of claim 39, wherein the cancer is breast cancer. 42. The method of claim 39, wherein the tumor has been characterized as being resistant to treatment with the combination of pertuzumab and trastuzumab. 43. The method of claim 39, wherein the tumor has been characterized as being resistant to treatment with pertuzumab alone. 44. The method of claim 40, wherein trastuzumab is administered concurrently with the antibody or antigen binding fragment thereof. 45. The method of claim 40, wherein trastuzumab is administered sequentially with the antibody or antigen binding fragment thereof. 46. The method of claim 39, wherein the method achieves reduction or inhibition of growth of the tumor for a period of at least about 0.5 month, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months. 47. The method of claim 40, wherein trastuzumab is administered after the antibody or antigen binding fragment thereof. 48. The method of claim 40, wherein the antibody or antigen binding fragment thereof is administered for a first period of time and a second period of time, wherein there is a period of rest between the first period of time and the second period of time, wherein the antibody or antigen binding fragment thereof is not administered to the subject during the period of rest. 49. The method of claim 48, wherein the trastuzumab is administered during the first period of time and the second period of time, and wherein the trastuzumab is not administered to the subject during the period of rest. 50. The method of claim 48, wherein the period of rest is 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, or 26 weeks. 51. The method of claim 48, comprising measuring the expression level of HER2. 52. The method of claim 48, comprising measuring the expression level of HER2, and starting the period of rest when the expression level of HER2 has decreased relative to the expression level of HER2 during the first period of time. 53. The method of claim 51, comprising starting the second period of time when the expression level of HER2 has increased relative to the expression level of HER2 during the period of rest. 54. The method of claim 52, wherein the expression level of HER2 has decreased by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%. 55. The method of claim 53, wherein the expression level of HER2 has increased by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%. 56. A method of resensitizing a tumor or tumor cell in a subject to an EGFR targeted therapy, comprising administering to the subject a therapeutically effective amount of the antibody or antigen binding fragment thereof of which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5
GEX6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFDI
[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 57. The method of claim 56, further comprising administering to the subject a therapeutically effective amount of an EGFR targeted therapy. 58. The method of claim 56, wherein the cancer is characterized as expressing heregulin. 59. The method of claim 57, wherein the EGFR targeted therapy is cetuximab. 60. The method of claim 56, wherein the cancer was previous treated with the EGFR targeted therapy and had acquired resistance to the EGFR targeted therapy. 61. The method of claim 56, wherein the tumor or tumor cell is a lung cancer tumor or tumor cell, colorectal cancer tumor or tumor cell, or head and neck cancer tumor or tumor cell. 62. The method of claim 56, wherein the tumor or tumor cell had acquired resistance to the EGFR targeted therapy following treatment with the EGFR targeted therapy. 63. The method of claim 56, wherein the antibody or antigen binding fragment thereof is administered after surgical removal of a tumor of the cancer. 64. The method of claim 57, wherein the EGFR targeted therapy and the antibody or antigen binding fragment thereof are administered after surgical removal of a tumor of the cancer. 65. The method of claim 57, further comprising administering an anti-cancer agent. 66. The method of claim 65, wherein the anticancer agent is an antimetabolite, alkylating agent, topoisomerase inhibitor, or microtubule targeting agent. 67. The method of claim 57, wherein the antibody or antigen binding fragment thereof is administered for a first period of time and a second period of time, wherein there is a period of rest between the first period of time and the second period of time, wherein the antibody or antigen binding fragment thereof is not administered to the subject during the period of rest. 68. The method of claim 67, wherein the EGFR targeted therapy is administered during the first period of time and the second period of time, and wherein the EGFR targeted therapy is not administered to the subject during the period of rest. 69. The method of claim 67, wherein the period of rest is 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, or 26 weeks. 70. The method of claim 57, wherein the cancer is lung cancer, head and neck cancer, or colorectal cancer. 71. A method of reducing or inhibiting growth of a tumor or tumor cell in a subject, comprising administering to a subject identified as having, or suspected of having, cancer resistant to treatment with a HER targeted therapy a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5
GEX6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFDI
[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 72. A method of reducing or inhibiting growth of a HER2 amplified tumor or tumor cell in a subject, comprising administering to a subject identified as having, or suspected of having, cancer resistant to treatment with a HER2 targeted therapy a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5
GEX6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFDI
[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 73. A method of reducing or inhibiting growth of a tumor resistant to trastuzumab in a subject, comprising administering to a subject diagnosed as having a cancer resistant to treatment with trastuzumab a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5
GEX6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFDI
[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 74. A method of reducing or inhibiting growth of a tumor or tumor cell in a subject, comprising administering to a subject identified as having, or suspected of having, cancer resistant to treatment with an EGFR targeted therapy a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5
GEX6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFDI
[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 75. A method of managing or treating cancer in a subject, comprising administering to a subject diagnosed as having, or suspected of having, a cancer resistant to treatment with a HER targeted therapy a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5G
EX6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFD
I[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 76. A method of managing or treating cancer in a subject, comprising the steps of:
(a) identifying a subject with a tumor expressing HER3 and is resistant to treatment with a HER targeted therapy; and (b) administering to the subject a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein (i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5GE
X6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFD
I[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 77. A method of managing or treating cancer in a subject, comprising administering to a subject diagnosed as having, or suspected of having, a cancer resistant to treatment with a HER2 targeted therapy a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5GE
X6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFD
I[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 78. A method of managing or treating cancer in a subject, comprising the steps of:
(a) identifying a subject with a HER2 amplified tumor which expresses HER3 and is resistant to treatment with a HER2 targeted therapy; and (b) administering to the subject a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein (i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5GE
X6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFD
I[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 79. A method of managing or treating cancer in a subject, comprising administering to a subject diagnosed as having, or suspected of having, a cancer resistant to treatment with trastuzumab a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5GE
X6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFD
I[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 80. The method of claim 79 further comprising administering to the subject a therapeutically effective amount of trastuzumab. 81. A method of managing or treating cancer in a subject, comprising administering to a subject identified as having a cancer resistant to treatment with pertuzumab or the combination of pertuzumab and trastuzumab a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5GE
X6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFD
I[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 82. The method of claim 81 further comprising administering to the subject a therapeutically effective amount of trastuzumab. 83. A method of managing or treating cancer in a subject, comprising the steps of:
(a) identifying a subject with a HER2/HER3-positive cancer that is resistant to treatment with trastuzumab; and (b) administering to the subject a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein (i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5GE
X6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFD
I[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 84. The method of claim 83, wherein the cancer is characterized as expressing heregulin. 85. The method of claim 83 further comprising administering to the subject a therapeutically effective amount of trastuzumab. 86. The method of any one of claims 1-85, wherein the VH and VL of CL16 comprise SEQ ID NOs: 2 and 1, respectively, and the VH and VL of 2C2 comprise SEQ ID NOs: 2 and 3, respectively. 87. The method of any one of claims 1-85, wherein the antibody or antigen binding fragment is affinity matured. 88. The method of any one of claims 1-85, wherein
(i) FW1 comprises SEQ ID NO: 40 or 44, FW2 comprises SEQ ID NO: 41, FW3 comprises SEQ ID NO: 42, and FW4 comprises SEQ ID NO: 43; or (ii) FW5 comprises SEQ ID NO: 36, FW6 comprises SEQ ID NO: 37, FW7 comprises SEQ ID NO: 38 and FW8 comprises SEQ ID NO: 39; or (iii) FW1 comprises SEQ ID NO: 40 or 44, FW2 comprises SEQ ID NO: 41, FW3 comprises SEQ ID NO: 42, FW4 comprises SEQ ID NO: 43, FW5 comprises SEQ ID NO: 36, FW6 comprises SEQ ID NO: 37, FW7 comprises SEQ ID NO: 38, and FW8 comprises SEQ ID NO: 39. 89. The method of any one of claims 1-85, wherein the antibody or antigen binding fragment thereof comprises
(i) an antibody VL, wherein the VL comprises a VL complementarity determining region-1 (VL-CDR1) amino acid sequence identical to, or identical except for four, three, two or one amino acid substitutions to: SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO: 20; or (ii) an antibody VL, wherein the VL comprises a VL complementarity determining region-2 (VL-CDR2) amino acid sequence identical to, or identical except for four, three, two or one amino acid substitutions to SEQ ID NO: 21; or (iii) an antibody VL, wherein the VL comprises a complementarity determining region-3 (VL-CDR3) amino acid sequence identical to, or identical except for four, three, two, or one amino acid substitutions to: SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, or SEQ ID NO: 30; or (iv) an antibody VH, wherein the VH comprises a complementarity determining region-1 (VH-CDR1) amino acid sequence identical to, or identical except for four, three, two, or one amino acid substitutions to SEQ ID NO: 31; or (v) an antibody VH, wherein the VH comprises a complementarity determining region-2 (VH-CDR2) amino acid sequence identical to, or identical except for four, three, two, or one amino acid substitutions to: SEQ ID NO: 32, SEQ ID NO: 33, or SEQ ID NO: 34; or (vi) an antibody VH, wherein the VH comprises a complementarity determining region-3 (VH-CDR3) amino acid sequence identical to, or identical except for four, three, two, or one amino acid substitutions to SEQ ID NO: 35; or (vii) an antibody VL, wherein the VL comprises VL-CDR1, VL-CDR2, and VL-CDR3 amino acid sequences identical to, or identical except for four, three, two, or one amino acid substitutions in one or more of the VL-CDRS to: SEQ ID NOs: 18, 21 and 22, SEQ ID NOs: 18, 21, and 26, SEQ ID NOs: 18, 21, and 27, SEQ ID NOs: 20, 21, and 22, SEQ ID NOs: 19, 21, and 22, SEQ ID NOs: 18, 21, and 25, SEQ ID NOs: 18, 21, and 28, SEQ ID NOs: 18, 21, and 29, SEQ ID NOs: 18, 21, and 30, SEQ ID NOs: 18, 21, and 23, SEQ ID NOs: 19, 21, and 23, SEQ ID NOs: 20, 21, and 23, SEQ ID NOs: 18, 21, and 24, or SEQ ID NOs: 18, 21, and 25, respectively; or (viii) an antibody VH, wherein the VH comprises VH-CDR1, VH-CDR2, and VH-CDR3 amino acid sequences identical to, or identical except for four, three, two, or one amino acid substitutions in one or more of the VH-CDRS to: SEQ ID NOs: 31, 32 and 35, SEQ ID NOs: 31, 33, and 35, or SEQ ID NOs: 31, 34, and 35, respectively; or (ix) a VL and a VH comprising VL-CDR1, VL-CRD2, VL-CDR3, VH-CDR1, VH-CDR2, and VH-CDR3 amino acid sequences identical or identical except for four, three, two, or one amino acid substitutions in one or more CDRs to: SEQ ID NOs: 18, 21, 22, 31, 32, and 35, SEQ ID NOs: 18, 21, 26, 31, 32 and 35, SEQ ID NOs: 18, 21, 27, 31, 32 and 35, SEQ ID NOs: 20, 21, 22, 31, 32 and 35, SEQ ID NOs: 19, 21, 22, 31, 32 and 35, SEQ ID NOs: 18, 21, 25, 31, 32 and 35, SEQ ID NOs: 18, 21, 28, 31, 32 and 35, SEQ ID NOs: 18, 21, 29, 31, 32 and 35, SEQ ID NOs: 18, 21, 30, 31, 32 and 35, SEQ ID NOs: 18, 21, 23, 31, 32 and 35, SEQ ID NOs: 19, 21, 23, 31, 32 and 35, SEQ ID NOs: 20, 21, 23, 31, 32 and 35, SEQ ID NOs: 18, 21, 24, 31, 32 and 35, or SEQ ID NOs: 18, 21, 25, 31, 32 and 35, respectively; or (x) an antibody VL and an antibody VH, wherein the VL comprises an amino acid sequence at least about 90% to about 100% identical to a reference amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17; or (xi) an antibody VL and an antibody VH, wherein the VH comprises an amino acid sequence at least about 90% to about 100% identical to a reference amino acid sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 12 and SEQ ID NO: 13; or (xii) a VL comprising a sequence at least about 90% to about 100% identical to a reference amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17, and wherein the antibody or antigen binding fragment comprises a VH comprising a sequence at least about 90% to about 100% identical to a reference amino acid sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 12 and SEQ ID NO: 13; or (xiii) a VL comprising the VL consensus sequence provided in Table 4 and a VH comprising the VH consensus sequence provided in Table 4. 90. The method of any one of claims 1-85, wherein the antibody or antigen binding fragment comprises a VL comprising SEQ ID NO: 3 and a VH comprising SEQ ID NO: 2. 91. The method of any one of claims 1-85, wherein the antibody or antigen binding fragment comprises a heavy chain constant region or fragment thereof. 92. The method of any one of claims 1-85, wherein the antibody or antigen binding fragment comprises the heavy chain constant region or fragment thereof is an IgG constant region. 93. The method of claim 92, wherein the IgG constant region is selected from an IgG1 constant region, an IgG2 constant region, an IgG3 constant region and an IgG4 constant region. 94. The method of claim 92, wherein the IgG constant region is an IgG1 constant region. 95. The method of any one of claims 1-85, wherein the antibody or antigen binding fragment comprises a light chain constant region selected from the group consisting of a human kappa constant region and a human lambda constant region. 96. The method of claim 92, wherein the IgG constant region comprises one or more amino acid substitutions relative to a wild-type IgG constant region wherein the modified IgG has an increased half-life compared to the half-life of an IgG having the wild-type IgG constant region. 97. The method of claim 92, wherein the IgG constant region comprises one or more amino acid substitutions of amino acid residues at positions 251-257, 285-290, 308-314, 385-389, and 428-436, wherein the numbering is according to the EU index as set forth in Kabat. 98. The method of claim 97, wherein at least one IgG constant region amino acid substitution is selected from the group consisting of:
(a) substitution of the amino acid at position 252 with Tyrosine (Y), Phenylalanine (F), Tryptophan (W), or Threonine (T), (b) substitution of the amino acid at position 254 with Threonine (T), (c) substitution of the amino acid at position 256 with Serine (S), Arginine (R), Glutamine (Q), Glutamic acid (E), Aspartic acid (D), or Threonine (T), (d) substitution of the amino acid at position 257 with Leucine (L), (e) substitution of the amino acid at position 309 with Proline (P), (f) substitution of the amino acid at position 311 with Serine (S), (g) substitution of the amino acid at position 428 with Threonine (T), Leucine (L), Phenylalanine (F), or Serine (S), (h) substitution of the amino acid at position 433 with Arginine (R), Serine (S), Isoleucine (I), Proline (P), or Glutamine (Q), (i) substitution of the amino acid at position 434 with Tryptophan (W), Methionine (M), Serine (S), Histidine (H), Phenylalanine (F), or Tyrosine, and (j) a combination of two or more of said substitutions, wherein the numbering is according to the EU index as set forth in Kabat. 99. The method of claim 98, wherein the human IgG constant region comprises amino acid substitutions relative to a wild-type human IgG constant region at positions 252, 254, and 256, wherein
(a) the amino acid at position 252 is substituted with Tyrosine (Y), (b) the amino acid at position 254 is substituted with Threonine (T), and (c) the amino acid at position 256 is substituted with Glutamic acid (E), wherein the numbering is according to the EU index as set forth in Kabat. 100. The method of claim 98, wherein
(i) the amino acid at position 434 is substituted with an amino acid selected from the group consisting of Tryptophan (W), Methionine (M), Tyrosine (Y), and Serine (S), and wherein the numbering is according to the EU index as set forth in Kabat; or (ii) the amino acid at position 428 is substituted with an amino acid selected from the group consisting of Threonine (T), Leucine (L), Phenylalanine (F), and Serine (S), and wherein the numbering is according to the EU index as set forth in Kabat; or (iii) the amino acid at position 257 is substituted with Leucine (L), and the amino acid at Kabat position 434 is substituted with Tyrosine (Y), and wherein the numbering is according to the EU index as set forth in Kabat; or (iv) the amino acid at Kabat position 428 is substituted with Leucine (L), and the amino acid at Kabat position 434 is substituted with Serine (S). 101. The method of any one of claims 1-85, wherein the antibody or antigen binding fragment thereof comprises an antibody VL of SEQ ID NO:3, an antibody VH of SEQ ID NO: 2, and an IgG1 constant region of SEQ ID 46. 102. The method of any one of claims 1-85, wherein the antibody is a fully human antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a multispecific antibody, or an antigen-binding fragment thereof. 103. The method of any one of claims 1-85, which antigen binding fragment is a Fv, Fab, F(ab′)2, Fab′, dsFv, scFv, and sc(Fv)2. 104. The method of any one of claims 1-85, wherein the antibody or antigen binding fragment is conjugated to at least one heterologous agent.
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Provided herein are antibodies and antigen binding fragments thereof that bind the extracellular domain of the HER3 receptor and inhibit various HER3 receptor related functions via ligand-dependent and/or ligand-independent mechanisms. Also provided are compositions with increased half-life, as well as compositions and methods for diagnosing and treating diseases associated with HER3 mediated signal transduction.1. A method of resensitizing a tumor or tumor cell in a subject to a HER targeted therapy, comprising administering to the subject a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5GE
X6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFDI
[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 2. The method of claim 1 further comprising administering to the subject a therapeutically effective amount of a HER targeted therapy. 3. The method of claim 1, wherein the cancer is characterized as expressing heregulin. 4. The method of claim 1, wherein the HER targeted therapy is an anti-EGFR antibody, anti-HER2 antibody, anti-HER3 antibody or anti-HER4 antibody or a small molecule inhibiting the activity of EGFR, HER2, HER3 or HER4. 5. The method of claim 4, wherein the HER targeted therapy is an anti-EGFR antibody. 6. The method of claim 1, wherein the cancer was previous treated with the HER targeted therapy and had acquired resistance to the HER targeted therapy. 7. The method of claim 1, wherein the tumor is a lung cancer tumor. 8. The method of claim 1, wherein the tumor or tumor cell had acquired resistance to the HER targeted therapy following treatment with the HER targeted therapy. 9. The method of claim 1, wherein the antibody or antigen binding fragment thereof is administered after surgical removal of a tumor of the cancer. 10. The method of claim 2, wherein the HER targeted therapy and the antibody or antigen binding fragment thereof are administered after surgical removal of a tumor of the cancer. 11. The method of claim 2, further comprising administering an anti-cancer agent. 12. The method of claim 11, wherein the anticancer agent is an antimetabolite, alkylating agent, topoisomerase inhibitor, or microtubule targeting agent. 13. The method of claim 2, wherein the antibody or antigen binding fragment thereof is administered for a first period of time and a second period of time, wherein there is a period of rest between the first period of time and the second period of time, wherein the antibody or antigen binding fragment thereof is not administered to the subject during the period of rest. 14. The method of claim 13, wherein the HER targeted therapy is administered during the first period of time and the second period of time, and wherein the HER targeted therapy is not administered to the subject during the period of rest. 15. The method of claim 13, wherein the period of rest is 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, or 26 weeks. 16. A method of resensitizing a HER2 amplified tumor or tumor cell in a subject to a HER2 targeted therapy, comprising administering to the subject a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5GE
X6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFDI
[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 17. The method of claim 16 further comprising administering to the subject a therapeutically effective amount of a HER2 targeted therapy. 18. The method of claim 16, wherein the cancer is characterized as expressing heregulin. 19. The method of claim 16, wherein the HER2 targeted therapy is neratinib, lapatinib, afatinib, trastuzumab, or pertuzumab. 20. The method of claim 16, wherein the cancer is breast cancer. 21. The method of claim 16, wherein the cancer was previous treated with the HER2 targeted therapy and had acquired resistance to the HER2 targeted therapy. 22. The method of claim 17, wherein the tumor is a breast cancer tumor. 23. The method of claim 16, wherein the tumor or tumor cell had acquired resistance to the HER2 targeted therapy following treatment with the HER2 targeted therapy. 24. The method claim 17, wherein the HER2 targeted therapy is administered concurrently with the antibody or antigen binding fragment thereof. 25. The method claim 17, wherein the HER2 targeted therapy and the antibody or antigen binding fragment thereof are administered sequentially. 26. The method of claim 16, wherein the antibody or antigen binding fragment thereof is administered after surgical removal of a tumor of the cancer. 27. The method of claim 17, wherein the HER2 targeted therapy and the antibody or antigen binding fragment thereof are administered after surgical removal of a tumor of the cancer. 28. The method of claim 16, further comprising administering an anti-cancer agent. 29. The method of claim 28, wherein the anticancer agent is an antimetabolite, alkylating agent, topoisomerase inhibitor, or microtubule targeting agent. 30. The method of claim 16, wherein the antibody or antigen binding fragment thereof is administered for a first period of time and a second period of time, wherein there is a period of rest between the first period of time and the second period of time, wherein the antibody or antigen binding fragment thereof is not administered to the subject during the period of rest. 31. The method of claim 30, wherein the HER2 targeted therapy is administered during the first period of time and the second period of time, and wherein the trastuzumab is not administered to the subject during the period of rest. 32. The method of claim 31, wherein the period of rest is 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, or 26 weeks. 33. The method of any one of claim 32, comprising measuring the expression level of HER2. 34. The method of claim 33, comprising measuring the expression level of HER2, and starting the period of rest when the expression level of HER2 has decreased relative to the expression level of HER2 during the first period of time. 35. The method of claim 33, comprising starting the second period of time when the expression level of HER2 has increased relative to the expression level of HER2 during the period of rest. 36. The method of claim 34, wherein the expression level of HER2 has decreased by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%. 37. The method of claim 35, wherein the expression level of HER2 has increased by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%. 38. The method of claim 17, further comprising administering to the subject a therapeutically effective amount of pertuzumab. 39. A method of resensitizing a tumor in a subject to trastuzumab, comprising administering to a subject diagnosed as having a cancer resistant to treatment with trastuzumab a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5
GEX6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFDI
[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 40. The method of claim 39 further comprising administering to the subject a therapeutically effective amount of trastuzumab. 41. The method of claim 39, wherein the cancer is breast cancer. 42. The method of claim 39, wherein the tumor has been characterized as being resistant to treatment with the combination of pertuzumab and trastuzumab. 43. The method of claim 39, wherein the tumor has been characterized as being resistant to treatment with pertuzumab alone. 44. The method of claim 40, wherein trastuzumab is administered concurrently with the antibody or antigen binding fragment thereof. 45. The method of claim 40, wherein trastuzumab is administered sequentially with the antibody or antigen binding fragment thereof. 46. The method of claim 39, wherein the method achieves reduction or inhibition of growth of the tumor for a period of at least about 0.5 month, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months. 47. The method of claim 40, wherein trastuzumab is administered after the antibody or antigen binding fragment thereof. 48. The method of claim 40, wherein the antibody or antigen binding fragment thereof is administered for a first period of time and a second period of time, wherein there is a period of rest between the first period of time and the second period of time, wherein the antibody or antigen binding fragment thereof is not administered to the subject during the period of rest. 49. The method of claim 48, wherein the trastuzumab is administered during the first period of time and the second period of time, and wherein the trastuzumab is not administered to the subject during the period of rest. 50. The method of claim 48, wherein the period of rest is 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, or 26 weeks. 51. The method of claim 48, comprising measuring the expression level of HER2. 52. The method of claim 48, comprising measuring the expression level of HER2, and starting the period of rest when the expression level of HER2 has decreased relative to the expression level of HER2 during the first period of time. 53. The method of claim 51, comprising starting the second period of time when the expression level of HER2 has increased relative to the expression level of HER2 during the period of rest. 54. The method of claim 52, wherein the expression level of HER2 has decreased by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%. 55. The method of claim 53, wherein the expression level of HER2 has increased by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%. 56. A method of resensitizing a tumor or tumor cell in a subject to an EGFR targeted therapy, comprising administering to the subject a therapeutically effective amount of the antibody or antigen binding fragment thereof of which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5
GEX6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFDI
[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 57. The method of claim 56, further comprising administering to the subject a therapeutically effective amount of an EGFR targeted therapy. 58. The method of claim 56, wherein the cancer is characterized as expressing heregulin. 59. The method of claim 57, wherein the EGFR targeted therapy is cetuximab. 60. The method of claim 56, wherein the cancer was previous treated with the EGFR targeted therapy and had acquired resistance to the EGFR targeted therapy. 61. The method of claim 56, wherein the tumor or tumor cell is a lung cancer tumor or tumor cell, colorectal cancer tumor or tumor cell, or head and neck cancer tumor or tumor cell. 62. The method of claim 56, wherein the tumor or tumor cell had acquired resistance to the EGFR targeted therapy following treatment with the EGFR targeted therapy. 63. The method of claim 56, wherein the antibody or antigen binding fragment thereof is administered after surgical removal of a tumor of the cancer. 64. The method of claim 57, wherein the EGFR targeted therapy and the antibody or antigen binding fragment thereof are administered after surgical removal of a tumor of the cancer. 65. The method of claim 57, further comprising administering an anti-cancer agent. 66. The method of claim 65, wherein the anticancer agent is an antimetabolite, alkylating agent, topoisomerase inhibitor, or microtubule targeting agent. 67. The method of claim 57, wherein the antibody or antigen binding fragment thereof is administered for a first period of time and a second period of time, wherein there is a period of rest between the first period of time and the second period of time, wherein the antibody or antigen binding fragment thereof is not administered to the subject during the period of rest. 68. The method of claim 67, wherein the EGFR targeted therapy is administered during the first period of time and the second period of time, and wherein the EGFR targeted therapy is not administered to the subject during the period of rest. 69. The method of claim 67, wherein the period of rest is 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, or 26 weeks. 70. The method of claim 57, wherein the cancer is lung cancer, head and neck cancer, or colorectal cancer. 71. A method of reducing or inhibiting growth of a tumor or tumor cell in a subject, comprising administering to a subject identified as having, or suspected of having, cancer resistant to treatment with a HER targeted therapy a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5
GEX6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFDI
[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 72. A method of reducing or inhibiting growth of a HER2 amplified tumor or tumor cell in a subject, comprising administering to a subject identified as having, or suspected of having, cancer resistant to treatment with a HER2 targeted therapy a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5
GEX6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFDI
[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 73. A method of reducing or inhibiting growth of a tumor resistant to trastuzumab in a subject, comprising administering to a subject diagnosed as having a cancer resistant to treatment with trastuzumab a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5
GEX6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFDI
[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 74. A method of reducing or inhibiting growth of a tumor or tumor cell in a subject, comprising administering to a subject identified as having, or suspected of having, cancer resistant to treatment with an EGFR targeted therapy a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5
GEX6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFDI
[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 75. A method of managing or treating cancer in a subject, comprising administering to a subject diagnosed as having, or suspected of having, a cancer resistant to treatment with a HER targeted therapy a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5G
EX6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFD
I[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 76. A method of managing or treating cancer in a subject, comprising the steps of:
(a) identifying a subject with a tumor expressing HER3 and is resistant to treatment with a HER targeted therapy; and (b) administering to the subject a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein (i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5GE
X6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFD
I[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 77. A method of managing or treating cancer in a subject, comprising administering to a subject diagnosed as having, or suspected of having, a cancer resistant to treatment with a HER2 targeted therapy a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5GE
X6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFD
I[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 78. A method of managing or treating cancer in a subject, comprising the steps of:
(a) identifying a subject with a HER2 amplified tumor which expresses HER3 and is resistant to treatment with a HER2 targeted therapy; and (b) administering to the subject a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein (i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5GE
X6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFD
I[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 79. A method of managing or treating cancer in a subject, comprising administering to a subject diagnosed as having, or suspected of having, a cancer resistant to treatment with trastuzumab a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5GE
X6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFD
I[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 80. The method of claim 79 further comprising administering to the subject a therapeutically effective amount of trastuzumab. 81. A method of managing or treating cancer in a subject, comprising administering to a subject identified as having a cancer resistant to treatment with pertuzumab or the combination of pertuzumab and trastuzumab a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein
(i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5GE
X6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFD
I[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 82. The method of claim 81 further comprising administering to the subject a therapeutically effective amount of trastuzumab. 83. A method of managing or treating cancer in a subject, comprising the steps of:
(a) identifying a subject with a HER2/HER3-positive cancer that is resistant to treatment with trastuzumab; and (b) administering to the subject a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein (i) the antibody or antigen binding fragment thereof binds to the same HER3 epitope as an antibody or antigen-binding fragment thereof comprising the heavy chain variable region (VH) and light chain variable region (VL) of CL16 or 2C2; or (ii) the antibody or antigen binding fragment thereof competitively inhibits HER3 binding by an antibody or antigen-binding fragment thereof comprising the VH and VL of CL16 or 2C2; or (iii) the antibody or antigen binding fragment thereof comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS[FW2]RNNQRPS[FW3]AAWDDX3X4X5GE
X6[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and
wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ[FW6]X7IGSSGGVTNYADSVKG[FW7]VGLGDAFD
I[FW8]
wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and
wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V). 84. The method of claim 83, wherein the cancer is characterized as expressing heregulin. 85. The method of claim 83 further comprising administering to the subject a therapeutically effective amount of trastuzumab. 86. The method of any one of claims 1-85, wherein the VH and VL of CL16 comprise SEQ ID NOs: 2 and 1, respectively, and the VH and VL of 2C2 comprise SEQ ID NOs: 2 and 3, respectively. 87. The method of any one of claims 1-85, wherein the antibody or antigen binding fragment is affinity matured. 88. The method of any one of claims 1-85, wherein
(i) FW1 comprises SEQ ID NO: 40 or 44, FW2 comprises SEQ ID NO: 41, FW3 comprises SEQ ID NO: 42, and FW4 comprises SEQ ID NO: 43; or (ii) FW5 comprises SEQ ID NO: 36, FW6 comprises SEQ ID NO: 37, FW7 comprises SEQ ID NO: 38 and FW8 comprises SEQ ID NO: 39; or (iii) FW1 comprises SEQ ID NO: 40 or 44, FW2 comprises SEQ ID NO: 41, FW3 comprises SEQ ID NO: 42, FW4 comprises SEQ ID NO: 43, FW5 comprises SEQ ID NO: 36, FW6 comprises SEQ ID NO: 37, FW7 comprises SEQ ID NO: 38, and FW8 comprises SEQ ID NO: 39. 89. The method of any one of claims 1-85, wherein the antibody or antigen binding fragment thereof comprises
(i) an antibody VL, wherein the VL comprises a VL complementarity determining region-1 (VL-CDR1) amino acid sequence identical to, or identical except for four, three, two or one amino acid substitutions to: SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO: 20; or (ii) an antibody VL, wherein the VL comprises a VL complementarity determining region-2 (VL-CDR2) amino acid sequence identical to, or identical except for four, three, two or one amino acid substitutions to SEQ ID NO: 21; or (iii) an antibody VL, wherein the VL comprises a complementarity determining region-3 (VL-CDR3) amino acid sequence identical to, or identical except for four, three, two, or one amino acid substitutions to: SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, or SEQ ID NO: 30; or (iv) an antibody VH, wherein the VH comprises a complementarity determining region-1 (VH-CDR1) amino acid sequence identical to, or identical except for four, three, two, or one amino acid substitutions to SEQ ID NO: 31; or (v) an antibody VH, wherein the VH comprises a complementarity determining region-2 (VH-CDR2) amino acid sequence identical to, or identical except for four, three, two, or one amino acid substitutions to: SEQ ID NO: 32, SEQ ID NO: 33, or SEQ ID NO: 34; or (vi) an antibody VH, wherein the VH comprises a complementarity determining region-3 (VH-CDR3) amino acid sequence identical to, or identical except for four, three, two, or one amino acid substitutions to SEQ ID NO: 35; or (vii) an antibody VL, wherein the VL comprises VL-CDR1, VL-CDR2, and VL-CDR3 amino acid sequences identical to, or identical except for four, three, two, or one amino acid substitutions in one or more of the VL-CDRS to: SEQ ID NOs: 18, 21 and 22, SEQ ID NOs: 18, 21, and 26, SEQ ID NOs: 18, 21, and 27, SEQ ID NOs: 20, 21, and 22, SEQ ID NOs: 19, 21, and 22, SEQ ID NOs: 18, 21, and 25, SEQ ID NOs: 18, 21, and 28, SEQ ID NOs: 18, 21, and 29, SEQ ID NOs: 18, 21, and 30, SEQ ID NOs: 18, 21, and 23, SEQ ID NOs: 19, 21, and 23, SEQ ID NOs: 20, 21, and 23, SEQ ID NOs: 18, 21, and 24, or SEQ ID NOs: 18, 21, and 25, respectively; or (viii) an antibody VH, wherein the VH comprises VH-CDR1, VH-CDR2, and VH-CDR3 amino acid sequences identical to, or identical except for four, three, two, or one amino acid substitutions in one or more of the VH-CDRS to: SEQ ID NOs: 31, 32 and 35, SEQ ID NOs: 31, 33, and 35, or SEQ ID NOs: 31, 34, and 35, respectively; or (ix) a VL and a VH comprising VL-CDR1, VL-CRD2, VL-CDR3, VH-CDR1, VH-CDR2, and VH-CDR3 amino acid sequences identical or identical except for four, three, two, or one amino acid substitutions in one or more CDRs to: SEQ ID NOs: 18, 21, 22, 31, 32, and 35, SEQ ID NOs: 18, 21, 26, 31, 32 and 35, SEQ ID NOs: 18, 21, 27, 31, 32 and 35, SEQ ID NOs: 20, 21, 22, 31, 32 and 35, SEQ ID NOs: 19, 21, 22, 31, 32 and 35, SEQ ID NOs: 18, 21, 25, 31, 32 and 35, SEQ ID NOs: 18, 21, 28, 31, 32 and 35, SEQ ID NOs: 18, 21, 29, 31, 32 and 35, SEQ ID NOs: 18, 21, 30, 31, 32 and 35, SEQ ID NOs: 18, 21, 23, 31, 32 and 35, SEQ ID NOs: 19, 21, 23, 31, 32 and 35, SEQ ID NOs: 20, 21, 23, 31, 32 and 35, SEQ ID NOs: 18, 21, 24, 31, 32 and 35, or SEQ ID NOs: 18, 21, 25, 31, 32 and 35, respectively; or (x) an antibody VL and an antibody VH, wherein the VL comprises an amino acid sequence at least about 90% to about 100% identical to a reference amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17; or (xi) an antibody VL and an antibody VH, wherein the VH comprises an amino acid sequence at least about 90% to about 100% identical to a reference amino acid sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 12 and SEQ ID NO: 13; or (xii) a VL comprising a sequence at least about 90% to about 100% identical to a reference amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17, and wherein the antibody or antigen binding fragment comprises a VH comprising a sequence at least about 90% to about 100% identical to a reference amino acid sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 12 and SEQ ID NO: 13; or (xiii) a VL comprising the VL consensus sequence provided in Table 4 and a VH comprising the VH consensus sequence provided in Table 4. 90. The method of any one of claims 1-85, wherein the antibody or antigen binding fragment comprises a VL comprising SEQ ID NO: 3 and a VH comprising SEQ ID NO: 2. 91. The method of any one of claims 1-85, wherein the antibody or antigen binding fragment comprises a heavy chain constant region or fragment thereof. 92. The method of any one of claims 1-85, wherein the antibody or antigen binding fragment comprises the heavy chain constant region or fragment thereof is an IgG constant region. 93. The method of claim 92, wherein the IgG constant region is selected from an IgG1 constant region, an IgG2 constant region, an IgG3 constant region and an IgG4 constant region. 94. The method of claim 92, wherein the IgG constant region is an IgG1 constant region. 95. The method of any one of claims 1-85, wherein the antibody or antigen binding fragment comprises a light chain constant region selected from the group consisting of a human kappa constant region and a human lambda constant region. 96. The method of claim 92, wherein the IgG constant region comprises one or more amino acid substitutions relative to a wild-type IgG constant region wherein the modified IgG has an increased half-life compared to the half-life of an IgG having the wild-type IgG constant region. 97. The method of claim 92, wherein the IgG constant region comprises one or more amino acid substitutions of amino acid residues at positions 251-257, 285-290, 308-314, 385-389, and 428-436, wherein the numbering is according to the EU index as set forth in Kabat. 98. The method of claim 97, wherein at least one IgG constant region amino acid substitution is selected from the group consisting of:
(a) substitution of the amino acid at position 252 with Tyrosine (Y), Phenylalanine (F), Tryptophan (W), or Threonine (T), (b) substitution of the amino acid at position 254 with Threonine (T), (c) substitution of the amino acid at position 256 with Serine (S), Arginine (R), Glutamine (Q), Glutamic acid (E), Aspartic acid (D), or Threonine (T), (d) substitution of the amino acid at position 257 with Leucine (L), (e) substitution of the amino acid at position 309 with Proline (P), (f) substitution of the amino acid at position 311 with Serine (S), (g) substitution of the amino acid at position 428 with Threonine (T), Leucine (L), Phenylalanine (F), or Serine (S), (h) substitution of the amino acid at position 433 with Arginine (R), Serine (S), Isoleucine (I), Proline (P), or Glutamine (Q), (i) substitution of the amino acid at position 434 with Tryptophan (W), Methionine (M), Serine (S), Histidine (H), Phenylalanine (F), or Tyrosine, and (j) a combination of two or more of said substitutions, wherein the numbering is according to the EU index as set forth in Kabat. 99. The method of claim 98, wherein the human IgG constant region comprises amino acid substitutions relative to a wild-type human IgG constant region at positions 252, 254, and 256, wherein
(a) the amino acid at position 252 is substituted with Tyrosine (Y), (b) the amino acid at position 254 is substituted with Threonine (T), and (c) the amino acid at position 256 is substituted with Glutamic acid (E), wherein the numbering is according to the EU index as set forth in Kabat. 100. The method of claim 98, wherein
(i) the amino acid at position 434 is substituted with an amino acid selected from the group consisting of Tryptophan (W), Methionine (M), Tyrosine (Y), and Serine (S), and wherein the numbering is according to the EU index as set forth in Kabat; or (ii) the amino acid at position 428 is substituted with an amino acid selected from the group consisting of Threonine (T), Leucine (L), Phenylalanine (F), and Serine (S), and wherein the numbering is according to the EU index as set forth in Kabat; or (iii) the amino acid at position 257 is substituted with Leucine (L), and the amino acid at Kabat position 434 is substituted with Tyrosine (Y), and wherein the numbering is according to the EU index as set forth in Kabat; or (iv) the amino acid at Kabat position 428 is substituted with Leucine (L), and the amino acid at Kabat position 434 is substituted with Serine (S). 101. The method of any one of claims 1-85, wherein the antibody or antigen binding fragment thereof comprises an antibody VL of SEQ ID NO:3, an antibody VH of SEQ ID NO: 2, and an IgG1 constant region of SEQ ID 46. 102. The method of any one of claims 1-85, wherein the antibody is a fully human antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a multispecific antibody, or an antigen-binding fragment thereof. 103. The method of any one of claims 1-85, which antigen binding fragment is a Fv, Fab, F(ab′)2, Fab′, dsFv, scFv, and sc(Fv)2. 104. The method of any one of claims 1-85, wherein the antibody or antigen binding fragment is conjugated to at least one heterologous agent.
| 1,600 |
965 | 16,165,813 | 1,647 |
Modified bovine G-CSF polypeptides and uses thereof are provided.
|
1-67. (canceled) 68. A method of treating an animal having a disorder modulated by bG-SCF comprising administering to the animal a therapeutically-effective amount of a bG-CSF polypeptide comprising the sequence of SEQ ID NO: 1 or SEQ ID NO: 2, wherein position 133 of SEQ ID NO: 1 or position 134 of SEQ ID NO: 2 is substituted with a non-naturally encoded amino acid,
wherein the non-naturally encoded amino acid is para-acetylphenylalanine, and wherein the non-naturally encoded amino acid is linked to a water soluble polymer comprising a poly(ethylene) glycol moiety having a molecular weight of between about 1 kDa and about 100 kDa. 69.-101. (canceled) 102. A method of treating an animal with an infection modulated by bG-CSF comprising administering to the animal a therapeutically-effective amount of a bG-CSF polypeptide comprising the sequence of SEQ ID NO: 1 or SEQ ID NO: 2, wherein position 133 of SEQ ID NO: 1 or position 134 of SEQ ID NO: 2 is substituted with a non-naturally encoded amino acid,
wherein the non-naturally encoded amino acid is para-acetylphenylalanine, and wherein the non-naturally encoded amino acid is linked to a water soluble polymer comprising a poly(ethylene) glycol moiety having a molecular weight of between about 1 kDa and about 100 kDa. 103. (canceled) 104. A method of preventing infection in an animal comprising administering to the animal a therapeutically-effective amount of a bG-CSF polypeptide comprising the sequence of SEQ ID NO: 1 or SEQ ID NO: 2, wherein position 133 of SEQ ID NO: 1 or position 134 of SEQ ID NO: 2 is substituted with a non-naturally encoded amino acid,
wherein the non-naturally encoded amino acid is para-acetylphenylalanine, and wherein the non-naturally encoded amino acid is linked to a water soluble polymer comprising a poly(ethylene) glycol moiety having a molecular weight of between about 1 kDa and about 100 kDa. 105. The method according to claim 68 wherein the animal is a bovine. 106. The method according to claim 102 wherein the animal is a bovine. 107. The method according to claim 104 wherein the animal is a bovine. 108. The method according to claim 105 wherein the bovine is a periparturient bovine. 109. The method according to claim 106 wherein the bovine is a periparturient bovine. 110. The method according to claim 107 wherein the bovine is a periparturient bovine. 111. The method according to claim 105 wherein the infection is selected from the group consisting of postpartum intrauterine infections, mastitis, shipping fever, pneumonia, bovine respiratory disease. 112. The method according to claim 106 wherein the infection is selected from the group consisting of postpartum intrauterine infections, mastitis, shipping fever, pneumonia, bovine respiratory disease. 113. The method according to claim 107 wherein the infection is selected from the group consisting of postpartum intrauterine infections, mastitis, shipping fever, pneumonia, bovine respiratory disease. 114. The method according to claim 108 wherein the infection is selected from the group consisting of postpartum intrauterine infections, mastitis, shipping fever, pneumonia, bovine respiratory disease. 115. The method according to claim 109 wherein the infection is selected from the group consisting of postpartum intrauterine infections, mastitis, shipping fever, pneumonia, bovine respiratory disease. 116. The method according to claim 110 wherein the infection is selected from the group consisting of postpartum intrauterine infections, mastitis, shipping fever, pneumonia, bovine respiratory disease.
|
Modified bovine G-CSF polypeptides and uses thereof are provided.1-67. (canceled) 68. A method of treating an animal having a disorder modulated by bG-SCF comprising administering to the animal a therapeutically-effective amount of a bG-CSF polypeptide comprising the sequence of SEQ ID NO: 1 or SEQ ID NO: 2, wherein position 133 of SEQ ID NO: 1 or position 134 of SEQ ID NO: 2 is substituted with a non-naturally encoded amino acid,
wherein the non-naturally encoded amino acid is para-acetylphenylalanine, and wherein the non-naturally encoded amino acid is linked to a water soluble polymer comprising a poly(ethylene) glycol moiety having a molecular weight of between about 1 kDa and about 100 kDa. 69.-101. (canceled) 102. A method of treating an animal with an infection modulated by bG-CSF comprising administering to the animal a therapeutically-effective amount of a bG-CSF polypeptide comprising the sequence of SEQ ID NO: 1 or SEQ ID NO: 2, wherein position 133 of SEQ ID NO: 1 or position 134 of SEQ ID NO: 2 is substituted with a non-naturally encoded amino acid,
wherein the non-naturally encoded amino acid is para-acetylphenylalanine, and wherein the non-naturally encoded amino acid is linked to a water soluble polymer comprising a poly(ethylene) glycol moiety having a molecular weight of between about 1 kDa and about 100 kDa. 103. (canceled) 104. A method of preventing infection in an animal comprising administering to the animal a therapeutically-effective amount of a bG-CSF polypeptide comprising the sequence of SEQ ID NO: 1 or SEQ ID NO: 2, wherein position 133 of SEQ ID NO: 1 or position 134 of SEQ ID NO: 2 is substituted with a non-naturally encoded amino acid,
wherein the non-naturally encoded amino acid is para-acetylphenylalanine, and wherein the non-naturally encoded amino acid is linked to a water soluble polymer comprising a poly(ethylene) glycol moiety having a molecular weight of between about 1 kDa and about 100 kDa. 105. The method according to claim 68 wherein the animal is a bovine. 106. The method according to claim 102 wherein the animal is a bovine. 107. The method according to claim 104 wherein the animal is a bovine. 108. The method according to claim 105 wherein the bovine is a periparturient bovine. 109. The method according to claim 106 wherein the bovine is a periparturient bovine. 110. The method according to claim 107 wherein the bovine is a periparturient bovine. 111. The method according to claim 105 wherein the infection is selected from the group consisting of postpartum intrauterine infections, mastitis, shipping fever, pneumonia, bovine respiratory disease. 112. The method according to claim 106 wherein the infection is selected from the group consisting of postpartum intrauterine infections, mastitis, shipping fever, pneumonia, bovine respiratory disease. 113. The method according to claim 107 wherein the infection is selected from the group consisting of postpartum intrauterine infections, mastitis, shipping fever, pneumonia, bovine respiratory disease. 114. The method according to claim 108 wherein the infection is selected from the group consisting of postpartum intrauterine infections, mastitis, shipping fever, pneumonia, bovine respiratory disease. 115. The method according to claim 109 wherein the infection is selected from the group consisting of postpartum intrauterine infections, mastitis, shipping fever, pneumonia, bovine respiratory disease. 116. The method according to claim 110 wherein the infection is selected from the group consisting of postpartum intrauterine infections, mastitis, shipping fever, pneumonia, bovine respiratory disease.
| 1,600 |
966 | 15,152,956 | 1,616 |
The present disclosure relates to methods for treating hair with lactones. The lactones form a covalent thio-ester bond with free thiols groups on chemically treated hair, and thereby impart a “repairing” or “conditioning” effect to the hair, for example, by making the hair more hydrophobic. Typically, after hair has been treated with a composition comprising one or more reducing agents that reduce disulfide bonds of hair to free thiols, a composition comprising one or more lactones is applied to the hair and the one or more lactones react with the free thiols to form a covalent thio-ester bond. Treatment with the lactones prevents reversion of the repaired bonds to their free thiol state after a single application.
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1. A method for treating hair having two or more free thiol groups, comprising applying to the hair a composition comprising one or more lactones in an effective amount to covalently bind the free thiol groups. 2. The method of claim 1, wherein the lactones and the free thiol groups form a thio-ester bond. 3. The method of claim 1, wherein the one or more lactones comprises a compound of formula (I)
wherein,
R1 is a linear or branched C1-C28 alkyl or alkyenyl radical, or a linear or branched C1-C28 hydroxyalkyl or hydroxyalkenyl radical; and
n is 0, 1, 2, or 3. 4. The method of claim 3, wherein the compound of formula (I) is selected from the group consisting of butyrolactone, gamma-caprolactone, delta-decalactone, gamma-decalatone, meadowfoam delta-lactone (meadowlactone), gamma-nonalactone, and gamma-undecalactone. 5. The method of claim 4, wherein the compound of formula (I) is meadowfoam delta-lactone (meadowlactone). 6. The method of claim 1, wherein the composition comprising one or more lactones is applied to the hair and allowed to remain on the hair for about 1 to about 30 minutes at a temperature of about 20 to about 45° C. 7. The method of claim 1, wherein the total amount of the one or more lactones in the composition is from about 0.1 to 100 wt. %, based on the total amount of the composition. 8. A method for treating hair comprising:
(a) applying to the hair a composition comprising one or more reducing agents that reduces disulfide bonds of the hair to free thiols; and (b) applying a composition comprising one or more lactones to the hair and reacting the one or more lactones with the free thiols to form a covalent thio-ester bond. 9. The method of claim 8, wherein the one or more reducing agents of (a) are selected from the group consisting of an alkali metal sulphite, an alkali metal bisulphites, an alkaline-earth metal sulphite, an alkaline-earth metal bisulphite, an ammonium sulphite, and an ammonium bisulphite, and a thiol. 10. The method of claim 9, wherein the one or more reducing agents of (a) comprises a thiol. 11. The method of claim 10, wherein the thiol is selected from the group consisting of cysteine or a derivative of cysteine, cysteamine or a derivative of cysteamine, thiolactic acid or an ester of thiolactic acid, thioclycolic acid or an ester of thioglycolic acid, and thioglycerol. 12. The method of claim 11, wherein the thiol is glyceryl or glycol monothioglycolate, diammonium dithiodiglycolate, or ammonium thioglycolate. 13. The method of claim 8, wherein the total amount of the one or more reducing agents in the composition of (a) is about 0.5 to about 20 wt. %, based on the total weight of the composition of (a). 14. The method of claim 8, wherein the one or more lactones of (b) comprises a compound of formula (I)
wherein,
R1 is a linear or branched C1-C28 alkyl or alkyenyl radical, or a linear or branched C1-C28 hydroxyalkyl or hydroxyalkenyl radical; and
n is 0, 1, 2, or 3. 15. The method of claim 14, wherein the compound of formula (I) is selected from the group consisting of butyrolactone, gamma-caprolactone, delta-decalactone, gamma-decalatone, meadowfoam delta-lactone (meadowlactone), gamma-nonalactone, gamma-undecalactone. 16. The method of claim 15, wherein the compound of formula (I) is meadowfoam delta-lactone (meadowlactone). 17. The method of claim 8, wherein the composition of (a) is applied to the hair and allowed to remain on the hair for about 1 to about 30 minutes at a temperature of about 20 to about 45° C. 18. The method of claim 1, wherein the method for treating hair is a method for imparting hydrophobicity to hair, the method comprising applying to hair having two or more free thiol groups a composition comprising one or more lactones in an effective amount to covalently bind the free thiol groups. 19. The method of claim 1, wherein the method for treating hair is a method for improving curl retention of curled hair having two or more free thiol groups, the method comprising applying to the hair a composition comprising one or more lactones in an effective amount to covalently bind the free thiol groups. 20. A kit comprising:
(a) a composition comprising one or more reducing agents that reduce disulfide bonds of hair to free thiols; and separately (b) a composition comprising one or more lactones that react with free thiols to form a covalent thio-ester bond.
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The present disclosure relates to methods for treating hair with lactones. The lactones form a covalent thio-ester bond with free thiols groups on chemically treated hair, and thereby impart a “repairing” or “conditioning” effect to the hair, for example, by making the hair more hydrophobic. Typically, after hair has been treated with a composition comprising one or more reducing agents that reduce disulfide bonds of hair to free thiols, a composition comprising one or more lactones is applied to the hair and the one or more lactones react with the free thiols to form a covalent thio-ester bond. Treatment with the lactones prevents reversion of the repaired bonds to their free thiol state after a single application.1. A method for treating hair having two or more free thiol groups, comprising applying to the hair a composition comprising one or more lactones in an effective amount to covalently bind the free thiol groups. 2. The method of claim 1, wherein the lactones and the free thiol groups form a thio-ester bond. 3. The method of claim 1, wherein the one or more lactones comprises a compound of formula (I)
wherein,
R1 is a linear or branched C1-C28 alkyl or alkyenyl radical, or a linear or branched C1-C28 hydroxyalkyl or hydroxyalkenyl radical; and
n is 0, 1, 2, or 3. 4. The method of claim 3, wherein the compound of formula (I) is selected from the group consisting of butyrolactone, gamma-caprolactone, delta-decalactone, gamma-decalatone, meadowfoam delta-lactone (meadowlactone), gamma-nonalactone, and gamma-undecalactone. 5. The method of claim 4, wherein the compound of formula (I) is meadowfoam delta-lactone (meadowlactone). 6. The method of claim 1, wherein the composition comprising one or more lactones is applied to the hair and allowed to remain on the hair for about 1 to about 30 minutes at a temperature of about 20 to about 45° C. 7. The method of claim 1, wherein the total amount of the one or more lactones in the composition is from about 0.1 to 100 wt. %, based on the total amount of the composition. 8. A method for treating hair comprising:
(a) applying to the hair a composition comprising one or more reducing agents that reduces disulfide bonds of the hair to free thiols; and (b) applying a composition comprising one or more lactones to the hair and reacting the one or more lactones with the free thiols to form a covalent thio-ester bond. 9. The method of claim 8, wherein the one or more reducing agents of (a) are selected from the group consisting of an alkali metal sulphite, an alkali metal bisulphites, an alkaline-earth metal sulphite, an alkaline-earth metal bisulphite, an ammonium sulphite, and an ammonium bisulphite, and a thiol. 10. The method of claim 9, wherein the one or more reducing agents of (a) comprises a thiol. 11. The method of claim 10, wherein the thiol is selected from the group consisting of cysteine or a derivative of cysteine, cysteamine or a derivative of cysteamine, thiolactic acid or an ester of thiolactic acid, thioclycolic acid or an ester of thioglycolic acid, and thioglycerol. 12. The method of claim 11, wherein the thiol is glyceryl or glycol monothioglycolate, diammonium dithiodiglycolate, or ammonium thioglycolate. 13. The method of claim 8, wherein the total amount of the one or more reducing agents in the composition of (a) is about 0.5 to about 20 wt. %, based on the total weight of the composition of (a). 14. The method of claim 8, wherein the one or more lactones of (b) comprises a compound of formula (I)
wherein,
R1 is a linear or branched C1-C28 alkyl or alkyenyl radical, or a linear or branched C1-C28 hydroxyalkyl or hydroxyalkenyl radical; and
n is 0, 1, 2, or 3. 15. The method of claim 14, wherein the compound of formula (I) is selected from the group consisting of butyrolactone, gamma-caprolactone, delta-decalactone, gamma-decalatone, meadowfoam delta-lactone (meadowlactone), gamma-nonalactone, gamma-undecalactone. 16. The method of claim 15, wherein the compound of formula (I) is meadowfoam delta-lactone (meadowlactone). 17. The method of claim 8, wherein the composition of (a) is applied to the hair and allowed to remain on the hair for about 1 to about 30 minutes at a temperature of about 20 to about 45° C. 18. The method of claim 1, wherein the method for treating hair is a method for imparting hydrophobicity to hair, the method comprising applying to hair having two or more free thiol groups a composition comprising one or more lactones in an effective amount to covalently bind the free thiol groups. 19. The method of claim 1, wherein the method for treating hair is a method for improving curl retention of curled hair having two or more free thiol groups, the method comprising applying to the hair a composition comprising one or more lactones in an effective amount to covalently bind the free thiol groups. 20. A kit comprising:
(a) a composition comprising one or more reducing agents that reduce disulfide bonds of hair to free thiols; and separately (b) a composition comprising one or more lactones that react with free thiols to form a covalent thio-ester bond.
| 1,600 |
967 | 15,063,211 | 1,662 |
The present invention is directed to methods and compositions to eliminate cold storage-induced sweetening of potato or sweet potato. The invention is accomplished in part by silencing the vacuolar acid invertase gene using RNAi technology. The resulting potatoes withstand cold storage without significant hexogenesis, producing potatoes or sweet potatoes that have reduced Maillard reactions when fried in hot oil. The fried products accumulate significantly lower levels of acrylamide compared to controls.
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1-20. (canceled) 21. A transgenic plant cell comprising a nucleic acid sequence having at least 95% sequence identity to a sequence selected from the group consisting of SEQ ID NO:9, 10, 11, 23, and 24, wherein a sense copy and an antisense copy of the nucleic acid sequence are on the same strand of a double-stranded vector and separated by a spacer sequence such that when transcribed the vector produces hairpin RNA (hpRNA) having a double-stranded RNA (d5RNA) region, the plant cell comprising a level of vacuolar invertase activity at least 85% lower than that of a plant cell not comprising the vector. 22. A transgenic plant containing transgenic plant cells according to claim 21, wherein the genetically modified plant is substantially morphologically indistinguishable from a plant that does not comprise the vector. 23. The transgenic plant of claim 22, wherein the plant is Solanum sp. 24. The transgenic plant of claim 23, wherein the plant is Solanum tuberosum. 25. A tuber produced by the transgenic plant of claim 22, wherein the tuber is substantially morphologically indistinguishable from tubers produced by a plant that does not comprise the vector. 26. The tuber of claim 25 that has been subjected to cold storage conditions. 27. The tuber of claim 26, wherein the tuber subjected to cold storage conditions exhibits decreased cold-induced sweetening and comprises fructose and glucose at levels lower than a tuber produced by a plant that does not comprise the vector but which was subjected to cold storage conditions. 28. The tuber of claim 26, wherein the tuber was subjected to cold storage conditions for at least 60 days. 29. The tuber of claim 26, wherein the tuber was subjected to cold storage conditions for at least 90 days. 30. The tuber of claim 26, wherein the tuber was subjected to cold storage conditions for at least 180 days. 31. The tuber of claim 25, wherein the tuber is selected from the group consisting of a potato, sweet potato, yam, and Cassava. 32. A method for producing a cold-stored tuber, the method comprising subjecting the tuber of claim 5 to cold storage conditions to produce a cold-stored tuber comprising fructose and glucose at levels lower than a tuber produced by a plant that does not comprise the vector but which was subjected to cold storage conditions. 33. The method of claim 32, wherein the tuber is subjected to cold storage conditions for at least 60 days. 34. The method of claim 32, wherein the tuber is subjected to cold storage conditions for at least 90 days. 35. The method of claim 32, wherein the tuber was subjected to cold storage conditions for at least 180 days. 36. The method of claim 32, wherein the tuber is selected from the group consisting of a potato, sweet potato, yam, and Cassava. 37. A method for producing a low acrylamide, heat-processed tuber product, the method comprising heat-processing the tuber of claim 6 to produce a heat-processed tuber product comprising acrylamide at a level at least 8-fold lower than an acrylamide level of a heat-processed tuber of a plant that does not comprise the vector. 38. A heat-processed tuber product produced according to the method of claim 37. 39. The heat-processed tuber product of claim 38, wherein the product is selected from the group consisting of a crisp, chip, French fry, potato stick, and shoestring potato. 40. The heat-processed tuber product of claim 38, wherein the tuber is a potato, sweet potato, yam, or Cassava.
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The present invention is directed to methods and compositions to eliminate cold storage-induced sweetening of potato or sweet potato. The invention is accomplished in part by silencing the vacuolar acid invertase gene using RNAi technology. The resulting potatoes withstand cold storage without significant hexogenesis, producing potatoes or sweet potatoes that have reduced Maillard reactions when fried in hot oil. The fried products accumulate significantly lower levels of acrylamide compared to controls.1-20. (canceled) 21. A transgenic plant cell comprising a nucleic acid sequence having at least 95% sequence identity to a sequence selected from the group consisting of SEQ ID NO:9, 10, 11, 23, and 24, wherein a sense copy and an antisense copy of the nucleic acid sequence are on the same strand of a double-stranded vector and separated by a spacer sequence such that when transcribed the vector produces hairpin RNA (hpRNA) having a double-stranded RNA (d5RNA) region, the plant cell comprising a level of vacuolar invertase activity at least 85% lower than that of a plant cell not comprising the vector. 22. A transgenic plant containing transgenic plant cells according to claim 21, wherein the genetically modified plant is substantially morphologically indistinguishable from a plant that does not comprise the vector. 23. The transgenic plant of claim 22, wherein the plant is Solanum sp. 24. The transgenic plant of claim 23, wherein the plant is Solanum tuberosum. 25. A tuber produced by the transgenic plant of claim 22, wherein the tuber is substantially morphologically indistinguishable from tubers produced by a plant that does not comprise the vector. 26. The tuber of claim 25 that has been subjected to cold storage conditions. 27. The tuber of claim 26, wherein the tuber subjected to cold storage conditions exhibits decreased cold-induced sweetening and comprises fructose and glucose at levels lower than a tuber produced by a plant that does not comprise the vector but which was subjected to cold storage conditions. 28. The tuber of claim 26, wherein the tuber was subjected to cold storage conditions for at least 60 days. 29. The tuber of claim 26, wherein the tuber was subjected to cold storage conditions for at least 90 days. 30. The tuber of claim 26, wherein the tuber was subjected to cold storage conditions for at least 180 days. 31. The tuber of claim 25, wherein the tuber is selected from the group consisting of a potato, sweet potato, yam, and Cassava. 32. A method for producing a cold-stored tuber, the method comprising subjecting the tuber of claim 5 to cold storage conditions to produce a cold-stored tuber comprising fructose and glucose at levels lower than a tuber produced by a plant that does not comprise the vector but which was subjected to cold storage conditions. 33. The method of claim 32, wherein the tuber is subjected to cold storage conditions for at least 60 days. 34. The method of claim 32, wherein the tuber is subjected to cold storage conditions for at least 90 days. 35. The method of claim 32, wherein the tuber was subjected to cold storage conditions for at least 180 days. 36. The method of claim 32, wherein the tuber is selected from the group consisting of a potato, sweet potato, yam, and Cassava. 37. A method for producing a low acrylamide, heat-processed tuber product, the method comprising heat-processing the tuber of claim 6 to produce a heat-processed tuber product comprising acrylamide at a level at least 8-fold lower than an acrylamide level of a heat-processed tuber of a plant that does not comprise the vector. 38. A heat-processed tuber product produced according to the method of claim 37. 39. The heat-processed tuber product of claim 38, wherein the product is selected from the group consisting of a crisp, chip, French fry, potato stick, and shoestring potato. 40. The heat-processed tuber product of claim 38, wherein the tuber is a potato, sweet potato, yam, or Cassava.
| 1,600 |
968 | 14,132,533 | 1,627 |
The disclosure relates to methods, compositions, and kits for treatment of parasite-mediated disease. In one embodiment, the disclosure relates to compounds, compositions, methods and kits for the treatment of malaria. In still another embodiment, the disclosure relates to a method for treating malaria comprising the use of a Syk kinase inhibitor.
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1. A method for treating malaria comprising:
(a) identifying a patient in need of treatment from malaria; and (b) administering to said patient a therapeutically effective amount of a Syk kinase inhibitor to treat malaria. 2. The method of claim 1, wherein said malaria is selected from the group consisting of: Quartan malaria, Falciparum malaria, Biduoterian fever, Blackwater fever, Tertian malaria, Plasmodium, uncomplicated malaria and severe malaria 3. The method of claim 1, wherein administering to said patient a therapeutically effective amount of a Syk kinase inhibitor comprises administering a Syk kinase inhibitor selected from the group consisting of Syk kinase inhibitor II, Syk kinase inhibitor IV, imatinib mesylate and combinations thereof. 4. The method of claim 1, wherein administering to said patient a therapeutically effective amount of a Syk kinase inhibitor comprises administering a Syk kinase inhibitor selected from the group consisting of a purine-2-benzamine derivative, a pyrimidine-5-carboxamide derivative, a 1,6-naphthyridine derivative, BAY 61-3606, piceatannol, 3,4-dimethyl-10-(3-aminopropyl)-9-acridone oxalate), R406, R788, and combinations thereof. 5. The method of claim 1, wherein said Syk kinase inhibitor is Syk kinase inhibitor II. 6. The method of claim 1, wherein said Syk kinase inhibitor is Syk kinase inhibitor IV. 7. The method of claim 1, wherein said Syk kinase inhibitor is imatinib mesylate. 8. The method of claim 1, further comprising administering an antimalarial drug. 9. The method of claim 1, wherein imatinib mesylate is administered to said patient from about 800 mg/day to about 1000 mg/day. 10. A method for reducing the incidence of malaria comprising:
(a) identifying a subject who may be a carrier of malaria; and (b) administering a therapeutically effective amount of a Syk kinase inhibitor to said subject. 11. The method of claim 10, wherein administering to said patient a therapeutically effective amount of a Syk kinase inhibitor comprises administering a Syk kinase inhibitor selected from the group consisting of Syk kinase inhibitor II, Syk kinase inhibitor IV, imatinib mesylate and combinations thereof. 12. The method of claim 10, wherein said Syk kinase inhibitor is imatinib mesylate. 13. The method of claim 10, further comprising administering an antimalarial drug. 14. The method of claim 10, wherein imatinib mesylate is administered to said patient from about 800 mg/day to about 1000 mg/day. 15. A method for treating drug resistant malaria comprising:
(a) identifying a patient with drug resistant malaria; and (b) administering to said patient a therapeutically effective amount of a Syk kinase inhibitor to treat malaria. 16. The method of claim 15, wherein administering to said patient a therapeutically effective amount of a Syk kinase inhibitor comprises administering a Syk kinase inhibitor selected from the group consisting of Syk kinase inhibitor II, Syk kinase inhibitor IV, imatinib mesylate and combinations thereof. 17. The method of claim 15, wherein said Syk kinase inhibitor is imatinib mesylate. 18. The method of claim 15, wherein imatinib mesylate is administered to said patient from about 800 mg/day to about 1000 mg/day. 19. The method of claim 15, further comprising administering an antimalarial drug. 20. The method of claim 19, wherein the antimalarial drug is selected from the group consisting of: artimisinin, chloroquine, quninine, and indolone N-oxides (INODS) of various structures.
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The disclosure relates to methods, compositions, and kits for treatment of parasite-mediated disease. In one embodiment, the disclosure relates to compounds, compositions, methods and kits for the treatment of malaria. In still another embodiment, the disclosure relates to a method for treating malaria comprising the use of a Syk kinase inhibitor.1. A method for treating malaria comprising:
(a) identifying a patient in need of treatment from malaria; and (b) administering to said patient a therapeutically effective amount of a Syk kinase inhibitor to treat malaria. 2. The method of claim 1, wherein said malaria is selected from the group consisting of: Quartan malaria, Falciparum malaria, Biduoterian fever, Blackwater fever, Tertian malaria, Plasmodium, uncomplicated malaria and severe malaria 3. The method of claim 1, wherein administering to said patient a therapeutically effective amount of a Syk kinase inhibitor comprises administering a Syk kinase inhibitor selected from the group consisting of Syk kinase inhibitor II, Syk kinase inhibitor IV, imatinib mesylate and combinations thereof. 4. The method of claim 1, wherein administering to said patient a therapeutically effective amount of a Syk kinase inhibitor comprises administering a Syk kinase inhibitor selected from the group consisting of a purine-2-benzamine derivative, a pyrimidine-5-carboxamide derivative, a 1,6-naphthyridine derivative, BAY 61-3606, piceatannol, 3,4-dimethyl-10-(3-aminopropyl)-9-acridone oxalate), R406, R788, and combinations thereof. 5. The method of claim 1, wherein said Syk kinase inhibitor is Syk kinase inhibitor II. 6. The method of claim 1, wherein said Syk kinase inhibitor is Syk kinase inhibitor IV. 7. The method of claim 1, wherein said Syk kinase inhibitor is imatinib mesylate. 8. The method of claim 1, further comprising administering an antimalarial drug. 9. The method of claim 1, wherein imatinib mesylate is administered to said patient from about 800 mg/day to about 1000 mg/day. 10. A method for reducing the incidence of malaria comprising:
(a) identifying a subject who may be a carrier of malaria; and (b) administering a therapeutically effective amount of a Syk kinase inhibitor to said subject. 11. The method of claim 10, wherein administering to said patient a therapeutically effective amount of a Syk kinase inhibitor comprises administering a Syk kinase inhibitor selected from the group consisting of Syk kinase inhibitor II, Syk kinase inhibitor IV, imatinib mesylate and combinations thereof. 12. The method of claim 10, wherein said Syk kinase inhibitor is imatinib mesylate. 13. The method of claim 10, further comprising administering an antimalarial drug. 14. The method of claim 10, wherein imatinib mesylate is administered to said patient from about 800 mg/day to about 1000 mg/day. 15. A method for treating drug resistant malaria comprising:
(a) identifying a patient with drug resistant malaria; and (b) administering to said patient a therapeutically effective amount of a Syk kinase inhibitor to treat malaria. 16. The method of claim 15, wherein administering to said patient a therapeutically effective amount of a Syk kinase inhibitor comprises administering a Syk kinase inhibitor selected from the group consisting of Syk kinase inhibitor II, Syk kinase inhibitor IV, imatinib mesylate and combinations thereof. 17. The method of claim 15, wherein said Syk kinase inhibitor is imatinib mesylate. 18. The method of claim 15, wherein imatinib mesylate is administered to said patient from about 800 mg/day to about 1000 mg/day. 19. The method of claim 15, further comprising administering an antimalarial drug. 20. The method of claim 19, wherein the antimalarial drug is selected from the group consisting of: artimisinin, chloroquine, quninine, and indolone N-oxides (INODS) of various structures.
| 1,600 |
969 | 15,738,194 | 1,619 |
The present invention relates to a purgative composition for cleansing an intestinal tract and, specifically, to a purgative composition for cleansing an intestinal tract, the composition containing 40-60 g of polyethylene glycol, 10-28 g of sorbitol, and 1-10 mg of sodium picosulfate, on the basis of 100 ml of the composition, or 40-60 g of polyethylene glycol, 10-28 g of sorbitol, and 1-15 mg of bisacodyl, on the basis of 100 ml of the composition. The purgative composition according to the present invention has higher drug compliance while showing an excellent intestinal tract cleansing rate. In addition, the purgative composition exhibits a sufficient intestinal tract cleansing effect even when taken together with a small amount of water, thereby relieving the suffering that a patient must take a large amount of medicine when taking a purgative.
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1. A purgative composition for cleansing an intestinal tract comprising polyethylene glycol, sorbitol and sodium picosulfate. 2. The purgative composition for cleansing an intestinal tract according to claim 1, wherein the composition comprises 40 to 60 g of polyethylene glycol, 10 to 28 g of sorbitol, and 1 to 10 mg of sodium picosulfate per 100 ml of the composition in a liquid dosage form. 3. A purgative composition for cleansing an intestinal tract comprising polyethylene glycol, sorbitol and bisacodyl. 4. The purgative composition for cleansing an intestinal tract according to claim 3, wherein the composition comprises 40 to 60 g of polyethylene glycol, 10 to 28 g of sorbitol, and 1 to 15 mg of bisacodyl per 100 ml of the composition in a liquid dosage form. 5. The purgative composition for cleansing an intestinal tract according to claim 1, wherein the polyethylene glycol has a number average molecular weight between 1,000 and 10,000. 6. The purgative composition for cleansing an intestinal tract according to claim 5, wherein the polyethylene glycol has a number average molecular weight between 3,000 and 4,800. 7. The purgative composition for cleansing an intestinal tract according to claim 1, wherein the composition is prepared in a form of any one of a solution, a suspension, and an emulsion. 8. The purgative composition for cleansing an intestinal tract according to claim 1, wherein 100˜200 mL of the composition diluted in 300˜400 mL of water is taken within 20˜40 minutes after the dilution, followed by intake of additional 400˜600 mL of water within 20˜40 minutes and a rest for 50˜70 minutes, and administration is repeated once more by a same method. 9. The purgative composition for cleansing an intestinal tract according to claim 1, wherein the composition is taken with 5 to 10 vol % of water per volume of the composition. 10. The purgative composition for cleansing an intestinal tract according to claim 9, wherein a total volume of the composition and water taken is 3.5 liters or less. 11. A purgative product for cleansing an intestinal tract comprising:
a purgative composition for cleansing an intestinal tract comprising polyethylene glycol, sorbitol and sodium picosulfate, or polyethylene glycol, sorbitol and bisacodyl; and medication instructions stating that the composition be taken with 5 to 10 vol % of water per volume of the composition. 12. The purgative product for cleansing an intestinal tract according to claim 11, wherein the composition comprises 40 to 60 g of polyethylene glycol, 10 to 28 g of sorbitol, and 1 to 10 mg of sodium picosulfate per 100 ml of the composition in a liquid dosage form, or the composition comprises 40 to 60 g of polyethylene glycol, 10 to 28 g of sorbitol, and 1 to 15 mg of bisacodyl per 100 ml of the composition in a liquid dosage form. 13. The purgative product for cleansing an intestinal tract according to claim 11, wherein the medication instructions states that 100˜200 mL of the composition diluted in 300˜400 mL of water be taken within 20˜40 minutes after the dilution, followed by intake of additional 400˜600 mL of water within 20˜40 minutes and a rest for 50˜70 minutes, and administration is repeated once more by a same method.
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The present invention relates to a purgative composition for cleansing an intestinal tract and, specifically, to a purgative composition for cleansing an intestinal tract, the composition containing 40-60 g of polyethylene glycol, 10-28 g of sorbitol, and 1-10 mg of sodium picosulfate, on the basis of 100 ml of the composition, or 40-60 g of polyethylene glycol, 10-28 g of sorbitol, and 1-15 mg of bisacodyl, on the basis of 100 ml of the composition. The purgative composition according to the present invention has higher drug compliance while showing an excellent intestinal tract cleansing rate. In addition, the purgative composition exhibits a sufficient intestinal tract cleansing effect even when taken together with a small amount of water, thereby relieving the suffering that a patient must take a large amount of medicine when taking a purgative.1. A purgative composition for cleansing an intestinal tract comprising polyethylene glycol, sorbitol and sodium picosulfate. 2. The purgative composition for cleansing an intestinal tract according to claim 1, wherein the composition comprises 40 to 60 g of polyethylene glycol, 10 to 28 g of sorbitol, and 1 to 10 mg of sodium picosulfate per 100 ml of the composition in a liquid dosage form. 3. A purgative composition for cleansing an intestinal tract comprising polyethylene glycol, sorbitol and bisacodyl. 4. The purgative composition for cleansing an intestinal tract according to claim 3, wherein the composition comprises 40 to 60 g of polyethylene glycol, 10 to 28 g of sorbitol, and 1 to 15 mg of bisacodyl per 100 ml of the composition in a liquid dosage form. 5. The purgative composition for cleansing an intestinal tract according to claim 1, wherein the polyethylene glycol has a number average molecular weight between 1,000 and 10,000. 6. The purgative composition for cleansing an intestinal tract according to claim 5, wherein the polyethylene glycol has a number average molecular weight between 3,000 and 4,800. 7. The purgative composition for cleansing an intestinal tract according to claim 1, wherein the composition is prepared in a form of any one of a solution, a suspension, and an emulsion. 8. The purgative composition for cleansing an intestinal tract according to claim 1, wherein 100˜200 mL of the composition diluted in 300˜400 mL of water is taken within 20˜40 minutes after the dilution, followed by intake of additional 400˜600 mL of water within 20˜40 minutes and a rest for 50˜70 minutes, and administration is repeated once more by a same method. 9. The purgative composition for cleansing an intestinal tract according to claim 1, wherein the composition is taken with 5 to 10 vol % of water per volume of the composition. 10. The purgative composition for cleansing an intestinal tract according to claim 9, wherein a total volume of the composition and water taken is 3.5 liters or less. 11. A purgative product for cleansing an intestinal tract comprising:
a purgative composition for cleansing an intestinal tract comprising polyethylene glycol, sorbitol and sodium picosulfate, or polyethylene glycol, sorbitol and bisacodyl; and medication instructions stating that the composition be taken with 5 to 10 vol % of water per volume of the composition. 12. The purgative product for cleansing an intestinal tract according to claim 11, wherein the composition comprises 40 to 60 g of polyethylene glycol, 10 to 28 g of sorbitol, and 1 to 10 mg of sodium picosulfate per 100 ml of the composition in a liquid dosage form, or the composition comprises 40 to 60 g of polyethylene glycol, 10 to 28 g of sorbitol, and 1 to 15 mg of bisacodyl per 100 ml of the composition in a liquid dosage form. 13. The purgative product for cleansing an intestinal tract according to claim 11, wherein the medication instructions states that 100˜200 mL of the composition diluted in 300˜400 mL of water be taken within 20˜40 minutes after the dilution, followed by intake of additional 400˜600 mL of water within 20˜40 minutes and a rest for 50˜70 minutes, and administration is repeated once more by a same method.
| 1,600 |
970 | 14,775,144 | 1,615 |
The present invention is directed to alkoxylated alcohol alkyl ethers. In some embodiments, these ethers include a very short chain ether end cap, such as a methyl or ethyl group. In some embodiments, the long chain fatty alcohol used is unsaturated and/or branched. In some embodiments, a compound of the invention includes:
R 1 O—(PO) n —R 2 (Formula Xa)
wherein P is a branched alkyl group having 3 carbons; n is an integer ranging from 2 to 10; R 1 is a branched or unsaturated hydrocarbon having 16 to 24 carbons which are substituted or unsubstituted; and wherein R 2 is a methyl group. In some embodiments, n is 3 and R 1 is an isostearyl group.
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1. A compound having Formula X:
R1O-A-R2 (Formula X)
wherein:
i) A is one selected from the group consisting of:
a) (PO)n, where P is a branched alkyl group having 3 carbons and n is an integer ranging from 2 to 10;
b) (EO)m, where E is an alkyl group having 2 carbons and m is an integer ranging from 2 to 6; and
c) (PO)n-(EO)m, where P is a branched alkyl group having 3 carbons, E is an alkyl group having 2 carbons, n and m are integers, n≧1, m≧1, and n+m=2 to 25, and PO and EO can be in any order;
ii) R2 is a methyl or ethyl group; and
iii) when A is (PO)n and R2 is methyl, or when A is (PO)n-(EO)m, R1 is a branched or unsaturated hydrocarbon having 16 to 24 carbons which are substituted or unsubstituted; or
when A is (PO)n and R2 is ethyl, or when A is (EO)m, R1 is a branched or unsaturated hydrocarbon having 14 to 24 carbons which are substituted or unsubstituted. 2. The compound of claim 1, wherein R2 is methyl, A is (PO)n, and n is 3 or n is 6. 3. The compound of claim 1, wherein R2 is methyl, A is (PO)n, and R1 is an isostearyl group or a behenyl group. 4. The compound of claim 1, wherein R2 is ethyl, A is (PO)n, and n ranges from 3 to 4. 5. The compound of claim 1, wherein R2 is ethyl, A is (PO)n, and R1 is unsaturated. 6. A compound of Formula X:
R1O-A-R2 (Formula X)
wherein:
i) A is one selected from the group consisting of:
a) (PO)n, where P is a branched alkyl group having 3 carbons and n is an integer ranging from 2 to 10;
b) (EO)m, where E is an alkyl group having 2 carbons and m is an integer ranging from 2 to 20; and
c) (PO)n-(EO)m, where P is a branched alkyl group having 3 carbons, E is an alkyl group having 2 carbons, n and m are integers, n≧1, m≧1, and n+m=2 to 25, and PO and EO can be in any order;
ii) R1 is branched or unsaturated hydrocarbon having 8 to 24 carbons which are substituted or unsubstituted; and
iii) R2 is a linear or branched alkyl group having 3 to 5 carbons, or a substituted or unsubstituted aromatic ring. 7. The compound of claim 6, wherein A is (PO)n and n is 3. 8. The compound of claim 6, wherein A is (PO)n and R1 is an isostearyl group. 9. The compound of claim 6, wherein A is (PO)n and R2 is a benzyl group. 10. The compound of claim 6, wherein A is (PO)n-(EO)m and n is 3. 11. The compound of claim 6, wherein A is (PO)n-(EO)m and m is 4. 12. The compound of claim 6, wherein A is (PO)n-(EO)m and R1 is a behenyl group. 13. The compound of claim 6, wherein A is (PO)n-(EO)m and R2 is a benzyl group. 14. A personal care product comprising:
(I) at least about 0.25% by weight of a compound of Formula X:
R1O-A-R2 (Formula X)
wherein: i) A is one selected from the group consisting of:
a) (PO)n, where P is a branched alkyl group having 3 carbons and n is an integer ranging from 2 to 10;
b) (EO)m, where E is an alkyl group having 2 carbons and m is an integer ranging from 2 to 20; and
c) (PO)n-(EO)m, where P is a branched alkyl group having 3 carbons, E is an alkyl group having 2 carbons, n and m are integers, n≧1, m≧1, and n+m=2 to 25, and PO and EO can be in any order;
ii) R1 is a branched or unsaturated hydrocarbon having 8-24 carbons which are substituted or unsubstituted; and iii) R2 is a methyl group, an ethyl group, a linear or branched alkyl group having 3 to 5 carbons, or a substituted or unsubstituted aromatic ring; and (II) a dermatologically acceptable excipient. 15. The personal care product of claim 14, wherein R2 is a methyl, an ethyl, or a benzyl group. 16. The personal care product of claim 14, wherein A is (PO)n, R2 is a methyl group, and R1 is a branched or unsaturated hydrocarbon having 16 to 24 carbons which are substituted or unsubstituted. 17. The personal care product of claim 14, wherein A is (PO)n, R2 is a methyl group, n is 3, and R1 is isostearyl or a behenyl group. 18. The personal care product of claim 14, wherein A is (PO)n, R2 is a methyl group, n is 6, and R1 is an isostearyl group. 19. The personal care product of claim 14, wherein A is (PO)n, and R2 is an ethyl group, and R1 is a branched or unsaturated hydrocarbon having 14-24 carbons, which are substituted or unsubstituted. 20. The personal care product of claim 19, wherein n is 4 and R1 is a cetearyl group. 21. The personal care product of claim 14, wherein A is (EO)m, R1 is a branched or unsaturated hydrocarbon having 14 to 24 carbons which are substituted or unsubstituted, and n is 2 to 6. 22. The personal care product of claim 14, wherein A is (PO)n-(EO)m and R1 is a behenyl group. 23. The personal care product of claim 14, wherein A is (PO)n-(EO)m and R2 is a benzyl group. 24. The personal care product of claim 14, wherein the personal care product is stable to hydrolysis at a pH ranging from about 1 to about 14. 25. A method of applying a personal care product, the method comprising applying the personal care product of claim 14 to the human body. 26. A method of imparting conditioning to hair comprising applying the personal care product of claim 14 to hair. 27. A method of preserving the degree of hair color in synthetically colored hair comprising applying the personal care product of claim 14 to hair. 28. A method of imparting coloring to facial tissues comprising applying the personal care product of claim 14 to facial tissues.
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The present invention is directed to alkoxylated alcohol alkyl ethers. In some embodiments, these ethers include a very short chain ether end cap, such as a methyl or ethyl group. In some embodiments, the long chain fatty alcohol used is unsaturated and/or branched. In some embodiments, a compound of the invention includes:
R 1 O—(PO) n —R 2 (Formula Xa)
wherein P is a branched alkyl group having 3 carbons; n is an integer ranging from 2 to 10; R 1 is a branched or unsaturated hydrocarbon having 16 to 24 carbons which are substituted or unsubstituted; and wherein R 2 is a methyl group. In some embodiments, n is 3 and R 1 is an isostearyl group.1. A compound having Formula X:
R1O-A-R2 (Formula X)
wherein:
i) A is one selected from the group consisting of:
a) (PO)n, where P is a branched alkyl group having 3 carbons and n is an integer ranging from 2 to 10;
b) (EO)m, where E is an alkyl group having 2 carbons and m is an integer ranging from 2 to 6; and
c) (PO)n-(EO)m, where P is a branched alkyl group having 3 carbons, E is an alkyl group having 2 carbons, n and m are integers, n≧1, m≧1, and n+m=2 to 25, and PO and EO can be in any order;
ii) R2 is a methyl or ethyl group; and
iii) when A is (PO)n and R2 is methyl, or when A is (PO)n-(EO)m, R1 is a branched or unsaturated hydrocarbon having 16 to 24 carbons which are substituted or unsubstituted; or
when A is (PO)n and R2 is ethyl, or when A is (EO)m, R1 is a branched or unsaturated hydrocarbon having 14 to 24 carbons which are substituted or unsubstituted. 2. The compound of claim 1, wherein R2 is methyl, A is (PO)n, and n is 3 or n is 6. 3. The compound of claim 1, wherein R2 is methyl, A is (PO)n, and R1 is an isostearyl group or a behenyl group. 4. The compound of claim 1, wherein R2 is ethyl, A is (PO)n, and n ranges from 3 to 4. 5. The compound of claim 1, wherein R2 is ethyl, A is (PO)n, and R1 is unsaturated. 6. A compound of Formula X:
R1O-A-R2 (Formula X)
wherein:
i) A is one selected from the group consisting of:
a) (PO)n, where P is a branched alkyl group having 3 carbons and n is an integer ranging from 2 to 10;
b) (EO)m, where E is an alkyl group having 2 carbons and m is an integer ranging from 2 to 20; and
c) (PO)n-(EO)m, where P is a branched alkyl group having 3 carbons, E is an alkyl group having 2 carbons, n and m are integers, n≧1, m≧1, and n+m=2 to 25, and PO and EO can be in any order;
ii) R1 is branched or unsaturated hydrocarbon having 8 to 24 carbons which are substituted or unsubstituted; and
iii) R2 is a linear or branched alkyl group having 3 to 5 carbons, or a substituted or unsubstituted aromatic ring. 7. The compound of claim 6, wherein A is (PO)n and n is 3. 8. The compound of claim 6, wherein A is (PO)n and R1 is an isostearyl group. 9. The compound of claim 6, wherein A is (PO)n and R2 is a benzyl group. 10. The compound of claim 6, wherein A is (PO)n-(EO)m and n is 3. 11. The compound of claim 6, wherein A is (PO)n-(EO)m and m is 4. 12. The compound of claim 6, wherein A is (PO)n-(EO)m and R1 is a behenyl group. 13. The compound of claim 6, wherein A is (PO)n-(EO)m and R2 is a benzyl group. 14. A personal care product comprising:
(I) at least about 0.25% by weight of a compound of Formula X:
R1O-A-R2 (Formula X)
wherein: i) A is one selected from the group consisting of:
a) (PO)n, where P is a branched alkyl group having 3 carbons and n is an integer ranging from 2 to 10;
b) (EO)m, where E is an alkyl group having 2 carbons and m is an integer ranging from 2 to 20; and
c) (PO)n-(EO)m, where P is a branched alkyl group having 3 carbons, E is an alkyl group having 2 carbons, n and m are integers, n≧1, m≧1, and n+m=2 to 25, and PO and EO can be in any order;
ii) R1 is a branched or unsaturated hydrocarbon having 8-24 carbons which are substituted or unsubstituted; and iii) R2 is a methyl group, an ethyl group, a linear or branched alkyl group having 3 to 5 carbons, or a substituted or unsubstituted aromatic ring; and (II) a dermatologically acceptable excipient. 15. The personal care product of claim 14, wherein R2 is a methyl, an ethyl, or a benzyl group. 16. The personal care product of claim 14, wherein A is (PO)n, R2 is a methyl group, and R1 is a branched or unsaturated hydrocarbon having 16 to 24 carbons which are substituted or unsubstituted. 17. The personal care product of claim 14, wherein A is (PO)n, R2 is a methyl group, n is 3, and R1 is isostearyl or a behenyl group. 18. The personal care product of claim 14, wherein A is (PO)n, R2 is a methyl group, n is 6, and R1 is an isostearyl group. 19. The personal care product of claim 14, wherein A is (PO)n, and R2 is an ethyl group, and R1 is a branched or unsaturated hydrocarbon having 14-24 carbons, which are substituted or unsubstituted. 20. The personal care product of claim 19, wherein n is 4 and R1 is a cetearyl group. 21. The personal care product of claim 14, wherein A is (EO)m, R1 is a branched or unsaturated hydrocarbon having 14 to 24 carbons which are substituted or unsubstituted, and n is 2 to 6. 22. The personal care product of claim 14, wherein A is (PO)n-(EO)m and R1 is a behenyl group. 23. The personal care product of claim 14, wherein A is (PO)n-(EO)m and R2 is a benzyl group. 24. The personal care product of claim 14, wherein the personal care product is stable to hydrolysis at a pH ranging from about 1 to about 14. 25. A method of applying a personal care product, the method comprising applying the personal care product of claim 14 to the human body. 26. A method of imparting conditioning to hair comprising applying the personal care product of claim 14 to hair. 27. A method of preserving the degree of hair color in synthetically colored hair comprising applying the personal care product of claim 14 to hair. 28. A method of imparting coloring to facial tissues comprising applying the personal care product of claim 14 to facial tissues.
| 1,600 |
971 | 13,511,768 | 1,639 |
The hemitartrate salt of a compound represented by the following structural formula: (Formula I Hemitartrate), which may be used in pharmaceutical applications, are disclosed. Particular single crystalline forms of the Formula (I) Hemitartrate are characterized by a variety of properties and physical measurements. As well, methods of producing crystalline Formula (I) Hemitartrate, and using it to inhibit glucosylceramide synthase or lowering glycosphingolipid concentrations in subjects to treat a number of diseases, are also discussed. Pharmaceutical compositions are also described.
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1. The hemitartrate salt of a compound represented by the following structural formula:
wherein the salt is an amorphous salt. 2. The hemitartrate salt of a compound represented by the following structural formula:
wherein at least 70% by weight of the salt is crystalline. 3. The hemitartrate salt of a compound represented by the following structural formula:
wherein at least 90% by weight of the salt is in a single crystalline form. 4. (canceled) 5. The salt of claim 3, wherein at least 99% by weight of the salt is in a single crystalline form. 6. (canceled) 7. The hemitartrate salt of claim 1, wherein the hemitartrate salt is L-hemitartrate. 8-9. (canceled) 10. The salt of claim 3, wherein the single crystalline form is characterized by at least two major x-ray powder diffraction peaks at 2θ angles of 5.1°, 6.6°, 10.7°, 11.0°, 15.9°, and 21.7°. 11-12. (canceled) 13. The salt of claim 3, wherein the single crystalline form is characterized by major x-ray powder diffraction peaks at 2θ angles of 5.1°, 6.6°, 10.7°, 11.0°, 15.9°, and 21.7°. 14. The salt of claim 3, wherein the single crystalline form is characterized by x-ray powder diffraction peaks at 2θ angles of 5.1°, 6.6°, 10.7°, 11.0°, 13.3°, 15.1°, 15.9°, 16.5°, 17.6°, 18.6°, 18.7°, 19.0°, 20.2°, 21.7°, and 23.5°. 15. (canceled) 16. A pharmaceutical composition comprising the hemitartrate salt of a compound represented by the following structural formula:
and a pharmaceutically acceptable carrier or diluent. 17. The pharmaceutical composition of claim 16, wherein at least 90% by weight of the salt is in a single crystalline form. 18-31. (canceled) 32. A method of treating a subject with Gaucher disease or Fabry disease, or inhibiting glucosylceramide synthase or lowering glycosphingolipid concentrations in a subject in need thereof comprising administering to the subject an effective amount of the hemitartrate salt of claim 16. 33-36. (canceled) 37. A method of treating a subject with Gaucher disease, comprising administering to the subject an effective amount of a first compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof in combination with an effective amount of a second therapeutic agent that is effective for treating Gaucher disease. 38-40. (canceled) 41. A method of treating a subject with Fabry disease, the method comprising administering to the subject an effective amount of a first therapeutic agent represented by the following structural formula:
or a pharmaceutically acceptable salt thereof in combination with an effective amount of a second therapeutic agent that is effective for treating Fabry disease. 42-45. (canceled) 46. The method of claim 37, wherein treatment with the first therapeutic agent is begun after treatment with the second therapeutic agent and wherein treatment with the first therapeutic agent is initiated after the subject's platelet count is equal to or greater than 100,000 mm3; hemoglobin concentration is equal to or greater than 11 g/dl (female) or 12 g/dl (male); and/or the subject's spleen volume is less than or equal to 10 multiples of normal and liver volumes are less than or equal to 1.5 multiples of normal. 47-49. (canceled) 50. A pharmaceutical composition comprising:
the hemitartrate salt of a compound represented by the following structural formula:
at least one water-soluble filler;
at least one water-insoluble filler;
at least one binder; and
at least one lubricant. 51-66. (canceled) 67. A method of treating a subject with Fabry disease or Gaucher disease, the method comprising:
a) administering to the subject an effective amount of a compound of Formula (I):
or a pharmaceutically acceptable salt thereof;
b) testing the subject to determine whether the subject is a poor, intermediate or extensive/ultra rapid P450 metabolizer;
c) if the subject is an intermediate or extensive/ultra rapid P450 metabolizer, determining an adjusted effective amount of the compound; and
d) administering to the subject an adjusted effective amount of the compound of Formula (I) if the subject is an intermediate or extensive/ultra rapid P450 metabolizer and administering to the subject an effective amount of the compound of Formula (I) if the subject is a poor P450 metabolizer. 68-70. (canceled) 71. The method of claim 67, wherein testing comprises monitoring trough plasma levels of the compound in the subject for a period of at least ten weeks. 72. (canceled) 73. The method of claim 67, wherein the subject is a poor P450 enzyme if plasma trough levels of the compound are at least 5 ng/ml after being administered an effective amount of the compound. 74-81. (canceled) 82. A method of treating a subject with Fabry disease or Gaucher disease comprising the steps of:
a) administering to the subject an effective amount of a compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof;
b) assessing trough plasma levels of the compound in the subject;
c) adjusting the amount of compound administered to the subject so that the trough plasma levels of the compound in the subject are at least 5 ng/ml. 83-93. (canceled) 94. The method of claim 41, wherein treatment with the first therapeutic agent is begun after treatment with the second therapeutic agent and wherein treatment with the first therapeutic agent is initiated after the subject's platelet count is equal to or greater than 100,000 mm3; hemoglobin concentration is equal to or greater than 11 g/dl (female) or 12 g/dl (male); and/or the subject's spleen volume is less than or equal to 10 multiples of normal and liver volumes are less than or equal to 1.5 multiples of normal.
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The hemitartrate salt of a compound represented by the following structural formula: (Formula I Hemitartrate), which may be used in pharmaceutical applications, are disclosed. Particular single crystalline forms of the Formula (I) Hemitartrate are characterized by a variety of properties and physical measurements. As well, methods of producing crystalline Formula (I) Hemitartrate, and using it to inhibit glucosylceramide synthase or lowering glycosphingolipid concentrations in subjects to treat a number of diseases, are also discussed. Pharmaceutical compositions are also described.1. The hemitartrate salt of a compound represented by the following structural formula:
wherein the salt is an amorphous salt. 2. The hemitartrate salt of a compound represented by the following structural formula:
wherein at least 70% by weight of the salt is crystalline. 3. The hemitartrate salt of a compound represented by the following structural formula:
wherein at least 90% by weight of the salt is in a single crystalline form. 4. (canceled) 5. The salt of claim 3, wherein at least 99% by weight of the salt is in a single crystalline form. 6. (canceled) 7. The hemitartrate salt of claim 1, wherein the hemitartrate salt is L-hemitartrate. 8-9. (canceled) 10. The salt of claim 3, wherein the single crystalline form is characterized by at least two major x-ray powder diffraction peaks at 2θ angles of 5.1°, 6.6°, 10.7°, 11.0°, 15.9°, and 21.7°. 11-12. (canceled) 13. The salt of claim 3, wherein the single crystalline form is characterized by major x-ray powder diffraction peaks at 2θ angles of 5.1°, 6.6°, 10.7°, 11.0°, 15.9°, and 21.7°. 14. The salt of claim 3, wherein the single crystalline form is characterized by x-ray powder diffraction peaks at 2θ angles of 5.1°, 6.6°, 10.7°, 11.0°, 13.3°, 15.1°, 15.9°, 16.5°, 17.6°, 18.6°, 18.7°, 19.0°, 20.2°, 21.7°, and 23.5°. 15. (canceled) 16. A pharmaceutical composition comprising the hemitartrate salt of a compound represented by the following structural formula:
and a pharmaceutically acceptable carrier or diluent. 17. The pharmaceutical composition of claim 16, wherein at least 90% by weight of the salt is in a single crystalline form. 18-31. (canceled) 32. A method of treating a subject with Gaucher disease or Fabry disease, or inhibiting glucosylceramide synthase or lowering glycosphingolipid concentrations in a subject in need thereof comprising administering to the subject an effective amount of the hemitartrate salt of claim 16. 33-36. (canceled) 37. A method of treating a subject with Gaucher disease, comprising administering to the subject an effective amount of a first compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof in combination with an effective amount of a second therapeutic agent that is effective for treating Gaucher disease. 38-40. (canceled) 41. A method of treating a subject with Fabry disease, the method comprising administering to the subject an effective amount of a first therapeutic agent represented by the following structural formula:
or a pharmaceutically acceptable salt thereof in combination with an effective amount of a second therapeutic agent that is effective for treating Fabry disease. 42-45. (canceled) 46. The method of claim 37, wherein treatment with the first therapeutic agent is begun after treatment with the second therapeutic agent and wherein treatment with the first therapeutic agent is initiated after the subject's platelet count is equal to or greater than 100,000 mm3; hemoglobin concentration is equal to or greater than 11 g/dl (female) or 12 g/dl (male); and/or the subject's spleen volume is less than or equal to 10 multiples of normal and liver volumes are less than or equal to 1.5 multiples of normal. 47-49. (canceled) 50. A pharmaceutical composition comprising:
the hemitartrate salt of a compound represented by the following structural formula:
at least one water-soluble filler;
at least one water-insoluble filler;
at least one binder; and
at least one lubricant. 51-66. (canceled) 67. A method of treating a subject with Fabry disease or Gaucher disease, the method comprising:
a) administering to the subject an effective amount of a compound of Formula (I):
or a pharmaceutically acceptable salt thereof;
b) testing the subject to determine whether the subject is a poor, intermediate or extensive/ultra rapid P450 metabolizer;
c) if the subject is an intermediate or extensive/ultra rapid P450 metabolizer, determining an adjusted effective amount of the compound; and
d) administering to the subject an adjusted effective amount of the compound of Formula (I) if the subject is an intermediate or extensive/ultra rapid P450 metabolizer and administering to the subject an effective amount of the compound of Formula (I) if the subject is a poor P450 metabolizer. 68-70. (canceled) 71. The method of claim 67, wherein testing comprises monitoring trough plasma levels of the compound in the subject for a period of at least ten weeks. 72. (canceled) 73. The method of claim 67, wherein the subject is a poor P450 enzyme if plasma trough levels of the compound are at least 5 ng/ml after being administered an effective amount of the compound. 74-81. (canceled) 82. A method of treating a subject with Fabry disease or Gaucher disease comprising the steps of:
a) administering to the subject an effective amount of a compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof;
b) assessing trough plasma levels of the compound in the subject;
c) adjusting the amount of compound administered to the subject so that the trough plasma levels of the compound in the subject are at least 5 ng/ml. 83-93. (canceled) 94. The method of claim 41, wherein treatment with the first therapeutic agent is begun after treatment with the second therapeutic agent and wherein treatment with the first therapeutic agent is initiated after the subject's platelet count is equal to or greater than 100,000 mm3; hemoglobin concentration is equal to or greater than 11 g/dl (female) or 12 g/dl (male); and/or the subject's spleen volume is less than or equal to 10 multiples of normal and liver volumes are less than or equal to 1.5 multiples of normal.
| 1,600 |
972 | 15,436,919 | 1,649 |
The invention relates to compounds which activate the BASIGIN signalling pathway, preferably agonists of BASIGIN, for the treatment of neurodegenerative disorders.
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1-9. (canceled) 10. A method for screening a drug for the treatment of a retinal neurodegenerative disorder comprising the steps consisting of:
a) providing a plurality of neurons expressing BASIGIN on their surface, wherein said neurons are cone photoreceptors; b) incubating said neurons with a candidate compound; c) determining whether said candidate compound binds to and activates BASIGIN; and d) selecting the candidate compound that binds to and activates BASIGIN. 11. The method according to claim 10, wherein said BASIGIN contains three immunoglobulin-like domains in its extracellular portion.
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The invention relates to compounds which activate the BASIGIN signalling pathway, preferably agonists of BASIGIN, for the treatment of neurodegenerative disorders.1-9. (canceled) 10. A method for screening a drug for the treatment of a retinal neurodegenerative disorder comprising the steps consisting of:
a) providing a plurality of neurons expressing BASIGIN on their surface, wherein said neurons are cone photoreceptors; b) incubating said neurons with a candidate compound; c) determining whether said candidate compound binds to and activates BASIGIN; and d) selecting the candidate compound that binds to and activates BASIGIN. 11. The method according to claim 10, wherein said BASIGIN contains three immunoglobulin-like domains in its extracellular portion.
| 1,600 |
973 | 15,497,122 | 1,633 |
Methods for introducing exogenous material into a cell are provided, which include exposing the cell to a transient decrease in pressure in the presence of the exogenous material. Also provided are devices for performing the method of the invention.
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1. A method for introducing an exogenous material into a cell, comprising exposing said cell to a transient decrease in pressure and unsteady flow in the presence of said exogenous material to thereby introduce said exogenous material into said cell. 2. The method of claim 1, wherein the cell is viable after being exposed to the transient decrease in pressure and unsteady flow. 3. The method of claim 1, wherein said cell is selected from the group consisting of a bacterial cell, a mammalian cell, a yeast cell, a plant cell and an insect cell. 4. The method of claim 1, wherein said exogenous material is selected from the group consisting of a small organic molecule, a nucleic acid, a nucleotide, an oligonucleotide, a protein, a peptide, an amino acid, a lipid, a polysaccharide, a quantum dot, a carbon nanotube, a nanoparticle, a gold particle, a monosaccharide, a vitamin and a steroid. 5. The method of claim 1, wherein said exogenous material is introduced into the cytoplasm of said cell. 6. The method of claim 1, wherein said cell is a mammalian cell, a yeast cell or an insect cell and said exogenous material is introduced into the nucleus of said cell. 7. The method of claim 1, wherein said cell is exposed to said transient decrease in pressure in the presence of said exogenous material for at least 10 nanoseconds. 8. The method of claim 1, wherein said exogenous material and said cell are in a liquid when being exposed to said transient decrease in pressure and unsteady flow. 9. The method of claim 8, wherein said cell is exposed to said transient decrease in pressure and unsteady flow within an enclosed channel with dimensions configured to allow the flow of said liquid comprising said exogenous material and said cell therethrough. 10. The method of claim 9, wherein said flow of said liquid in said channel has a fluctuating velocity. 11. The method of claim 9, wherein said channel is configured to influence unsteady flow of said liquid. 12. The method of claim 11, wherein the flow of liquid is influenced by one or more flow diverters within said enclosed channel. 13. The method of claim 12, wherein the object Reynolds number (Reo) of the unsteady flow of the liquid around a flow diverter in at least one of said regions within the channel is sufficient to induce unsteady flow. 14. The method of claim 13, wherein said one or more regions within the channel where unsteady flow of said liquid is downstream of said flow diverter. 15. The method of claim 14, wherein said cell is exposed to said transient decrease in pressure downstream of said flow diverter. 16. The method of claim 12, wherein said flow diverter is an obstacle placed within said enclosed channel. 17. The method of claim 1, wherein unsteady flow is at least one of a laminar vortex street, a transitional vortex street, a turbulent vortex street, transitional flow or turbulent flow. 18. A device for use in a method for introducing exogenous material into a cell in a liquid, comprising:
an at least partially enclosed channel with dimensions configured to allow a flow of said cell and exogenous material suspended in a liquid therethrough; and one or more flow diverters within said channel; wherein the flow diverter results in at least one region of decreased pressure and unsteady flow immediately downstream of said flow diverter. 19. The device of claim 18, wherein the device is a microfluidic device. 20. A kit comprising a device for use in a method for introducing exogenous material into a cell in a liquid, including:
an at least partially enclosed channel with dimensions configured to allow a flow of said cell and exogenous material suspended in a liquid therethrough; and one or more flow diverters within said channel; wherein the flow diverter results in at least one region of decreased pressure and unsteady flow immediately downstream of said flow diverter.
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Methods for introducing exogenous material into a cell are provided, which include exposing the cell to a transient decrease in pressure in the presence of the exogenous material. Also provided are devices for performing the method of the invention.1. A method for introducing an exogenous material into a cell, comprising exposing said cell to a transient decrease in pressure and unsteady flow in the presence of said exogenous material to thereby introduce said exogenous material into said cell. 2. The method of claim 1, wherein the cell is viable after being exposed to the transient decrease in pressure and unsteady flow. 3. The method of claim 1, wherein said cell is selected from the group consisting of a bacterial cell, a mammalian cell, a yeast cell, a plant cell and an insect cell. 4. The method of claim 1, wherein said exogenous material is selected from the group consisting of a small organic molecule, a nucleic acid, a nucleotide, an oligonucleotide, a protein, a peptide, an amino acid, a lipid, a polysaccharide, a quantum dot, a carbon nanotube, a nanoparticle, a gold particle, a monosaccharide, a vitamin and a steroid. 5. The method of claim 1, wherein said exogenous material is introduced into the cytoplasm of said cell. 6. The method of claim 1, wherein said cell is a mammalian cell, a yeast cell or an insect cell and said exogenous material is introduced into the nucleus of said cell. 7. The method of claim 1, wherein said cell is exposed to said transient decrease in pressure in the presence of said exogenous material for at least 10 nanoseconds. 8. The method of claim 1, wherein said exogenous material and said cell are in a liquid when being exposed to said transient decrease in pressure and unsteady flow. 9. The method of claim 8, wherein said cell is exposed to said transient decrease in pressure and unsteady flow within an enclosed channel with dimensions configured to allow the flow of said liquid comprising said exogenous material and said cell therethrough. 10. The method of claim 9, wherein said flow of said liquid in said channel has a fluctuating velocity. 11. The method of claim 9, wherein said channel is configured to influence unsteady flow of said liquid. 12. The method of claim 11, wherein the flow of liquid is influenced by one or more flow diverters within said enclosed channel. 13. The method of claim 12, wherein the object Reynolds number (Reo) of the unsteady flow of the liquid around a flow diverter in at least one of said regions within the channel is sufficient to induce unsteady flow. 14. The method of claim 13, wherein said one or more regions within the channel where unsteady flow of said liquid is downstream of said flow diverter. 15. The method of claim 14, wherein said cell is exposed to said transient decrease in pressure downstream of said flow diverter. 16. The method of claim 12, wherein said flow diverter is an obstacle placed within said enclosed channel. 17. The method of claim 1, wherein unsteady flow is at least one of a laminar vortex street, a transitional vortex street, a turbulent vortex street, transitional flow or turbulent flow. 18. A device for use in a method for introducing exogenous material into a cell in a liquid, comprising:
an at least partially enclosed channel with dimensions configured to allow a flow of said cell and exogenous material suspended in a liquid therethrough; and one or more flow diverters within said channel; wherein the flow diverter results in at least one region of decreased pressure and unsteady flow immediately downstream of said flow diverter. 19. The device of claim 18, wherein the device is a microfluidic device. 20. A kit comprising a device for use in a method for introducing exogenous material into a cell in a liquid, including:
an at least partially enclosed channel with dimensions configured to allow a flow of said cell and exogenous material suspended in a liquid therethrough; and one or more flow diverters within said channel; wherein the flow diverter results in at least one region of decreased pressure and unsteady flow immediately downstream of said flow diverter.
| 1,600 |
974 | 15,510,278 | 1,653 |
An enzymatic processing plant for continuous flow-based enzymatic processing of organic molecules, comprises an enzymatic processing area, wherein the enzymatic processing area comprises a turbulence-generating pipe with a repeatedly changing centre-line and/or a repeatedly changing cross-section, for generating turbulence to mix a reaction mixture and prevent sedimentation of particles as the reaction mixture is flowing through the turbulence-generating pipe, and wherein the enzymatic processing plant and the enzymatic processing area are arranged such that the reaction mixture is subjected to turbulence within the enzymatic processing area for a reaction time of 15 minutes or more.
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1. An enzymatic processing plant for continuous flow-based enzymatic processing of organic molecules, comprising an enzymatic processing area, wherein the enzymatic processing area comprises a turbulence-generating pipe with a repeatedly changing centre-line and/or a repeatedly changing cross-section, for generating turbulence to mix a reaction mixture and prevent sedimentation of particles as the reaction mixture is flowing through the turbulence-generating pipe, and wherein the enzymatic processing plant and the enzymatic processing area are arranged such that the reaction mixture is subjected to turbulence within the enzymatic processing area for a reaction time of 15 minutes or more. 2. A plant as claimed in claim 1, wherein the reaction time is more than 30 minutes 3. A plant as claimed in claim 1 or 2, wherein the turbulence-generating pipe has a changing cross-sectional area. 4. A plant as claimed in any preceding claim, wherein the turbulence-generating pipe is a corrugated pipe. 5. A plant as claimed in any preceding claim, wherein the turbulence-generating pipe comprises a number of notional repeating units, wherein the number of repeating units is greater than 10, more preferably greater than 20, and most preferably greater than 50. 6. A plant as claimed in any preceding claim, wherein the plant is arranged to operate with the reaction mixture having a flow velocity of less than 2 m/s through the turbulence generating pipe, optionally less than 1 m/s and optionally less than 0.5 m/s. 7. A plant as claimed in any preceding claim, wherein the enzymatic processing area includes one or more turbulence generating pipe(s) with a total length of at least at least 50 m, optionally at least 100 m. 8. A plant as claimed in any preceding claim, wherein the turbulence-generating pipe has an average diameter in the range of 20 mm to 200 mm, and preferably in the range of 40 mm to 100 mm, most preferably in the range of 50 mm to 90 mm. 9. A plant as claimed in any preceding claim, wherein the flow of the reaction mixture within the turbulence-generating pipe is turbulent at Reynolds numbers of less than 1000, more preferably at Reynolds numbers of less than 800, and most preferably at Reynolds numbers of less than 600. 10. A plant as claimed in any preceding claim, wherein the turbulence generating pipe includes a layer of immobilised enzymes attached to the inner surface of the pipe. 11. A plant as claimed in any preceding claim, comprising an injection point for introducing reagents which change the characteristics of the reaction mixture, preferably wherein the reagent is an acid, a base or water. 12. A plant as claimed in any preceding claim, comprising a heat exchanger for heating at least a portion of the turbulence-generating pipe. 13. A plant as claimed in any preceding claim, comprising a separator system, preferably wherein the separator system comprises a three-phase decanter operable to output a flow of oil and oil-soluble components, a flow of water-soluble components, and a flow of sediment, and/or a centrifuges and/or a filter. 14. A plant as claimed in any preceding claim, wherein the plant is a modular system. 15. A ship fitted with the plant of any preceding claim. 16. A method of enzymatic processing of organic molecules comprising passing a reaction mixture through a first enzymatic processing area comprising a turbulence-generating pipe, the turbulence-generating pipe having a repeatedly changing centre-line and/or a repeatedly changing cross-section, the turbulence generated by the turbulence-generating pipe being used to mix the reaction mixture and to prevent sedimentation of particles as the mixture is flowing through the turbulence generating pipe, wherein the reaction mixture is subjected to turbulence within the enzymatic processing area for a reaction time of 15 minutes or more. 17. A method according to claim 16, comprising using the apparatus of any of claims 1 to 15. 18. A method according to claim 16 or 17 comprising passing the reaction mixture through a second enzymatic processing area downstream of the first enzymatic processing area, wherein a chemical reaction carried out in the second enzymatic processing area is different from a chemical reaction carried out in the first enzymatic processing area. 19. A method according to claim 16, 17 or 18 wherein the reaction mixture comprises a raw material selected from: birds, fish, crustaceans, molluscs, mammals, marine and freshwater algae, yeast or oilseeds. 20. A method of manufacturing a modular enzymatic processing plant for enzymatic processing of a reaction mixture, the method comprising determining a required enzymatic processing process and manufacturing a suitable enzymatic processing plant from a kit of modular parts by providing:
a pump for pumping the reaction mixture through the enzymatic processing plant; a first enzymatic processing area for performing a first stage of enzymatic processing; a separator system comprising a decanter for separating a flow of water soluble components, oil-soluble components and solid components;
the method further comprising:
considering whether or not each of the following components are necessary for a processing plant capable of performing the required enzymatic processing process: a filter; a second enzymatic processing stage; a third enzymatic processing stage; a post-separator system stage; a flow division stage; and a flow combining stage; and,
including the necessary components in the modular plant. 21. A method according to claim 20, comprising providing a second enzymatic processing stage,
preferably wherein the second enzymatic processing stage is provided downstream of the first enzymatic processing stage, and is configured to be in communication with the first enzymatic processing area such that in use, the second enzymatic processing stage receives at least a portion of the reaction output from the first enzymatic processing area; or wherein the second enzymatic processing stage is provided downstream of the separator system, and may be configured to be in communication with the separator system such that in use, the second enzymatic processing stage receives one of the following output from the separator system: the flow of water soluble components, the flow of oil-soluble components, or the solid components. 22. A method according to claim 21, comprising providing a third enzymatic processing stage,
preferably wherein the third enzymatic processing stage is provided downstream of the second enzymatic processing stage, and is configured to be in communication with the second enzymatic processing area such that in use, the third enzymatic processing stage receives at least a portion of the reaction output from the second enzymatic processing area; or wherein the third enzymatic processing stage is provided downstream of the separator system, and may be configured to be in communication with the separator system such that in use, the third enzymatic processing stage receives one of the following output from the separator system: the flow of water soluble components, the flow of oil-soluble components, or the solid components. 23. A method according to claim 20, 21 or 22, comprising considering whether or not each of the following post-separator system stages are necessary for a processing plant capable of providing the necessary processing: a further enzymatic processing stage, a drier or a polisher. 24. A method according to claim 20, 21, 22 or 23 comprising providing a post-separator system stage. 25. A method according to any of claims 20 to 24 comprising providing a drier for drying solid components. 26. A method according to any of claims 20 to 25 comprising providing a polisher for cleaning oil-soluble components. 27. A method according to any of claims 20 to 26 comprising providing a flow division stage at which the flow is divided into two or more flows, preferably wherein the two or more flows are routed to different stages downstream, or one or more of the divided flows are routed to an upstream stage. 28. A method according to claim 27, wherein the flow division stage is provided after the first enzymatic processing stage, or after the separator system. 29. A method according to claim 27 or 28, wherein the flow division stage is provided after the second enzymatic processing stage. 30. A method according to claim 27, 28 or 29, wherein the flow division stage is provided after the third enzymatic processing stage. 31. A method according to claim 27, 28, 29 or 30, comprising providing a flow combination stage at which a divided flow is combined with a flow at an upstream stage. 32. A method according to claim 31, wherein the flow combination stage is provided before the first enzymatic processing stage, or before the separator system. 33. A method according to claim 31 or 32, wherein the flow combination stage is provided before the second enzymatic processing stage. 34. A method according to claim 31, 32 or 33, wherein the flow combination stage is provided before the third enzymatic processing stage. 35. A method according to claim 31, 32, 33 or 34, wherein the flow combination stage is provided before drier. 36. A method according to any of claims 20 to 35 comprising providing an injection point prior to a stage for introducing chemicals to modify reaction conditions within the stage. 37. A method according to claim 36, wherein the injection point is provided before the first enzymatic processing stage, and/or before the separator system. 38. A method according to claim 36 or 37, wherein the injection point is provided before the second enzymatic processing stage. 39. A method according to claim 36, 37 or 38, wherein the injection point stage is provided before the third enzymatic processing stage. 40. A method according to claim 36, 37, 38 or 39, wherein the injection point is provided before the drier. 41. A method according to any of claims 16 to 40 comprising providing a heat exchanger. 42. A method according to any of claims 16 to 41 comprising providing an enclosed mixing chamber upstream of the first enzymatic processing stage. 43. A method according to any of claims 16 to 42 comprising providing a filter for separating from the reaction mixture components with a given molecular size, or larger. 44. A kit of parts for making an enzymatic processing plant for enzymatic processing of organic compounds in a reaction mixture, the kit of parts comprising:
a pump for pumping the reaction mixture through the enzymatic processing plant; a first enzymatic processing area for performing a first stage of enzymatic processing; and a separator system comprising a decanter for separating a flow of water soluble components, oil-soluble components and solid components; and the kit of parts further comprising one or more of: a filter; a second enzymatic processing stage; a third enzymatic processing stage; a flow division stage; a flow combining stage; an injection point; a mixing chamber; a polisher; and a drier. 45. A kit of parts as claimed in claim 44 comprising parts selected in order to meet the requirements of the method of manufacturing a modular enzymatic processing plant as claimed in any of claims 16 to 44.
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An enzymatic processing plant for continuous flow-based enzymatic processing of organic molecules, comprises an enzymatic processing area, wherein the enzymatic processing area comprises a turbulence-generating pipe with a repeatedly changing centre-line and/or a repeatedly changing cross-section, for generating turbulence to mix a reaction mixture and prevent sedimentation of particles as the reaction mixture is flowing through the turbulence-generating pipe, and wherein the enzymatic processing plant and the enzymatic processing area are arranged such that the reaction mixture is subjected to turbulence within the enzymatic processing area for a reaction time of 15 minutes or more.1. An enzymatic processing plant for continuous flow-based enzymatic processing of organic molecules, comprising an enzymatic processing area, wherein the enzymatic processing area comprises a turbulence-generating pipe with a repeatedly changing centre-line and/or a repeatedly changing cross-section, for generating turbulence to mix a reaction mixture and prevent sedimentation of particles as the reaction mixture is flowing through the turbulence-generating pipe, and wherein the enzymatic processing plant and the enzymatic processing area are arranged such that the reaction mixture is subjected to turbulence within the enzymatic processing area for a reaction time of 15 minutes or more. 2. A plant as claimed in claim 1, wherein the reaction time is more than 30 minutes 3. A plant as claimed in claim 1 or 2, wherein the turbulence-generating pipe has a changing cross-sectional area. 4. A plant as claimed in any preceding claim, wherein the turbulence-generating pipe is a corrugated pipe. 5. A plant as claimed in any preceding claim, wherein the turbulence-generating pipe comprises a number of notional repeating units, wherein the number of repeating units is greater than 10, more preferably greater than 20, and most preferably greater than 50. 6. A plant as claimed in any preceding claim, wherein the plant is arranged to operate with the reaction mixture having a flow velocity of less than 2 m/s through the turbulence generating pipe, optionally less than 1 m/s and optionally less than 0.5 m/s. 7. A plant as claimed in any preceding claim, wherein the enzymatic processing area includes one or more turbulence generating pipe(s) with a total length of at least at least 50 m, optionally at least 100 m. 8. A plant as claimed in any preceding claim, wherein the turbulence-generating pipe has an average diameter in the range of 20 mm to 200 mm, and preferably in the range of 40 mm to 100 mm, most preferably in the range of 50 mm to 90 mm. 9. A plant as claimed in any preceding claim, wherein the flow of the reaction mixture within the turbulence-generating pipe is turbulent at Reynolds numbers of less than 1000, more preferably at Reynolds numbers of less than 800, and most preferably at Reynolds numbers of less than 600. 10. A plant as claimed in any preceding claim, wherein the turbulence generating pipe includes a layer of immobilised enzymes attached to the inner surface of the pipe. 11. A plant as claimed in any preceding claim, comprising an injection point for introducing reagents which change the characteristics of the reaction mixture, preferably wherein the reagent is an acid, a base or water. 12. A plant as claimed in any preceding claim, comprising a heat exchanger for heating at least a portion of the turbulence-generating pipe. 13. A plant as claimed in any preceding claim, comprising a separator system, preferably wherein the separator system comprises a three-phase decanter operable to output a flow of oil and oil-soluble components, a flow of water-soluble components, and a flow of sediment, and/or a centrifuges and/or a filter. 14. A plant as claimed in any preceding claim, wherein the plant is a modular system. 15. A ship fitted with the plant of any preceding claim. 16. A method of enzymatic processing of organic molecules comprising passing a reaction mixture through a first enzymatic processing area comprising a turbulence-generating pipe, the turbulence-generating pipe having a repeatedly changing centre-line and/or a repeatedly changing cross-section, the turbulence generated by the turbulence-generating pipe being used to mix the reaction mixture and to prevent sedimentation of particles as the mixture is flowing through the turbulence generating pipe, wherein the reaction mixture is subjected to turbulence within the enzymatic processing area for a reaction time of 15 minutes or more. 17. A method according to claim 16, comprising using the apparatus of any of claims 1 to 15. 18. A method according to claim 16 or 17 comprising passing the reaction mixture through a second enzymatic processing area downstream of the first enzymatic processing area, wherein a chemical reaction carried out in the second enzymatic processing area is different from a chemical reaction carried out in the first enzymatic processing area. 19. A method according to claim 16, 17 or 18 wherein the reaction mixture comprises a raw material selected from: birds, fish, crustaceans, molluscs, mammals, marine and freshwater algae, yeast or oilseeds. 20. A method of manufacturing a modular enzymatic processing plant for enzymatic processing of a reaction mixture, the method comprising determining a required enzymatic processing process and manufacturing a suitable enzymatic processing plant from a kit of modular parts by providing:
a pump for pumping the reaction mixture through the enzymatic processing plant; a first enzymatic processing area for performing a first stage of enzymatic processing; a separator system comprising a decanter for separating a flow of water soluble components, oil-soluble components and solid components;
the method further comprising:
considering whether or not each of the following components are necessary for a processing plant capable of performing the required enzymatic processing process: a filter; a second enzymatic processing stage; a third enzymatic processing stage; a post-separator system stage; a flow division stage; and a flow combining stage; and,
including the necessary components in the modular plant. 21. A method according to claim 20, comprising providing a second enzymatic processing stage,
preferably wherein the second enzymatic processing stage is provided downstream of the first enzymatic processing stage, and is configured to be in communication with the first enzymatic processing area such that in use, the second enzymatic processing stage receives at least a portion of the reaction output from the first enzymatic processing area; or wherein the second enzymatic processing stage is provided downstream of the separator system, and may be configured to be in communication with the separator system such that in use, the second enzymatic processing stage receives one of the following output from the separator system: the flow of water soluble components, the flow of oil-soluble components, or the solid components. 22. A method according to claim 21, comprising providing a third enzymatic processing stage,
preferably wherein the third enzymatic processing stage is provided downstream of the second enzymatic processing stage, and is configured to be in communication with the second enzymatic processing area such that in use, the third enzymatic processing stage receives at least a portion of the reaction output from the second enzymatic processing area; or wherein the third enzymatic processing stage is provided downstream of the separator system, and may be configured to be in communication with the separator system such that in use, the third enzymatic processing stage receives one of the following output from the separator system: the flow of water soluble components, the flow of oil-soluble components, or the solid components. 23. A method according to claim 20, 21 or 22, comprising considering whether or not each of the following post-separator system stages are necessary for a processing plant capable of providing the necessary processing: a further enzymatic processing stage, a drier or a polisher. 24. A method according to claim 20, 21, 22 or 23 comprising providing a post-separator system stage. 25. A method according to any of claims 20 to 24 comprising providing a drier for drying solid components. 26. A method according to any of claims 20 to 25 comprising providing a polisher for cleaning oil-soluble components. 27. A method according to any of claims 20 to 26 comprising providing a flow division stage at which the flow is divided into two or more flows, preferably wherein the two or more flows are routed to different stages downstream, or one or more of the divided flows are routed to an upstream stage. 28. A method according to claim 27, wherein the flow division stage is provided after the first enzymatic processing stage, or after the separator system. 29. A method according to claim 27 or 28, wherein the flow division stage is provided after the second enzymatic processing stage. 30. A method according to claim 27, 28 or 29, wherein the flow division stage is provided after the third enzymatic processing stage. 31. A method according to claim 27, 28, 29 or 30, comprising providing a flow combination stage at which a divided flow is combined with a flow at an upstream stage. 32. A method according to claim 31, wherein the flow combination stage is provided before the first enzymatic processing stage, or before the separator system. 33. A method according to claim 31 or 32, wherein the flow combination stage is provided before the second enzymatic processing stage. 34. A method according to claim 31, 32 or 33, wherein the flow combination stage is provided before the third enzymatic processing stage. 35. A method according to claim 31, 32, 33 or 34, wherein the flow combination stage is provided before drier. 36. A method according to any of claims 20 to 35 comprising providing an injection point prior to a stage for introducing chemicals to modify reaction conditions within the stage. 37. A method according to claim 36, wherein the injection point is provided before the first enzymatic processing stage, and/or before the separator system. 38. A method according to claim 36 or 37, wherein the injection point is provided before the second enzymatic processing stage. 39. A method according to claim 36, 37 or 38, wherein the injection point stage is provided before the third enzymatic processing stage. 40. A method according to claim 36, 37, 38 or 39, wherein the injection point is provided before the drier. 41. A method according to any of claims 16 to 40 comprising providing a heat exchanger. 42. A method according to any of claims 16 to 41 comprising providing an enclosed mixing chamber upstream of the first enzymatic processing stage. 43. A method according to any of claims 16 to 42 comprising providing a filter for separating from the reaction mixture components with a given molecular size, or larger. 44. A kit of parts for making an enzymatic processing plant for enzymatic processing of organic compounds in a reaction mixture, the kit of parts comprising:
a pump for pumping the reaction mixture through the enzymatic processing plant; a first enzymatic processing area for performing a first stage of enzymatic processing; and a separator system comprising a decanter for separating a flow of water soluble components, oil-soluble components and solid components; and the kit of parts further comprising one or more of: a filter; a second enzymatic processing stage; a third enzymatic processing stage; a flow division stage; a flow combining stage; an injection point; a mixing chamber; a polisher; and a drier. 45. A kit of parts as claimed in claim 44 comprising parts selected in order to meet the requirements of the method of manufacturing a modular enzymatic processing plant as claimed in any of claims 16 to 44.
| 1,600 |
975 | 15,577,783 | 1,612 |
The present invention relates to an oral care composition having an anionic surfactant, a cationic or amphoteric surfactant, and a potassium salt, wherein the oral care composition does not include a non-ionic surfactant.
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1. An oral care composition comprising:
a) an anionic surfactant; b) a cationic or amphoteric surfactant; and c) a potassium salt; wherein the oral care composition does not comprise a non-ionic surfactant. 2. The oral care composition of claim 1, further comprising a thickener. 3. The oral care composition of claim 2, wherein the thickener is selected from the group consisting of carboxymethyl cellulose, xanthan gum, and a methyl vinyl ether/maleic acid copolymer. 4. The oral care composition of claim 2, wherein the thickener is present in an amount of from 0.1 to 1.8 weight %; preferably from 0.2 to 1.00 weight %; most preferably from 0.4 to 0.65 weight %. 5. The oral care composition of claim 1, wherein the anionic surfactant is a sulfur containing aliphatic surfactant. 6. The oral care composition of claim 5, wherein the sulfur containing aliphatic surfactant is sodium lauryl sulfate (SLS). 7. The oral care composition of claim 1, wherein the cationic or amphoteric surfactant is a betaine. 8. The oral care composition of claim 7, wherein the betaine is cocamidopropyl betaine (CAPB). 9. The oral care composition of claim 1, wherein the composition further comprises a zinc ion source. 10. The oral care composition of claim 9, wherein the zinc ion source is at least one selected from zinc citrate, zinc oxide, zinc acetate, zinc gluconate, zinc glycinate, zinc sulfate, zinc phosphate and sodium zinc citrate. 11. The oral care composition of claim 1, wherein the composition further comprises silica. 12. The oral care composition of claim 11, wherein the silica is at least one of an abrasive silica and/or a thickening silica, or combinations thereof. 13. The oral care composition of claim 1, wherein the composition further comprises a tartar control agent. 14. The oral care composition of claim 13, wherein the tartar control agent is tetrapotassium pyrophosphate and the total concentration of the tartar control agent is from 1 weight % to 4 weight %; preferably from 2 weight % to 3 weight %; preferably from 2.4 weight % to 2.6 weight %; 2.4 weight % or 2.5 weight %. 15. The oral care composition of claim 13, wherein the tartar control agent is tetrasodium pyrophosphate and the total concentration of the tartar control agent is from 0.2 to 0.8 weight %; preferably from 0.3 to 0.7 weight %; preferably from 0.4 to 0.6 weight %; or preferably 0.5 weight %. 16. The oral care composition of claim 1, wherein the potassium salt is potassium nitrate.
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The present invention relates to an oral care composition having an anionic surfactant, a cationic or amphoteric surfactant, and a potassium salt, wherein the oral care composition does not include a non-ionic surfactant.1. An oral care composition comprising:
a) an anionic surfactant; b) a cationic or amphoteric surfactant; and c) a potassium salt; wherein the oral care composition does not comprise a non-ionic surfactant. 2. The oral care composition of claim 1, further comprising a thickener. 3. The oral care composition of claim 2, wherein the thickener is selected from the group consisting of carboxymethyl cellulose, xanthan gum, and a methyl vinyl ether/maleic acid copolymer. 4. The oral care composition of claim 2, wherein the thickener is present in an amount of from 0.1 to 1.8 weight %; preferably from 0.2 to 1.00 weight %; most preferably from 0.4 to 0.65 weight %. 5. The oral care composition of claim 1, wherein the anionic surfactant is a sulfur containing aliphatic surfactant. 6. The oral care composition of claim 5, wherein the sulfur containing aliphatic surfactant is sodium lauryl sulfate (SLS). 7. The oral care composition of claim 1, wherein the cationic or amphoteric surfactant is a betaine. 8. The oral care composition of claim 7, wherein the betaine is cocamidopropyl betaine (CAPB). 9. The oral care composition of claim 1, wherein the composition further comprises a zinc ion source. 10. The oral care composition of claim 9, wherein the zinc ion source is at least one selected from zinc citrate, zinc oxide, zinc acetate, zinc gluconate, zinc glycinate, zinc sulfate, zinc phosphate and sodium zinc citrate. 11. The oral care composition of claim 1, wherein the composition further comprises silica. 12. The oral care composition of claim 11, wherein the silica is at least one of an abrasive silica and/or a thickening silica, or combinations thereof. 13. The oral care composition of claim 1, wherein the composition further comprises a tartar control agent. 14. The oral care composition of claim 13, wherein the tartar control agent is tetrapotassium pyrophosphate and the total concentration of the tartar control agent is from 1 weight % to 4 weight %; preferably from 2 weight % to 3 weight %; preferably from 2.4 weight % to 2.6 weight %; 2.4 weight % or 2.5 weight %. 15. The oral care composition of claim 13, wherein the tartar control agent is tetrasodium pyrophosphate and the total concentration of the tartar control agent is from 0.2 to 0.8 weight %; preferably from 0.3 to 0.7 weight %; preferably from 0.4 to 0.6 weight %; or preferably 0.5 weight %. 16. The oral care composition of claim 1, wherein the potassium salt is potassium nitrate.
| 1,600 |
976 | 15,145,337 | 1,612 |
A preparation in the form of a powder containing: (a) at least one carotenoid, (b) at least one modified starch, and (c) sucrose; wherein the at least one carotenoid is present in the powder in an amount of 1 to 25% by weight, based on the weight of the powder; and wherein the at least one carotenoid and the sucrose are present in the powder in a ratio by weight of 1:2 to 1:80:
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1-20. (canceled) 21. A preparation in powder form comprising:
(a) at least one carotenoid, (b) at least one modified starch, and (c) sucrose; wherein the at least one carotenoid is present in the powder in an amount of 1 to 25% by weight, based on the weight of the powder; and wherein the at least one carotenoid and the sucrose are present in the powder in a ratio by weight of 1:2 to 1:80. 22. The preparation according to claim 21, wherein the at least one modified starch comprises octenylsuccinate starch. 23. The preparation according to claim 21, wherein the at least one carotenoid comprises a compound selected from the group consisting of β-carotene, lycopene, zeaxanthin, lutein, and mixtures thereof. 24. The preparation according to claim 22, wherein the at least one carotenoid comprises a compound selected from the group consisting of β-carotene, lycopene, zeaxanthin, lutein, and mixtures thereof. 25. The preparation according to claim 21, Which further comprises component d) from 0.1 to 10% by weight of an antioxidant based on the total mass of the preparation in powder form. 26. The preparation according to claim 24, which further comprises component d) from 0.1 to 10% by weight of an antioxidant based on the total mass of the preparation in powder form. 27. The preparation according to claim 21, wherein the at least one carotenoid comprises β-carotene. 28. The preparation according to claim 21, wherein the at least one carotenoid comprises lycopene. 29. The preparation according to claim 21, wherein the at least one carotenoid comprises zeaxanthin. 30. The preparation according to claim 21, wherein the at least one carotenoid comprises lutein. 31. A composition comprising: an additive amount of a powder according to claim 21; and a component selected from the group consisting of human foods, dietary supplements, animal feeds, pharmaceutical preparations and cosmetic preparations. 32. The preparation according to claim 21, wherein the at least one carotenoid is present in the powder in an amount of 2 to 20% by weight, based on the weight of the powder; and wherein the at least one carotenoid and the sucrose are present in the powder in a ratio by weight of 1:3 to 1:40. 33. The preparation according to claim 21, wherein the at least one carotenoid is present in the powder in an amount of 5 to 15% by weight, based on the weight of the powder; and wherein the at least one carotenoid and the sucrose are present in the powder in a ratio by weight of 1:4 to 1:18. 34. The preparation according to claim 21, wherein the at least one carotenoid is present in the powder in an amount of 8 to 13% by weight, based on the weight of the powder; and wherein the at least one carotenoid and the sucrose are present in the powder in a ratio by weight of 1:5 to 1:10. 35. The preparation according to claim 26, wherein the at least one carotenoid is present in the powder in an amount of 8 to 13% by weight, based on the weight of the powder; and wherein the at least one carotenoid and the sucrose are present in the powder in a ratio by weight of 1:5 to 1:10. 36. The preparation according to claim 21, wherein said at least one modified starch is present in an amount from 8 to 26% by weight. 37. The preparation according to claim 35, which further comprises component d) from 1 to 2% by weight of an antioxidant based on the total mass of the preparation in powder form and said at least one modified starch is present in an amount from 8 to 26% by weight. 38. The preparation according to claim 21, which further comprises component d) from 1 to 2% by weight of an antioxidant based on the total mass of the preparation in powder form. 39. The preparation according to claim 21, the carotenoid has a degree of crystallinity in the range from 90 to 99% determined by X-ray diffraction.
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A preparation in the form of a powder containing: (a) at least one carotenoid, (b) at least one modified starch, and (c) sucrose; wherein the at least one carotenoid is present in the powder in an amount of 1 to 25% by weight, based on the weight of the powder; and wherein the at least one carotenoid and the sucrose are present in the powder in a ratio by weight of 1:2 to 1:80:1-20. (canceled) 21. A preparation in powder form comprising:
(a) at least one carotenoid, (b) at least one modified starch, and (c) sucrose; wherein the at least one carotenoid is present in the powder in an amount of 1 to 25% by weight, based on the weight of the powder; and wherein the at least one carotenoid and the sucrose are present in the powder in a ratio by weight of 1:2 to 1:80. 22. The preparation according to claim 21, wherein the at least one modified starch comprises octenylsuccinate starch. 23. The preparation according to claim 21, wherein the at least one carotenoid comprises a compound selected from the group consisting of β-carotene, lycopene, zeaxanthin, lutein, and mixtures thereof. 24. The preparation according to claim 22, wherein the at least one carotenoid comprises a compound selected from the group consisting of β-carotene, lycopene, zeaxanthin, lutein, and mixtures thereof. 25. The preparation according to claim 21, Which further comprises component d) from 0.1 to 10% by weight of an antioxidant based on the total mass of the preparation in powder form. 26. The preparation according to claim 24, which further comprises component d) from 0.1 to 10% by weight of an antioxidant based on the total mass of the preparation in powder form. 27. The preparation according to claim 21, wherein the at least one carotenoid comprises β-carotene. 28. The preparation according to claim 21, wherein the at least one carotenoid comprises lycopene. 29. The preparation according to claim 21, wherein the at least one carotenoid comprises zeaxanthin. 30. The preparation according to claim 21, wherein the at least one carotenoid comprises lutein. 31. A composition comprising: an additive amount of a powder according to claim 21; and a component selected from the group consisting of human foods, dietary supplements, animal feeds, pharmaceutical preparations and cosmetic preparations. 32. The preparation according to claim 21, wherein the at least one carotenoid is present in the powder in an amount of 2 to 20% by weight, based on the weight of the powder; and wherein the at least one carotenoid and the sucrose are present in the powder in a ratio by weight of 1:3 to 1:40. 33. The preparation according to claim 21, wherein the at least one carotenoid is present in the powder in an amount of 5 to 15% by weight, based on the weight of the powder; and wherein the at least one carotenoid and the sucrose are present in the powder in a ratio by weight of 1:4 to 1:18. 34. The preparation according to claim 21, wherein the at least one carotenoid is present in the powder in an amount of 8 to 13% by weight, based on the weight of the powder; and wherein the at least one carotenoid and the sucrose are present in the powder in a ratio by weight of 1:5 to 1:10. 35. The preparation according to claim 26, wherein the at least one carotenoid is present in the powder in an amount of 8 to 13% by weight, based on the weight of the powder; and wherein the at least one carotenoid and the sucrose are present in the powder in a ratio by weight of 1:5 to 1:10. 36. The preparation according to claim 21, wherein said at least one modified starch is present in an amount from 8 to 26% by weight. 37. The preparation according to claim 35, which further comprises component d) from 1 to 2% by weight of an antioxidant based on the total mass of the preparation in powder form and said at least one modified starch is present in an amount from 8 to 26% by weight. 38. The preparation according to claim 21, which further comprises component d) from 1 to 2% by weight of an antioxidant based on the total mass of the preparation in powder form. 39. The preparation according to claim 21, the carotenoid has a degree of crystallinity in the range from 90 to 99% determined by X-ray diffraction.
| 1,600 |
977 | 15,803,967 | 1,653 |
The present invention discloses the method of preparation and use of soft tissue membranous structures into slip resistant membranes with regularly spaced surface projections on one side and concave depressions on the other side with perforations or without perforations which enhance vascular ingrowth and tissue incorporation.
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1. A method of making smooth two-sided wetted or non-dried biological membranes into three-dimensional membrane structures with regularly or irregularly spaced surface concave depressions on an at least first side and projections on at least the opposite second side, the method comprising the steps of:
acquiring a smooth two sided wetted or non-dried membrane for drying; placing the smooth wetted or non-dried membrane on a support surface of a perforated plate, the perforated plate having a plurality of holes or depressions on the support surface of the plate for forming depressions on a first side of the membrane and projections on an opposite second side adjacent the support surface; and drying the smooth wetted or non-dried membrane on the perforated plate wherein the smooth wetted or non-dried membrane locally sags or sinks into the perforations forming depressions on the first side and corresponding projections on the opposite second side of the membrane converting the membrane into a three-dimensional structure when dried. 2. The method of claim 1 further comprises the step of perforating at least one or more of the surface projections on the second side and concave depressions on the first side in the membranes to form open perforations at an end of the at least one or more projections of the three-dimensional membrane structure. 3. The method of claim 1 wherein the smooth two-sided wetted or non-dried membrane is freeze-dried on perforated plates and retained in place by compressing the membrane with solid plates or under vacuum. 4. The method of claim 1 wherein either prior to drying or post drying the three-dimensional structure has projections formed on the first side with the concave depressions so the membrane has the first side with a configuration of projections and concave depressions and the second side similarly has a combination of concave depressions and projections. 5. The method of claim 3 wherein the membranes to be freeze-dried are covered with perforated cellophane. 6. The method of claim 1 wherein the biological membrane material is one of dermis, full thickness skin, amniotic membrane, pericardium, dura mater or fascia. 7. The method of claim 6 wherein the dermis can be intact or decellularized. 8. The method of claim 6 wherein the dermis, full-thickness skin, amniotic membrane, fascia, pericardium, dura mater or other membranes can be human or animal 9. The method of claim 2 wherein the step of perforating the at least one or more projections and concave depressions provides a fluid pathway for vascularization when implanted. 10. The method of claim 1 wherein the projections or depressions form a non-slip surface when implanted. 11. A three-dimensional membrane structure comprises:
a smooth two-sided biological membrane with regular or irregularly spaced surface concave depressions on a first side and projections on an opposite second side. 12. The three-dimensional membrane structure of claim 11 wherein at least one or more of the surface projections on the second side and concave depressions on the first side in the membranes form open perforations at an end of the at least one or more projections of the three-dimensional membrane structure. 13. The three-dimensional membrane structure of claim 11 wherein the three-dimensional membrane is a dried membrane. 14. The three-dimensional membrane structure of claim 13 wherein the dried membrane has been freeze-dried. 15. The three-dimensional membrane structure of claim 11 wherein the biological membrane material is one of dermis, full thickness skin, amniotic membrane, pericardium, dura mater or fascia. 16. The three-dimensional membrane structure of claim 15 wherein the dermis can be intact or decellularized. 17. The three-dimensional membrane structure of claim 15 wherein the dermis, full-thickness skin, amniotic membrane, fascia, pericardium, dura mater or other membranes can be human or animal.
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The present invention discloses the method of preparation and use of soft tissue membranous structures into slip resistant membranes with regularly spaced surface projections on one side and concave depressions on the other side with perforations or without perforations which enhance vascular ingrowth and tissue incorporation.1. A method of making smooth two-sided wetted or non-dried biological membranes into three-dimensional membrane structures with regularly or irregularly spaced surface concave depressions on an at least first side and projections on at least the opposite second side, the method comprising the steps of:
acquiring a smooth two sided wetted or non-dried membrane for drying; placing the smooth wetted or non-dried membrane on a support surface of a perforated plate, the perforated plate having a plurality of holes or depressions on the support surface of the plate for forming depressions on a first side of the membrane and projections on an opposite second side adjacent the support surface; and drying the smooth wetted or non-dried membrane on the perforated plate wherein the smooth wetted or non-dried membrane locally sags or sinks into the perforations forming depressions on the first side and corresponding projections on the opposite second side of the membrane converting the membrane into a three-dimensional structure when dried. 2. The method of claim 1 further comprises the step of perforating at least one or more of the surface projections on the second side and concave depressions on the first side in the membranes to form open perforations at an end of the at least one or more projections of the three-dimensional membrane structure. 3. The method of claim 1 wherein the smooth two-sided wetted or non-dried membrane is freeze-dried on perforated plates and retained in place by compressing the membrane with solid plates or under vacuum. 4. The method of claim 1 wherein either prior to drying or post drying the three-dimensional structure has projections formed on the first side with the concave depressions so the membrane has the first side with a configuration of projections and concave depressions and the second side similarly has a combination of concave depressions and projections. 5. The method of claim 3 wherein the membranes to be freeze-dried are covered with perforated cellophane. 6. The method of claim 1 wherein the biological membrane material is one of dermis, full thickness skin, amniotic membrane, pericardium, dura mater or fascia. 7. The method of claim 6 wherein the dermis can be intact or decellularized. 8. The method of claim 6 wherein the dermis, full-thickness skin, amniotic membrane, fascia, pericardium, dura mater or other membranes can be human or animal 9. The method of claim 2 wherein the step of perforating the at least one or more projections and concave depressions provides a fluid pathway for vascularization when implanted. 10. The method of claim 1 wherein the projections or depressions form a non-slip surface when implanted. 11. A three-dimensional membrane structure comprises:
a smooth two-sided biological membrane with regular or irregularly spaced surface concave depressions on a first side and projections on an opposite second side. 12. The three-dimensional membrane structure of claim 11 wherein at least one or more of the surface projections on the second side and concave depressions on the first side in the membranes form open perforations at an end of the at least one or more projections of the three-dimensional membrane structure. 13. The three-dimensional membrane structure of claim 11 wherein the three-dimensional membrane is a dried membrane. 14. The three-dimensional membrane structure of claim 13 wherein the dried membrane has been freeze-dried. 15. The three-dimensional membrane structure of claim 11 wherein the biological membrane material is one of dermis, full thickness skin, amniotic membrane, pericardium, dura mater or fascia. 16. The three-dimensional membrane structure of claim 15 wherein the dermis can be intact or decellularized. 17. The three-dimensional membrane structure of claim 15 wherein the dermis, full-thickness skin, amniotic membrane, fascia, pericardium, dura mater or other membranes can be human or animal.
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978 | 15,325,472 | 1,642 |
The invention features methods, devices, and kits for predicting the responsiveness of a cancer patient (e.g., a breast cancer patient, such as a grade 1, 2, or 3 breast cancer patient) to anthracycline treatment by determining the expression levels of four chromosomal instability (CIN) genes including HDGF, KIAA0286, RFC4, and MSH6, collectively referred to as CIN4. Patients that have a low CIN4 score benefit from anthracycline treatment compared patients with a high CIN4 score.
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1. A method of predicting the responsiveness of a cancer patient to anthracycline treatment comprising
a) determining the level of expression of at least one biomarker selected from the group consisting of HDGF, KIAA0286, RFC4, and MSH6 in a sample from the cancer patient, and b) i) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a first reference patient known to be responsive to anthracycline treatment, or
ii) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a second reference patient known to be non-responsive to anthracycline treatment,
wherein a determination that the level of expression of the biomarker in the sample from the cancer patient is similar to the level of expression of the biomarker in the sample from the first reference patient indicates that the cancer patient is responsive to said anthracycline treatment, or wherein a determination that the level of expression of the biomarker in the sample from the cancer patient is dissimilar to the level of expression of the biomarker in the sample from the second reference patient indicates that the cancer patient is responsive to said anthracycline treatment. 2. A method of predicting the responsiveness of a cancer patient to anthracycline treatment comprising
a) determining the level of expression of a biomarker having all or a portion of the sequence of SEQ ID NO: 1 in a sample from the cancer patient, and b) i) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a first reference patient known to be responsive to anthracycline treatment, or
ii) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a second reference patient known to be non-responsive to anthracycline treatment,
wherein a determination that the level of expression of the biomarker in the sample from the cancer patient is similar to the level of expression of the biomarker in the sample from the first reference patient indicates that the cancer patient is responsive to said anthracycline treatment, or wherein a determination that the level of expression of the biomarker in the sample from the cancer patient is dissimilar to the level of expression of the biomarker in the sample from the second reference patient indicates that the cancer patient is responsive to said anthracycline treatment. 3. A method of predicting the responsiveness of a cancer patient to anthracycline treatment comprising
a) determining the level of expression of a biomarker having all or a portion of the sequence of SEQ ID NO: 2 in a sample from the cancer patient, and b) i) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a first reference patient known to be responsive to anthracycline treatment, or
ii) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a second reference patient known to be non-responsive to anthracycline treatment,
wherein a determination that the level of expression of the biomarker in the sample from the cancer patient is similar to the level of expression of the biomarker in the sample from the first reference patient indicates that the cancer patient is responsive to said anthracycline treatment, or wherein a determination that the level of expression of the biomarker in the sample from the cancer patient is dissimilar to the level of expression of the biomarker in the sample from the second reference patient indicates that the cancer patient is responsive to said anthracycline treatment. 4. A method of predicting the responsiveness of a cancer patient to anthracycline treatment comprising
a) determining the level of expression of a biomarker having all or a portion of the sequence of SEQ ID NO: 3 in a sample from the cancer patient, and b) i) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a first reference patient known to be responsive to anthracycline treatment, or
ii) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a second reference patient known to be non-responsive to anthracycline treatment,
wherein a determination that the level of expression of the biomarker in the sample from the cancer patient is similar to the level of expression of the biomarker in the sample from the first reference patient indicates that the cancer patient is responsive to said anthracycline treatment, or wherein a determination that the level of expression of the biomarker in the sample from the cancer patient is dissimilar to the level of expression of the biomarker in the sample from the second reference patient indicates that the cancer patient is responsive to said anthracycline treatment. 5. A method of predicting the responsiveness of a cancer patient to anthracycline treatment comprising
a) determining the level of expression of a biomarker having all or a portion of the sequence of SEQ ID NO: 4 in a sample from the cancer patient, and b) i) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a first reference patient known to be responsive to anthracycline treatment, or
ii) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a second reference patient known to be non-responsive to anthracycline treatment,
wherein a determination that the level of expression of the biomarker in the sample from the cancer patient is similar to the level of expression of the biomarker in the sample from the first reference patient indicates that the cancer patient is responsive to said anthracycline treatment, or wherein a determination that the level of expression of the biomarker in the sample from the cancer patient is dissimilar to the level of expression of the biomarker in the sample from the second reference patient indicates that the cancer patient is responsive to said anthracycline treatment. 6. A method of predicting the responsiveness of a cancer patient to anthracycline treatment comprising
a) determining the level of expression of a biomarker having all or a portion of the sequence of any one of SEQ ID NOs: 1-4 in a sample from the cancer patient, and b) i) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a first reference patient known to be responsive to anthracycline treatment, or
ii) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a second reference patient known to be non-responsive to anthracycline treatment,
wherein a determination that the level of expression of the biomarker in the sample from the cancer patient is similar to the level of expression of the biomarker in the sample from the first reference patient indicates that the cancer patient is responsive to said anthracycline treatment, or wherein a determination that the level of expression of the biomarker in the sample from the cancer patient is dissimilar to the level of expression of the biomarker in the sample from the second reference patient indicates that the cancer patient is responsive to said anthracycline treatment. 7. The method of any one of claims 1 to 6, wherein the sample is a tissue sample. 8. The method of claim 7, wherein the sample is a tumor sample. 9. The method of any one of claims 1 to 6, wherein the cancer is a breast cancer. 10. The method of claim 9, wherein the cancer is grade 1, 2, or 3. 11. The method of any one of claims 1 to 6, wherein said determining occurs in said patient after a first cancer treatment. 12. The method of any one of claims 1 to 6, wherein said determining occurs in said patient prior to a first cancer treatment. 13. The method of any one of claims 1 to 6, wherein said determining occurs in said patient after a first cancer treatment, but before a second cancer treatment. 14. The method of any one of claims 1 to 6, wherein said determining occurs in said patient after a second cancer treatment. 15. The method of claim 11, wherein said first cancer treatment comprises one or more of surgery, radiation therapy, and chemotherapy, preferably wherein said first cancer treatment is surgery. 16. The method of claim 12, wherein said first cancer treatment comprises one or more of surgery, radiation therapy, and chemotherapy, preferably wherein said first cancer treatment is surgery. 17. The method of claim 13, wherein said first or second cancer treatment comprises one or more of surgery, radiation therapy, and chemotherapy, preferably wherein said first or second cancer treatment is surgery. 18. The method of claim 14, wherein said second cancer treatment comprises one or more of surgery, radiation therapy, and chemotherapy, preferably wherein said second cancer treatment is surgery. 19. The method of any one of claims 1 to 6, wherein the level of expression of said biomarker in said sample is determined by collecting nucleic acid molecules from said sample and, optionally, detecting said nucleic acid molecules using one or more fluorescent probes or using a quantitative reverse transcription-polymerase chain reaction (qRT-PCR) to amplify said nucleic acid molecules. 20. The method of any one of claims 1 to 6, further comprising treating said cancer patient predicted to be responsive to anthracycline treatment with an anthracycline. 21. The method of claim 20, wherein said anthracycline is selected from the group consisting of epirubicin, daunorubicin, doxorubicin, idarubicin, valrubicin, actinomycin-D, bleomycin, mitomycin-C, and mitoxantrone. 22. The method of claim 21, wherein said anthracycline is epirubicin. 23. The method of any one of claims 1 to 6, further comprising treating said cancer patient predicted to be non-responsive to anthracycline treatment with one or more chemotherapeutic agents listed in Table 2. 24. The method of any one of claims 1 to 6, wherein said the level of expression of said biomarker is determined using a microarray device. 25. The method of any one of claims 1 to 6, wherein said method comprises determining the level of expression of said biomarker using a qRT-PCR. 26. A method of treating a cancer in a cancer patient determined to have a similar level of expression of at least one biomarker selected from the group consisting of HDGF, KIAA0286, RFC4, and MSH6 relative to the level of expression of the biomarker in a first reference patient known to be responsive to anthracycline treatment, said method comprising administering an anthracycline to the cancer patient. 27. A method of treating a cancer in a cancer patient determined to have a similar level of expression of a biomarker having all or a portion of the sequence of SEQ ID NO: 1 relative to the level of expression of the biomarker in a first reference patient known to be responsive to anthracycline treatment, said method comprising administering an anthracycline to the cancer patient. 28. A method of treating a cancer in a cancer patient determined to have a similar level of expression of a biomarker having all or a portion of the sequence of SEQ ID NO: 2 relative to the level of expression of the biomarker in a first reference patient known to be responsive to anthracycline treatment, said method comprising administering an anthracycline to the cancer patient. 29. A method of treating a cancer in a cancer patient determined to have a similar level of expression of a biomarker having all or a portion of the sequence of SEQ ID NO: 3 relative to the level of expression of the biomarker in a first reference patient known to be responsive to anthracycline treatment, said method comprising administering an anthracycline to the cancer patient. 30. A method of treating a cancer in a cancer patient determined to have a similar level of expression of a biomarker having all or a portion of the sequence of SEQ ID NO: 4 relative to the level of expression of the biomarker in a first reference patient known to be responsive to anthracycline treatment, said method comprising administering an anthracycline to the cancer patient. 31. A method of treating a cancer in a cancer patient determined to have a similar level of expression of a biomarker having all or a portion of the sequence of any one of SEQ ID NOs: 1-4 relative to the level of expression of the biomarker in a first reference patient known to be responsive to anthracycline treatment, said method comprising administering an anthracycline to the cancer patient. 32. The method of any one of claims 26 to 31, wherein said anthracycline is selected from the group consisting of epirubicin, daunorubicin, doxorubicin, idarubicin, valrubicin, actinomycin-D, bleomycin, mitomycin-C, and mitoxantrone. 33. The method of claim 32, wherein said anthracycline is epirubicin. 34. The method of any one of claims 26 to 31, wherein said cancer patient is determined to have a similar level of expression of the biomarker relative to the level of expression of the biomarker in a first reference patient known to be responsive to anthracycline treatment by:
a) determining the level of expression of the biomarker in a sample from the cancer patient, and
b) i) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a first reference patient known to be responsive to anthracycline treatment, or
ii) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a second reference patient known to be non-responsive to anthracycline treatment. 35. A device comprising at least one single-stranded nucleic acid molecule having at least 85% sequence identity to a target nucleic acid molecule having a sequence that is complementary or identical to at least 5 consecutive nucleotides of at least one biomarker selected from HDGF, KIAA0286, RFC4, and MSH6 in a sample from a cancer patient, wherein said at least one single-stranded nucleic acid molecule is sufficient for the detection of the level of expression of said biomarker and allows specific hybridization between said single stranded nucleic acid molecule and said target nucleic acid molecule. 36. A device comprising at least one single-stranded nucleic acid molecule having at least 85% identity to a target nucleic acid molecule having a sequence that is complementary or identical to at least 5 consecutive nucleotides of a biomarker having the sequence of SEQ ID NO: 1 in a sample from a cancer patient, wherein said at least one single-stranded nucleic acid molecule is sufficient for the detection of the level of expression of said biomarker and allows specific hybridization between said single stranded nucleic acid molecule and said target nucleic acid molecule. 37. A device comprising at least one single-stranded nucleic acid molecule having at least 85% identity to a target nucleic acid molecule having a sequence that is complementary or identical to at least 5 consecutive nucleotides of a biomarker having the sequence of SEQ ID NO: 2 in a sample from a cancer patient, wherein said at least one single-stranded nucleic acid molecule is sufficient for the detection of the level of expression of said biomarker and allows specific hybridization between said single stranded nucleic acid molecule and said target nucleic acid molecule. 38. A device comprising at least one single-stranded nucleic acid molecule having at least 85% identity to a target nucleic acid molecule having a sequence that is complementary or identical to at least 5 consecutive nucleotides of a biomarker having the sequence of SEQ ID NO: 3 in a sample from a cancer patient, wherein said at least one single-stranded nucleic acid molecule is sufficient for the detection of the level of expression of said biomarker and allows specific hybridization between said single stranded nucleic acid molecule and said target nucleic acid molecule. 39. A device comprising at least one single-stranded nucleic acid molecule having at least 85% identity to a target nucleic acid molecule having a sequence that is complementary or identical to at least 5 consecutive nucleotides of a biomarker having the sequence of SEQ ID NO: 4 in a sample from a cancer patient, wherein said at least one single-stranded nucleic acid molecule is sufficient for the detection of the level of expression of said biomarker and allows specific hybridization between said single stranded nucleic acid molecule and said target nucleic acid molecule. 40. A device comprising at least one single-stranded nucleic acid molecule having at least 85% identity to a target nucleic acid molecule having a sequence that is complementary or identical to at least 5 consecutive nucleotides of a biomarker having the sequence of any one of SEQ ID NOs: 1-4 in a sample from a cancer patient, wherein said at least one single-stranded nucleic acid molecule is sufficient for the detection of the level of expression of said biomarker and allows specific hybridization between said single stranded nucleic acid molecule and said target nucleic acid molecule. 41. The device of any one of claims 35 to 40, wherein the target nucleic acid molecule has a sequence that is complementary or identical to at least 10 to 100, at least 20 to 100, at least 30 to 100, at least 40 to 100, at least 50 to 100, at least 60 to 100, at least 70 to 100, at least 80 to 100, or at least 90 to 100 consecutive nucleotides. 42. The device of any one of claims 35 to 40, wherein said at least one single-stranded nucleic acid molecule has a length in the range of 10 to 100 nucleotides. 43. The device of any one of claims 35 to 40, said device allowing, when contacted with a diverse population of nucleic acid molecules prepared from a sample under conditions allowing hybridization to occur, the determination of the level of expression of said at least one biomarker. 44. The device of any one of claims 35 to 40, wherein the device is a microarray device. 45. A method for predicting responsiveness of a cancer patient to anthracycline treatment comprising determining the level of expression of at least one biomarker in a patient sample using the device of any one of claims 28 to 33, wherein the level of expression of said biomarker is predictive of responsiveness of said cancer patient to anthracycline treatment. 46. The method of claim 45, wherein the sample is a tissue sample. 47. The method of claim 46, wherein the sample is a tumor sample. 48. The method of claim 45, wherein the cancer is a breast cancer. 49. The method of claim 48, wherein the cancer is grade 1, 2, or 3. 50. The method of claim 45, wherein said determining occurs in said patient after a first cancer treatment. 51. The method of claim 45, wherein said determining occurs in said patient prior to a first cancer treatment. 52. The method of claim 45, wherein said determining occurs in said patient after a first cancer treatment, but before a second cancer treatment. 53. The method of claim 45, wherein said determining occurs in said patient after a second cancer treatment. 54. The method of claim 50, wherein said first cancer treatment comprises any combination of one or more of surgery, radiation therapy, and chemotherapy. 55. The method of claim 51, wherein said first cancer treatment comprises one or more of surgery, radiation therapy, and chemotherapy and combinations thereof. 56. The method of claim 52, wherein said first or second cancer treatment comprises one or more of surgery, radiation therapy, and chemotherapy and combinations thereof. 57. The method of claim 53, wherein said second cancer treatment comprises one or more of surgery, radiation therapy, and chemotherapy and combinations thereof. 58. A kit comprising reagents for collecting nucleic acid molecules from a sample from a cancer patient, reagents for amplifying said nucleic acid molecules collected from said sample to produce an amplified sample, and at least one device for detecting the level of expression of at least one biomarker having the sequence of any one of SEQ ID NOs: 1-4 in said amplified sample. 59. The kit of claim 58, wherein a quantitative reverse transcription-polymerase chain reaction (qRT-PCR) is used to produce said amplified sample. 60. The kit of claim 58, further comprising instructions for predicting responsiveness of a cancer patient to anthracycline treatment based on the level of expression of said at least one biomarker. 61. The kit of claim 58, wherein said device is the device of any one of claims 28 to 33. 62. The kit of claim 58, further comprising instructions for applying nucleic acid molecules collected from the sample to said device, and/or instructions for determining the level of expression of said at least one biomarker by detecting hybridization of said at least one single-stranded nucleic acid molecule to said biomarker or its complement sequence. 63. The kit of claim 62, further comprising instructions for predicting responsiveness of a cancer patient to anthracycline treatment based on the level of expression of said at least one biomarker as detected using the device. 64. A method of predicting the responsiveness of a cancer patient to anthracycline treatment comprising
a) determining a CIN4 signature of the cancer patient, and b) i) comparing the CIN4 signature of the cancer patient to a CIN4 signature of a first reference patient known to be responsive to anthracycline treatment, or
ii) comparing the CIN4 signature of the cancer patient to a CIN4 signature of a second reference patient known to be non-responsive to anthracycline treatment,
wherein a determination that the CIN4 signature of the cancer patient is similar to the CIN4 signature of the first reference patient indicates that the cancer patient is responsive to said anthracycline treatment, or wherein a determination that the CIN4 signature of the cancer patient is dissimilar to the CIN4 signature of the second reference patient indicates that the cancer patient is responsive to said anthracycline treatment. 65. The method of any one of claims 1 to 8, wherein the cancer is a breast cancer. 66. The method of claim 65, wherein the cancer is grade 1, 2, or 3. 67. The method of any one of claims 1 to 8, 65, and 66, wherein said determining occurs in said patient after a first cancer treatment. 68. The method of any one of claims 1 to 8 and 65 to 67, wherein said determining occurs in said patient prior to a first cancer treatment. 69. The method of any one of claims 1 to 8 and 65 to 68, wherein said determining occurs in said patient after a first cancer treatment, but before a second cancer treatment. 70. The method of any one of claims 1 to 8 and 65 to 69, wherein said determining occurs in said patient after a second cancer treatment. 71. The method of any one of claims 1 to 8 and 65 to 70, wherein said treatment comprises one or more of surgery, radiation therapy, and chemotherapy and combinations thereof, preferably said cancer treatment is surgery. 72. The method of any one of claims 1 to 8 and 65 to 71, wherein the level of expression of said biomarker in said sample is determined by collecting nucleic acid molecules from said sample and, optionally, detecting said nucleic acid molecules using one or more fluorescent probes or using a quantitative reverse transcription-polymerase chain reaction (qRT-PCR) to amplify said nucleic acid molecules. 73. The method of any one of claims 1 to 8 and 65 to 72, further comprising treating said cancer patient predicted to be responsive to anthracycline treatment with an anthracycline. 74. The method of claim 73, wherein said anthracycline is selected from the group consisting of epirubicin, daunorubicin, doxorubicin, idarubicin, valrubicin, actinomycin-D, bleomycin, mitomycin-C, and mitoxantrone. 75. The method of claim 73 or 74, wherein said anthracycline is epirubicin. 76. The method of any one of claims 1 to 8 and 65 to 72, further comprising treating said cancer patient predicted to be non-responsive to anthracycline treatment with one or more chemotherapeutic agents listed in Table 2. 77. The method of any one of claims 1 to 8 and 65 to 76, wherein said the level of expression of said biomarker is determined using a microarray device. 78. The method of any one of claims 1 to 8 and 65 to 77, wherein said method comprises determining the level of expression of said biomarker using a qRT-PCR. 79. The device of any one of claims 35 to 41, wherein said at least one single-stranded nucleic acid molecule has a length in the range of 10 to 100 nucleotides. 80. The device of any one of claims 35 to 41 and 79, wherein said device allowing, when contacted with a diverse population of nucleic acid molecules prepared from a sample under conditions allowing hybridization to occur, the determination of the level of expression of said at least one biomarker. 81. The device of any one of claims 35 to 41, 79, and 80, wherein the device is a microarray device. 82. The method of any one of claims 45 to 47, wherein the cancer is a breast cancer. 83. The method of claim 82, wherein the cancer is grade 1, 2, or 3. 84. The method of any one of claims 45 to 47, 82, and 83, wherein said determining occurs in said patient after a first cancer treatment. 85. The method of any one of claims 45 to 47 and 82 to 83, wherein said determining occurs in said patient prior to a first cancer treatment. 86. The method of any one of claims 45 to 47 and 82 to 84, wherein said determining occurs in said patient after a first cancer treatment, but before a second treatment. 87. The method of any one of claims 45 to 47 and 82 to 84, wherein said determining occurs in said patient after a second cancer treatment. 88. The method of any one of claims 84 to 87, wherein said treatment comprises one or more of surgery, radiation therapy, and chemotherapy and combinations thereof. 89. The kit of claim 58 or 59, further comprising instructions for predicting responsiveness of a cancer patient to anthracycline treatment based on the level of expression of said at least one biomarker. 90. The kit of any one of claims 58, 59 and 89, wherein said device is the device of any one of claims 35 to 41 and 79 to 81. 91. The kit of any one of claims 58, 59, 89, and 90, further comprising instructions for applying nucleic acid molecules collected from the sample to said device, and/or instructions for determining the level of expression of said at least one biomarker by detecting hybridization of said at least one single-stranded nucleic acid molecule to said biomarker or its complement sequence. 92. The kit of any one of claims 58, 59, and 89 to 91, further comprising instructions for predicting responsiveness of a cancer patient to anthracycline treatment based on the level of expression of said at least one biomarker as detected using the device.
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The invention features methods, devices, and kits for predicting the responsiveness of a cancer patient (e.g., a breast cancer patient, such as a grade 1, 2, or 3 breast cancer patient) to anthracycline treatment by determining the expression levels of four chromosomal instability (CIN) genes including HDGF, KIAA0286, RFC4, and MSH6, collectively referred to as CIN4. Patients that have a low CIN4 score benefit from anthracycline treatment compared patients with a high CIN4 score.1. A method of predicting the responsiveness of a cancer patient to anthracycline treatment comprising
a) determining the level of expression of at least one biomarker selected from the group consisting of HDGF, KIAA0286, RFC4, and MSH6 in a sample from the cancer patient, and b) i) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a first reference patient known to be responsive to anthracycline treatment, or
ii) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a second reference patient known to be non-responsive to anthracycline treatment,
wherein a determination that the level of expression of the biomarker in the sample from the cancer patient is similar to the level of expression of the biomarker in the sample from the first reference patient indicates that the cancer patient is responsive to said anthracycline treatment, or wherein a determination that the level of expression of the biomarker in the sample from the cancer patient is dissimilar to the level of expression of the biomarker in the sample from the second reference patient indicates that the cancer patient is responsive to said anthracycline treatment. 2. A method of predicting the responsiveness of a cancer patient to anthracycline treatment comprising
a) determining the level of expression of a biomarker having all or a portion of the sequence of SEQ ID NO: 1 in a sample from the cancer patient, and b) i) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a first reference patient known to be responsive to anthracycline treatment, or
ii) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a second reference patient known to be non-responsive to anthracycline treatment,
wherein a determination that the level of expression of the biomarker in the sample from the cancer patient is similar to the level of expression of the biomarker in the sample from the first reference patient indicates that the cancer patient is responsive to said anthracycline treatment, or wherein a determination that the level of expression of the biomarker in the sample from the cancer patient is dissimilar to the level of expression of the biomarker in the sample from the second reference patient indicates that the cancer patient is responsive to said anthracycline treatment. 3. A method of predicting the responsiveness of a cancer patient to anthracycline treatment comprising
a) determining the level of expression of a biomarker having all or a portion of the sequence of SEQ ID NO: 2 in a sample from the cancer patient, and b) i) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a first reference patient known to be responsive to anthracycline treatment, or
ii) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a second reference patient known to be non-responsive to anthracycline treatment,
wherein a determination that the level of expression of the biomarker in the sample from the cancer patient is similar to the level of expression of the biomarker in the sample from the first reference patient indicates that the cancer patient is responsive to said anthracycline treatment, or wherein a determination that the level of expression of the biomarker in the sample from the cancer patient is dissimilar to the level of expression of the biomarker in the sample from the second reference patient indicates that the cancer patient is responsive to said anthracycline treatment. 4. A method of predicting the responsiveness of a cancer patient to anthracycline treatment comprising
a) determining the level of expression of a biomarker having all or a portion of the sequence of SEQ ID NO: 3 in a sample from the cancer patient, and b) i) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a first reference patient known to be responsive to anthracycline treatment, or
ii) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a second reference patient known to be non-responsive to anthracycline treatment,
wherein a determination that the level of expression of the biomarker in the sample from the cancer patient is similar to the level of expression of the biomarker in the sample from the first reference patient indicates that the cancer patient is responsive to said anthracycline treatment, or wherein a determination that the level of expression of the biomarker in the sample from the cancer patient is dissimilar to the level of expression of the biomarker in the sample from the second reference patient indicates that the cancer patient is responsive to said anthracycline treatment. 5. A method of predicting the responsiveness of a cancer patient to anthracycline treatment comprising
a) determining the level of expression of a biomarker having all or a portion of the sequence of SEQ ID NO: 4 in a sample from the cancer patient, and b) i) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a first reference patient known to be responsive to anthracycline treatment, or
ii) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a second reference patient known to be non-responsive to anthracycline treatment,
wherein a determination that the level of expression of the biomarker in the sample from the cancer patient is similar to the level of expression of the biomarker in the sample from the first reference patient indicates that the cancer patient is responsive to said anthracycline treatment, or wherein a determination that the level of expression of the biomarker in the sample from the cancer patient is dissimilar to the level of expression of the biomarker in the sample from the second reference patient indicates that the cancer patient is responsive to said anthracycline treatment. 6. A method of predicting the responsiveness of a cancer patient to anthracycline treatment comprising
a) determining the level of expression of a biomarker having all or a portion of the sequence of any one of SEQ ID NOs: 1-4 in a sample from the cancer patient, and b) i) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a first reference patient known to be responsive to anthracycline treatment, or
ii) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a second reference patient known to be non-responsive to anthracycline treatment,
wherein a determination that the level of expression of the biomarker in the sample from the cancer patient is similar to the level of expression of the biomarker in the sample from the first reference patient indicates that the cancer patient is responsive to said anthracycline treatment, or wherein a determination that the level of expression of the biomarker in the sample from the cancer patient is dissimilar to the level of expression of the biomarker in the sample from the second reference patient indicates that the cancer patient is responsive to said anthracycline treatment. 7. The method of any one of claims 1 to 6, wherein the sample is a tissue sample. 8. The method of claim 7, wherein the sample is a tumor sample. 9. The method of any one of claims 1 to 6, wherein the cancer is a breast cancer. 10. The method of claim 9, wherein the cancer is grade 1, 2, or 3. 11. The method of any one of claims 1 to 6, wherein said determining occurs in said patient after a first cancer treatment. 12. The method of any one of claims 1 to 6, wherein said determining occurs in said patient prior to a first cancer treatment. 13. The method of any one of claims 1 to 6, wherein said determining occurs in said patient after a first cancer treatment, but before a second cancer treatment. 14. The method of any one of claims 1 to 6, wherein said determining occurs in said patient after a second cancer treatment. 15. The method of claim 11, wherein said first cancer treatment comprises one or more of surgery, radiation therapy, and chemotherapy, preferably wherein said first cancer treatment is surgery. 16. The method of claim 12, wherein said first cancer treatment comprises one or more of surgery, radiation therapy, and chemotherapy, preferably wherein said first cancer treatment is surgery. 17. The method of claim 13, wherein said first or second cancer treatment comprises one or more of surgery, radiation therapy, and chemotherapy, preferably wherein said first or second cancer treatment is surgery. 18. The method of claim 14, wherein said second cancer treatment comprises one or more of surgery, radiation therapy, and chemotherapy, preferably wherein said second cancer treatment is surgery. 19. The method of any one of claims 1 to 6, wherein the level of expression of said biomarker in said sample is determined by collecting nucleic acid molecules from said sample and, optionally, detecting said nucleic acid molecules using one or more fluorescent probes or using a quantitative reverse transcription-polymerase chain reaction (qRT-PCR) to amplify said nucleic acid molecules. 20. The method of any one of claims 1 to 6, further comprising treating said cancer patient predicted to be responsive to anthracycline treatment with an anthracycline. 21. The method of claim 20, wherein said anthracycline is selected from the group consisting of epirubicin, daunorubicin, doxorubicin, idarubicin, valrubicin, actinomycin-D, bleomycin, mitomycin-C, and mitoxantrone. 22. The method of claim 21, wherein said anthracycline is epirubicin. 23. The method of any one of claims 1 to 6, further comprising treating said cancer patient predicted to be non-responsive to anthracycline treatment with one or more chemotherapeutic agents listed in Table 2. 24. The method of any one of claims 1 to 6, wherein said the level of expression of said biomarker is determined using a microarray device. 25. The method of any one of claims 1 to 6, wherein said method comprises determining the level of expression of said biomarker using a qRT-PCR. 26. A method of treating a cancer in a cancer patient determined to have a similar level of expression of at least one biomarker selected from the group consisting of HDGF, KIAA0286, RFC4, and MSH6 relative to the level of expression of the biomarker in a first reference patient known to be responsive to anthracycline treatment, said method comprising administering an anthracycline to the cancer patient. 27. A method of treating a cancer in a cancer patient determined to have a similar level of expression of a biomarker having all or a portion of the sequence of SEQ ID NO: 1 relative to the level of expression of the biomarker in a first reference patient known to be responsive to anthracycline treatment, said method comprising administering an anthracycline to the cancer patient. 28. A method of treating a cancer in a cancer patient determined to have a similar level of expression of a biomarker having all or a portion of the sequence of SEQ ID NO: 2 relative to the level of expression of the biomarker in a first reference patient known to be responsive to anthracycline treatment, said method comprising administering an anthracycline to the cancer patient. 29. A method of treating a cancer in a cancer patient determined to have a similar level of expression of a biomarker having all or a portion of the sequence of SEQ ID NO: 3 relative to the level of expression of the biomarker in a first reference patient known to be responsive to anthracycline treatment, said method comprising administering an anthracycline to the cancer patient. 30. A method of treating a cancer in a cancer patient determined to have a similar level of expression of a biomarker having all or a portion of the sequence of SEQ ID NO: 4 relative to the level of expression of the biomarker in a first reference patient known to be responsive to anthracycline treatment, said method comprising administering an anthracycline to the cancer patient. 31. A method of treating a cancer in a cancer patient determined to have a similar level of expression of a biomarker having all or a portion of the sequence of any one of SEQ ID NOs: 1-4 relative to the level of expression of the biomarker in a first reference patient known to be responsive to anthracycline treatment, said method comprising administering an anthracycline to the cancer patient. 32. The method of any one of claims 26 to 31, wherein said anthracycline is selected from the group consisting of epirubicin, daunorubicin, doxorubicin, idarubicin, valrubicin, actinomycin-D, bleomycin, mitomycin-C, and mitoxantrone. 33. The method of claim 32, wherein said anthracycline is epirubicin. 34. The method of any one of claims 26 to 31, wherein said cancer patient is determined to have a similar level of expression of the biomarker relative to the level of expression of the biomarker in a first reference patient known to be responsive to anthracycline treatment by:
a) determining the level of expression of the biomarker in a sample from the cancer patient, and
b) i) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a first reference patient known to be responsive to anthracycline treatment, or
ii) comparing the level of expression of the biomarker in the sample from the cancer patient to the level of expression of the biomarker in a sample from a second reference patient known to be non-responsive to anthracycline treatment. 35. A device comprising at least one single-stranded nucleic acid molecule having at least 85% sequence identity to a target nucleic acid molecule having a sequence that is complementary or identical to at least 5 consecutive nucleotides of at least one biomarker selected from HDGF, KIAA0286, RFC4, and MSH6 in a sample from a cancer patient, wherein said at least one single-stranded nucleic acid molecule is sufficient for the detection of the level of expression of said biomarker and allows specific hybridization between said single stranded nucleic acid molecule and said target nucleic acid molecule. 36. A device comprising at least one single-stranded nucleic acid molecule having at least 85% identity to a target nucleic acid molecule having a sequence that is complementary or identical to at least 5 consecutive nucleotides of a biomarker having the sequence of SEQ ID NO: 1 in a sample from a cancer patient, wherein said at least one single-stranded nucleic acid molecule is sufficient for the detection of the level of expression of said biomarker and allows specific hybridization between said single stranded nucleic acid molecule and said target nucleic acid molecule. 37. A device comprising at least one single-stranded nucleic acid molecule having at least 85% identity to a target nucleic acid molecule having a sequence that is complementary or identical to at least 5 consecutive nucleotides of a biomarker having the sequence of SEQ ID NO: 2 in a sample from a cancer patient, wherein said at least one single-stranded nucleic acid molecule is sufficient for the detection of the level of expression of said biomarker and allows specific hybridization between said single stranded nucleic acid molecule and said target nucleic acid molecule. 38. A device comprising at least one single-stranded nucleic acid molecule having at least 85% identity to a target nucleic acid molecule having a sequence that is complementary or identical to at least 5 consecutive nucleotides of a biomarker having the sequence of SEQ ID NO: 3 in a sample from a cancer patient, wherein said at least one single-stranded nucleic acid molecule is sufficient for the detection of the level of expression of said biomarker and allows specific hybridization between said single stranded nucleic acid molecule and said target nucleic acid molecule. 39. A device comprising at least one single-stranded nucleic acid molecule having at least 85% identity to a target nucleic acid molecule having a sequence that is complementary or identical to at least 5 consecutive nucleotides of a biomarker having the sequence of SEQ ID NO: 4 in a sample from a cancer patient, wherein said at least one single-stranded nucleic acid molecule is sufficient for the detection of the level of expression of said biomarker and allows specific hybridization between said single stranded nucleic acid molecule and said target nucleic acid molecule. 40. A device comprising at least one single-stranded nucleic acid molecule having at least 85% identity to a target nucleic acid molecule having a sequence that is complementary or identical to at least 5 consecutive nucleotides of a biomarker having the sequence of any one of SEQ ID NOs: 1-4 in a sample from a cancer patient, wherein said at least one single-stranded nucleic acid molecule is sufficient for the detection of the level of expression of said biomarker and allows specific hybridization between said single stranded nucleic acid molecule and said target nucleic acid molecule. 41. The device of any one of claims 35 to 40, wherein the target nucleic acid molecule has a sequence that is complementary or identical to at least 10 to 100, at least 20 to 100, at least 30 to 100, at least 40 to 100, at least 50 to 100, at least 60 to 100, at least 70 to 100, at least 80 to 100, or at least 90 to 100 consecutive nucleotides. 42. The device of any one of claims 35 to 40, wherein said at least one single-stranded nucleic acid molecule has a length in the range of 10 to 100 nucleotides. 43. The device of any one of claims 35 to 40, said device allowing, when contacted with a diverse population of nucleic acid molecules prepared from a sample under conditions allowing hybridization to occur, the determination of the level of expression of said at least one biomarker. 44. The device of any one of claims 35 to 40, wherein the device is a microarray device. 45. A method for predicting responsiveness of a cancer patient to anthracycline treatment comprising determining the level of expression of at least one biomarker in a patient sample using the device of any one of claims 28 to 33, wherein the level of expression of said biomarker is predictive of responsiveness of said cancer patient to anthracycline treatment. 46. The method of claim 45, wherein the sample is a tissue sample. 47. The method of claim 46, wherein the sample is a tumor sample. 48. The method of claim 45, wherein the cancer is a breast cancer. 49. The method of claim 48, wherein the cancer is grade 1, 2, or 3. 50. The method of claim 45, wherein said determining occurs in said patient after a first cancer treatment. 51. The method of claim 45, wherein said determining occurs in said patient prior to a first cancer treatment. 52. The method of claim 45, wherein said determining occurs in said patient after a first cancer treatment, but before a second cancer treatment. 53. The method of claim 45, wherein said determining occurs in said patient after a second cancer treatment. 54. The method of claim 50, wherein said first cancer treatment comprises any combination of one or more of surgery, radiation therapy, and chemotherapy. 55. The method of claim 51, wherein said first cancer treatment comprises one or more of surgery, radiation therapy, and chemotherapy and combinations thereof. 56. The method of claim 52, wherein said first or second cancer treatment comprises one or more of surgery, radiation therapy, and chemotherapy and combinations thereof. 57. The method of claim 53, wherein said second cancer treatment comprises one or more of surgery, radiation therapy, and chemotherapy and combinations thereof. 58. A kit comprising reagents for collecting nucleic acid molecules from a sample from a cancer patient, reagents for amplifying said nucleic acid molecules collected from said sample to produce an amplified sample, and at least one device for detecting the level of expression of at least one biomarker having the sequence of any one of SEQ ID NOs: 1-4 in said amplified sample. 59. The kit of claim 58, wherein a quantitative reverse transcription-polymerase chain reaction (qRT-PCR) is used to produce said amplified sample. 60. The kit of claim 58, further comprising instructions for predicting responsiveness of a cancer patient to anthracycline treatment based on the level of expression of said at least one biomarker. 61. The kit of claim 58, wherein said device is the device of any one of claims 28 to 33. 62. The kit of claim 58, further comprising instructions for applying nucleic acid molecules collected from the sample to said device, and/or instructions for determining the level of expression of said at least one biomarker by detecting hybridization of said at least one single-stranded nucleic acid molecule to said biomarker or its complement sequence. 63. The kit of claim 62, further comprising instructions for predicting responsiveness of a cancer patient to anthracycline treatment based on the level of expression of said at least one biomarker as detected using the device. 64. A method of predicting the responsiveness of a cancer patient to anthracycline treatment comprising
a) determining a CIN4 signature of the cancer patient, and b) i) comparing the CIN4 signature of the cancer patient to a CIN4 signature of a first reference patient known to be responsive to anthracycline treatment, or
ii) comparing the CIN4 signature of the cancer patient to a CIN4 signature of a second reference patient known to be non-responsive to anthracycline treatment,
wherein a determination that the CIN4 signature of the cancer patient is similar to the CIN4 signature of the first reference patient indicates that the cancer patient is responsive to said anthracycline treatment, or wherein a determination that the CIN4 signature of the cancer patient is dissimilar to the CIN4 signature of the second reference patient indicates that the cancer patient is responsive to said anthracycline treatment. 65. The method of any one of claims 1 to 8, wherein the cancer is a breast cancer. 66. The method of claim 65, wherein the cancer is grade 1, 2, or 3. 67. The method of any one of claims 1 to 8, 65, and 66, wherein said determining occurs in said patient after a first cancer treatment. 68. The method of any one of claims 1 to 8 and 65 to 67, wherein said determining occurs in said patient prior to a first cancer treatment. 69. The method of any one of claims 1 to 8 and 65 to 68, wherein said determining occurs in said patient after a first cancer treatment, but before a second cancer treatment. 70. The method of any one of claims 1 to 8 and 65 to 69, wherein said determining occurs in said patient after a second cancer treatment. 71. The method of any one of claims 1 to 8 and 65 to 70, wherein said treatment comprises one or more of surgery, radiation therapy, and chemotherapy and combinations thereof, preferably said cancer treatment is surgery. 72. The method of any one of claims 1 to 8 and 65 to 71, wherein the level of expression of said biomarker in said sample is determined by collecting nucleic acid molecules from said sample and, optionally, detecting said nucleic acid molecules using one or more fluorescent probes or using a quantitative reverse transcription-polymerase chain reaction (qRT-PCR) to amplify said nucleic acid molecules. 73. The method of any one of claims 1 to 8 and 65 to 72, further comprising treating said cancer patient predicted to be responsive to anthracycline treatment with an anthracycline. 74. The method of claim 73, wherein said anthracycline is selected from the group consisting of epirubicin, daunorubicin, doxorubicin, idarubicin, valrubicin, actinomycin-D, bleomycin, mitomycin-C, and mitoxantrone. 75. The method of claim 73 or 74, wherein said anthracycline is epirubicin. 76. The method of any one of claims 1 to 8 and 65 to 72, further comprising treating said cancer patient predicted to be non-responsive to anthracycline treatment with one or more chemotherapeutic agents listed in Table 2. 77. The method of any one of claims 1 to 8 and 65 to 76, wherein said the level of expression of said biomarker is determined using a microarray device. 78. The method of any one of claims 1 to 8 and 65 to 77, wherein said method comprises determining the level of expression of said biomarker using a qRT-PCR. 79. The device of any one of claims 35 to 41, wherein said at least one single-stranded nucleic acid molecule has a length in the range of 10 to 100 nucleotides. 80. The device of any one of claims 35 to 41 and 79, wherein said device allowing, when contacted with a diverse population of nucleic acid molecules prepared from a sample under conditions allowing hybridization to occur, the determination of the level of expression of said at least one biomarker. 81. The device of any one of claims 35 to 41, 79, and 80, wherein the device is a microarray device. 82. The method of any one of claims 45 to 47, wherein the cancer is a breast cancer. 83. The method of claim 82, wherein the cancer is grade 1, 2, or 3. 84. The method of any one of claims 45 to 47, 82, and 83, wherein said determining occurs in said patient after a first cancer treatment. 85. The method of any one of claims 45 to 47 and 82 to 83, wherein said determining occurs in said patient prior to a first cancer treatment. 86. The method of any one of claims 45 to 47 and 82 to 84, wherein said determining occurs in said patient after a first cancer treatment, but before a second treatment. 87. The method of any one of claims 45 to 47 and 82 to 84, wherein said determining occurs in said patient after a second cancer treatment. 88. The method of any one of claims 84 to 87, wherein said treatment comprises one or more of surgery, radiation therapy, and chemotherapy and combinations thereof. 89. The kit of claim 58 or 59, further comprising instructions for predicting responsiveness of a cancer patient to anthracycline treatment based on the level of expression of said at least one biomarker. 90. The kit of any one of claims 58, 59 and 89, wherein said device is the device of any one of claims 35 to 41 and 79 to 81. 91. The kit of any one of claims 58, 59, 89, and 90, further comprising instructions for applying nucleic acid molecules collected from the sample to said device, and/or instructions for determining the level of expression of said at least one biomarker by detecting hybridization of said at least one single-stranded nucleic acid molecule to said biomarker or its complement sequence. 92. The kit of any one of claims 58, 59, and 89 to 91, further comprising instructions for predicting responsiveness of a cancer patient to anthracycline treatment based on the level of expression of said at least one biomarker as detected using the device.
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979 | 16,289,416 | 1,615 |
The present disclosure generally relates to film-forming compositions and capsules formed from such compositions, including processes for using such compositions to make capsules. In some embodiments, the film-forming compositions are free of animal products and carrageenan.
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1. A film-forming composition, the composition comprising:
(a) from 1 to 60 percent by weight of a hydroxyalkylated plant starch, a plant sugar, or a combination thereof; (b) from 1 to 30 percent by weight agar; and (c) from 30 to 80 percent by weight water; wherein the percents by weight are based on the total weight of the film-forming composition. 2. The film-forming composition of claim 1, comprising from 1 to 30 percent by weight of a hydroxyalkylated plant starch, based on the total weight of the composition. 3. The film-forming composition of claim 1, wherein the hydroxyalkylated plant starch is a hydroxyethylated plant starch, a hydroxypropylated plant starch, or a combination thereof. 4. The film-forming composition of claim 1, wherein the hydroxyalkylated plant starch is a hydroxyethylated plant starch, which is a hydroxyethylated starch of plants selected from the group consisting of: beans, wheat, potatoes, cassava, tapioca, corn, soybeans, peas, rice, acorns, arrowroot, arracacha, bananas, barley, breadfruit, buckwheat, canna, colacasia, katakuri, kudzu, malanga, millet, oats, oca, polynesian arrowroot, sago, sorghum, sweet potatoes, rye, taro, chestnuts, water chestnuts and yams, and any combinations thereof. 5. The film-forming composition of claim 1, wherein the hydroxyalkylated plant starch is a hydroxypropylated plant starch, which is a hydroxypropylated starch of plants selected from the group consisting of: beans, wheat, potatoes, cassava, tapioca, corn, soybeans, peas, rice, acorns, arrowroot, arracacha, bananas, barley, breadfruit, buckwheat, canna, colacasia, katakuri, kudzu, malanga, millet, oats, oca, polynesian arrowroot, sago, sorghum, sweet potatoes, rye, taro, chestnuts, water chestnuts and yams, and any combinations thereof. 6. The film-forming composition of claim 5, wherein the hydroxyalkylated plant starch comprises hydroxypropylated tapioca starch. 7. The film-forming composition of claim 1, comprising from 1 to 30 percent by weight of a plant sugar, based on the total weight of the composition. 8. The film-forming composition of claim 7, wherein the plant sugar is a pentose, a hexose, or any dimers thereof. 9. The film-forming composition of claim 8, wherein the plant sugar is a hexose, which is selected from the group consisting of: allose, altrose, glucose, mannose, gulose, idose, galactose, talose, psicose, fructose, sorbose, tagatose, any dimers of the foregoing, and any combinations thereof. 10. The film-forming composition of claim 1, further comprising from 1 to 15 percent by weight of low-molecular-weight polyols. 11. The film-forming composition of claim 10, wherein the low-molecular-weight polyols comprise ethylene glycol, 1,3-propylene glycol, 1,2-propylene glycol, glycerin, or combinations thereof. 12. The film-forming composition of claim 1, further comprising from 1 to 15 percent by weight of sugar alcohols. 13. The film-forming composition of claim 12, wherein the sugar alcohols comprise maltitol, sorbitol, xylitol, erythritol, isomalt, or combinations thereof. 14. The film-forming composition of claim 1, further comprising a plant starch. 15. The film-forming composition of claim 14, wherein the plant starch is a starch from plants selected from the group consisting of: beans (including favas, lentils, mung beans, peas, and chickpeas), wheat, potatoes, cassava, tapioca, corn, soybeans, peas, rice, acorns, arrowroot, arracacha, bananas, barley, breadfruit, buckwheat, canna, colacasia, katakuri, kudzu, malanga, millet, oats, oca, polynesian arrowroot, sago, sorghum, sweet potatoes, rye, taro, chestnuts, water chestnuts and yams, and any combinations thereof. 16. The film-forming composition of claim 1, further comprising one or more phosphoglycerides. 17. The film-forming composition of claim 16, wherein the one or more phosphoglycerides comprise lecithin. 18. The film-forming composition of claim 1, further comprising one or more additives. 19. The film-forming composition of claim 1, wherein the composition comprises no more than 5 percent by weight of products derived from animals, based on the total weight of the composition. 20. The film-forming composition of claim 1, wherein the composition is substantially free of carrageenan. 21. A soft capsule, comprising:
(a) a fill material; and (b) an outer shell encapsulating the fill material, wherein the outer shell is formed by encapsulating the fill material with the film-forming composition of any one of claims 1 to 20. 22. A method of forming a soft capsule, the method comprising:
(a) providing the film-forming composition of claim and a fill material; and (b) encapsulating the fill material within the film-forming composition to form a sealed capsule. 23. A soft capsule, comprising:
(a) a fill material; and (b) an outer shell encapsulating the fill material, wherein the outer shell comprises: (i) from 1 to 80 percent by weight of a hydroxyalkylated plant starch, a plant sugar, or a combination thereof; and (ii) from 1 to 60 percent by weight agar; wherein the percents by weight are based on the total weight of the outer shell. 24. The soft capsule of claim 23, wherein the outer shell comprises from 1 to 60 percent by weight of a hydroxyalkylated plant starch, based on the total weight of the composition. 25. The soft capsule of claim 23, wherein the hydroxyalkylated plant starch is a hydroxyethylated plant starch, a hydroxypropylated plant starch, or a combination thereof. 26. The soft capsule of claim 23, wherein the hydroxyalkylated plant starch is a hydroxyethylated plant starch, which is a hydroxyethylated starch of plants selected from the group consisting of: beans, wheat, potatoes, cassava, tapioca, corn, soybeans, peas, rice, acorns, arrowroot, arracacha, bananas, barley, breadfruit, buckwheat, canna, colacasia, katakuri, kudzu, malanga, millet, oats, oca, polynesian arrowroot, sago, sorghum, sweet potatoes, rye, taro, chestnuts, water chestnuts and yams, and any combinations thereof. 27. The soft capsule of claim 23, wherein the hydroxyalkylated plant starch is a hydroxypropylated plant starch, which is a hydroxypropylated starch of plants selected from the group consisting of: beans, wheat, potatoes, cassava, tapioca, corn, soybeans, peas, rice, acorns, arrowroot, arracacha, bananas, barley, breadfruit, buckwheat, canna, colacasia, katakuri, kudzu, malanga, millet, oats, oca, polynesian arrowroot, sago, sorghum, sweet potatoes, rye, taro, chestnuts, water chestnuts and yams, and any combinations thereof. 28. The soft capsule of claim 27, wherein the hydroxyalkylated plant starch comprises hydroxypropylated tapioca starch. 29. The soft capsule of claim 23, wherein the outer shell comprises from 1 to 50 percent by weight of a plant sugar, based on the total weight of the composition. 30. The soft capsule of claim 29, wherein the plant sugar is a pentose, a hexose, or any dimers thereof. 31. The soft capsule of claim 30, wherein the plant sugar is a hexose, which is selected from the group consisting of: allose, altrose, glucose, mannose, gulose, idose, galactose, talose, psicose, fructose, sorbose, tagatose, any dimers of the foregoing, and any combinations thereof. 32. The soft capsule of claim 23, wherein the outer shell further comprises from 1 to 20 percent by weight of low-molecular-weight polyols. 33. The soft capsule of claim 32, wherein the low-molecular-weight polyols comprise ethylene glycol, 1,3-propylene glycol, 1,2-propylene glycol, glycerin, or combinations thereof. 34. The soft capsule of claim 23, wherein the outer shell further comprises from 1 to 20 percent by weight of sugar alcohols. 35. The soft capsule of claim 34, wherein the sugar alcohols comprise maltitol, sorbitol, xylitol, erythritol, isomalt, or combinations thereof. 36. The soft capsule of claim 23, wherein the outer shell further comprises a plant starch. 37. The soft capsule of claim 36, wherein the plant starch is a starch from plants selected from the group consisting of: beans), wheat, potatoes, cassava, tapioca, corn, soybeans, peas, rice, acorns, arrowroot, arracacha, bananas, barley, breadfruit, buckwheat, canna, colacasia, katakuri, kudzu, malanga, millet, oats, oca, polynesian arrowroot, sago, sorghum, sweet potatoes, rye, taro, chestnuts, water chestnuts and yams, and any combinations thereof. 38. The soft capsule of claim 23, wherein the outer shell further comprises one or more phosphoglycerides. 39. The soft capsule of claim 38, wherein the one or more phosphoglycerides comprise lecithin. 40. The soft capsule of claim 23, wherein the outer shell further comprises one or more additives. 41. The soft capsule of claim 23, wherein the outer shell comprises no more than 5 percent by weight of products derived from animals, based on the total weight of the outer shell. 42. The soft capsule of claim 23, wherein the outer shell is substantially free of carrageenan.
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The present disclosure generally relates to film-forming compositions and capsules formed from such compositions, including processes for using such compositions to make capsules. In some embodiments, the film-forming compositions are free of animal products and carrageenan.1. A film-forming composition, the composition comprising:
(a) from 1 to 60 percent by weight of a hydroxyalkylated plant starch, a plant sugar, or a combination thereof; (b) from 1 to 30 percent by weight agar; and (c) from 30 to 80 percent by weight water; wherein the percents by weight are based on the total weight of the film-forming composition. 2. The film-forming composition of claim 1, comprising from 1 to 30 percent by weight of a hydroxyalkylated plant starch, based on the total weight of the composition. 3. The film-forming composition of claim 1, wherein the hydroxyalkylated plant starch is a hydroxyethylated plant starch, a hydroxypropylated plant starch, or a combination thereof. 4. The film-forming composition of claim 1, wherein the hydroxyalkylated plant starch is a hydroxyethylated plant starch, which is a hydroxyethylated starch of plants selected from the group consisting of: beans, wheat, potatoes, cassava, tapioca, corn, soybeans, peas, rice, acorns, arrowroot, arracacha, bananas, barley, breadfruit, buckwheat, canna, colacasia, katakuri, kudzu, malanga, millet, oats, oca, polynesian arrowroot, sago, sorghum, sweet potatoes, rye, taro, chestnuts, water chestnuts and yams, and any combinations thereof. 5. The film-forming composition of claim 1, wherein the hydroxyalkylated plant starch is a hydroxypropylated plant starch, which is a hydroxypropylated starch of plants selected from the group consisting of: beans, wheat, potatoes, cassava, tapioca, corn, soybeans, peas, rice, acorns, arrowroot, arracacha, bananas, barley, breadfruit, buckwheat, canna, colacasia, katakuri, kudzu, malanga, millet, oats, oca, polynesian arrowroot, sago, sorghum, sweet potatoes, rye, taro, chestnuts, water chestnuts and yams, and any combinations thereof. 6. The film-forming composition of claim 5, wherein the hydroxyalkylated plant starch comprises hydroxypropylated tapioca starch. 7. The film-forming composition of claim 1, comprising from 1 to 30 percent by weight of a plant sugar, based on the total weight of the composition. 8. The film-forming composition of claim 7, wherein the plant sugar is a pentose, a hexose, or any dimers thereof. 9. The film-forming composition of claim 8, wherein the plant sugar is a hexose, which is selected from the group consisting of: allose, altrose, glucose, mannose, gulose, idose, galactose, talose, psicose, fructose, sorbose, tagatose, any dimers of the foregoing, and any combinations thereof. 10. The film-forming composition of claim 1, further comprising from 1 to 15 percent by weight of low-molecular-weight polyols. 11. The film-forming composition of claim 10, wherein the low-molecular-weight polyols comprise ethylene glycol, 1,3-propylene glycol, 1,2-propylene glycol, glycerin, or combinations thereof. 12. The film-forming composition of claim 1, further comprising from 1 to 15 percent by weight of sugar alcohols. 13. The film-forming composition of claim 12, wherein the sugar alcohols comprise maltitol, sorbitol, xylitol, erythritol, isomalt, or combinations thereof. 14. The film-forming composition of claim 1, further comprising a plant starch. 15. The film-forming composition of claim 14, wherein the plant starch is a starch from plants selected from the group consisting of: beans (including favas, lentils, mung beans, peas, and chickpeas), wheat, potatoes, cassava, tapioca, corn, soybeans, peas, rice, acorns, arrowroot, arracacha, bananas, barley, breadfruit, buckwheat, canna, colacasia, katakuri, kudzu, malanga, millet, oats, oca, polynesian arrowroot, sago, sorghum, sweet potatoes, rye, taro, chestnuts, water chestnuts and yams, and any combinations thereof. 16. The film-forming composition of claim 1, further comprising one or more phosphoglycerides. 17. The film-forming composition of claim 16, wherein the one or more phosphoglycerides comprise lecithin. 18. The film-forming composition of claim 1, further comprising one or more additives. 19. The film-forming composition of claim 1, wherein the composition comprises no more than 5 percent by weight of products derived from animals, based on the total weight of the composition. 20. The film-forming composition of claim 1, wherein the composition is substantially free of carrageenan. 21. A soft capsule, comprising:
(a) a fill material; and (b) an outer shell encapsulating the fill material, wherein the outer shell is formed by encapsulating the fill material with the film-forming composition of any one of claims 1 to 20. 22. A method of forming a soft capsule, the method comprising:
(a) providing the film-forming composition of claim and a fill material; and (b) encapsulating the fill material within the film-forming composition to form a sealed capsule. 23. A soft capsule, comprising:
(a) a fill material; and (b) an outer shell encapsulating the fill material, wherein the outer shell comprises: (i) from 1 to 80 percent by weight of a hydroxyalkylated plant starch, a plant sugar, or a combination thereof; and (ii) from 1 to 60 percent by weight agar; wherein the percents by weight are based on the total weight of the outer shell. 24. The soft capsule of claim 23, wherein the outer shell comprises from 1 to 60 percent by weight of a hydroxyalkylated plant starch, based on the total weight of the composition. 25. The soft capsule of claim 23, wherein the hydroxyalkylated plant starch is a hydroxyethylated plant starch, a hydroxypropylated plant starch, or a combination thereof. 26. The soft capsule of claim 23, wherein the hydroxyalkylated plant starch is a hydroxyethylated plant starch, which is a hydroxyethylated starch of plants selected from the group consisting of: beans, wheat, potatoes, cassava, tapioca, corn, soybeans, peas, rice, acorns, arrowroot, arracacha, bananas, barley, breadfruit, buckwheat, canna, colacasia, katakuri, kudzu, malanga, millet, oats, oca, polynesian arrowroot, sago, sorghum, sweet potatoes, rye, taro, chestnuts, water chestnuts and yams, and any combinations thereof. 27. The soft capsule of claim 23, wherein the hydroxyalkylated plant starch is a hydroxypropylated plant starch, which is a hydroxypropylated starch of plants selected from the group consisting of: beans, wheat, potatoes, cassava, tapioca, corn, soybeans, peas, rice, acorns, arrowroot, arracacha, bananas, barley, breadfruit, buckwheat, canna, colacasia, katakuri, kudzu, malanga, millet, oats, oca, polynesian arrowroot, sago, sorghum, sweet potatoes, rye, taro, chestnuts, water chestnuts and yams, and any combinations thereof. 28. The soft capsule of claim 27, wherein the hydroxyalkylated plant starch comprises hydroxypropylated tapioca starch. 29. The soft capsule of claim 23, wherein the outer shell comprises from 1 to 50 percent by weight of a plant sugar, based on the total weight of the composition. 30. The soft capsule of claim 29, wherein the plant sugar is a pentose, a hexose, or any dimers thereof. 31. The soft capsule of claim 30, wherein the plant sugar is a hexose, which is selected from the group consisting of: allose, altrose, glucose, mannose, gulose, idose, galactose, talose, psicose, fructose, sorbose, tagatose, any dimers of the foregoing, and any combinations thereof. 32. The soft capsule of claim 23, wherein the outer shell further comprises from 1 to 20 percent by weight of low-molecular-weight polyols. 33. The soft capsule of claim 32, wherein the low-molecular-weight polyols comprise ethylene glycol, 1,3-propylene glycol, 1,2-propylene glycol, glycerin, or combinations thereof. 34. The soft capsule of claim 23, wherein the outer shell further comprises from 1 to 20 percent by weight of sugar alcohols. 35. The soft capsule of claim 34, wherein the sugar alcohols comprise maltitol, sorbitol, xylitol, erythritol, isomalt, or combinations thereof. 36. The soft capsule of claim 23, wherein the outer shell further comprises a plant starch. 37. The soft capsule of claim 36, wherein the plant starch is a starch from plants selected from the group consisting of: beans), wheat, potatoes, cassava, tapioca, corn, soybeans, peas, rice, acorns, arrowroot, arracacha, bananas, barley, breadfruit, buckwheat, canna, colacasia, katakuri, kudzu, malanga, millet, oats, oca, polynesian arrowroot, sago, sorghum, sweet potatoes, rye, taro, chestnuts, water chestnuts and yams, and any combinations thereof. 38. The soft capsule of claim 23, wherein the outer shell further comprises one or more phosphoglycerides. 39. The soft capsule of claim 38, wherein the one or more phosphoglycerides comprise lecithin. 40. The soft capsule of claim 23, wherein the outer shell further comprises one or more additives. 41. The soft capsule of claim 23, wherein the outer shell comprises no more than 5 percent by weight of products derived from animals, based on the total weight of the outer shell. 42. The soft capsule of claim 23, wherein the outer shell is substantially free of carrageenan.
| 1,600 |
980 | 13,355,768 | 1,618 |
Solid pharmaceutical dosage form for the release of nicotine in the oral cavity comprising a core encapsulated by at least one film coating, wherein the core comprises nicotine and wherein the film coating comprises at least one film-forming polymer and at least one component for reduction of one or more organoleptically disturbing sensations, and where the at least one film coating is devoid of nicotine and devoid of buffer.
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1. A solid pharmaceutical dosage form comprising a core encapsulated by at least one film coating, wherein the core comprises nicotine and the film coating comprises at least one film-forming polymer and at least one component for reduction of one or more organoleptically disturbing sensations, and wherein the at least one film coating is devoid of nicotine and devoid of buffer. 2. The dosage form according to claim 1, further said core further comprises a zinc containing compound selected from the group consisting of zinc salts and zinc complexes. 3. The dosage form according to claim 1, wherein said at least one film coating preferably has a thickness from about 10 to about 500 microns. 4. The dosage form according to claim 3, wherein said at least one film coating has a thickness of from about 20 to about 250 microns. 5. The dosage form according to claim 4, wherein said at least one film coating has a thickness of from about 30 to about 150 microns. 6. The dosage form according to claim 1, wherein said core has a weight from about 50 mg to about 2000 mg 7. The dosage form according to claim 1, wherein said core has a weight from about 90 mg to about 1200 mg 8. The dosage form according to claim 1, wherein said film coating has a weight of from about 1% to about 15% of the weight of the core. 9. The dosage form according to claim 1, wherein the organoleptically disturbing sensation is selected from the group consisting of irritation, acridity, taste alteration, taste blocking, burning, astringing, bitterness, tingling, sour taste, salty taste, metallic taste, soapy taste, musty taste, sulphurous taste, pungent taste, fatty taste, or mixtures thereof. 10. The dosage form according to claim 1, wherein the one or more organoleptically disturbing sensations is induced by the nicotine. 11. The dosage form according to claim 1, wherein the nicotine is in a form selected from the group consisting of a nicotine salt, the free base form of nicotine, a nicotine cation exchanger, a nicotine inclusion complex, nicotine in any non-covalent binding, nicotine bound to zeolites, nicotine bound to cellulose and mixtures thereof. 12. The dosage form according to claim 1, wherein the dosage form is selected from the group consisting of a lozenge, a sublingual tablet, a buccal tablet, or an orally disintegrating tablet, where upon administration the nicotine is capable of being completely dissolved in the oral cavity. 13. The dosage form according to claim 1, wherein at least one component for reduction of one or more organoleptically disturbing sensations comprises one or more flavoring agents. 14. The dosage form according to claim 1, wherein at least one component for reduction of one or more organoleptically disturbing sensations comprises of one or more sweeteners. 15. The dosage form according to claim 1, wherein the at least one component for reduction of one or more organoleptically disturbing sensations comprises one or more flavoring agents and one or more sweeteners. 16. The dosage form according claim 1, wherein the at least one film-forming polymer is selected from the group consisting of hydroxy propyl methyl cellulose (HPMC), methyl hydroxy ethyl cellulose (MHEC), hydroxy propyl cellulose (HPC), hydroxyethyl cellulose (HEC), ethyl hydroxyl ethyl cellulose (EHEC), methacrylic acid copolymer-type C sodium carboxy methyl cellulose, polydextrose, polyvinyl acrylate (PVA), polyvinyl alcohol-polyethylene glycol graft copolymers, povidone, polyvinyl alcohol, microcrystalline cellulose, carrageenan, pregelatinized starch, polyethylene glycol, and combinations thereof. 17. The dosage form according to claim 1, wherein said core further comprises an additional ingredient that induces an organoleptically disturbing sensation selected from the group consisting of carbonate, glycinate, as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate, glycerophosphate; trisodium citrate, tripotassium citrate, ammonium citrate or mixtures thereof. 18. The dosage form according to claim 1, wherein the at least one film coating dissolves upon administration to the oral cavity in less than about 2 minutes. 19. The dosage form according to claim 1, wherein the core comprises nicotine in an amount from about 0.5 mg to about 12 mg nicotine base, the at least one film coating comprises a film-forming polymer at about 80% (w/w) of said coating, surfactant at about 0.3% (w/w) of said coating and a sweetener at about 8% of said coating. 20. The dosage form according to claim 1, wherein the at least one coating comprises film-forming polymer about 80.5% (w/w) of said coating, plasticizer about 8% (w/w) of said coating; surfactant about 0.1% (w/w) of said coating, high intensity sweetener about 4% (w/w) of said coating and flavor about 1.25% (w/w) of said coating.
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Solid pharmaceutical dosage form for the release of nicotine in the oral cavity comprising a core encapsulated by at least one film coating, wherein the core comprises nicotine and wherein the film coating comprises at least one film-forming polymer and at least one component for reduction of one or more organoleptically disturbing sensations, and where the at least one film coating is devoid of nicotine and devoid of buffer.1. A solid pharmaceutical dosage form comprising a core encapsulated by at least one film coating, wherein the core comprises nicotine and the film coating comprises at least one film-forming polymer and at least one component for reduction of one or more organoleptically disturbing sensations, and wherein the at least one film coating is devoid of nicotine and devoid of buffer. 2. The dosage form according to claim 1, further said core further comprises a zinc containing compound selected from the group consisting of zinc salts and zinc complexes. 3. The dosage form according to claim 1, wherein said at least one film coating preferably has a thickness from about 10 to about 500 microns. 4. The dosage form according to claim 3, wherein said at least one film coating has a thickness of from about 20 to about 250 microns. 5. The dosage form according to claim 4, wherein said at least one film coating has a thickness of from about 30 to about 150 microns. 6. The dosage form according to claim 1, wherein said core has a weight from about 50 mg to about 2000 mg 7. The dosage form according to claim 1, wherein said core has a weight from about 90 mg to about 1200 mg 8. The dosage form according to claim 1, wherein said film coating has a weight of from about 1% to about 15% of the weight of the core. 9. The dosage form according to claim 1, wherein the organoleptically disturbing sensation is selected from the group consisting of irritation, acridity, taste alteration, taste blocking, burning, astringing, bitterness, tingling, sour taste, salty taste, metallic taste, soapy taste, musty taste, sulphurous taste, pungent taste, fatty taste, or mixtures thereof. 10. The dosage form according to claim 1, wherein the one or more organoleptically disturbing sensations is induced by the nicotine. 11. The dosage form according to claim 1, wherein the nicotine is in a form selected from the group consisting of a nicotine salt, the free base form of nicotine, a nicotine cation exchanger, a nicotine inclusion complex, nicotine in any non-covalent binding, nicotine bound to zeolites, nicotine bound to cellulose and mixtures thereof. 12. The dosage form according to claim 1, wherein the dosage form is selected from the group consisting of a lozenge, a sublingual tablet, a buccal tablet, or an orally disintegrating tablet, where upon administration the nicotine is capable of being completely dissolved in the oral cavity. 13. The dosage form according to claim 1, wherein at least one component for reduction of one or more organoleptically disturbing sensations comprises one or more flavoring agents. 14. The dosage form according to claim 1, wherein at least one component for reduction of one or more organoleptically disturbing sensations comprises of one or more sweeteners. 15. The dosage form according to claim 1, wherein the at least one component for reduction of one or more organoleptically disturbing sensations comprises one or more flavoring agents and one or more sweeteners. 16. The dosage form according claim 1, wherein the at least one film-forming polymer is selected from the group consisting of hydroxy propyl methyl cellulose (HPMC), methyl hydroxy ethyl cellulose (MHEC), hydroxy propyl cellulose (HPC), hydroxyethyl cellulose (HEC), ethyl hydroxyl ethyl cellulose (EHEC), methacrylic acid copolymer-type C sodium carboxy methyl cellulose, polydextrose, polyvinyl acrylate (PVA), polyvinyl alcohol-polyethylene glycol graft copolymers, povidone, polyvinyl alcohol, microcrystalline cellulose, carrageenan, pregelatinized starch, polyethylene glycol, and combinations thereof. 17. The dosage form according to claim 1, wherein said core further comprises an additional ingredient that induces an organoleptically disturbing sensation selected from the group consisting of carbonate, glycinate, as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate, glycerophosphate; trisodium citrate, tripotassium citrate, ammonium citrate or mixtures thereof. 18. The dosage form according to claim 1, wherein the at least one film coating dissolves upon administration to the oral cavity in less than about 2 minutes. 19. The dosage form according to claim 1, wherein the core comprises nicotine in an amount from about 0.5 mg to about 12 mg nicotine base, the at least one film coating comprises a film-forming polymer at about 80% (w/w) of said coating, surfactant at about 0.3% (w/w) of said coating and a sweetener at about 8% of said coating. 20. The dosage form according to claim 1, wherein the at least one coating comprises film-forming polymer about 80.5% (w/w) of said coating, plasticizer about 8% (w/w) of said coating; surfactant about 0.1% (w/w) of said coating, high intensity sweetener about 4% (w/w) of said coating and flavor about 1.25% (w/w) of said coating.
| 1,600 |
981 | 15,568,206 | 1,627 |
Disclosed are methods of treating an ibrutinib-resistant disease in a mammal with a compound of Formula (I): wherein R is described herein. In certain embodiments, a compound of Formula (I) inhibits the activity of a variant Btk, providing a method of treating ibrutinib-resistant diseases, such as ibrutinib-resistant lymphoma.
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1. A method of treating an ibrutinib-resistant disease in a mammal, the method comprising administering an effective amount of a compound of Formula (I):
wherein R is hydrogen, —CH2OP(O)(O−)2X− 2, or —CH2OP(O)(O−)2Y2+, and each X is independently a hydrogen ion or a monovalent cation, and Y2+ is a divalent cation;
or a pharmaceutically acceptable salt, hydrate or solvate thereof;
to the mammal. 2. The method of claim 1, wherein the mammal has an ibrutinib resistance-conferring mutation of an enzyme that mediates growth and/or proliferation of the disease. 3. The method of claim 2, wherein the ibrutinib resistance-conferring mutation is of Btk. 4. The method of claim 3, wherein the mutation of the Btk is of the Cys481 residue. 5. The method of claim 4, wherein the mutation is C481S. 6. The method of claim 1, wherein the ibrutinib-resistant disease is ibrutinib-resistant cancer. 7. The method of claim 6, wherein the ibrutinib-resistant cancer is ibrutinib-resistant lymphoma. 8. The method of claim 7, wherein the ibrutinib-resistant lymphoma is chronic lymphocytic leukemia (CLL), mantle cell lymphoma, Waldenstrom's macroglobulinemia, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, marginal zone lymphoma, multiple myeloma, acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL). 9. The method of claim 1, wherein the compound is of Formula (Ia):
wherein each X+is an alkali metal cation;
or a hydrate or solvate thereof. 10. The method of claim 9, wherein the compound is Compound (I):
or a hydrate or solvate thereof. 11. The method of claim 1, wherein the compound is of Formula (Ib):
wherein the divalent cation Y2− is an alkali earth metal;
or a hydrate or solvate thereof. 12. The method of claim 1, wherein the compound is Compound (II):
or a pharmaceutically acceptable salt, hydrate or solvate thereof. 13. The method of claim 1, further comprising the administration of a second Syk inhibitor. 14. The method of claim 1, further comprising first identifying a mammal with an ibrutinib-resistant disease. 15. The method of claim 14, wherein the identifying comprises DNA sequencing. 16. The method of claim 15, wherein the DNA sequencing comprises whole-exome sequencing. 17. A method for inhibiting a variant Btk, comprising contacting the variant Btk with an effective amount of a compound of formula (I):
wherein R is hydrogen, —CH2OP(O)(O−)2X+ 2, or —CH2OP(O)(O−)2Y2+, and each X is independently a hydrogen ion or a monovalent cation, and Y2− is a divalent cation;
or a pharmaceutically acceptable salt, hydrate or solvate thereof. 18. The method of claim 17, wherein the variant Btk is a Cys481 variant. 19. The method of claim 17, wherein the variant Btk is contacted in a cell. 20. The method of claim 19 wherein the cell is a B-cell. 21. The method of claim 19, wherein the cell is a lymphoma cell. 22. The method of claim 17, wherein the compound is of Formula (Ia):
wherein each X+ is an alkali metal cation;
or a hydrate or solvate thereof. 23. The method of claim 17, wherein the compound is Compound (I):
or a hydrate or solvate thereof. 24. The method of claim 17, wherein the compound is of Formula (Ib):
wherein the divalent cation Y2− is an alkali earth metal;
or a hydrate or solvate thereof. 25. The method of claim 17, wherein the compound is Compound (II):
or a pharmaceutically acceptable salt, hydrate or solvate thereof. 26. The method of claim 17, further comprising contacting the variant Btk with a second Syk inhibitor. 27. The method of claim 17, further comprising first identifying a cell with a variant Btk.
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Disclosed are methods of treating an ibrutinib-resistant disease in a mammal with a compound of Formula (I): wherein R is described herein. In certain embodiments, a compound of Formula (I) inhibits the activity of a variant Btk, providing a method of treating ibrutinib-resistant diseases, such as ibrutinib-resistant lymphoma.1. A method of treating an ibrutinib-resistant disease in a mammal, the method comprising administering an effective amount of a compound of Formula (I):
wherein R is hydrogen, —CH2OP(O)(O−)2X− 2, or —CH2OP(O)(O−)2Y2+, and each X is independently a hydrogen ion or a monovalent cation, and Y2+ is a divalent cation;
or a pharmaceutically acceptable salt, hydrate or solvate thereof;
to the mammal. 2. The method of claim 1, wherein the mammal has an ibrutinib resistance-conferring mutation of an enzyme that mediates growth and/or proliferation of the disease. 3. The method of claim 2, wherein the ibrutinib resistance-conferring mutation is of Btk. 4. The method of claim 3, wherein the mutation of the Btk is of the Cys481 residue. 5. The method of claim 4, wherein the mutation is C481S. 6. The method of claim 1, wherein the ibrutinib-resistant disease is ibrutinib-resistant cancer. 7. The method of claim 6, wherein the ibrutinib-resistant cancer is ibrutinib-resistant lymphoma. 8. The method of claim 7, wherein the ibrutinib-resistant lymphoma is chronic lymphocytic leukemia (CLL), mantle cell lymphoma, Waldenstrom's macroglobulinemia, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, marginal zone lymphoma, multiple myeloma, acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL). 9. The method of claim 1, wherein the compound is of Formula (Ia):
wherein each X+is an alkali metal cation;
or a hydrate or solvate thereof. 10. The method of claim 9, wherein the compound is Compound (I):
or a hydrate or solvate thereof. 11. The method of claim 1, wherein the compound is of Formula (Ib):
wherein the divalent cation Y2− is an alkali earth metal;
or a hydrate or solvate thereof. 12. The method of claim 1, wherein the compound is Compound (II):
or a pharmaceutically acceptable salt, hydrate or solvate thereof. 13. The method of claim 1, further comprising the administration of a second Syk inhibitor. 14. The method of claim 1, further comprising first identifying a mammal with an ibrutinib-resistant disease. 15. The method of claim 14, wherein the identifying comprises DNA sequencing. 16. The method of claim 15, wherein the DNA sequencing comprises whole-exome sequencing. 17. A method for inhibiting a variant Btk, comprising contacting the variant Btk with an effective amount of a compound of formula (I):
wherein R is hydrogen, —CH2OP(O)(O−)2X+ 2, or —CH2OP(O)(O−)2Y2+, and each X is independently a hydrogen ion or a monovalent cation, and Y2− is a divalent cation;
or a pharmaceutically acceptable salt, hydrate or solvate thereof. 18. The method of claim 17, wherein the variant Btk is a Cys481 variant. 19. The method of claim 17, wherein the variant Btk is contacted in a cell. 20. The method of claim 19 wherein the cell is a B-cell. 21. The method of claim 19, wherein the cell is a lymphoma cell. 22. The method of claim 17, wherein the compound is of Formula (Ia):
wherein each X+ is an alkali metal cation;
or a hydrate or solvate thereof. 23. The method of claim 17, wherein the compound is Compound (I):
or a hydrate or solvate thereof. 24. The method of claim 17, wherein the compound is of Formula (Ib):
wherein the divalent cation Y2− is an alkali earth metal;
or a hydrate or solvate thereof. 25. The method of claim 17, wherein the compound is Compound (II):
or a pharmaceutically acceptable salt, hydrate or solvate thereof. 26. The method of claim 17, further comprising contacting the variant Btk with a second Syk inhibitor. 27. The method of claim 17, further comprising first identifying a cell with a variant Btk.
| 1,600 |
982 | 14,645,276 | 1,647 |
Methods of treating an autoimmune disease such as rheumatoid arthritis, methods of increasing apoptosis of pro-inflammatory immune cells or synoviocytes, methods of increasing the quantity of the anti-inflammatory regulatory T cells, and methods of slowing the progression of inflammation in a subject include systemically administering to the subject a pharmaceutical composition including an effective amount of a TRAIL-conjugate. Preferably, the TRAIL-conjugate is effective for at least 3 days, more preferably at least 7 days, without being part of a nanocomplex that modulates the circulation half-life or release kinetics of the TRAIL-conjugate. Combination therapies including administering a second active agent, most preferably a TNF-α inhibitor, as well as pharmaceutical composition dosage units including a TRAIL-conjugate and a TNF-α inhibitor in an effective amount for a single once weekly dose for treatment of rheumatoid arthritis are also provided.
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1. A method of treating an autoimmune disease, of increasing apoptosis of pro-inflammatory immune cells or synoviocytes, or reducing or slowing the progression of inflammation, comprising systemically administering a subject with the autoimmune disease a pharmaceutical composition comprising an effective amount of TRAIL-conjugate to reduce one or more symptoms of the autoimmune disease,
wherein the pharmaceutical composition is administered to the subject less frequently than once a day, more preferably, twice weekly, or less frequently. 2. The method of claim 1 wherein the TRAIL-conjugate reduces, or prevents an increase, in joint swelling, erythema, joint rigidity, inflammatory cell infiltration into the joint(s), synovitis, pannus formation, destruction of articular cartilage, bone erosion, elevated erythrocyte sedimentation rates (ESR), anaemia or combinations thereof. 3. The method of claim 1 wherein the TRAIL-conjugate reduces, or prevents an increase, in expression or circulating levels of one or more inflammatory or pro-inflammatory molecules selected for the group consisting of ICAM-1, COX-2, iNOS, TNF-α, IL-1β, IFN-γ, IL-2, IL-6, IL-17 or combination thereof. 4. The method of claim 1 wherein the TRAIL-conjugate reduces, or prevents an increase, in expression or circulating levels of autoantibodies. 5. The method of claim 1 wherein the autoimmune disease is rheumatoid arthritis. 6. The method of claim 1 wherein the TRAIL-conjugate increases the quantity of the anti-inflammatory regulatory T cells (Treg) and modulating Treg immune response, optionally wherein the regulatory T cells (Treg) are Foxp3+. 7. The method wherein the TRAIL-conjugate increases the expression or circulating levels of anti-inflammatory cytokines TGF-β or IL-10, or combination thereof. 8. The method of claim 1 comprising increasing the quantity of regulator T cells and expression of anti-inflammatory cytokines in autoimmune diseases. 9. The method of claim 1 wherein the autoimmune disease is rheumatoid arthritis. 10. The method of claim 1 wherein the pharmaceutical composition is administered to the subject no more than once weekly. 11. The method of claim 1 wherein the pharmaceutical composition is administered to the subject no more than once every 10 days. 12. The method of claim 1 wherein the subject does not have cancer. 13. The method of claim 1 wherein the TRAIL-conjugate is not part of a nanocomplex that modulates the circulation half-life or release kinetics of the TRAIL-conjugate. 14. The method of claim 1 further comprising administering to the subject a second active agent. 15. The method of claim 14 wherein the second active agent is a TNF-α inhibitor. 16. The method of claim 15 wherein the TNF-α inhibitor is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. 17. The method of claim 14 wherein the TRAIL-conjugate and the second active agent are co-administered as part of the same pharmaceutical composition. 18. The method of claim 14 wherein the TRAIL-conjugate and the second active agent are co-administered in different pharmaceutical compositions. 19. The method of claim 18 wherein the TRAIL-conjugate and the second active agent are administered separately but simultaneously. 20. The method of claim 18 wherein the TRAIL-conjugate and the second active agent are administered sequentially. 21. The method of claim 1 wherein the TRAIL-conjugate comprises a TRAIL polypeptide linked to a polyethylene glycol molecule or a derivative thereof. 22. The method of claim 21 wherein the TRAIL polypeptide comprises a fragment of human TRAIL effective to bind to and induce apoptotic signaling through TRAIL-R1 or TRAIL-R2. 23. The method of claim 22 wherein the human TRAIL comprises the amino acid sequence of SEQ ID NO:1, or a variant thereof with at least 70% identity to SEQ ID NO:1. 24. The method of claim 23 wherein the fragment of human TRAIL comprises amino acids 114-281 of SEQ ID NO:1. 25. The method of claim 21 wherein the TRAIL polypeptide is a fusion protein further comprising a multimerization domain that allows trimerization of three TRAIL-conjugate monomers. 26. The method of claim 25 wherein the multimerization domain comprises a zipper motif. 27. The method of claim 26 wherein the zipper motif is an isoleucine zipper motif. 28. The method of claim 21 wherein the polyethylene glycol derivative is selected from the group consisting of methoxypolyethylene glycol succinimidyl propionate, methoxypolyethylene glycol N-hydroxysuccinimide, methoxypolyethylene glycol aldehyde, methoxypolyethylene glycol maleimide and multiple-branched polyethylene glycol. 29. The method of claim 21 wherein the polyethylene glycol or derivative thereof is at least 5,000 Da 30. The method of claim 29 wherein the polyethylene glycol is of sufficient size that the TRIAL-conjugate is effective when administered only once weekly. 31. The method of claim 30 wherein the polyethylene glycol or derivative thereof is at least 30,000 Da. 32. The method of claim 1 wherein the TRAIL-conjugate is administered in a dosage of 0.01-1,000 mg/kg, 1-100 mg/kg, 5-50 mg/kg, or 10-20 mg/kg. 33. The method of claim 1 wherein the TRAIL-conjugate is administered in a dosage of 1-1,000 mg/m2, or 10-100 mg/m2, or 25-75 mg/m2, or 40-60 mg/m2 or about 45 mg/m2. 34. A pharmaceutical composition for use in claim 1. 35. The pharmaceutical composition of claim 34 comprising a TRAIL-conjugate comprising a fusion protein comprising an isoleucine zipper domain fused to amino acids 114-281 of SEQ ID NO:1 linked to one or more polyethylene glycol molecules, and optionally, a TNF-α inhibitor. 36. The pharmaceutical composition of claim 34 in a dosage unit comprising a dosage of the TRAIL-conjugate effective to treat rheumatoid arthritis for at least one week. 37. The pharmaceutical composition of claim 36 comprising long-acting TRAIL.
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Methods of treating an autoimmune disease such as rheumatoid arthritis, methods of increasing apoptosis of pro-inflammatory immune cells or synoviocytes, methods of increasing the quantity of the anti-inflammatory regulatory T cells, and methods of slowing the progression of inflammation in a subject include systemically administering to the subject a pharmaceutical composition including an effective amount of a TRAIL-conjugate. Preferably, the TRAIL-conjugate is effective for at least 3 days, more preferably at least 7 days, without being part of a nanocomplex that modulates the circulation half-life or release kinetics of the TRAIL-conjugate. Combination therapies including administering a second active agent, most preferably a TNF-α inhibitor, as well as pharmaceutical composition dosage units including a TRAIL-conjugate and a TNF-α inhibitor in an effective amount for a single once weekly dose for treatment of rheumatoid arthritis are also provided.1. A method of treating an autoimmune disease, of increasing apoptosis of pro-inflammatory immune cells or synoviocytes, or reducing or slowing the progression of inflammation, comprising systemically administering a subject with the autoimmune disease a pharmaceutical composition comprising an effective amount of TRAIL-conjugate to reduce one or more symptoms of the autoimmune disease,
wherein the pharmaceutical composition is administered to the subject less frequently than once a day, more preferably, twice weekly, or less frequently. 2. The method of claim 1 wherein the TRAIL-conjugate reduces, or prevents an increase, in joint swelling, erythema, joint rigidity, inflammatory cell infiltration into the joint(s), synovitis, pannus formation, destruction of articular cartilage, bone erosion, elevated erythrocyte sedimentation rates (ESR), anaemia or combinations thereof. 3. The method of claim 1 wherein the TRAIL-conjugate reduces, or prevents an increase, in expression or circulating levels of one or more inflammatory or pro-inflammatory molecules selected for the group consisting of ICAM-1, COX-2, iNOS, TNF-α, IL-1β, IFN-γ, IL-2, IL-6, IL-17 or combination thereof. 4. The method of claim 1 wherein the TRAIL-conjugate reduces, or prevents an increase, in expression or circulating levels of autoantibodies. 5. The method of claim 1 wherein the autoimmune disease is rheumatoid arthritis. 6. The method of claim 1 wherein the TRAIL-conjugate increases the quantity of the anti-inflammatory regulatory T cells (Treg) and modulating Treg immune response, optionally wherein the regulatory T cells (Treg) are Foxp3+. 7. The method wherein the TRAIL-conjugate increases the expression or circulating levels of anti-inflammatory cytokines TGF-β or IL-10, or combination thereof. 8. The method of claim 1 comprising increasing the quantity of regulator T cells and expression of anti-inflammatory cytokines in autoimmune diseases. 9. The method of claim 1 wherein the autoimmune disease is rheumatoid arthritis. 10. The method of claim 1 wherein the pharmaceutical composition is administered to the subject no more than once weekly. 11. The method of claim 1 wherein the pharmaceutical composition is administered to the subject no more than once every 10 days. 12. The method of claim 1 wherein the subject does not have cancer. 13. The method of claim 1 wherein the TRAIL-conjugate is not part of a nanocomplex that modulates the circulation half-life or release kinetics of the TRAIL-conjugate. 14. The method of claim 1 further comprising administering to the subject a second active agent. 15. The method of claim 14 wherein the second active agent is a TNF-α inhibitor. 16. The method of claim 15 wherein the TNF-α inhibitor is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. 17. The method of claim 14 wherein the TRAIL-conjugate and the second active agent are co-administered as part of the same pharmaceutical composition. 18. The method of claim 14 wherein the TRAIL-conjugate and the second active agent are co-administered in different pharmaceutical compositions. 19. The method of claim 18 wherein the TRAIL-conjugate and the second active agent are administered separately but simultaneously. 20. The method of claim 18 wherein the TRAIL-conjugate and the second active agent are administered sequentially. 21. The method of claim 1 wherein the TRAIL-conjugate comprises a TRAIL polypeptide linked to a polyethylene glycol molecule or a derivative thereof. 22. The method of claim 21 wherein the TRAIL polypeptide comprises a fragment of human TRAIL effective to bind to and induce apoptotic signaling through TRAIL-R1 or TRAIL-R2. 23. The method of claim 22 wherein the human TRAIL comprises the amino acid sequence of SEQ ID NO:1, or a variant thereof with at least 70% identity to SEQ ID NO:1. 24. The method of claim 23 wherein the fragment of human TRAIL comprises amino acids 114-281 of SEQ ID NO:1. 25. The method of claim 21 wherein the TRAIL polypeptide is a fusion protein further comprising a multimerization domain that allows trimerization of three TRAIL-conjugate monomers. 26. The method of claim 25 wherein the multimerization domain comprises a zipper motif. 27. The method of claim 26 wherein the zipper motif is an isoleucine zipper motif. 28. The method of claim 21 wherein the polyethylene glycol derivative is selected from the group consisting of methoxypolyethylene glycol succinimidyl propionate, methoxypolyethylene glycol N-hydroxysuccinimide, methoxypolyethylene glycol aldehyde, methoxypolyethylene glycol maleimide and multiple-branched polyethylene glycol. 29. The method of claim 21 wherein the polyethylene glycol or derivative thereof is at least 5,000 Da 30. The method of claim 29 wherein the polyethylene glycol is of sufficient size that the TRIAL-conjugate is effective when administered only once weekly. 31. The method of claim 30 wherein the polyethylene glycol or derivative thereof is at least 30,000 Da. 32. The method of claim 1 wherein the TRAIL-conjugate is administered in a dosage of 0.01-1,000 mg/kg, 1-100 mg/kg, 5-50 mg/kg, or 10-20 mg/kg. 33. The method of claim 1 wherein the TRAIL-conjugate is administered in a dosage of 1-1,000 mg/m2, or 10-100 mg/m2, or 25-75 mg/m2, or 40-60 mg/m2 or about 45 mg/m2. 34. A pharmaceutical composition for use in claim 1. 35. The pharmaceutical composition of claim 34 comprising a TRAIL-conjugate comprising a fusion protein comprising an isoleucine zipper domain fused to amino acids 114-281 of SEQ ID NO:1 linked to one or more polyethylene glycol molecules, and optionally, a TNF-α inhibitor. 36. The pharmaceutical composition of claim 34 in a dosage unit comprising a dosage of the TRAIL-conjugate effective to treat rheumatoid arthritis for at least one week. 37. The pharmaceutical composition of claim 36 comprising long-acting TRAIL.
| 1,600 |
983 | 15,606,042 | 1,632 |
A method is used for making an artificial micro-gland by taxis. A monodisperse multiple emulsion is produced with a first fluid; a second fluid confined within the first fluid; a third fluid within the second fluid. Interfaces between the fluids permit living cells dispersed in the one of the fluids to migrate towards an adjacent fluid having a different concentration of an agent affecting the metabolic activity of the living cells. Waiting, usually about 30 minutes, allows the living cells to migrate to the interface, forming the continuous membrane. Once formed, the artificial micro-gland is removed from the remains of the emulsion. The artificial micro-gland may also be given a second layer of different cells when the emission of the cells of the artificial micro-gland is used as the agent to attract the different cells. The method may also be used to produce an artificial micro-gland within an artificial micro-gland.
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1. A method of making an artificial micro-gland by taxis, the artificial micro-gland comprising a continuous membrane of living cells, the continuous membrane defining an enclosed volume, the enclosed volume comprising a reservoir serving as a bioreactor, the method comprising the steps of:
producing a monodisperse multiple emulsion, the monodisperse multiple emulsion comprising:
a first fluid serving as a host environment;
a second fluid confined within the host environment, the second fluid being immiscible in the first fluid;
a third fluid within the second fluid, the third fluid being immiscible in the second fluid such that there is an interface between the second fluid and the third fluid, the third fluid comprising a plurality of living cells dispersed therein, said living cells capable of metabolic activity; and,
an agent capable of affecting the metabolic activity of the living cells, the agent present within the second fluid at a higher concentration than in the third fluid;
waiting until the living cells migrate to the interface between the second fluid and the third fluid to form the continuous membrane around the third fluid; and, removing the first fluid and the second fluid from the monodisperse multiple emulsion to produce the artificial micro-gland. 2. The method of claim 1, wherein the:
first fluid of the host environment comprises water; second fluid comprises oil; third fluid comprises water; agent is selected from the group consisting of: oxygen; carbon dioxide; nitrogen oxide; sugar; phosphates, nitrates, sulphates, and potassium salts; cyclic adenosine monophosphate (CAMP); inositon phospholipid (mPIP3); actin; histamine; serotonin (5HT); plaletet acting factors (PAF); arachidonic acid metabolites; diacykglyseril (IP3); leukotine B4; lipoxins; prostaglandins; cytotaxin; f-met-leu-phe tripeptide; cytokines; kinins,cytotaxins; anaphylatoxin peptide (C5a); aspartic acid (ASP); serine (SER); and, chemo-attractants; and, living cells are selected from the group consisting of: eukaryotic cells; and; prokaryotic cells. 3. A method of making an artificial micro-gland by taxis, the artificial micro-gland comprising a continuous membrane of living cells, the continuous membrane defining an enclosed volume, the enclosed volume comprising a reservoir serving as a bioreactor, the method comprising the steps of:
producing a monodisperse multiple emulsion, the monodisperse multiple emulsion comprising:
a first fluid serving as a host environment;
a second fluid within the host environment, the second fluid comprising a plurality of living cells dispersed therein, said living cells capable of metabolic activity;
a third fluid within the second fluid being immiscible in the second fluid such that there is an interface between the second fluid and the third fluid;
an agent capable of affecting the metabolic activity of the living cells, the agent present within the third fluid at a higher concentration than in the second fluid;
wherein the first fluid serving as the host environment maintains a relatively low concentration of the agent compared to the third fluid; and,
waiting until the living cells to migrate to the interface between the second fluid and the third fluid to form the continuous membrane around the third fluid; and, removing the first fluid and the second fluid from the multiple emulsion to produce the artificial micro-gland, 4. The method of claim 3, wherein the:
first fluid comprises a first oil; second fluid comprises water; third fluid comprises a second oil; agent is selected from the group consisting of: oxygen; carbon dioxide; nitrogen oxide; sugar; phosphates, nitrates, sulphates, and potassium salts; cyclic adenosine monophosphate (cAMP); inositon phospholipid (mPIP3); actin; histamine; serotonin (5HT); plaletet acting factors (PAF); arachidonic acid metabolites; diacykglyseril (IP3); leukotine B4; lipoxins; prostaglandins; cytotaxia; f-met-leu-phe tripeptide; cytokines; kinins,cytotaxins; anaphylatoxin peptide (C5a); aspartic acid (ASP); serine (SER); and chemo-attractants; and, living cells are selected from the group consisting of: eukaryotic cells; and; prokaryotic cells. 5. A method of making an artificial micro-gland by taxis, the artificial micro-gland comprising a continuous membrane of living cells, the continuous membrane defining an enclosed volume, the enclosed volume comprising a reservoir serving as a bioreactor, the method comprising the steps of:
producing a monodisperse multiple emulsion, the monodisperse multiple emulsion comprising:
a first fluid serving as a host environment;
a second fluid within the host environment, the second fluid being immiscible in the first fluid such that there is an interface between the first fluid and the second fluid, the second fluid comprising a plurality of living cells dispersed therein, said living cells capable of metabolic activity;
a third fluid within the second fluid; and,
an agent capable of affecting the metabolic activity of the living cells, the agent present within the first fluid at a higher concentration than in the second fluid and in the third fluid;
waiting until the living cells migrate to the interface between the first fluid and the second fluid to form the continuous membrane around the second fluid; and, removing the first fluid from the monodisperse multiple emulsion to produce the artificial micro-gland. 6. The method of claim 5, wherein the:
first fluid comprises a first oil; second fluid comprises water; third fluid comprises a second oil; agent is selected from the group consisting of: oxygen; carbon dioxide; nitrogen oxide; sugar; phosphates, nitrates, sulphates, and potassium salts; cyclic adenosine monophosphate (cAMP); inositon phospholipid (mPIP3); actin; histamine; serotonin (5HT); plaletet acting factors (PAF); arachidonic acid metabolites; diacykglyseril (IP3); leukotine B4; lipoxins; prostaglandins; cytotaxin; f-met-leu-phe tripeptide; cytokines; kinins,cytotaxins; anaphylatoxin peptide (C5a); aspartic acid (ASP); serine (SER); and, chemo-attractants; and, the living cells are selected from the group consisting of: eukaryotic cells; and; prokaryotic cells. 7. A method of making a multi-shell artificial micro-gland by taxis, the multi-shell artificial micro-gland comprising a plurality of continuous membranes of first living cells, the continuous membranes defining an enclosed volume, the enclosed volume comprising a reservoir serving as a bioreactor, the method comprising the steps of:
producing a monodisperse emulsion, the monodisperse emulsion comprising:
a fluid serving as a host environment;
an artificial micro-gland within the host environment, the artificial micro-gland comprising a first continuous membrane of first living cells surrounding a reservoir; and,
a plurality of second living cells dispersed within the fluid, said second living cells capable of metabolic activity stimulated by discharges of an agent from the first living cells;
waiting until the second living cells migrate to the living cells to form a second continuous membrane covering the first living cells; and, removing the fluid from the emulsion to produce the multi-shell artificial micro-gland. 8. The method of claim 7, wherein the:
fluid comprises oil or water; first living cells are selected from the group consisting of: eukaryotic cells; and; prokaryotic cells; and, second living cells are selected from the group consisting of: eukaryotic cells; and; prokaryotic cells, provided that the selected second living cells are different than the first living cells. 9. A method of making an artificial micro-gland by taxis, the artificial micro-gland comprising a first artificial micro-gland within a second artificial micro-gland, the method comprising the steps of:
producing a monodisperse multiple emulsion, the monodisperse multiple emulsion comprising:
a first fluid serving as a host environment;
a second fluid confined within the host environment, the second fluid being immiscible in the first fluid such that there is a first interface between the first fluid and the second fluid;
a third fluid within the second fluid, the third fluid being immiscible in the second fluid such that there is a second interface between the second fluid and the third fluid, the third fluid comprising a plurality of first living cells dispersed therein, said first living cells capable of metabolic activity; and,
an agent capable of affecting the metabolic activity of the living cells, the agent present within the second fluid at a higher concentration than in the third fluid;
waiting until the first living cells migrate to the second interface between the second fluid and the third fluid to form a continuous membrane around the third fluid, forming a first artificial micro-gland within the second fluid; adding second living cells to the first fluid; waiting until the second living cells migrate to the first interface between the first fluid and the second fluid to form a second continuous membrane covering the second fluid and forming the second artificial micro-gland; and, removing the first fluid from the monodisperse multiple emulsion to produce the artificial micro-gland comprising a first artificial micro-gland within a second artificial micro-gland. 10. The method of claim 9, wherein the:
first fluid comprises water; second fluid comprises oil; third fluid comprises water; agent is selected from the group consisting of: oxygen; and, carbon dioxide; first living cells are selected from the group consisting of: eukaryotic cells; and; prokaryotic cells; and; second living cells are selected from the group consisting of: eukaryotic cells; and; prokaryotic cells.
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A method is used for making an artificial micro-gland by taxis. A monodisperse multiple emulsion is produced with a first fluid; a second fluid confined within the first fluid; a third fluid within the second fluid. Interfaces between the fluids permit living cells dispersed in the one of the fluids to migrate towards an adjacent fluid having a different concentration of an agent affecting the metabolic activity of the living cells. Waiting, usually about 30 minutes, allows the living cells to migrate to the interface, forming the continuous membrane. Once formed, the artificial micro-gland is removed from the remains of the emulsion. The artificial micro-gland may also be given a second layer of different cells when the emission of the cells of the artificial micro-gland is used as the agent to attract the different cells. The method may also be used to produce an artificial micro-gland within an artificial micro-gland.1. A method of making an artificial micro-gland by taxis, the artificial micro-gland comprising a continuous membrane of living cells, the continuous membrane defining an enclosed volume, the enclosed volume comprising a reservoir serving as a bioreactor, the method comprising the steps of:
producing a monodisperse multiple emulsion, the monodisperse multiple emulsion comprising:
a first fluid serving as a host environment;
a second fluid confined within the host environment, the second fluid being immiscible in the first fluid;
a third fluid within the second fluid, the third fluid being immiscible in the second fluid such that there is an interface between the second fluid and the third fluid, the third fluid comprising a plurality of living cells dispersed therein, said living cells capable of metabolic activity; and,
an agent capable of affecting the metabolic activity of the living cells, the agent present within the second fluid at a higher concentration than in the third fluid;
waiting until the living cells migrate to the interface between the second fluid and the third fluid to form the continuous membrane around the third fluid; and, removing the first fluid and the second fluid from the monodisperse multiple emulsion to produce the artificial micro-gland. 2. The method of claim 1, wherein the:
first fluid of the host environment comprises water; second fluid comprises oil; third fluid comprises water; agent is selected from the group consisting of: oxygen; carbon dioxide; nitrogen oxide; sugar; phosphates, nitrates, sulphates, and potassium salts; cyclic adenosine monophosphate (CAMP); inositon phospholipid (mPIP3); actin; histamine; serotonin (5HT); plaletet acting factors (PAF); arachidonic acid metabolites; diacykglyseril (IP3); leukotine B4; lipoxins; prostaglandins; cytotaxin; f-met-leu-phe tripeptide; cytokines; kinins,cytotaxins; anaphylatoxin peptide (C5a); aspartic acid (ASP); serine (SER); and, chemo-attractants; and, living cells are selected from the group consisting of: eukaryotic cells; and; prokaryotic cells. 3. A method of making an artificial micro-gland by taxis, the artificial micro-gland comprising a continuous membrane of living cells, the continuous membrane defining an enclosed volume, the enclosed volume comprising a reservoir serving as a bioreactor, the method comprising the steps of:
producing a monodisperse multiple emulsion, the monodisperse multiple emulsion comprising:
a first fluid serving as a host environment;
a second fluid within the host environment, the second fluid comprising a plurality of living cells dispersed therein, said living cells capable of metabolic activity;
a third fluid within the second fluid being immiscible in the second fluid such that there is an interface between the second fluid and the third fluid;
an agent capable of affecting the metabolic activity of the living cells, the agent present within the third fluid at a higher concentration than in the second fluid;
wherein the first fluid serving as the host environment maintains a relatively low concentration of the agent compared to the third fluid; and,
waiting until the living cells to migrate to the interface between the second fluid and the third fluid to form the continuous membrane around the third fluid; and, removing the first fluid and the second fluid from the multiple emulsion to produce the artificial micro-gland, 4. The method of claim 3, wherein the:
first fluid comprises a first oil; second fluid comprises water; third fluid comprises a second oil; agent is selected from the group consisting of: oxygen; carbon dioxide; nitrogen oxide; sugar; phosphates, nitrates, sulphates, and potassium salts; cyclic adenosine monophosphate (cAMP); inositon phospholipid (mPIP3); actin; histamine; serotonin (5HT); plaletet acting factors (PAF); arachidonic acid metabolites; diacykglyseril (IP3); leukotine B4; lipoxins; prostaglandins; cytotaxia; f-met-leu-phe tripeptide; cytokines; kinins,cytotaxins; anaphylatoxin peptide (C5a); aspartic acid (ASP); serine (SER); and chemo-attractants; and, living cells are selected from the group consisting of: eukaryotic cells; and; prokaryotic cells. 5. A method of making an artificial micro-gland by taxis, the artificial micro-gland comprising a continuous membrane of living cells, the continuous membrane defining an enclosed volume, the enclosed volume comprising a reservoir serving as a bioreactor, the method comprising the steps of:
producing a monodisperse multiple emulsion, the monodisperse multiple emulsion comprising:
a first fluid serving as a host environment;
a second fluid within the host environment, the second fluid being immiscible in the first fluid such that there is an interface between the first fluid and the second fluid, the second fluid comprising a plurality of living cells dispersed therein, said living cells capable of metabolic activity;
a third fluid within the second fluid; and,
an agent capable of affecting the metabolic activity of the living cells, the agent present within the first fluid at a higher concentration than in the second fluid and in the third fluid;
waiting until the living cells migrate to the interface between the first fluid and the second fluid to form the continuous membrane around the second fluid; and, removing the first fluid from the monodisperse multiple emulsion to produce the artificial micro-gland. 6. The method of claim 5, wherein the:
first fluid comprises a first oil; second fluid comprises water; third fluid comprises a second oil; agent is selected from the group consisting of: oxygen; carbon dioxide; nitrogen oxide; sugar; phosphates, nitrates, sulphates, and potassium salts; cyclic adenosine monophosphate (cAMP); inositon phospholipid (mPIP3); actin; histamine; serotonin (5HT); plaletet acting factors (PAF); arachidonic acid metabolites; diacykglyseril (IP3); leukotine B4; lipoxins; prostaglandins; cytotaxin; f-met-leu-phe tripeptide; cytokines; kinins,cytotaxins; anaphylatoxin peptide (C5a); aspartic acid (ASP); serine (SER); and, chemo-attractants; and, the living cells are selected from the group consisting of: eukaryotic cells; and; prokaryotic cells. 7. A method of making a multi-shell artificial micro-gland by taxis, the multi-shell artificial micro-gland comprising a plurality of continuous membranes of first living cells, the continuous membranes defining an enclosed volume, the enclosed volume comprising a reservoir serving as a bioreactor, the method comprising the steps of:
producing a monodisperse emulsion, the monodisperse emulsion comprising:
a fluid serving as a host environment;
an artificial micro-gland within the host environment, the artificial micro-gland comprising a first continuous membrane of first living cells surrounding a reservoir; and,
a plurality of second living cells dispersed within the fluid, said second living cells capable of metabolic activity stimulated by discharges of an agent from the first living cells;
waiting until the second living cells migrate to the living cells to form a second continuous membrane covering the first living cells; and, removing the fluid from the emulsion to produce the multi-shell artificial micro-gland. 8. The method of claim 7, wherein the:
fluid comprises oil or water; first living cells are selected from the group consisting of: eukaryotic cells; and; prokaryotic cells; and, second living cells are selected from the group consisting of: eukaryotic cells; and; prokaryotic cells, provided that the selected second living cells are different than the first living cells. 9. A method of making an artificial micro-gland by taxis, the artificial micro-gland comprising a first artificial micro-gland within a second artificial micro-gland, the method comprising the steps of:
producing a monodisperse multiple emulsion, the monodisperse multiple emulsion comprising:
a first fluid serving as a host environment;
a second fluid confined within the host environment, the second fluid being immiscible in the first fluid such that there is a first interface between the first fluid and the second fluid;
a third fluid within the second fluid, the third fluid being immiscible in the second fluid such that there is a second interface between the second fluid and the third fluid, the third fluid comprising a plurality of first living cells dispersed therein, said first living cells capable of metabolic activity; and,
an agent capable of affecting the metabolic activity of the living cells, the agent present within the second fluid at a higher concentration than in the third fluid;
waiting until the first living cells migrate to the second interface between the second fluid and the third fluid to form a continuous membrane around the third fluid, forming a first artificial micro-gland within the second fluid; adding second living cells to the first fluid; waiting until the second living cells migrate to the first interface between the first fluid and the second fluid to form a second continuous membrane covering the second fluid and forming the second artificial micro-gland; and, removing the first fluid from the monodisperse multiple emulsion to produce the artificial micro-gland comprising a first artificial micro-gland within a second artificial micro-gland. 10. The method of claim 9, wherein the:
first fluid comprises water; second fluid comprises oil; third fluid comprises water; agent is selected from the group consisting of: oxygen; and, carbon dioxide; first living cells are selected from the group consisting of: eukaryotic cells; and; prokaryotic cells; and; second living cells are selected from the group consisting of: eukaryotic cells; and; prokaryotic cells.
| 1,600 |
984 | 14,806,802 | 1,633 |
A transgenic non-human mammal containing a heterologous lambda light chain gene locus, and/or a heterologous kappa light chain gene locus, and/or a heterologous heavy chain gene locus, each of which can re-arrange so that immunoglobulin heavy and light chain genes are formed and expressed in B-cells following antigen challenge.
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1. A transgenic non-human mammal comprising a heterologous immunoglobulin heavy chain locus comprising human VH gene segments, one or more human D gene segments, human J gene segments, and rat constant region gene segments, wherein the human VH gene segments comprise VH1-69, VH4-59, VH3-53, VH3-49, VH4-34, VH3-48, VH3-33, VH3-30, VH3-23, VH1-18, VH3-15, VH4-39, VH1-8, VH3-07, VH2-5, VH4-4, VH1-2, and VH6-1, the human J gene segments comprise all six human J gene segments, and the rat constant region gene segments comprise at least Cμ and a Cγ. 2. A transgenic non-human mammal comprising a heterologous immunoglobulin kappa light chain locus comprising human Vκ gene segments, human J gene segments, and a rat constant region gene segment, wherein the human Vκ gene segments comprise Vκ2-30, Vκ1-39, Vκ2-28, Vκ1-27, Vκ3-20, Vκ3-15, Vκ3-11, Vκ1-33, Vκ1-9, Vκ1-5, and Vκ4-1, the human J gene segments comprise all five human Jκ gene segments, and the constant region gene segment comprises Cκ. 3. A transgenic non-human mammal comprising a heterologous immunoglobulin lambda light chain locus comprising at least two human Vλ gene segments, two human Jλ gene segments, and two rat constant region gene segments, wherein the human Vλ gene segments comprise Vλ3-1 and Vλ2-8, and the constant region gene segments comprise Cλ2 and Cλ3. 4. The transgenic non-human mammal of claim 1, further comprising a heterologous immunoglobulin kappa light chain locus comprising human Vκ gene segments, human J gene segments, and a rat constant region gene segment, wherein the human Vκ gene segments comprise Vκ2-30, Vκ1-39, Vκ2-28, Vκ1-27, Vκ3-20, Vκ3-15, Vκ3-11, Vκ1-33, Vκ1-9, Vκ1-5, and Vκ4-1, the human J gene segments comprise all five human Jκ gene segments, and the constant region gene segment comprises Cκ. 5. The transgenic non-human mammal of claim 4, further comprising a heterologous immunoglobulin lambda light chain locus comprising at least two Vλ gene segments, two human Jλ gene segments, and two rat constant region gene segments, wherein the human Vλ gene segments comprise at least Vλ3-1 and Vλ2-8, and the constant region gene segments comprise Cλ2 and Cλ3. 6. The transgenic non-human mammal of claim 1, further comprising a heterologous immunoglobulin lambda light chain locus comprising at least two human Vλ gene segments, two human Jλ gene segments, and two rat constant region gene segments, wherein the human Vλ gene segments comprise at least Vλ3-1 and Vλ2-8, and the constant region gene segments comprise Cλ2 and Cλ3. 7. The transgenic non-human mammal according to any one of claims 1 to 3, wherein said locus or loci further comprise a selectable marker. 8. The transgenic non-human mammal according to claim 7, wherein more than one transgene is present, and each transgene comprises a different selectable marker. 9. The transgenic non-human mammal according to any one of claims 1 to 3, wherein the mammal is a rodent. 10. The transgenic non-human mammal according to claim 9, wherein the rodent is a mouse. 11. A method of producing an antigen-specific heterologous hybrid monoclonal antibody comprising:
(a) immunising a non-human transgenic mammal of any one of claims 4 to 6 with the antigen; (b) preparing hybridomas or immortalised B-cell lines each of which produces a monoclonal antibody from the B-cells of the immunised transgenic mammal; (c) optionally selecting at least one hybridoma or immortalised B-cell line expressing the heterologous antibody by use of the dominant selective marker genes present in the transgenes comprising the heterologous immunoglobulin light chain and heavy chain loci; and (d) selecting at least one hybridoma or immortalised B-cell line which produces an antibody which binds specifically to the antigen. 12. A method of deriving a human, antibody from a hybrid antibody comprising:
(a) carrying out the method of claim 12; (b) selecting at least one hybridoma or immortalised B-cell line which produces an antibody which binds specifically to the antigen and comprises VH and VL binding domains of the species of choice; (c) cloning and sequencing the VH and VL domains; (d) recloning selected sequences comprising the VH and VL binding domain coding sequences with constant effectors domains of choice from the same species; and (e) co-expressing the recloned sequences encoding heavy and light chain polypeptides of the desired species using an expression vector in a cell type of choice.
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A transgenic non-human mammal containing a heterologous lambda light chain gene locus, and/or a heterologous kappa light chain gene locus, and/or a heterologous heavy chain gene locus, each of which can re-arrange so that immunoglobulin heavy and light chain genes are formed and expressed in B-cells following antigen challenge.1. A transgenic non-human mammal comprising a heterologous immunoglobulin heavy chain locus comprising human VH gene segments, one or more human D gene segments, human J gene segments, and rat constant region gene segments, wherein the human VH gene segments comprise VH1-69, VH4-59, VH3-53, VH3-49, VH4-34, VH3-48, VH3-33, VH3-30, VH3-23, VH1-18, VH3-15, VH4-39, VH1-8, VH3-07, VH2-5, VH4-4, VH1-2, and VH6-1, the human J gene segments comprise all six human J gene segments, and the rat constant region gene segments comprise at least Cμ and a Cγ. 2. A transgenic non-human mammal comprising a heterologous immunoglobulin kappa light chain locus comprising human Vκ gene segments, human J gene segments, and a rat constant region gene segment, wherein the human Vκ gene segments comprise Vκ2-30, Vκ1-39, Vκ2-28, Vκ1-27, Vκ3-20, Vκ3-15, Vκ3-11, Vκ1-33, Vκ1-9, Vκ1-5, and Vκ4-1, the human J gene segments comprise all five human Jκ gene segments, and the constant region gene segment comprises Cκ. 3. A transgenic non-human mammal comprising a heterologous immunoglobulin lambda light chain locus comprising at least two human Vλ gene segments, two human Jλ gene segments, and two rat constant region gene segments, wherein the human Vλ gene segments comprise Vλ3-1 and Vλ2-8, and the constant region gene segments comprise Cλ2 and Cλ3. 4. The transgenic non-human mammal of claim 1, further comprising a heterologous immunoglobulin kappa light chain locus comprising human Vκ gene segments, human J gene segments, and a rat constant region gene segment, wherein the human Vκ gene segments comprise Vκ2-30, Vκ1-39, Vκ2-28, Vκ1-27, Vκ3-20, Vκ3-15, Vκ3-11, Vκ1-33, Vκ1-9, Vκ1-5, and Vκ4-1, the human J gene segments comprise all five human Jκ gene segments, and the constant region gene segment comprises Cκ. 5. The transgenic non-human mammal of claim 4, further comprising a heterologous immunoglobulin lambda light chain locus comprising at least two Vλ gene segments, two human Jλ gene segments, and two rat constant region gene segments, wherein the human Vλ gene segments comprise at least Vλ3-1 and Vλ2-8, and the constant region gene segments comprise Cλ2 and Cλ3. 6. The transgenic non-human mammal of claim 1, further comprising a heterologous immunoglobulin lambda light chain locus comprising at least two human Vλ gene segments, two human Jλ gene segments, and two rat constant region gene segments, wherein the human Vλ gene segments comprise at least Vλ3-1 and Vλ2-8, and the constant region gene segments comprise Cλ2 and Cλ3. 7. The transgenic non-human mammal according to any one of claims 1 to 3, wherein said locus or loci further comprise a selectable marker. 8. The transgenic non-human mammal according to claim 7, wherein more than one transgene is present, and each transgene comprises a different selectable marker. 9. The transgenic non-human mammal according to any one of claims 1 to 3, wherein the mammal is a rodent. 10. The transgenic non-human mammal according to claim 9, wherein the rodent is a mouse. 11. A method of producing an antigen-specific heterologous hybrid monoclonal antibody comprising:
(a) immunising a non-human transgenic mammal of any one of claims 4 to 6 with the antigen; (b) preparing hybridomas or immortalised B-cell lines each of which produces a monoclonal antibody from the B-cells of the immunised transgenic mammal; (c) optionally selecting at least one hybridoma or immortalised B-cell line expressing the heterologous antibody by use of the dominant selective marker genes present in the transgenes comprising the heterologous immunoglobulin light chain and heavy chain loci; and (d) selecting at least one hybridoma or immortalised B-cell line which produces an antibody which binds specifically to the antigen. 12. A method of deriving a human, antibody from a hybrid antibody comprising:
(a) carrying out the method of claim 12; (b) selecting at least one hybridoma or immortalised B-cell line which produces an antibody which binds specifically to the antigen and comprises VH and VL binding domains of the species of choice; (c) cloning and sequencing the VH and VL domains; (d) recloning selected sequences comprising the VH and VL binding domain coding sequences with constant effectors domains of choice from the same species; and (e) co-expressing the recloned sequences encoding heavy and light chain polypeptides of the desired species using an expression vector in a cell type of choice.
| 1,600 |
985 | 12,783,477 | 1,641 |
The present invention refers to a flow-through method of functionalizing an inner surface of a microfluidic device. The method can comprise transporting a silanizing solution through the microfluidic device to silanize the inner surface of the microfluidic device. The method can further comprise reacting the silanized surface with an oxidized polysaccharide to bind the oxidized polysaccharide to the silanized surface by transporting the oxidized polysaccharide through the microfluidic device. The present invention also refers to a microfluidic device which has been subjected to a flow-through method of the present invention so that at least a part of the inner surface or the entire inner surface of the microfluidic device is functionalized.
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1. A flow-through method of functionalizing an inner surface of a microfluidic device, wherein the method comprises:
transporting a silanizing solution through the microfluidic device to silanize the inner surface of the microfluidic device; and reacting the silanized surface with an oxidized polysaccharide to bind the oxidized polysaccharide to the silanized surface by transporting the oxidized polysaccharide through the microfluidic device. 2. The flow-through method of claim 1, wherein the oxidized polysaccharide bound to the silanized surface is further oxidized by transporting a glycol cleaving agent through the microfluidic device. 3. The flow-through method of claim 1, wherein the inner surface of the microfluidic device is oxidized before silanization. 4. The flow-through method of claim 1, wherein a part or the entire inner surface of the microfluidic device is functionalized with the flow-through method. 5. The flow-through method of claim 1, wherein the microfluidic device is made of a material selected from the group consisting of a silica based material, a ceramic material, a polymeric material and combinations of the aforementioned materials. 6. The flow-through method of claim 5, wherein the silica based material is a glass. 7. The flow-through method of claim 6, wherein the glass is selected from the group consisting of borosilicate glass, fused silica glass, and quartz. 8. The flow-through method of claim 5, wherein the polymeric material is selected from the group consisting of poly(methyl methacrylate) (PMMA), acetonitrile-butadiene-styrene (ABS), polyethylene terephthalate (PET), poly-(dimethylsiloxane) (PDMS), polycarbonate, polyethylene, polystyrene, polyolefin, polypropylene, polyimide, and a polymeric organosilicon. 9. The flow-through method of claim 8, wherein the polymeric organosilicon is poly(dimethyl siloxane) (PDMS) or poly(methyl hydrosiloxane) (PMHS). 10. The flow-through method of claim 1, wherein the polysaccharide is a glucan. 11. The flow-through method of claim 10, wherein the glucan is a α-glucan or a β-glucan or a mixture of both. 12. The flow-through method of claim 11, wherein the α-glucan is at least one α-glucan selected from the group consisting of dextran, glycogen, pullulan and starch. 13. The flow-through method of claim 11, wherein the β-glucan is at least one β-glucan selected from the group consisting of cellulose, curdlan, laminarin, chrysolaminarin, lentinan, lichenin, pleuran and zymosan. 14. The flow-through method of claim 1, wherein at least one target molecule is bound to the polysaccharide, wherein the at least one target molecule is selected from the group consisting of a peptide, a polypeptide, a peptoid, an inorganic molecule, a small organic molecule, nucleotides, carbohydrates and a protein. 15. The flow-through method of claim 14, wherein the polypeptide is selected from the group consisting of an antibody, a fragment of an antibody and a proteinaceous binding molecule with antibody-like functions. 16. The flow-through method of claim 14, wherein the antibody fragment is selected from the group consisting of an Fab fragment, a Fv fragment, a single-chain Fv fragment (scFv), a diabody and a domain antibody. 17. The flow-through method of claim 14, wherein the proteinaceous binding molecule is selected from the group consisting of a lipocalin, an AdNectins, a tetranectin, an avimer and a glubody. 18. The flow-through method of claim 14, wherein the protein is an enzyme or an antibody or an antigen or a cytokine. 19. The flow-through method of claim 1, wherein the silanizing solution comprises a silane coupling agent selected from the group consisting of a vinylsilane, an acryloxysilane, a methacrylatesilane, an isocyanatesilane, an epoxysilane, an aminosilane and a mercaptosilane. 20. The flow-through method of claim 1, wherein the silanizing solution comprises a silane coupling agent selected from the group consisting of mercaptopropyltrimethoxysilane, aminopropyltriethoxysilane, and glycidoxypropyltrimethoxysilane. 21. The flow-through method of claim 19, wherein the silanizing solution comprises the silane coupling agent in a concentration of between about 10% to 100%. 22. The flow-through method of claim 3, wherein the surface oxidizing agent is selected from the group consisting of a mixture of hydrochloric acid and hydrogen peroxide in an aqueous solution, piranha solution, UV/ozone oxidation, ultraviolet treatment, and ultraviolet/ozone treatment. 23. The flow-through method of claim 2, wherein the glycol cleaving agent is selected from the group consisting of a sugar oxidase, sodium hypochlorite, tetra-acetate, hydrogen peroxide, periodic acid, peracetic acid, alkali metal salts of periodate, or alkaline earth metal salts of periodate, transition metal salts of periodate, hypochlorite, perbromate, chlorite, chlorate, soluble peroxide salts, persulfate salts, percarboxylic acids, oxyhalo acids, and any combination of the aforementioned polysaccharide glycol cleaving agents in any proportion thereof. 24. The flow-through method of claims 1, wherein to obtain the oxidized polysaccharide a polysaccharide is oxidized using a polysaccharide oxidizing agent which is selected from the group consisting of sodium hypochlorite, tetra-acetate, hydrogen peroxide, periodic acid, peracetic acid, alkali metal salts of periodate, or alkaline earth metal salts of periodate, transition metal salts of periodate, hypochlorite, perbromate, chlorite, chlorate, soluble peroxide salts, persulfate salts, percarboxylic acids, oxyhalo acids, and any combination of the aforementioned polysaccharide glycol cleaving agents in any proportion thereof. 25. The flow-through method of claims 1, wherein the silanisation is carried out at ambient temperatures. 26. A microfluidic device which has been subjected to a flow-through method of claim 1 so that at least a part of the inner surface or the entire inner surface of the microfluidic device is functionalized. 27. The microfluidic device of claim 26, wherein the microfluidic device is a portable microfluidic device. 28. The microfluidic device of claim 26 for carrying out an enzyme-linked immunosorbent assay (ELISA), fluorescent, chemiluminescent, electrochemical immunoassay. 29. The microfluidic device of claim 26 for detecting multiple analytes simultaneously.
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The present invention refers to a flow-through method of functionalizing an inner surface of a microfluidic device. The method can comprise transporting a silanizing solution through the microfluidic device to silanize the inner surface of the microfluidic device. The method can further comprise reacting the silanized surface with an oxidized polysaccharide to bind the oxidized polysaccharide to the silanized surface by transporting the oxidized polysaccharide through the microfluidic device. The present invention also refers to a microfluidic device which has been subjected to a flow-through method of the present invention so that at least a part of the inner surface or the entire inner surface of the microfluidic device is functionalized.1. A flow-through method of functionalizing an inner surface of a microfluidic device, wherein the method comprises:
transporting a silanizing solution through the microfluidic device to silanize the inner surface of the microfluidic device; and reacting the silanized surface with an oxidized polysaccharide to bind the oxidized polysaccharide to the silanized surface by transporting the oxidized polysaccharide through the microfluidic device. 2. The flow-through method of claim 1, wherein the oxidized polysaccharide bound to the silanized surface is further oxidized by transporting a glycol cleaving agent through the microfluidic device. 3. The flow-through method of claim 1, wherein the inner surface of the microfluidic device is oxidized before silanization. 4. The flow-through method of claim 1, wherein a part or the entire inner surface of the microfluidic device is functionalized with the flow-through method. 5. The flow-through method of claim 1, wherein the microfluidic device is made of a material selected from the group consisting of a silica based material, a ceramic material, a polymeric material and combinations of the aforementioned materials. 6. The flow-through method of claim 5, wherein the silica based material is a glass. 7. The flow-through method of claim 6, wherein the glass is selected from the group consisting of borosilicate glass, fused silica glass, and quartz. 8. The flow-through method of claim 5, wherein the polymeric material is selected from the group consisting of poly(methyl methacrylate) (PMMA), acetonitrile-butadiene-styrene (ABS), polyethylene terephthalate (PET), poly-(dimethylsiloxane) (PDMS), polycarbonate, polyethylene, polystyrene, polyolefin, polypropylene, polyimide, and a polymeric organosilicon. 9. The flow-through method of claim 8, wherein the polymeric organosilicon is poly(dimethyl siloxane) (PDMS) or poly(methyl hydrosiloxane) (PMHS). 10. The flow-through method of claim 1, wherein the polysaccharide is a glucan. 11. The flow-through method of claim 10, wherein the glucan is a α-glucan or a β-glucan or a mixture of both. 12. The flow-through method of claim 11, wherein the α-glucan is at least one α-glucan selected from the group consisting of dextran, glycogen, pullulan and starch. 13. The flow-through method of claim 11, wherein the β-glucan is at least one β-glucan selected from the group consisting of cellulose, curdlan, laminarin, chrysolaminarin, lentinan, lichenin, pleuran and zymosan. 14. The flow-through method of claim 1, wherein at least one target molecule is bound to the polysaccharide, wherein the at least one target molecule is selected from the group consisting of a peptide, a polypeptide, a peptoid, an inorganic molecule, a small organic molecule, nucleotides, carbohydrates and a protein. 15. The flow-through method of claim 14, wherein the polypeptide is selected from the group consisting of an antibody, a fragment of an antibody and a proteinaceous binding molecule with antibody-like functions. 16. The flow-through method of claim 14, wherein the antibody fragment is selected from the group consisting of an Fab fragment, a Fv fragment, a single-chain Fv fragment (scFv), a diabody and a domain antibody. 17. The flow-through method of claim 14, wherein the proteinaceous binding molecule is selected from the group consisting of a lipocalin, an AdNectins, a tetranectin, an avimer and a glubody. 18. The flow-through method of claim 14, wherein the protein is an enzyme or an antibody or an antigen or a cytokine. 19. The flow-through method of claim 1, wherein the silanizing solution comprises a silane coupling agent selected from the group consisting of a vinylsilane, an acryloxysilane, a methacrylatesilane, an isocyanatesilane, an epoxysilane, an aminosilane and a mercaptosilane. 20. The flow-through method of claim 1, wherein the silanizing solution comprises a silane coupling agent selected from the group consisting of mercaptopropyltrimethoxysilane, aminopropyltriethoxysilane, and glycidoxypropyltrimethoxysilane. 21. The flow-through method of claim 19, wherein the silanizing solution comprises the silane coupling agent in a concentration of between about 10% to 100%. 22. The flow-through method of claim 3, wherein the surface oxidizing agent is selected from the group consisting of a mixture of hydrochloric acid and hydrogen peroxide in an aqueous solution, piranha solution, UV/ozone oxidation, ultraviolet treatment, and ultraviolet/ozone treatment. 23. The flow-through method of claim 2, wherein the glycol cleaving agent is selected from the group consisting of a sugar oxidase, sodium hypochlorite, tetra-acetate, hydrogen peroxide, periodic acid, peracetic acid, alkali metal salts of periodate, or alkaline earth metal salts of periodate, transition metal salts of periodate, hypochlorite, perbromate, chlorite, chlorate, soluble peroxide salts, persulfate salts, percarboxylic acids, oxyhalo acids, and any combination of the aforementioned polysaccharide glycol cleaving agents in any proportion thereof. 24. The flow-through method of claims 1, wherein to obtain the oxidized polysaccharide a polysaccharide is oxidized using a polysaccharide oxidizing agent which is selected from the group consisting of sodium hypochlorite, tetra-acetate, hydrogen peroxide, periodic acid, peracetic acid, alkali metal salts of periodate, or alkaline earth metal salts of periodate, transition metal salts of periodate, hypochlorite, perbromate, chlorite, chlorate, soluble peroxide salts, persulfate salts, percarboxylic acids, oxyhalo acids, and any combination of the aforementioned polysaccharide glycol cleaving agents in any proportion thereof. 25. The flow-through method of claims 1, wherein the silanisation is carried out at ambient temperatures. 26. A microfluidic device which has been subjected to a flow-through method of claim 1 so that at least a part of the inner surface or the entire inner surface of the microfluidic device is functionalized. 27. The microfluidic device of claim 26, wherein the microfluidic device is a portable microfluidic device. 28. The microfluidic device of claim 26 for carrying out an enzyme-linked immunosorbent assay (ELISA), fluorescent, chemiluminescent, electrochemical immunoassay. 29. The microfluidic device of claim 26 for detecting multiple analytes simultaneously.
| 1,600 |
986 | 15,077,373 | 1,627 |
The present application relates to pharmaceutical compositions and methods for treatment of urogenital diseases and bone metastasis in a human, which pharmaceutical composition contains an effective amount of arsenous acid alkaline or earth alkaline metal salt and/or a pharmaceutically acceptable adjuvant. According to the present invention, the alkaline arsenous acid metal salt is sodium meta-arsenita (AsO 2 Na) or potassium meta-arsenite (AsO 2 K). The effective amount of arsenous acid alkaline or earth alkaline metal salt is 0.0001-1500 mg/kg, preferably 1-1000 mg/kg, more preferably 1-150 mg/kg, and most preferably 50-100 mg/kg of body weight/day. The administration form of the pharmaceutical compositions of the invention is preferably oral, such as a tablet, capsule, powder and/or solution with a pharmaceutically acceptable carrier, diluent or excipient.
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1. A method of treating multiple myeloma in a patient comprising administering a composition comprising a therapeutically effective amount of sodium meta arsenite to the patient. 2. The method of claim 1, wherein the sodium meta arsenite is administered orally. 3. The method of claim 1, wherein the therapeutically effective amount s from 2.5 to 15 mg. 4. The method of claim 1 further comprising administering radiation therapy to the patient. 5. The method of claim 1 further comprising administering a chemotherapy agent to the patient.
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The present application relates to pharmaceutical compositions and methods for treatment of urogenital diseases and bone metastasis in a human, which pharmaceutical composition contains an effective amount of arsenous acid alkaline or earth alkaline metal salt and/or a pharmaceutically acceptable adjuvant. According to the present invention, the alkaline arsenous acid metal salt is sodium meta-arsenita (AsO 2 Na) or potassium meta-arsenite (AsO 2 K). The effective amount of arsenous acid alkaline or earth alkaline metal salt is 0.0001-1500 mg/kg, preferably 1-1000 mg/kg, more preferably 1-150 mg/kg, and most preferably 50-100 mg/kg of body weight/day. The administration form of the pharmaceutical compositions of the invention is preferably oral, such as a tablet, capsule, powder and/or solution with a pharmaceutically acceptable carrier, diluent or excipient.1. A method of treating multiple myeloma in a patient comprising administering a composition comprising a therapeutically effective amount of sodium meta arsenite to the patient. 2. The method of claim 1, wherein the sodium meta arsenite is administered orally. 3. The method of claim 1, wherein the therapeutically effective amount s from 2.5 to 15 mg. 4. The method of claim 1 further comprising administering radiation therapy to the patient. 5. The method of claim 1 further comprising administering a chemotherapy agent to the patient.
| 1,600 |
987 | 15,615,423 | 1,627 |
The invention comprises a method for treatment of ADHD or ADHD-related disorders by a pharmaceutical agent exhibiting combined serotonergic or noradrenergic reuptake transporters and monoamine receptor activity.
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1. A method of antagonizing 5-HT7 and 5HT1B receptor activity in a patient suffering from ADHD, consisting of administering to the patient in need thereof a therapeutically effective amount of viloxazine, wherein the administration antagonizes both receptors. 2. The method of claim 1, wherein the therapeutically effective amount is from about 20 to about 800 mg a day. 3. The method of claim 1, wherein the therapeutically effective amount is from about 10 to about 600 mg a day. 4. The method of claim 3, wherein the therapeutically effective amount is from about 150 to about 400 mg a day. 5. The method of claim 4, wherein the therapeutically effective amount is from 150 to 300 mg a day. 6. The method of claim 1, which provides an improved adverse effect profile. 7. The method of claim 1, wherein the patient is a human child. 8. The method of claim 1, wherein the patient further suffers from anxiety, depression, or bipolar disorder. 9. The method of claim 1, wherein the patient further suffers from obsessive compulsive disorder, Tourette's Syndrome, or Post Traumatic Stress Disorder.
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The invention comprises a method for treatment of ADHD or ADHD-related disorders by a pharmaceutical agent exhibiting combined serotonergic or noradrenergic reuptake transporters and monoamine receptor activity.1. A method of antagonizing 5-HT7 and 5HT1B receptor activity in a patient suffering from ADHD, consisting of administering to the patient in need thereof a therapeutically effective amount of viloxazine, wherein the administration antagonizes both receptors. 2. The method of claim 1, wherein the therapeutically effective amount is from about 20 to about 800 mg a day. 3. The method of claim 1, wherein the therapeutically effective amount is from about 10 to about 600 mg a day. 4. The method of claim 3, wherein the therapeutically effective amount is from about 150 to about 400 mg a day. 5. The method of claim 4, wherein the therapeutically effective amount is from 150 to 300 mg a day. 6. The method of claim 1, which provides an improved adverse effect profile. 7. The method of claim 1, wherein the patient is a human child. 8. The method of claim 1, wherein the patient further suffers from anxiety, depression, or bipolar disorder. 9. The method of claim 1, wherein the patient further suffers from obsessive compulsive disorder, Tourette's Syndrome, or Post Traumatic Stress Disorder.
| 1,600 |
988 | 13,370,874 | 1,634 |
Assay methods for preparing a biomolecule analyte includes hybridizing a sequence specific oligonucleotide probe to a biomolecule template and reacting the resulting analyte with a binding moiety.
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1. A method for preparing a biomolecule analyte, the method comprising:
a. providing a single-stranded DNA or RNA template; b. hybridizing a first plurality of identical, sequence specific oligonucleotide probes to the template, each probe having a 5′ end and a 3′ end, to thereby form an analyte having at least one single-stranded region and at least two duplex regions; c. conducting a base extension reaction in the at least one single-stranded region from the 3′ end of a hybridized probe toward the 5′ end of an adjacent hybridized probe; d. terminating the base-extension reaction such that there remains for each single-stranded region a single-stranded portion thereof adjacent to the 5′ end of each hybridized probe; and e. reacting the resulting analyte with a binding moiety that selectively binds to the at least one single-stranded portion to thereby prepare the biomolecule analyte. 2. The method of claim 1, wherein the probes comprise single-stranded DNA. 3. The method of claim 1, wherein the probes comprise RNA. 4. The method of claim 1, wherein the base extension reaction is performed by a DNA or RNA polymerase. 5. The method of claim 1, wherein the binding moiety comprises a protein. 6. The method of claim 5, wherein said protein comprises one or more proteins selected from the group consisting of RecA, T4 gene 32 protein, f1 geneV protein, human replication protein A, Pf3 single-stranded binding protein, adenovirus DNA binding protein, and E. coli single-stranded binding protein. 7. The method of claim 1, wherein a length of each probe is selected from a range of 4 to 12 bases. 8. The method of claim 1, wherein the method comprises performing steps a-e sequentially. 9. The method of claim 1, further comprising repeating steps a-e sequentially by replacing said first plurality of probes with a subsequent plurality of different unique probes. 10. The method of claim 1, wherein at least a portion of the probes in the first plurality of probes has attached thereto a detectable tag. 11. The method of claim 1, wherein the biomolecule analyte is configured for detection of positional information in a nanopore system. 12. The method of claim 11, further comprising:
monitoring changes in an electrical property across a nanopore as the biomolecule analyte is translocated therethrough, the changes in the electrical property being indicative of regions including or lacking the binding moiety. 13. The method of claim 12, further comprising:
differentiating between regions of the biomolecule analyte including or lacking the binding moiety based, at least in part, on the changes in the electrical property, to thereby determine binding moiety locations. 14. The method of claim 1, wherein the biomolecule analyte is configured for detection of positional information in a fluidic channel system. 15. The method of claim 14, wherein the fluidic channel system comprises a micro-channel or a nano-channel. 16. The method of claim 14, further comprising:
monitoring changes in an electrical property across a fluidic channel as the biomolecule analyte is translocated therethrough, the changes in the electrical property being indicative of regions including or lacking the binding moiety. 17. The method of claim 16, further comprising:
differentiating between regions of the biomolecule analyte including or lacking the binding moiety based, at least in part, on the changes in the electrical property, to thereby determine binding moiety locations. 18. The method of claim 13, further comprising:
determining a sequence of at least a portion of the single-stranded DNA or RNA template according to the determined binding moiety locations. 19. The method of claim 1, wherein sequence specific oligonucleotide analog probes selected from the group consisting of LNAs, PNAs and 2′-methoxy nucleotide analogs are substituted for the sequence specific oligonucleotide probes. 20. The method of claim 1, wherein the first plurality of identical, sequence specific oligonucleotide probes is replaced by a pool of sequence specific oligonucleotide probes comprising at least a first plurality of identical, sequence specific oligonucleotide probes and a second plurality of identical, sequence specific oligonucleotide probes, wherein the probes of the second plurality are different from the probes of the first plurality. 21. A method for preparing a biomolecule analyte, the method comprising:
a. providing a single-stranded DNA template, b. hybridizing a first plurality of identical, sequence specific RNA probes to the template, each probe having a 5′ end and a 3′ end, to thereby form an analyte having at least one single-stranded region and at least one duplex region, c. conducting a base extension reaction in the at least one single-stranded region from the 3′ end of a hybridized probe, d. allowing the base-extension reaction to fill each single-stranded region on the analyte, e. removing the RNA probes to provide the analyte with at least one single-stranded segment in the region to which an RNA probe had been hybridized, and f. reacting the resulting analyte with a binding moiety that selectively binds to the single-stranded segment, to thereby prepare the biomolecule analyte. 22. The method of claim 21, wherein the base extension reaction is performed by a DNA or RNA polymerase. 23. The method of claim 21, wherein the binding moiety comprises a protein. 24. The method of claim 23, wherein said protein comprises one or more proteins selected from the group consisting of RecA, T4 gene 32 protein, f1 geneV protein, human replication protein A, Pf3 single-stranded binding protein, adenovirus DNA binding protein, and E. coli single-stranded binding protein. 25. The method of claim 21, wherein a length of each probe is selected from a range of 4 to 12 bases. 26. The method of claim 21, wherein the method comprises performing steps a-f sequentially. 27. The method of claim 21, further comprising repeating steps a-f sequentially by replacing said first plurality of probes with a subsequent plurality of different unique probes. 28. The method of claim 21, wherein removing the RNA probes comprises reacting the analyte with a hydroxyl ion. 29. The method of claim 21, wherein the biomolecule analyte is configured for detection of positional information in a nanopore system. 30. The method of claim 29, further comprising:
monitoring changes in an electrical property across a nanopore as the biomolecule analyte is translocated therethrough, the changes in the electrical property being indicative of regions including or lacking the binding moiety. 31. The method of claim 30, further comprising:
differentiating between regions of the biomolecule analyte including or lacking the binding moiety based, at least in part, on the changes in the electrical property, to thereby determine binding moiety locations. 32. The method of claim 21, wherein the biomolecule analyte is configured for detection of positional information in a fluidic channel system. 33. The method of claim 32, wherein the fluidic channel system comprises a micro-channel or a nano-channel. 34. The method of claim 32, further comprising:
monitoring changes in an electrical property across a fluidic channel as the biomolecule analyte is translocated therethrough, the changes in the electrical property being indicative of regions including or lacking the binding moiety. 35. The method of claim 34, further comprising:
differentiating between regions of the biomolecule analyte including or lacking the binding moiety based, at least in part, on the changes in the electrical property, to thereby determine binding moiety locations. 36. The method of claim 31, further comprising:
determining a sequence of at least a portion of the single-stranded DNA or RNA template according to the determined binding moiety locations. 37. The method of claim 21, wherein the first plurality of identical, sequence specific RNA probes is replaced by a pool of sequence specific RNA probes comprising at least a first plurality of identical, sequence specific RNA probes and a second plurality of identical, sequence specific RNA probes, wherein the probes of the second plurality are different from the probes of the first plurality. 38. A method for preparing a biomolecule analyte, the method comprising:
a. providing a single-stranded DNA or RNA template, b. hybridizing a first plurality of identical, sequence specific oligonucleotide probes to the template, to thereby form an analyte having at least one single-stranded region and at least one duplex region, and c. reacting the resulting analyte with a binding moiety that selectively binds to the at least one duplex region to thereby prepare the biomolecule analyte. 39. The method of claim 38, wherein the probes comprise single-stranded DNA. 40. The method of claim 38, wherein the probes comprise RNA. 41. The method of claim 38, wherein the binding moiety comprises a protein. 42. The method of claim 41, wherein said protein comprises one or more proteins selected from the group consisting of RecA, T4 gene 32 protein, f1 geneV protein, human replication protein A, Pf3 single-stranded binding protein, adenovirus DNA binding protein, and E. coli single-stranded binding protein. 43. The method of claim 38, wherein a length of each probe is selected from a range of 4 to 12 bases. 44. The method of claim 38, wherein the method comprises performing steps a-c sequentially. 45. The method of claim 38, wherein steps a-c are repeated sequentially by replacing said first plurality of probes with a subsequent plurality of different unique probes. 46. The method of claim 38, wherein at least a portion of the probes in the first plurality of probes has attached thereto a detectable tag. 47. The method of claim 38, wherein the biomolecule analyte is configured for detection of positional information in a nanopore system. 48. The method of claim 47, further comprising:
monitoring changes in an electrical property across a nanopore as the biomolecule analyte is translocated therethrough, the changes in the electrical property being indicative of regions including or lacking the binding moiety. 49. The method of claim 48, further comprising:
differentiating between regions of the biomolecule analyte including or lacking the binding moiety based, at least in part, on the changes in the electrical property, to thereby determine binding moiety locations. 50. The method of claim 38, wherein the biomolecule analyte is configured for detection of positional information in a fluidic channel system. 51. The method of claim 50, wherein the fluidic channel system comprises a micro-channel or a nano-channel. 52. The method of claim 50, further comprising:
monitoring changes in an electrical property across a fluidic channel as the biomolecule analyte is translocated therethrough, the changes in the electrical property being indicative of regions including or lacking the binding moiety. 53. The method of claim 52, further comprising:
differentiating between regions of the biomolecule analyte including or lacking the binding moiety based, at least in part, on the detected changes in the electrical property, to thereby determine binding moiety locations. 54. The method of claim 49, further comprising:
determining a sequence of at least a portion of the single-stranded DNA or RNA template according to the determined binding moiety locations. 55. The method of claim 38, wherein sequence specific oligonucleotide analog probes selected from the group consisting of LNAs, PNAs and 2′-methoxy nucleotide analogs are substituted for the sequence specific oligonucleotide probes. 56. The method of claim 38, wherein the first plurality of identical, sequence specific oligonucleotide probes is replaced by a pool of sequence specific oligonucleotide probes comprising at least a first plurality of identical, sequence specific oligonucleotide probes and a second plurality of identical, sequence specific oligonucleotide probes, wherein the probes of the second plurality are different from the probes of the first plurality. 57. A method for preparing a biomolecule analyte, the method comprising:
a. providing a single-stranded DNA or RNA template, b. hybridizing a first plurality of identical, sequence specific oligonucleotide probes to the template, to thereby form an analyte having at least one single-stranded region and at least one duplex region, and c. reacting the resulting analyte with a binding moiety that selectively binds to the at least one single-stranded region, to thereby prepare the biomolecule analyte. 58. The method of claim 57, wherein the probes comprise single-stranded DNA. 59. The method of claim 57, wherein the probes comprise RNA. 60. The method of claim 57, wherein the binding moiety comprises a protein. 61. The method of claim 60, wherein said protein comprises one or more proteins selected from the group consisting of RecA, T4 gene 32 protein, f1 geneV protein, human replication protein A, Pf3 single-stranded binding protein, adenovirus DNA binding protein, and E. coli single-stranded binding protein. 62. The method of claim 57, wherein a length of each probe is selected from a range of 4 to 12 bases. 63. The method of claim 57, wherein the method comprises performing steps a-c sequentially. 64. The method of claim 57, wherein steps a-c are repeated sequentially by replacing said first plurality of probes with a subsequent plurality of different unique probes. 65. The method of claim 57 wherein at least a portion of the probes in the first plurality of probes has attached thereto a detectable tag. 66. The method of claim 57, wherein the biomolecule analyte is configured for detection of positional information in a nanopore system. 67. The method of claim 66, further comprising:
monitoring changes in an electrical property across a nanopore as the biomolecule analyte is translocated therethrough, the changes in the electrical property being indicative of regions including or lacking the binding moiety. 68. The method of claim 67, further comprising:
differentiating between regions of the biomolecule analyte including or lacking the binding moiety based, at least in part, on the detected changes in the electrical property, to thereby determine binding moiety locations. 69. The method of claim 57, wherein the biomolecule analyte is configured for detection of positional information in a fluidic channel system. 70. The method of claim 69, wherein the fluidic channel system comprises a micro-channel or a nano-channel. 71. The method of claim 69, further comprising:
monitoring changes in an electrical property across a fluidic channel as the biomolecule analyte is translocated therethrough, the changes in the electrical property being indicative of regions including or lacking the binding moiety. 72. The method of claim 71, further comprising:
differentiating between regions of the biomolecule analyte including or lacking the binding moiety based, at least in part, on the detected changes in the electrical property, to thereby determine binding moiety locations. 73. The method of claim 68, further comprising:
determining a sequence of at least a portion of the single-stranded DNA or RNA template according to the determined binding moiety locations. 74. The method of claim 57, wherein sequence specific oligonucleotide analog probes selected from the group consisting of LNAs, PNAs and 2′-methoxy nucleotide analogs are substituted for the sequence specific oligonucleotide probes. 75. The method of claim 57, wherein the first plurality of identical, sequence specific oligonucleotide probes is replaced by a pool of sequence specific oligonucleotide probes comprising at least a first plurality of identical, sequence specific oligonucleotide probes and a second plurality of identical, sequence specific oligonucleotide probes, wherein the probes of the second plurality are different from the probes of the first plurality. 76. The method of claim 17, further comprising:
determining a sequence of at least a portion of the single-stranded DNA or RNA template according to the determined binding moiety locations. 77. The method of claim 35, further comprising:
determining a sequence of at least a portion of the single-stranded DNA or RNA template according to the determined binding moiety locations. 78. The method of claim 53, further comprising:
determining a sequence of at least a portion of the single-stranded DNA or RNA template according to the determined binding moiety locations. 79. The method of claim 71, further comprising:
determining a sequence of at least a portion of the single-stranded DNA or RNA template according to the determined binding moiety locations.
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Assay methods for preparing a biomolecule analyte includes hybridizing a sequence specific oligonucleotide probe to a biomolecule template and reacting the resulting analyte with a binding moiety.1. A method for preparing a biomolecule analyte, the method comprising:
a. providing a single-stranded DNA or RNA template; b. hybridizing a first plurality of identical, sequence specific oligonucleotide probes to the template, each probe having a 5′ end and a 3′ end, to thereby form an analyte having at least one single-stranded region and at least two duplex regions; c. conducting a base extension reaction in the at least one single-stranded region from the 3′ end of a hybridized probe toward the 5′ end of an adjacent hybridized probe; d. terminating the base-extension reaction such that there remains for each single-stranded region a single-stranded portion thereof adjacent to the 5′ end of each hybridized probe; and e. reacting the resulting analyte with a binding moiety that selectively binds to the at least one single-stranded portion to thereby prepare the biomolecule analyte. 2. The method of claim 1, wherein the probes comprise single-stranded DNA. 3. The method of claim 1, wherein the probes comprise RNA. 4. The method of claim 1, wherein the base extension reaction is performed by a DNA or RNA polymerase. 5. The method of claim 1, wherein the binding moiety comprises a protein. 6. The method of claim 5, wherein said protein comprises one or more proteins selected from the group consisting of RecA, T4 gene 32 protein, f1 geneV protein, human replication protein A, Pf3 single-stranded binding protein, adenovirus DNA binding protein, and E. coli single-stranded binding protein. 7. The method of claim 1, wherein a length of each probe is selected from a range of 4 to 12 bases. 8. The method of claim 1, wherein the method comprises performing steps a-e sequentially. 9. The method of claim 1, further comprising repeating steps a-e sequentially by replacing said first plurality of probes with a subsequent plurality of different unique probes. 10. The method of claim 1, wherein at least a portion of the probes in the first plurality of probes has attached thereto a detectable tag. 11. The method of claim 1, wherein the biomolecule analyte is configured for detection of positional information in a nanopore system. 12. The method of claim 11, further comprising:
monitoring changes in an electrical property across a nanopore as the biomolecule analyte is translocated therethrough, the changes in the electrical property being indicative of regions including or lacking the binding moiety. 13. The method of claim 12, further comprising:
differentiating between regions of the biomolecule analyte including or lacking the binding moiety based, at least in part, on the changes in the electrical property, to thereby determine binding moiety locations. 14. The method of claim 1, wherein the biomolecule analyte is configured for detection of positional information in a fluidic channel system. 15. The method of claim 14, wherein the fluidic channel system comprises a micro-channel or a nano-channel. 16. The method of claim 14, further comprising:
monitoring changes in an electrical property across a fluidic channel as the biomolecule analyte is translocated therethrough, the changes in the electrical property being indicative of regions including or lacking the binding moiety. 17. The method of claim 16, further comprising:
differentiating between regions of the biomolecule analyte including or lacking the binding moiety based, at least in part, on the changes in the electrical property, to thereby determine binding moiety locations. 18. The method of claim 13, further comprising:
determining a sequence of at least a portion of the single-stranded DNA or RNA template according to the determined binding moiety locations. 19. The method of claim 1, wherein sequence specific oligonucleotide analog probes selected from the group consisting of LNAs, PNAs and 2′-methoxy nucleotide analogs are substituted for the sequence specific oligonucleotide probes. 20. The method of claim 1, wherein the first plurality of identical, sequence specific oligonucleotide probes is replaced by a pool of sequence specific oligonucleotide probes comprising at least a first plurality of identical, sequence specific oligonucleotide probes and a second plurality of identical, sequence specific oligonucleotide probes, wherein the probes of the second plurality are different from the probes of the first plurality. 21. A method for preparing a biomolecule analyte, the method comprising:
a. providing a single-stranded DNA template, b. hybridizing a first plurality of identical, sequence specific RNA probes to the template, each probe having a 5′ end and a 3′ end, to thereby form an analyte having at least one single-stranded region and at least one duplex region, c. conducting a base extension reaction in the at least one single-stranded region from the 3′ end of a hybridized probe, d. allowing the base-extension reaction to fill each single-stranded region on the analyte, e. removing the RNA probes to provide the analyte with at least one single-stranded segment in the region to which an RNA probe had been hybridized, and f. reacting the resulting analyte with a binding moiety that selectively binds to the single-stranded segment, to thereby prepare the biomolecule analyte. 22. The method of claim 21, wherein the base extension reaction is performed by a DNA or RNA polymerase. 23. The method of claim 21, wherein the binding moiety comprises a protein. 24. The method of claim 23, wherein said protein comprises one or more proteins selected from the group consisting of RecA, T4 gene 32 protein, f1 geneV protein, human replication protein A, Pf3 single-stranded binding protein, adenovirus DNA binding protein, and E. coli single-stranded binding protein. 25. The method of claim 21, wherein a length of each probe is selected from a range of 4 to 12 bases. 26. The method of claim 21, wherein the method comprises performing steps a-f sequentially. 27. The method of claim 21, further comprising repeating steps a-f sequentially by replacing said first plurality of probes with a subsequent plurality of different unique probes. 28. The method of claim 21, wherein removing the RNA probes comprises reacting the analyte with a hydroxyl ion. 29. The method of claim 21, wherein the biomolecule analyte is configured for detection of positional information in a nanopore system. 30. The method of claim 29, further comprising:
monitoring changes in an electrical property across a nanopore as the biomolecule analyte is translocated therethrough, the changes in the electrical property being indicative of regions including or lacking the binding moiety. 31. The method of claim 30, further comprising:
differentiating between regions of the biomolecule analyte including or lacking the binding moiety based, at least in part, on the changes in the electrical property, to thereby determine binding moiety locations. 32. The method of claim 21, wherein the biomolecule analyte is configured for detection of positional information in a fluidic channel system. 33. The method of claim 32, wherein the fluidic channel system comprises a micro-channel or a nano-channel. 34. The method of claim 32, further comprising:
monitoring changes in an electrical property across a fluidic channel as the biomolecule analyte is translocated therethrough, the changes in the electrical property being indicative of regions including or lacking the binding moiety. 35. The method of claim 34, further comprising:
differentiating between regions of the biomolecule analyte including or lacking the binding moiety based, at least in part, on the changes in the electrical property, to thereby determine binding moiety locations. 36. The method of claim 31, further comprising:
determining a sequence of at least a portion of the single-stranded DNA or RNA template according to the determined binding moiety locations. 37. The method of claim 21, wherein the first plurality of identical, sequence specific RNA probes is replaced by a pool of sequence specific RNA probes comprising at least a first plurality of identical, sequence specific RNA probes and a second plurality of identical, sequence specific RNA probes, wherein the probes of the second plurality are different from the probes of the first plurality. 38. A method for preparing a biomolecule analyte, the method comprising:
a. providing a single-stranded DNA or RNA template, b. hybridizing a first plurality of identical, sequence specific oligonucleotide probes to the template, to thereby form an analyte having at least one single-stranded region and at least one duplex region, and c. reacting the resulting analyte with a binding moiety that selectively binds to the at least one duplex region to thereby prepare the biomolecule analyte. 39. The method of claim 38, wherein the probes comprise single-stranded DNA. 40. The method of claim 38, wherein the probes comprise RNA. 41. The method of claim 38, wherein the binding moiety comprises a protein. 42. The method of claim 41, wherein said protein comprises one or more proteins selected from the group consisting of RecA, T4 gene 32 protein, f1 geneV protein, human replication protein A, Pf3 single-stranded binding protein, adenovirus DNA binding protein, and E. coli single-stranded binding protein. 43. The method of claim 38, wherein a length of each probe is selected from a range of 4 to 12 bases. 44. The method of claim 38, wherein the method comprises performing steps a-c sequentially. 45. The method of claim 38, wherein steps a-c are repeated sequentially by replacing said first plurality of probes with a subsequent plurality of different unique probes. 46. The method of claim 38, wherein at least a portion of the probes in the first plurality of probes has attached thereto a detectable tag. 47. The method of claim 38, wherein the biomolecule analyte is configured for detection of positional information in a nanopore system. 48. The method of claim 47, further comprising:
monitoring changes in an electrical property across a nanopore as the biomolecule analyte is translocated therethrough, the changes in the electrical property being indicative of regions including or lacking the binding moiety. 49. The method of claim 48, further comprising:
differentiating between regions of the biomolecule analyte including or lacking the binding moiety based, at least in part, on the changes in the electrical property, to thereby determine binding moiety locations. 50. The method of claim 38, wherein the biomolecule analyte is configured for detection of positional information in a fluidic channel system. 51. The method of claim 50, wherein the fluidic channel system comprises a micro-channel or a nano-channel. 52. The method of claim 50, further comprising:
monitoring changes in an electrical property across a fluidic channel as the biomolecule analyte is translocated therethrough, the changes in the electrical property being indicative of regions including or lacking the binding moiety. 53. The method of claim 52, further comprising:
differentiating between regions of the biomolecule analyte including or lacking the binding moiety based, at least in part, on the detected changes in the electrical property, to thereby determine binding moiety locations. 54. The method of claim 49, further comprising:
determining a sequence of at least a portion of the single-stranded DNA or RNA template according to the determined binding moiety locations. 55. The method of claim 38, wherein sequence specific oligonucleotide analog probes selected from the group consisting of LNAs, PNAs and 2′-methoxy nucleotide analogs are substituted for the sequence specific oligonucleotide probes. 56. The method of claim 38, wherein the first plurality of identical, sequence specific oligonucleotide probes is replaced by a pool of sequence specific oligonucleotide probes comprising at least a first plurality of identical, sequence specific oligonucleotide probes and a second plurality of identical, sequence specific oligonucleotide probes, wherein the probes of the second plurality are different from the probes of the first plurality. 57. A method for preparing a biomolecule analyte, the method comprising:
a. providing a single-stranded DNA or RNA template, b. hybridizing a first plurality of identical, sequence specific oligonucleotide probes to the template, to thereby form an analyte having at least one single-stranded region and at least one duplex region, and c. reacting the resulting analyte with a binding moiety that selectively binds to the at least one single-stranded region, to thereby prepare the biomolecule analyte. 58. The method of claim 57, wherein the probes comprise single-stranded DNA. 59. The method of claim 57, wherein the probes comprise RNA. 60. The method of claim 57, wherein the binding moiety comprises a protein. 61. The method of claim 60, wherein said protein comprises one or more proteins selected from the group consisting of RecA, T4 gene 32 protein, f1 geneV protein, human replication protein A, Pf3 single-stranded binding protein, adenovirus DNA binding protein, and E. coli single-stranded binding protein. 62. The method of claim 57, wherein a length of each probe is selected from a range of 4 to 12 bases. 63. The method of claim 57, wherein the method comprises performing steps a-c sequentially. 64. The method of claim 57, wherein steps a-c are repeated sequentially by replacing said first plurality of probes with a subsequent plurality of different unique probes. 65. The method of claim 57 wherein at least a portion of the probes in the first plurality of probes has attached thereto a detectable tag. 66. The method of claim 57, wherein the biomolecule analyte is configured for detection of positional information in a nanopore system. 67. The method of claim 66, further comprising:
monitoring changes in an electrical property across a nanopore as the biomolecule analyte is translocated therethrough, the changes in the electrical property being indicative of regions including or lacking the binding moiety. 68. The method of claim 67, further comprising:
differentiating between regions of the biomolecule analyte including or lacking the binding moiety based, at least in part, on the detected changes in the electrical property, to thereby determine binding moiety locations. 69. The method of claim 57, wherein the biomolecule analyte is configured for detection of positional information in a fluidic channel system. 70. The method of claim 69, wherein the fluidic channel system comprises a micro-channel or a nano-channel. 71. The method of claim 69, further comprising:
monitoring changes in an electrical property across a fluidic channel as the biomolecule analyte is translocated therethrough, the changes in the electrical property being indicative of regions including or lacking the binding moiety. 72. The method of claim 71, further comprising:
differentiating between regions of the biomolecule analyte including or lacking the binding moiety based, at least in part, on the detected changes in the electrical property, to thereby determine binding moiety locations. 73. The method of claim 68, further comprising:
determining a sequence of at least a portion of the single-stranded DNA or RNA template according to the determined binding moiety locations. 74. The method of claim 57, wherein sequence specific oligonucleotide analog probes selected from the group consisting of LNAs, PNAs and 2′-methoxy nucleotide analogs are substituted for the sequence specific oligonucleotide probes. 75. The method of claim 57, wherein the first plurality of identical, sequence specific oligonucleotide probes is replaced by a pool of sequence specific oligonucleotide probes comprising at least a first plurality of identical, sequence specific oligonucleotide probes and a second plurality of identical, sequence specific oligonucleotide probes, wherein the probes of the second plurality are different from the probes of the first plurality. 76. The method of claim 17, further comprising:
determining a sequence of at least a portion of the single-stranded DNA or RNA template according to the determined binding moiety locations. 77. The method of claim 35, further comprising:
determining a sequence of at least a portion of the single-stranded DNA or RNA template according to the determined binding moiety locations. 78. The method of claim 53, further comprising:
determining a sequence of at least a portion of the single-stranded DNA or RNA template according to the determined binding moiety locations. 79. The method of claim 71, further comprising:
determining a sequence of at least a portion of the single-stranded DNA or RNA template according to the determined binding moiety locations.
| 1,600 |
989 | 15,522,819 | 1,619 |
The invention relates to a polymer comprising alkoxysilane groups, obtained by polycondensation of a diisocyanate, of a difunctional compound and of two different alkoxysilanes.
The invention also relates to a cosmetic composition comprising such a polymer and to a process for caring for or making up keratin materials by application of the composition to the keratin materials.
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1. A process for preparing a polymer comprising alkoxysilane groups which can be obtained by polycondensation, comprising, in a first step, the reaction between:
(i) a diisocyanate of formula (I): OCN—Z—NCO (I) in which Z denotes a divalent hydrocarbon-based radical containing from 4 to 20 carbon atoms; and (ii) a difunctional compound of formula (II): H-T-A-T-H (II) in which: T denotes a heteroatom chosen from O and S or an —N(R)— radical, R being H or a C1-C4 alkyl radical, A denotes a linear or branched, divalent hydrocarbon-based C2-C100 radical, optionally interrupted with one or more non-adjacent heteroatoms chosen from O and S, or an —N(R′)— group in which R′ denotes a hydrogen atom or a C1-C4 alkyl radical; in order to form a prepolymer (P) containing at least one isocyanate function; followed by a second step in which the prepolymer (P) obtained is reacted with a first alkoxysilane of formula (III) and a second alkoxysilane of formula (IV):
(R1O)(R2)(R3)Si—CH2—(NH-L1)p-X1—H (III)
in which p=0 or 1; X1 denotes —NRa—, S or O, Ra denoting H or a saturated or unsaturated C1-C8 (cyclo)alkyl radical, in particular methyl or cyclohexyl, or a C6-C10 aryl radical; R1 denotes a C1-C6 alkyl radical; R2 and R3, which may be identical or different, preferably identical are chosen from:
a C1-C6, in particular C1-C4, alkoxy radical;
a linear or branched C1-C6 alkyl radical;
L1 denotes a linear or branched, saturated divalent hydrocarbon-based C1-C20 radical;
(R′1O)(R′2)(R′3)Si—CH(R4)—CH(R5)-(L2)q-X2—H (IV)
in which: q=0 or 1; X2 denotes —NRb— or S or O or —NHCO—NRc-, Rb denoting H or a saturated or unsaturated C1-C8 (cyclo)alkyl radical, or a C6-C10 aryl radical; Rc denoting a saturated C1-C4 alkyl radical; R′1 denotes a C1-C6 alkyl radical; R′2 and R′3, which may be identical or different, are chosen from:
a C1-C6;
a linear or branched C1-C6 alkyl radical;
R4 denotes H or a C1-C4 alkyl radical; R5 denotes H or a C1-C4 alkyl radical optionally substituted with an —NH2 group; L2 denotes a linear or branched, saturated divalent hydrocarbon-based C1-C20 radical, optionally interrupted with an —NH— group, optionally substituted with an NH2 group; it being possible for the first and second alkoxysilanes (III) and (IV) to be added either simultaneously or sequentially by first introducing the first alkoxysiloxane (III) then the second alkoxysilane (IV), or by first introducing the second alkoxysilane (IV) then the first alkoxysilane (III). 2. The process according to claim 1, wherein, for the diisocyanate (I), the Z radical is chosen from the following radicals (1) to (6): 3. The process according to claim 1, wherein, for the difunctional compound of formula (II):
T denotes O or NH; A denotes a linear or branched hydrocarbon-based C2-C50 radical optionally interrupted with one or more non-adjacent oxygen atoms. 4. The process according to claim 1, wherein, for the first alkoxysilane (III):
X1 denotes —NRa;
R1 denotes a methyl or ethyl radical;
R2 and R3, which may be identical or different, are chosen from:
methoxy or ethoxy radicals;
methyl or ethyl;
L1 represents a linear or branched, saturated hydrocarbon-based C1-C10 radical. 5. The process according to claim 1, wherein the first alkoxysilane (III) is chosen from those of formula (IIIa) below:
(R1O)(R2)(R3)Si—CH2—(NH-L1)p-NRa—H (IIIa)
in which: p=0 or 1; R1 denotes a methyl or ethyl radical; R2 and R3, which may be identical or different, denote a methoxy, ethoxy, methyl or ethyl radical; when p=1, L1 represents a saturated divalent hydrocarbon-based C1-C8 radical; Ra denotes H or a saturated or unsaturated C1-C8 (cyclo)alkyl radical, or a phenyl radical; preferably, Ra denotes H or a cyclohexyl radical. 6. The process according to claim 1, wherein the first alkoxysilane (III) is chosen from:
1-(dimethoxymethylsilyl)methanamine 1-(diethoxymethylsilyl)methanamine 1-(triethoxysilyl)methanamine 1-(trimethoxysilyl)methanamine 1-(trimethoxysilyl)methanethiol 1-(diethoxymethylsilyl)methanethiol 1-(triethoxysilyl)methanethiol 1-(triethoxysilyl)methanol N-[(triethoxysilyl)methyl]benzenamine N-[(trimethoxysilyl)methyl]benzenamine N-[(diethoxymethylsilyl)methyl]cyclohexanamine N-[(triethoxysilyl)methyl]cyclohexanamine N-[(dimethoxymethylsilyl)methyl]-cyclohexanamine N-(diethoxymethylsilyl)-N-methylmethanamine N-methyl-1-(trimethoxysilyl)methanamine N-methyl-1-(triethoxysilyl)methanamine N-[(dimethoxy(methyl)silyl)methyl]benzenamine N-[(triethoxysilyl)methyl]-1,6-hexanediamine N-[(trimethoxysilyl)methyl]-1,6-hexanediamine N-[(diethoxymethylsilyl)methyl]-1,6-hexanediamine N-[(trimethoxysilyl)methyl]-1,2-ethanediamine. 7. The process according to claim 1, wherein, for the second alkoxysilane (IV):
X2 denotes —NRb— or S, Rb denoting H or a saturated or unsaturated C1-C8 (cyclo)alkyl radical, or a C6-C10 aryl radical; L2 represents a linear or branched, saturated hydrocarbon-based C1-C12 radical, optionally interrupted with an —NH— group; preferably, when q=1, L2 represents a saturated divalent C1-C10 radical, or else a divalent radical —(CH2)n—NH—(CH2)m with n and m denoting integers such that 2≦n+m≦4; R′1 denotes a methyl or ethyl radical, R′2 and R′3, which may be identical or different, are chosen from:
methoxy or ethoxy radicals;
methyl or ethyl;
R′4 and R′5 denote H. 8. The process according to claim 1, wherein
the second alkoxysilane (IV) is chosen from those of formula (IVa) below:
(R′1O)(R′2)(R3)Si—CH2—CH2-(L2)q-NRb—H (IVa)
in which: q=0 or 1; Rb denoting H or a saturated or unsaturated C1-C8 (cyclo)alkyl radical; R′1 denotes a methyl or ethyl radical; R′2 and R′3, which may be identical or different, denote a methoxy, ethoxy, methyl or ethyl radical; L2 denotes a linear or branched, saturated hydrocarbon-based C1-C12 radical, optionally interrupted with an —NH— group; when q=1, L2 represents a saturated divalent C1-C10 radical, or else a divalent radical —(CH2)—NH—(CH2)m with n and m denoting integers such that 2≦n+m≦4. 9. The process according to claim 1, wherein the second alkoxysilane (IV) is chosen from:
3-(dimethoxymethylsilyl)-1-propanamine 3-(trimethoxysilyl)-1-propanamine 3-(triethoxysilyl)-1-propanamine 3-(diethoxymethoxysilyl)-1-propanamine 2-methyl-3-(trimethoxysilyl)-1-propanamine 3-(triethoxysilyl)-1-propanamine 3-(diethoxymethylsilyl)-1-propanamine 3-(methyldipropoxysilyl)-1-propanamine 3-(diethoxyethylsilyl)-1-propanamine 3-(ethyldimethoxysilyl)-1-propanamine 4-(triethoxysilyl)-1-butanamine 4-(dimethoxymethylsilyl)-1-butanamine 4-(trimethoxysilyl)-1-butanamine 2,2-dimethyl-4-(trimethoxysilyl)-1-butanamine 4-(diethoxymethylsilyl)-1-butanamine 4-(dimethoxymethylsilyl)-2,2-dimethyl-1-butanamine 11-(triethoxysilyl)-1-undecamine 11-(trimethoxysilyl)-1-undecamine 2-[(dimethoxymethylsilyl)methyl]-1,4-butanediamine 2-[(trimethoxysilyl)methyl]-1,4-butanediamine N-(3-(trimethoxysilyl)propyl)butylamine N-ethyl-3-(trimethoxysilyl)-1-propanamine N-methyl-3-(trimethoxysilyl)propylamine N-[3-trimethoxysilyl]propyl]cyclohexylamine N-[3-trimethoxysilyl]propyl]aniline N-[3-trimethoxysilyl]propyl]ethylenediamine N-[3-triethoxysilyl]propyl]ethylenediamine 1-(trimethoxysilyl)-2-propanamine 2-(trimethoxysilyl)ethanamine 2-(triethoxysilyl)-1-propanamine 2-(dimethoxymethylsilyl)ethanamine 2-(diethoxymethylsilyl)-1-propanamine 2-(diethoxymethylsilyl)ethanamine 2-(triethoxysilyl)ethanamine 4-(trimethoxysilyl)-1-butanol 3-(trimethoxysilyl)-1-propanol 11-(trimethoxysilyl)-1-undecanethiol 4-(trimethoxysilyl)-2-butanethiol 2-(triethoxysilyl)ethanethiol 3-(triethoxysilyl)-1-propanethiol 2-(trimethoxysilyl)ethanethiol 3-(trimethoxysilyl)-1-propanethiol 3-(dimethoxymethylsilyl)-1-propanethiol N-[3-(trimethoxysilyl)propyl]acetamide. 10. The process according to claim 1, wherein the mixture of first and second alkoxysilanes (III) and (IV) used comprises from 5 to 95 mol % of alkoxysilane (III), relative to the total moles of alkoxysilanes (III) and (IV). 11. The process according to claim 1, wherein the reagents are used according to the following molar equivalents:
diisocyanate (I): 2 equivalents difunctional compound (II): 1 equivalent first alkoxysilane (III): u equivalent second alkoxysilane (IV): v equivalent with u+v=2, u and v not being zero. 12. The process according to claim 1, wherein the first step is carried out in the presence of a catalyst, in particular a tin-based organic catalyst. 13. The process according to claim 1, wherein the first step is carried out in an aprotic solvent at a temperature of between 40° C. and 120° C. 14. The process according to claim 1, wherein the second step is carried out at a temperature of between 20° C. and 60° C. 15. The process according to claim 1, wherein the second step is followed by a step of solvent exchange by elimination of the aprotic solvent and addition of a carrier solvent. 16. The process according to claim 1, wherein the obtained polymer comprising an alkoxysilane group is carried in a carrier solvent. 17. A product which is a polymer comprising an alkoxysilane group (Pf), which can be obtained with the preparation process according to claim 1. 18. A mixture of compounds C1, C2 and C3:
(R1O)(R2)(R3)Si—CH2—(NH-L1)p-X1—CO—NH—Z—NH—CO-T-A-T-CO—NH—Z—NH—CO—X1-(L1-NH—)p—CH2—Si(R1O)(R2)(R3) (C1)
(R1O)(R2)(R3)Si—CH2—(NH-L1)p-X1—CO—NH—Z—NH—CO-T-A-T-CO—NH—Z—NH—CO—X2-(L2)q-CH(R5)—CH(R4)— . . . Si(R′1O)(R′2)(R′3) (C2)
(R′1O)(R′2)(R′3)Si—CH(R4)—CH(R5)-(L2)q-X2—CO—NH—Z—NH—CO-T-A-T-CO—NH—Z—NH—CO—X2-(L2)q-CH(R5)—CH(R4)— . . . —Si(R′1O)(R′2)(R′3) (C3) 19. A compound of formula C2:
(R1O)(R2)(R3)Si—CH2—(NH-L1)p-X1—CO—NH—Z—NH—CO-T-A-T-CO—NH—Z—NH—CO—X2-(L2)q-CH(R5)—CH(R4)— . . . Si(R′1O)(R′2)(R′3) (C2)
in which Z, R1, R2, R3, R′1, R′2, R′3, R4, R5, L1, L2, X1, X2, p and q have the meanings defined in claim 1, and T denotes O or NH; A denotes a linear or branched hydrocarbon-based C2-C50 radical optionally interrupted with one or more non-adjacent oxygen atoms. 20. An anhydrous composition comprising, in a physiologically acceptable medium, a product or compound(s) as defined according to claim 17. 21. A composition according to claim 20, wherein the product or the compounds are present in a content ranging from 0.1% to 60% by weight, relative to the total weight of the composition. 22. The composition according to claim 20, wherein it comprises at least one volatile organic solvent. 23. A cosmetic process for caring for or making up keratin materials, in particular the nails or the hair or the skin, comprising the application to the keratin materials, in particular to the nails or the hair or the skin, of a composition according to claim 21.
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The invention relates to a polymer comprising alkoxysilane groups, obtained by polycondensation of a diisocyanate, of a difunctional compound and of two different alkoxysilanes.
The invention also relates to a cosmetic composition comprising such a polymer and to a process for caring for or making up keratin materials by application of the composition to the keratin materials.1. A process for preparing a polymer comprising alkoxysilane groups which can be obtained by polycondensation, comprising, in a first step, the reaction between:
(i) a diisocyanate of formula (I): OCN—Z—NCO (I) in which Z denotes a divalent hydrocarbon-based radical containing from 4 to 20 carbon atoms; and (ii) a difunctional compound of formula (II): H-T-A-T-H (II) in which: T denotes a heteroatom chosen from O and S or an —N(R)— radical, R being H or a C1-C4 alkyl radical, A denotes a linear or branched, divalent hydrocarbon-based C2-C100 radical, optionally interrupted with one or more non-adjacent heteroatoms chosen from O and S, or an —N(R′)— group in which R′ denotes a hydrogen atom or a C1-C4 alkyl radical; in order to form a prepolymer (P) containing at least one isocyanate function; followed by a second step in which the prepolymer (P) obtained is reacted with a first alkoxysilane of formula (III) and a second alkoxysilane of formula (IV):
(R1O)(R2)(R3)Si—CH2—(NH-L1)p-X1—H (III)
in which p=0 or 1; X1 denotes —NRa—, S or O, Ra denoting H or a saturated or unsaturated C1-C8 (cyclo)alkyl radical, in particular methyl or cyclohexyl, or a C6-C10 aryl radical; R1 denotes a C1-C6 alkyl radical; R2 and R3, which may be identical or different, preferably identical are chosen from:
a C1-C6, in particular C1-C4, alkoxy radical;
a linear or branched C1-C6 alkyl radical;
L1 denotes a linear or branched, saturated divalent hydrocarbon-based C1-C20 radical;
(R′1O)(R′2)(R′3)Si—CH(R4)—CH(R5)-(L2)q-X2—H (IV)
in which: q=0 or 1; X2 denotes —NRb— or S or O or —NHCO—NRc-, Rb denoting H or a saturated or unsaturated C1-C8 (cyclo)alkyl radical, or a C6-C10 aryl radical; Rc denoting a saturated C1-C4 alkyl radical; R′1 denotes a C1-C6 alkyl radical; R′2 and R′3, which may be identical or different, are chosen from:
a C1-C6;
a linear or branched C1-C6 alkyl radical;
R4 denotes H or a C1-C4 alkyl radical; R5 denotes H or a C1-C4 alkyl radical optionally substituted with an —NH2 group; L2 denotes a linear or branched, saturated divalent hydrocarbon-based C1-C20 radical, optionally interrupted with an —NH— group, optionally substituted with an NH2 group; it being possible for the first and second alkoxysilanes (III) and (IV) to be added either simultaneously or sequentially by first introducing the first alkoxysiloxane (III) then the second alkoxysilane (IV), or by first introducing the second alkoxysilane (IV) then the first alkoxysilane (III). 2. The process according to claim 1, wherein, for the diisocyanate (I), the Z radical is chosen from the following radicals (1) to (6): 3. The process according to claim 1, wherein, for the difunctional compound of formula (II):
T denotes O or NH; A denotes a linear or branched hydrocarbon-based C2-C50 radical optionally interrupted with one or more non-adjacent oxygen atoms. 4. The process according to claim 1, wherein, for the first alkoxysilane (III):
X1 denotes —NRa;
R1 denotes a methyl or ethyl radical;
R2 and R3, which may be identical or different, are chosen from:
methoxy or ethoxy radicals;
methyl or ethyl;
L1 represents a linear or branched, saturated hydrocarbon-based C1-C10 radical. 5. The process according to claim 1, wherein the first alkoxysilane (III) is chosen from those of formula (IIIa) below:
(R1O)(R2)(R3)Si—CH2—(NH-L1)p-NRa—H (IIIa)
in which: p=0 or 1; R1 denotes a methyl or ethyl radical; R2 and R3, which may be identical or different, denote a methoxy, ethoxy, methyl or ethyl radical; when p=1, L1 represents a saturated divalent hydrocarbon-based C1-C8 radical; Ra denotes H or a saturated or unsaturated C1-C8 (cyclo)alkyl radical, or a phenyl radical; preferably, Ra denotes H or a cyclohexyl radical. 6. The process according to claim 1, wherein the first alkoxysilane (III) is chosen from:
1-(dimethoxymethylsilyl)methanamine 1-(diethoxymethylsilyl)methanamine 1-(triethoxysilyl)methanamine 1-(trimethoxysilyl)methanamine 1-(trimethoxysilyl)methanethiol 1-(diethoxymethylsilyl)methanethiol 1-(triethoxysilyl)methanethiol 1-(triethoxysilyl)methanol N-[(triethoxysilyl)methyl]benzenamine N-[(trimethoxysilyl)methyl]benzenamine N-[(diethoxymethylsilyl)methyl]cyclohexanamine N-[(triethoxysilyl)methyl]cyclohexanamine N-[(dimethoxymethylsilyl)methyl]-cyclohexanamine N-(diethoxymethylsilyl)-N-methylmethanamine N-methyl-1-(trimethoxysilyl)methanamine N-methyl-1-(triethoxysilyl)methanamine N-[(dimethoxy(methyl)silyl)methyl]benzenamine N-[(triethoxysilyl)methyl]-1,6-hexanediamine N-[(trimethoxysilyl)methyl]-1,6-hexanediamine N-[(diethoxymethylsilyl)methyl]-1,6-hexanediamine N-[(trimethoxysilyl)methyl]-1,2-ethanediamine. 7. The process according to claim 1, wherein, for the second alkoxysilane (IV):
X2 denotes —NRb— or S, Rb denoting H or a saturated or unsaturated C1-C8 (cyclo)alkyl radical, or a C6-C10 aryl radical; L2 represents a linear or branched, saturated hydrocarbon-based C1-C12 radical, optionally interrupted with an —NH— group; preferably, when q=1, L2 represents a saturated divalent C1-C10 radical, or else a divalent radical —(CH2)n—NH—(CH2)m with n and m denoting integers such that 2≦n+m≦4; R′1 denotes a methyl or ethyl radical, R′2 and R′3, which may be identical or different, are chosen from:
methoxy or ethoxy radicals;
methyl or ethyl;
R′4 and R′5 denote H. 8. The process according to claim 1, wherein
the second alkoxysilane (IV) is chosen from those of formula (IVa) below:
(R′1O)(R′2)(R3)Si—CH2—CH2-(L2)q-NRb—H (IVa)
in which: q=0 or 1; Rb denoting H or a saturated or unsaturated C1-C8 (cyclo)alkyl radical; R′1 denotes a methyl or ethyl radical; R′2 and R′3, which may be identical or different, denote a methoxy, ethoxy, methyl or ethyl radical; L2 denotes a linear or branched, saturated hydrocarbon-based C1-C12 radical, optionally interrupted with an —NH— group; when q=1, L2 represents a saturated divalent C1-C10 radical, or else a divalent radical —(CH2)—NH—(CH2)m with n and m denoting integers such that 2≦n+m≦4. 9. The process according to claim 1, wherein the second alkoxysilane (IV) is chosen from:
3-(dimethoxymethylsilyl)-1-propanamine 3-(trimethoxysilyl)-1-propanamine 3-(triethoxysilyl)-1-propanamine 3-(diethoxymethoxysilyl)-1-propanamine 2-methyl-3-(trimethoxysilyl)-1-propanamine 3-(triethoxysilyl)-1-propanamine 3-(diethoxymethylsilyl)-1-propanamine 3-(methyldipropoxysilyl)-1-propanamine 3-(diethoxyethylsilyl)-1-propanamine 3-(ethyldimethoxysilyl)-1-propanamine 4-(triethoxysilyl)-1-butanamine 4-(dimethoxymethylsilyl)-1-butanamine 4-(trimethoxysilyl)-1-butanamine 2,2-dimethyl-4-(trimethoxysilyl)-1-butanamine 4-(diethoxymethylsilyl)-1-butanamine 4-(dimethoxymethylsilyl)-2,2-dimethyl-1-butanamine 11-(triethoxysilyl)-1-undecamine 11-(trimethoxysilyl)-1-undecamine 2-[(dimethoxymethylsilyl)methyl]-1,4-butanediamine 2-[(trimethoxysilyl)methyl]-1,4-butanediamine N-(3-(trimethoxysilyl)propyl)butylamine N-ethyl-3-(trimethoxysilyl)-1-propanamine N-methyl-3-(trimethoxysilyl)propylamine N-[3-trimethoxysilyl]propyl]cyclohexylamine N-[3-trimethoxysilyl]propyl]aniline N-[3-trimethoxysilyl]propyl]ethylenediamine N-[3-triethoxysilyl]propyl]ethylenediamine 1-(trimethoxysilyl)-2-propanamine 2-(trimethoxysilyl)ethanamine 2-(triethoxysilyl)-1-propanamine 2-(dimethoxymethylsilyl)ethanamine 2-(diethoxymethylsilyl)-1-propanamine 2-(diethoxymethylsilyl)ethanamine 2-(triethoxysilyl)ethanamine 4-(trimethoxysilyl)-1-butanol 3-(trimethoxysilyl)-1-propanol 11-(trimethoxysilyl)-1-undecanethiol 4-(trimethoxysilyl)-2-butanethiol 2-(triethoxysilyl)ethanethiol 3-(triethoxysilyl)-1-propanethiol 2-(trimethoxysilyl)ethanethiol 3-(trimethoxysilyl)-1-propanethiol 3-(dimethoxymethylsilyl)-1-propanethiol N-[3-(trimethoxysilyl)propyl]acetamide. 10. The process according to claim 1, wherein the mixture of first and second alkoxysilanes (III) and (IV) used comprises from 5 to 95 mol % of alkoxysilane (III), relative to the total moles of alkoxysilanes (III) and (IV). 11. The process according to claim 1, wherein the reagents are used according to the following molar equivalents:
diisocyanate (I): 2 equivalents difunctional compound (II): 1 equivalent first alkoxysilane (III): u equivalent second alkoxysilane (IV): v equivalent with u+v=2, u and v not being zero. 12. The process according to claim 1, wherein the first step is carried out in the presence of a catalyst, in particular a tin-based organic catalyst. 13. The process according to claim 1, wherein the first step is carried out in an aprotic solvent at a temperature of between 40° C. and 120° C. 14. The process according to claim 1, wherein the second step is carried out at a temperature of between 20° C. and 60° C. 15. The process according to claim 1, wherein the second step is followed by a step of solvent exchange by elimination of the aprotic solvent and addition of a carrier solvent. 16. The process according to claim 1, wherein the obtained polymer comprising an alkoxysilane group is carried in a carrier solvent. 17. A product which is a polymer comprising an alkoxysilane group (Pf), which can be obtained with the preparation process according to claim 1. 18. A mixture of compounds C1, C2 and C3:
(R1O)(R2)(R3)Si—CH2—(NH-L1)p-X1—CO—NH—Z—NH—CO-T-A-T-CO—NH—Z—NH—CO—X1-(L1-NH—)p—CH2—Si(R1O)(R2)(R3) (C1)
(R1O)(R2)(R3)Si—CH2—(NH-L1)p-X1—CO—NH—Z—NH—CO-T-A-T-CO—NH—Z—NH—CO—X2-(L2)q-CH(R5)—CH(R4)— . . . Si(R′1O)(R′2)(R′3) (C2)
(R′1O)(R′2)(R′3)Si—CH(R4)—CH(R5)-(L2)q-X2—CO—NH—Z—NH—CO-T-A-T-CO—NH—Z—NH—CO—X2-(L2)q-CH(R5)—CH(R4)— . . . —Si(R′1O)(R′2)(R′3) (C3) 19. A compound of formula C2:
(R1O)(R2)(R3)Si—CH2—(NH-L1)p-X1—CO—NH—Z—NH—CO-T-A-T-CO—NH—Z—NH—CO—X2-(L2)q-CH(R5)—CH(R4)— . . . Si(R′1O)(R′2)(R′3) (C2)
in which Z, R1, R2, R3, R′1, R′2, R′3, R4, R5, L1, L2, X1, X2, p and q have the meanings defined in claim 1, and T denotes O or NH; A denotes a linear or branched hydrocarbon-based C2-C50 radical optionally interrupted with one or more non-adjacent oxygen atoms. 20. An anhydrous composition comprising, in a physiologically acceptable medium, a product or compound(s) as defined according to claim 17. 21. A composition according to claim 20, wherein the product or the compounds are present in a content ranging from 0.1% to 60% by weight, relative to the total weight of the composition. 22. The composition according to claim 20, wherein it comprises at least one volatile organic solvent. 23. A cosmetic process for caring for or making up keratin materials, in particular the nails or the hair or the skin, comprising the application to the keratin materials, in particular to the nails or the hair or the skin, of a composition according to claim 21.
| 1,600 |
990 | 12,837,341 | 1,611 |
The present invention relates to compositions for improving the efficacy of acetaminophen comprising a unit dose of acetaminophen and a therapeutic efficacy-enhancing amount of N-acetylcysteine, such that acetaminophen and N-acetylcysteine are present in the composition in a molar ratio of acetaminophen to N-acetyl cysteine ranging from about 1:15 to about 1:0.000977, and use of such compositions for analgesic and antipyretic applications.
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1. A composition for improving therapeutic efficacy of acetaminophen comprising
(a) a unit dose of acetaminophen and (b) a therapeutic efficacy-enhancing amount of N-acetyl cysteine, acetaminophen and N-acetylcysteine are present in the composition in a molar ratio of acetaminophen to N-acetyl cysteine ranging from about 1:15 to about 1:0.000977, wherein the composition has a greater therapeutic effectiveness than the therapeutic effectiveness of acetaminophen alone when acetaminophen is administered at the unit dose of acetaminophen. 2. The composition according to claim 1, wherein
the unit dose of acetaminophen is a dose that is less than a standard maximum daily dose of acetaminophen, wherein the standard maximum daily dose of acetaminophen is 200 mg/day. 400 mg/day, 600 mg/day, 800 mg/day, 1200 mg/day, 1600 mg/day, 1625 mg/day, 2000 mg/day, 2400 mg/day, 3200 mg/day, or 4000 mg/day, and the composition has a therapeutic effectiveness equivalent to the therapeutic effectiveness of acetaminophen alone when acetaminophen is administered at the standard maximum daily dose of acetaminophen. 3. The composition according to claim 1, wherein therapeutic efficacy of the composition is maintained during long term use of the composition. 4. The composition according to claim 1, wherein the composition is an oral formulation or a non-oral formulation. 5. The composition according to claim 4, wherein the non-oral formulation is selected from a topical formulation, a parenteral formulation, a buccal formulation, an insufflation formulation, or a rectal formulation. 6. The composition according to claim 4, wherein the oral formulation is selected from a liquid solution, a syrup, an elixir, a suspension, an emulsion, a tablet, a capsule, a sustained release formulation, or a powder. 7. The composition according to claim 6, wherein the tablet is a compressed tablet. 8. The composition according to claim 6, wherein the tablet is a coated tablet. 9. The composition according to claim 6, wherein the tablet is an effervescent tablet 10. A method for improving therapeutic efficacy of acetaminophen, the method comprising the steps:
(a) providing a pharmaceutical composition comprising:
(i) a unit dose of acetaminophen and
(ii) a therapeutic efficacy-enhancing amount of N-acetylcysteine,
such that acetaminophen and N-acetylcysteine are present in the composition in a molar ratio of acetaminophen to N-acetyl cysteine ranging from about 1:15 to about 1:0.000977; wherein the therapeutic effectiveness of the composition is greater than the therapeutic effectiveness of acetaminophen alone when acetaminophen is administered at the unit dose of acetaminophen. 11. The method according to claim 10, wherein
the unit dose of acetaminophen is a dose that is less than a standard maximum daily dose of acetaminophen, wherein the standard maximum daily dose of acetaminophen is 200 mg/day, 400 mg/day, 600 mg/day, 800 mg/day, 1200 mg/day, 1600 mg/day, 1625 mg/day, 2000 mg/day, 2400 mg/day, 3200 mg/day, or 4000 mg/day, and the composition has a therapeutic effectiveness equivalent to the therapeutic effectiveness of acetaminophen alone when acetaminophen is administered at the standard maximum daily dose of acetaminophen. 12. The method according to claim 11, wherein therapeutic efficacy of the composition is maintained during long term use of the composition. 13. The method according to claim 11, wherein the composition is an oral formulation or a non-oral formulation. 14. The method according to claim 13, wherein the non-oral formulation is selected from a topical formulation, a parenteral formulation, a buccal formulation, an installation formulation, or a rectal formulation. 15. The method according to claim 13, wherein the oral formulation is selected from a liquid solution, a syrup, an elixir, a suspension, an emulsion, a tablet, a capsule, a sustained release formulation, or a powder. 16. The method according to claim 15, wherein the tablet is a compressed tablet. 17. The method according to claim 15, wherein the tablet is a coated tablet. 18. The method according to claim 15, wherein the tablet is an effervescent tablet. 19. A method for treating pain or fever, the method comprising the steps
(a) providing a composition comprising
(i) a unit dose of acetaminophen, and
(ii) a therapeutic efficacy-enhancing amount of N-acetyl cysteine;
such that acetaminophen and N-acetylcysteine are present in the composition in a molar ratio of acetaminophen to N-acetyl cysteine ranging from about 1:15 to about 1:0.000977; wherein the composition has a greater therapeutic effectiveness than the therapeutic effectiveness of acetaminophen alone when administered at the unit dose of acetaminophen. 20. The method according to claim 19, wherein
the unit dose of acetaminophen is a dose that is less than a standard maximum daily dose of acetaminophen, wherein the standard maximum daily dose of acetaminophen is 200 mg/day, 400 mg/day, 600 mg/day, 800 mg/day, 1200 mg/day, 1600 mg/day, 1625 mg/day, 2000 mg/day, 2400 mg/day, 3200 mg/day, or 4000 mg/day, and the composition has a therapeutic effectiveness equivalent to the therapeutic effectiveness of acetaminophen alone when acetaminophen is administered at the standard maximum daily dose of acetaminophen. 21. The method according to claim 19, wherein therapeutic efficacy of the composition is maintained during long term use of the composition. 22. The method according to claim 19, wherein the composition is an oral formulation or a non-oral formulation. 23. The method according to claim 22, wherein the non-oral formulation is selected from a topical formulation, a parenteral formulation, a buccal formulation, an insufflation formulation, or a rectal formulation. 24. The method according to claim 22, wherein the oral formulation is selected from a liquid solution, a syrup, an elixir, a suspension, an emulsion, a tablet, a capsule, a sustained release formulation, or a powder. 25. The method according to claim 24, wherein the tablet is a compressed tablet. 26. The method according to claim 24, wherein the tablet is a coated tablet. 27. The method according to claim 24, wherein the tablet is an effervescent tablet.
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The present invention relates to compositions for improving the efficacy of acetaminophen comprising a unit dose of acetaminophen and a therapeutic efficacy-enhancing amount of N-acetylcysteine, such that acetaminophen and N-acetylcysteine are present in the composition in a molar ratio of acetaminophen to N-acetyl cysteine ranging from about 1:15 to about 1:0.000977, and use of such compositions for analgesic and antipyretic applications.1. A composition for improving therapeutic efficacy of acetaminophen comprising
(a) a unit dose of acetaminophen and (b) a therapeutic efficacy-enhancing amount of N-acetyl cysteine, acetaminophen and N-acetylcysteine are present in the composition in a molar ratio of acetaminophen to N-acetyl cysteine ranging from about 1:15 to about 1:0.000977, wherein the composition has a greater therapeutic effectiveness than the therapeutic effectiveness of acetaminophen alone when acetaminophen is administered at the unit dose of acetaminophen. 2. The composition according to claim 1, wherein
the unit dose of acetaminophen is a dose that is less than a standard maximum daily dose of acetaminophen, wherein the standard maximum daily dose of acetaminophen is 200 mg/day. 400 mg/day, 600 mg/day, 800 mg/day, 1200 mg/day, 1600 mg/day, 1625 mg/day, 2000 mg/day, 2400 mg/day, 3200 mg/day, or 4000 mg/day, and the composition has a therapeutic effectiveness equivalent to the therapeutic effectiveness of acetaminophen alone when acetaminophen is administered at the standard maximum daily dose of acetaminophen. 3. The composition according to claim 1, wherein therapeutic efficacy of the composition is maintained during long term use of the composition. 4. The composition according to claim 1, wherein the composition is an oral formulation or a non-oral formulation. 5. The composition according to claim 4, wherein the non-oral formulation is selected from a topical formulation, a parenteral formulation, a buccal formulation, an insufflation formulation, or a rectal formulation. 6. The composition according to claim 4, wherein the oral formulation is selected from a liquid solution, a syrup, an elixir, a suspension, an emulsion, a tablet, a capsule, a sustained release formulation, or a powder. 7. The composition according to claim 6, wherein the tablet is a compressed tablet. 8. The composition according to claim 6, wherein the tablet is a coated tablet. 9. The composition according to claim 6, wherein the tablet is an effervescent tablet 10. A method for improving therapeutic efficacy of acetaminophen, the method comprising the steps:
(a) providing a pharmaceutical composition comprising:
(i) a unit dose of acetaminophen and
(ii) a therapeutic efficacy-enhancing amount of N-acetylcysteine,
such that acetaminophen and N-acetylcysteine are present in the composition in a molar ratio of acetaminophen to N-acetyl cysteine ranging from about 1:15 to about 1:0.000977; wherein the therapeutic effectiveness of the composition is greater than the therapeutic effectiveness of acetaminophen alone when acetaminophen is administered at the unit dose of acetaminophen. 11. The method according to claim 10, wherein
the unit dose of acetaminophen is a dose that is less than a standard maximum daily dose of acetaminophen, wherein the standard maximum daily dose of acetaminophen is 200 mg/day, 400 mg/day, 600 mg/day, 800 mg/day, 1200 mg/day, 1600 mg/day, 1625 mg/day, 2000 mg/day, 2400 mg/day, 3200 mg/day, or 4000 mg/day, and the composition has a therapeutic effectiveness equivalent to the therapeutic effectiveness of acetaminophen alone when acetaminophen is administered at the standard maximum daily dose of acetaminophen. 12. The method according to claim 11, wherein therapeutic efficacy of the composition is maintained during long term use of the composition. 13. The method according to claim 11, wherein the composition is an oral formulation or a non-oral formulation. 14. The method according to claim 13, wherein the non-oral formulation is selected from a topical formulation, a parenteral formulation, a buccal formulation, an installation formulation, or a rectal formulation. 15. The method according to claim 13, wherein the oral formulation is selected from a liquid solution, a syrup, an elixir, a suspension, an emulsion, a tablet, a capsule, a sustained release formulation, or a powder. 16. The method according to claim 15, wherein the tablet is a compressed tablet. 17. The method according to claim 15, wherein the tablet is a coated tablet. 18. The method according to claim 15, wherein the tablet is an effervescent tablet. 19. A method for treating pain or fever, the method comprising the steps
(a) providing a composition comprising
(i) a unit dose of acetaminophen, and
(ii) a therapeutic efficacy-enhancing amount of N-acetyl cysteine;
such that acetaminophen and N-acetylcysteine are present in the composition in a molar ratio of acetaminophen to N-acetyl cysteine ranging from about 1:15 to about 1:0.000977; wherein the composition has a greater therapeutic effectiveness than the therapeutic effectiveness of acetaminophen alone when administered at the unit dose of acetaminophen. 20. The method according to claim 19, wherein
the unit dose of acetaminophen is a dose that is less than a standard maximum daily dose of acetaminophen, wherein the standard maximum daily dose of acetaminophen is 200 mg/day, 400 mg/day, 600 mg/day, 800 mg/day, 1200 mg/day, 1600 mg/day, 1625 mg/day, 2000 mg/day, 2400 mg/day, 3200 mg/day, or 4000 mg/day, and the composition has a therapeutic effectiveness equivalent to the therapeutic effectiveness of acetaminophen alone when acetaminophen is administered at the standard maximum daily dose of acetaminophen. 21. The method according to claim 19, wherein therapeutic efficacy of the composition is maintained during long term use of the composition. 22. The method according to claim 19, wherein the composition is an oral formulation or a non-oral formulation. 23. The method according to claim 22, wherein the non-oral formulation is selected from a topical formulation, a parenteral formulation, a buccal formulation, an insufflation formulation, or a rectal formulation. 24. The method according to claim 22, wherein the oral formulation is selected from a liquid solution, a syrup, an elixir, a suspension, an emulsion, a tablet, a capsule, a sustained release formulation, or a powder. 25. The method according to claim 24, wherein the tablet is a compressed tablet. 26. The method according to claim 24, wherein the tablet is a coated tablet. 27. The method according to claim 24, wherein the tablet is an effervescent tablet.
| 1,600 |
991 | 15,518,838 | 1,612 |
An oral care composition comprising: (a) arginine, in free or salt form; (b) serine; (c) zinc oxide; and (d) zinc citrate.
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1. An oral care composition comprising:
a. arginine, in free or salt form; b. serine c. zinc oxide; and d. zinc citrate. 2. The oral care composition of claim 1, wherein the total concentration of zinc oxide and zinc citrate in the composition is from 0.2 weight % to 5 weight %, based on the total weight of the composition. 3. The oral care composition of claim 1, wherein the weight ratio of zinc oxide to zinc citrate is from 1.5:1 to 4.5:1. 4. (canceled) 5. The oral care composition of claim 1, wherein the composition comprises zinc oxide in an amount of from 0.5 weight % to 1.5 weight % and zinc citrate in an amount of from 0.25 weight % to 0.75 weight %, based on the total weight of the composition. 6. (canceled) 7. The oral care composition of claim 1, wherein the arginine is present, in free or salt form, in an amount of from 0.5 weight % to 8 weight %, and the serine is present in an amount of from 0.01 weight % to 0.8 weight %, based on the total weight of the composition. 8. (canceled) 9. The oral care composition of claim 1, wherein the weight ratio of serine to arginine is from 1:5 to 1:15, from 1:7 to 1:12, or about 1:10. 10-12. (canceled) 13. The oral care composition of claim 1, wherein the arginine is present as arginine hydrochloride, arginine bicarbonate, or arginine phosphate. 14. The oral care composition of claim 1, wherein the weight ratio of the zinc oxide and zinc citrate to the arginine and serine in the composition is from 2:1 to 1:1. 15-19. (canceled) 20. The oral care composition of claim 1, wherein the oral care composition is a dentifrice, a toothpaste, a gel, a tooth powder, a mouthwash, a mouthrinse, a lozenge, a tablet, a spray, a gum, or a film. 21. An oral care composition comprising:
a. arginine, in free or salt form; b. serine; c. zinc oxide; and d. zinc citrate
for use in reducing or inhibiting biofilm formation in an oral cavity. 22-25. (canceled) 26. The oral care composition of claim 21, wherein the composition comprises zinc oxide in an amount of about 1 weight % and zinc citrate in an amount of about 0.5 weight %, based on the total weight of the composition. 27-39. (canceled) 40. The oral care composition of claim 21, wherein the oral care composition is a dentifrice, a toothpaste, a gel, a tooth powder, a mouthwash, a mouthrinse, a lozenge, a tablet, a spray, a gum, or a film. 41. A method of reducing or inhibiting biofilm formation in an oral cavity, the method comprising: contacting the oral cavity with an oral care composition comprising
a. arginine, in free or salt form; b. serine; c. zinc oxide; and d. zinc citrate. 42. The method of claim 41, wherein the total concentration of zinc oxide and zinc citrate in the composition is from 0.2 weight % to 5 weight %, based on the total weight of the composition. 43. The method of claim 41, wherein the weight ratio of zinc oxide to zinc citrate in the composition is from 1.5:1 to 45:1. 44-59. (canceled) 60. The method of claim 41, wherein the oral care composition is a dentifrice, a toothpaste, a gel, a tooth powder, a mouthwash, a mouthrinse, a lozenge, a tablet, a spray, a gum, or a film. 61. (canceled)
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An oral care composition comprising: (a) arginine, in free or salt form; (b) serine; (c) zinc oxide; and (d) zinc citrate.1. An oral care composition comprising:
a. arginine, in free or salt form; b. serine c. zinc oxide; and d. zinc citrate. 2. The oral care composition of claim 1, wherein the total concentration of zinc oxide and zinc citrate in the composition is from 0.2 weight % to 5 weight %, based on the total weight of the composition. 3. The oral care composition of claim 1, wherein the weight ratio of zinc oxide to zinc citrate is from 1.5:1 to 4.5:1. 4. (canceled) 5. The oral care composition of claim 1, wherein the composition comprises zinc oxide in an amount of from 0.5 weight % to 1.5 weight % and zinc citrate in an amount of from 0.25 weight % to 0.75 weight %, based on the total weight of the composition. 6. (canceled) 7. The oral care composition of claim 1, wherein the arginine is present, in free or salt form, in an amount of from 0.5 weight % to 8 weight %, and the serine is present in an amount of from 0.01 weight % to 0.8 weight %, based on the total weight of the composition. 8. (canceled) 9. The oral care composition of claim 1, wherein the weight ratio of serine to arginine is from 1:5 to 1:15, from 1:7 to 1:12, or about 1:10. 10-12. (canceled) 13. The oral care composition of claim 1, wherein the arginine is present as arginine hydrochloride, arginine bicarbonate, or arginine phosphate. 14. The oral care composition of claim 1, wherein the weight ratio of the zinc oxide and zinc citrate to the arginine and serine in the composition is from 2:1 to 1:1. 15-19. (canceled) 20. The oral care composition of claim 1, wherein the oral care composition is a dentifrice, a toothpaste, a gel, a tooth powder, a mouthwash, a mouthrinse, a lozenge, a tablet, a spray, a gum, or a film. 21. An oral care composition comprising:
a. arginine, in free or salt form; b. serine; c. zinc oxide; and d. zinc citrate
for use in reducing or inhibiting biofilm formation in an oral cavity. 22-25. (canceled) 26. The oral care composition of claim 21, wherein the composition comprises zinc oxide in an amount of about 1 weight % and zinc citrate in an amount of about 0.5 weight %, based on the total weight of the composition. 27-39. (canceled) 40. The oral care composition of claim 21, wherein the oral care composition is a dentifrice, a toothpaste, a gel, a tooth powder, a mouthwash, a mouthrinse, a lozenge, a tablet, a spray, a gum, or a film. 41. A method of reducing or inhibiting biofilm formation in an oral cavity, the method comprising: contacting the oral cavity with an oral care composition comprising
a. arginine, in free or salt form; b. serine; c. zinc oxide; and d. zinc citrate. 42. The method of claim 41, wherein the total concentration of zinc oxide and zinc citrate in the composition is from 0.2 weight % to 5 weight %, based on the total weight of the composition. 43. The method of claim 41, wherein the weight ratio of zinc oxide to zinc citrate in the composition is from 1.5:1 to 45:1. 44-59. (canceled) 60. The method of claim 41, wherein the oral care composition is a dentifrice, a toothpaste, a gel, a tooth powder, a mouthwash, a mouthrinse, a lozenge, a tablet, a spray, a gum, or a film. 61. (canceled)
| 1,600 |
992 | 14,783,839 | 1,627 |
The invention is directed to a pharmaceutical composition comprising a progesterone receptor antagonist namely (11β,17β)-17-Hydroxy-11-[4-(methylsulphonyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one at the dosage of about 0.5 to 5 mg and more particularly 2 mg. Additionally, the invention is directed to the use of the novel pharmaceutical composition for treatment of and/or prophylaxis of gynaecological diseases, such as fibroids of the uterus (myomas, uterine leiomyoma), endometriosis or excessive menstrual bleeds, and method for obtaining such composition and oral dosage form.
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1. A pharmaceutical composition comprising about 0.5 to 5 mg of (11β,17β)-17-Hydroxy-11-[4-(methylsulphonyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one of formula
or a salt thereof. 2. The pharmaceutical composition according to claim 1 wherein the pharmaceutical composition comprises about 1 to 4 mg of (11β,17β)-17-Hydroxy-11-[4-(methylsulphonyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one. 3. The pharmaceutical composition according to claim 1 wherein the pharmaceutical composition comprises of 2 mg of (11β,17β)-17-Hydroxy-11-[4-(methylsulphonyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one. 4. The pharmaceutical composition according to claim 1, further comprising a pharmaceutically acceptable carrier. 5. The pharmaceutical composition according to claim 1 in a form of an oral dosage, wherein the oral dosage form is a tablet or a capsule. 6. A method of treatment and/or prophylaxis of a gynaecological disease characterized by excessive uterine bleeding, such as fibroids of the uterus (myomas, uterine leiomyoma), endometriosis or excessive menstrual bleeds comprising administering an effective amount of the pharmaceutical dosage form of claim 1 to a woman in need thereof. 7. The method of claim 6 wherein the gynaecological disease is fibroids of the uterus (myomas, uterine leiomyoma). 8. An oral dosage form comprising about 0.5 to 5 mg of (11β,17β)-17-Hydroxy-11-[4-(methylsulphonyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one of formula
or a salt thereof. 9. The oral dosage form according to claim 8 comprising about 2 mg of (11β,17β)-17-Hydroxy-11-[4-(methylsulphonyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one or a salt thereof. 10. A method of treatment and/or prophylaxis of a gynaecological disease that is characterized by excessive uterine bleeding, such as fibroids of the uterus (myomas, uterine leiomyoma), endometriosis or excessive menstrual bleeds comprising administering an effective amount of the oral dosage form of claim to a woman in need thereof. 11. The method of claim 10 wherein the gynaecological disease is fibroids of the uterus (myomas, uterine leiomyoma). 12. A method for obtaining the pharmaceutical composition of claim 1. 13. A method for obtaining the oral dosage form of claim 8.
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The invention is directed to a pharmaceutical composition comprising a progesterone receptor antagonist namely (11β,17β)-17-Hydroxy-11-[4-(methylsulphonyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one at the dosage of about 0.5 to 5 mg and more particularly 2 mg. Additionally, the invention is directed to the use of the novel pharmaceutical composition for treatment of and/or prophylaxis of gynaecological diseases, such as fibroids of the uterus (myomas, uterine leiomyoma), endometriosis or excessive menstrual bleeds, and method for obtaining such composition and oral dosage form.1. A pharmaceutical composition comprising about 0.5 to 5 mg of (11β,17β)-17-Hydroxy-11-[4-(methylsulphonyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one of formula
or a salt thereof. 2. The pharmaceutical composition according to claim 1 wherein the pharmaceutical composition comprises about 1 to 4 mg of (11β,17β)-17-Hydroxy-11-[4-(methylsulphonyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one. 3. The pharmaceutical composition according to claim 1 wherein the pharmaceutical composition comprises of 2 mg of (11β,17β)-17-Hydroxy-11-[4-(methylsulphonyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one. 4. The pharmaceutical composition according to claim 1, further comprising a pharmaceutically acceptable carrier. 5. The pharmaceutical composition according to claim 1 in a form of an oral dosage, wherein the oral dosage form is a tablet or a capsule. 6. A method of treatment and/or prophylaxis of a gynaecological disease characterized by excessive uterine bleeding, such as fibroids of the uterus (myomas, uterine leiomyoma), endometriosis or excessive menstrual bleeds comprising administering an effective amount of the pharmaceutical dosage form of claim 1 to a woman in need thereof. 7. The method of claim 6 wherein the gynaecological disease is fibroids of the uterus (myomas, uterine leiomyoma). 8. An oral dosage form comprising about 0.5 to 5 mg of (11β,17β)-17-Hydroxy-11-[4-(methylsulphonyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one of formula
or a salt thereof. 9. The oral dosage form according to claim 8 comprising about 2 mg of (11β,17β)-17-Hydroxy-11-[4-(methylsulphonyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one or a salt thereof. 10. A method of treatment and/or prophylaxis of a gynaecological disease that is characterized by excessive uterine bleeding, such as fibroids of the uterus (myomas, uterine leiomyoma), endometriosis or excessive menstrual bleeds comprising administering an effective amount of the oral dosage form of claim to a woman in need thereof. 11. The method of claim 10 wherein the gynaecological disease is fibroids of the uterus (myomas, uterine leiomyoma). 12. A method for obtaining the pharmaceutical composition of claim 1. 13. A method for obtaining the oral dosage form of claim 8.
| 1,600 |
993 | 15,622,682 | 1,619 |
Provided is a cosmetic method by topical route for treating and/or preventing unpleasant human body odours, which comprises applying, to the surface of a human keratinous substance, a composition comprising, in a physiologically acceptable medium, at least one monounsaturated fatty acid or one of its salts and/or one of its esters and/or one of its amides. Also provided is a cosmetic method by the oral route for treating and/or preventing unpleasant human body odours, comprising ingesting an oral composition comprising, in a physiologically acceptable medium, at least one monounsaturated fatty acid or one of its salts and/or one of its esters and/or one of its amides.
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1. A cosmetic method by oral route for treating and/or preventing unpleasant human body odours, which comprises ingesting an oral composition comprising, in a physiologically acceptable medium, at least one monounsaturated fatty acid or one of its salts and/or of its esters and/or one of its amides. 2. The cosmetic method according to claim 1, where the content of monounsaturated fatty acid is such that the daily dose varies from 0.5 to 2500 mg/d. 3. The cosmetic method according to claim 1, in which the said monounsaturated fatty acid is selected from the group consisting oleic acid, petroselinic acid, sapienic acid, cis-8-octadecenoic acid and cis-vaccenic acid, and their mixtures. 4. The cosmetic method according to claim 1, in which the said monounsaturated fatty acid is petroselinic acid in isolated form or in an oil comprising at least 40% by weight of petroselinic acid. 5. The cosmetic method according to claim 4 in which the said petroselinic acid is used in the form of oil of an umbellifer or of Geranium sanguineum. 6. The cosmetic method according to claim 5, in which the said umbellifer oil is selected from the group consisting of seed oils of coriander, chervil, carrot, celery, cumin, caraway, parsley and dill, and their mixtures. 7. A cosmetic method by topical route for treating and/or preventing unpleasant human body odours, which comprises applying, to the surface of a human keratinous substance, a composition comprising, in a physiologically acceptable medium, at least one monounsaturated fatty acid or one of its salts and/or one of its esters and/or one of its amides. 8. The cosmetic method according to claim 7, in which the said monounsaturated fatty acid is selected from the group consisting of oleic acid, petroselinic acid, sapienic acid, cis-8-octadecenoic acid and cis-vaccenic acid, and their mixtures. 9. The cosmetic method according to claim 7, in which the said monounsaturated fatty acid is petroselinic acid in isolated form or in an oil comprising at least 40% by weight of petroselinic acid. 10. The cosmetic method according to claim 9, in which the said petroselinic acid is used in the form of oil of an umbellifer or of Geranium sanguineum. 11. The cosmetic method according to claim 10, in which the said umbellifer oil is selected from the group consisting of seed oils of coriander, chervil, carrot, celery, cumin, caraway, parsley and dill, and their mixtures. 12. The cosmetic method according to claim 7, where the composition is in stick form. 13. The cosmetic method according to claim 7, where the composition is in the form of an aerosol.
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Provided is a cosmetic method by topical route for treating and/or preventing unpleasant human body odours, which comprises applying, to the surface of a human keratinous substance, a composition comprising, in a physiologically acceptable medium, at least one monounsaturated fatty acid or one of its salts and/or one of its esters and/or one of its amides. Also provided is a cosmetic method by the oral route for treating and/or preventing unpleasant human body odours, comprising ingesting an oral composition comprising, in a physiologically acceptable medium, at least one monounsaturated fatty acid or one of its salts and/or one of its esters and/or one of its amides.1. A cosmetic method by oral route for treating and/or preventing unpleasant human body odours, which comprises ingesting an oral composition comprising, in a physiologically acceptable medium, at least one monounsaturated fatty acid or one of its salts and/or of its esters and/or one of its amides. 2. The cosmetic method according to claim 1, where the content of monounsaturated fatty acid is such that the daily dose varies from 0.5 to 2500 mg/d. 3. The cosmetic method according to claim 1, in which the said monounsaturated fatty acid is selected from the group consisting oleic acid, petroselinic acid, sapienic acid, cis-8-octadecenoic acid and cis-vaccenic acid, and their mixtures. 4. The cosmetic method according to claim 1, in which the said monounsaturated fatty acid is petroselinic acid in isolated form or in an oil comprising at least 40% by weight of petroselinic acid. 5. The cosmetic method according to claim 4 in which the said petroselinic acid is used in the form of oil of an umbellifer or of Geranium sanguineum. 6. The cosmetic method according to claim 5, in which the said umbellifer oil is selected from the group consisting of seed oils of coriander, chervil, carrot, celery, cumin, caraway, parsley and dill, and their mixtures. 7. A cosmetic method by topical route for treating and/or preventing unpleasant human body odours, which comprises applying, to the surface of a human keratinous substance, a composition comprising, in a physiologically acceptable medium, at least one monounsaturated fatty acid or one of its salts and/or one of its esters and/or one of its amides. 8. The cosmetic method according to claim 7, in which the said monounsaturated fatty acid is selected from the group consisting of oleic acid, petroselinic acid, sapienic acid, cis-8-octadecenoic acid and cis-vaccenic acid, and their mixtures. 9. The cosmetic method according to claim 7, in which the said monounsaturated fatty acid is petroselinic acid in isolated form or in an oil comprising at least 40% by weight of petroselinic acid. 10. The cosmetic method according to claim 9, in which the said petroselinic acid is used in the form of oil of an umbellifer or of Geranium sanguineum. 11. The cosmetic method according to claim 10, in which the said umbellifer oil is selected from the group consisting of seed oils of coriander, chervil, carrot, celery, cumin, caraway, parsley and dill, and their mixtures. 12. The cosmetic method according to claim 7, where the composition is in stick form. 13. The cosmetic method according to claim 7, where the composition is in the form of an aerosol.
| 1,600 |
994 | 13,967,800 | 1,613 |
Polyurea capsules that encapsulate active materials in polymeric walls resulting from the polymerization of an aromatic or aliphatic polyisocyanate and a cross-linking agent are provided as are consumer products containing said polyurea capsules and for methods for producing such capsules.
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1. A method for preparing a polyurea capsule composition comprising
(a) preparing an oil phase comprising an active material and a polyisocyanate; (b) preparing a surfactant solution; (c) emulsifying the oil phase into the surfactant solution to form a fragrance emulsion; (d) adding a cross-linking agent to the fragrance emulsion to form a capsule slurry; and (e) curing the capsule slurry. 2. The method of claim 1, wherein the active material is a fragrance oil. 3. The method of claim 1, wherein the polyisocyanate is an aromatic polyisocyanate, aliphatic polyisocyanate, or mixture thereof. 4. The method of claim 3, wherein the aromatic polyisocyanate comprises a phenyl, a toluoyl, a xylyl, a naphthyl or a diphenyl moiety. 5. The method of claim 4, wherein the aromatic isocyanate is a polyisocyanurate of toluene diisocyanate, a trimethylol propane-adduct of toluene diisocyanate or a trimethylol propane-adduct of xylylene diisocyanate. 6. The method of claim 3, wherein the aliphatic polyisocyanate is selected from the group consisting of a trimer of hexamethylene diisocyanate, a trimer of isophorone diisocyanate and a biuret of hexamethylene diisocyanate. 7. The method of claim 3, wherein the mixture of aromatic polyisocyanate and aliphatic polyisocyanate is a mixture of a biuret of hexamethylene diisocyanate and a trimethylol propane-adduct of xylylene diisocyanate. 8. The method of claim 1, wherein the surfactant is polyvinyl alcohol, polystyrene sulfonate, carboxymethyl cellulose, sodium salt of naphthalene sulfonate condensate, or a mixture thereof. 9. The method of claim 1, wherein the cross-linking agent is a polyamine. 10. The method of claim 9, wherein the cross-linking agent is diethylenetriamine, bis(3-aminopropyl)amine, bis(hexanethylene)triamine, tris(2-aminoethyl)amine, triethylenetetramine, N,N′-bis(3-aminopropyl)-1,3-propanediamine, tetraethylenepentamine, pentaethylenehexamine, branched polyethylenimine, chitosan, nisin, gelatin, 1,3-diaminoguanidine monohydrochloride, 1,1-dimethylbiguanide hydrochloride, or guanidine carbonate. 11. The method of claim 1, wherein the step of adding the cross-linking agent to the fragrance emulsion is at a temperature of 35° C. 12. The method of claim 1, wherein the step of adding the cross-linking agent to the fragrance emulsion is at a temperature of 22° C. 13. The method of claim 1, wherein the capsule slurry is cured at a temperature greater than about 55° C., 65° C., 75° C., 85° C. or 95° C. 14. The method of claim 1, further comprising the step of washing the cured capsule slurry with water. 15. The method of claim 14, further comprising the step of adding a salt to the cured capsule slurry before washing the capsule slurry with water. 16. A polyurea capsule composition prepared by the method of claim 1 or 14. 17. The polyurea capsule composition of claim 16, wherein the polyurea capsule further comprises a deposition aid. 18. The polyurea capsule composition of claim 17, wherein the deposition aid is an anionic, cationic, nonionic or zwitterionic polymer. 19. A consumer product comprising the polyurea capsule composition of claim 16. 20. The consumer product of claim 19, wherein the consumer product is a shampoo, a hair conditioner, a soap, a body wash or other hygiene product, a cosmetic preparation, a body liquid detergent, an all-purpose cleaner, a fabric softener or refresher, an ironing water or a detergent, softener or drier sheet.
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Polyurea capsules that encapsulate active materials in polymeric walls resulting from the polymerization of an aromatic or aliphatic polyisocyanate and a cross-linking agent are provided as are consumer products containing said polyurea capsules and for methods for producing such capsules.1. A method for preparing a polyurea capsule composition comprising
(a) preparing an oil phase comprising an active material and a polyisocyanate; (b) preparing a surfactant solution; (c) emulsifying the oil phase into the surfactant solution to form a fragrance emulsion; (d) adding a cross-linking agent to the fragrance emulsion to form a capsule slurry; and (e) curing the capsule slurry. 2. The method of claim 1, wherein the active material is a fragrance oil. 3. The method of claim 1, wherein the polyisocyanate is an aromatic polyisocyanate, aliphatic polyisocyanate, or mixture thereof. 4. The method of claim 3, wherein the aromatic polyisocyanate comprises a phenyl, a toluoyl, a xylyl, a naphthyl or a diphenyl moiety. 5. The method of claim 4, wherein the aromatic isocyanate is a polyisocyanurate of toluene diisocyanate, a trimethylol propane-adduct of toluene diisocyanate or a trimethylol propane-adduct of xylylene diisocyanate. 6. The method of claim 3, wherein the aliphatic polyisocyanate is selected from the group consisting of a trimer of hexamethylene diisocyanate, a trimer of isophorone diisocyanate and a biuret of hexamethylene diisocyanate. 7. The method of claim 3, wherein the mixture of aromatic polyisocyanate and aliphatic polyisocyanate is a mixture of a biuret of hexamethylene diisocyanate and a trimethylol propane-adduct of xylylene diisocyanate. 8. The method of claim 1, wherein the surfactant is polyvinyl alcohol, polystyrene sulfonate, carboxymethyl cellulose, sodium salt of naphthalene sulfonate condensate, or a mixture thereof. 9. The method of claim 1, wherein the cross-linking agent is a polyamine. 10. The method of claim 9, wherein the cross-linking agent is diethylenetriamine, bis(3-aminopropyl)amine, bis(hexanethylene)triamine, tris(2-aminoethyl)amine, triethylenetetramine, N,N′-bis(3-aminopropyl)-1,3-propanediamine, tetraethylenepentamine, pentaethylenehexamine, branched polyethylenimine, chitosan, nisin, gelatin, 1,3-diaminoguanidine monohydrochloride, 1,1-dimethylbiguanide hydrochloride, or guanidine carbonate. 11. The method of claim 1, wherein the step of adding the cross-linking agent to the fragrance emulsion is at a temperature of 35° C. 12. The method of claim 1, wherein the step of adding the cross-linking agent to the fragrance emulsion is at a temperature of 22° C. 13. The method of claim 1, wherein the capsule slurry is cured at a temperature greater than about 55° C., 65° C., 75° C., 85° C. or 95° C. 14. The method of claim 1, further comprising the step of washing the cured capsule slurry with water. 15. The method of claim 14, further comprising the step of adding a salt to the cured capsule slurry before washing the capsule slurry with water. 16. A polyurea capsule composition prepared by the method of claim 1 or 14. 17. The polyurea capsule composition of claim 16, wherein the polyurea capsule further comprises a deposition aid. 18. The polyurea capsule composition of claim 17, wherein the deposition aid is an anionic, cationic, nonionic or zwitterionic polymer. 19. A consumer product comprising the polyurea capsule composition of claim 16. 20. The consumer product of claim 19, wherein the consumer product is a shampoo, a hair conditioner, a soap, a body wash or other hygiene product, a cosmetic preparation, a body liquid detergent, an all-purpose cleaner, a fabric softener or refresher, an ironing water or a detergent, softener or drier sheet.
| 1,600 |
995 | 13,492,173 | 1,627 |
Disclosed is a method of preparing a personal care composition wherein the composition comprising a dual cationic surfactant system of a mono-alkyl amine salt and di-alkyl cationic surfactant, high melting point fatty compounds and soluble salts, and wherein the method comprising the following steps: preparing oil phase at a higher temperature; preparing an aqueous phase at a lower temperature; and mixing them in a high shear field with a rotating member. By the addition of a soluble salt, the surfactants, together with high melting point fatty compounds, can effectively transform to emulsions.
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1. A method of preparing a personal care composition,
wherein the composition comprises: a cationic surfactant system comprising a mono-alkyl amine salt cationic surfactant and a di-alkyl cationic surfactant; a high melting point fatty compound; and an aqueous carrier, wherein the method comprises the steps: (1) preparing an oil phase comprising the surfactant and the high melting point fatty compound, wherein the temperature of the oil phase is higher than a melting point of the high melting point fatty compound; and (2) preparing an aqueous phase comprising the aqueous carrier, wherein the temperature of the aqueous phase is below the melting point of the high melting point fatty compounds; and (3) mixing the oil phase and the aqueous phase to form an emulsion; wherein the mixing step (3) comprises the following detailed steps: (3-1) feeding either of the oil phase or the aqueous phase into a high shear field having an energy density of about 1.0×102 J/m3 or more; (3-2) feeding the other phase directly to the field; and (3-3) forming an emulsion; wherein the mixing step (3) is conducted by using a homogenizer having a rotating member; wherein the oil phase contains from 0 to about 50% of the aqueous carrier by weight of the oil phase; and wherein the composition further comprises a soluble salt. 2. The method of claim 1, wherein the mixing step (3) comprises the following detailed steps:
(3-1) feeding the aqueous phase into a high shear field having an energy density of about 1.0×102 J/m3 or more ; (3-2) feeding the oil phase directly to the field; and (3-3) forming an emulsion. 3. The method of claim 1, wherein the high shear field having an energy density of from about 1.0×103 J/m3. 4. The method of claim 1, the two phases reach to the high shear field within 0.52 seconds or less, after first meeting. 5. The method of claim 1, wherein the homogenizer having a rotating member is a rotor-stator homogenizer. 6. The method of claim 1, wherein the temperature of the emulsion is from about 2° C. to about 60° C. lower than the melting point of the high melting point fatty compound. 7. The method of claim 1, wherein the level of water in oil phase is up to about 40% by weight of the oil phase. 8. The method of claim 1, wherein the level of water in oil phase is up to about 25% by weight of the oil phase. 9. The method of claim 1, wherein the emulsion is a gel matrix comprising cationic surfactant, high melting point fatty compound, and aqueous carrier. 10. The method of claim 9 wherein the weight ratio of the cationic surfactant and the high melting point fatty compound is within the range of from about 1:1 to about 1:4. 11. The method of claim 1, wherein the mono-alkyl amine salt cationic surfactant is mono-alkyl amidoamine salt cationic surfactant. 12. The method of claim 1, wherein the soluble salt is selected from the group consisting of disodium EDTA, sodium chloride, sodium citrate, sodium carbonate, and mixtures thereof. 13. The method of claim 1, wherein the soluble salt is added to the water phase. 14. A composition made by the method of claim 1.
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Disclosed is a method of preparing a personal care composition wherein the composition comprising a dual cationic surfactant system of a mono-alkyl amine salt and di-alkyl cationic surfactant, high melting point fatty compounds and soluble salts, and wherein the method comprising the following steps: preparing oil phase at a higher temperature; preparing an aqueous phase at a lower temperature; and mixing them in a high shear field with a rotating member. By the addition of a soluble salt, the surfactants, together with high melting point fatty compounds, can effectively transform to emulsions.1. A method of preparing a personal care composition,
wherein the composition comprises: a cationic surfactant system comprising a mono-alkyl amine salt cationic surfactant and a di-alkyl cationic surfactant; a high melting point fatty compound; and an aqueous carrier, wherein the method comprises the steps: (1) preparing an oil phase comprising the surfactant and the high melting point fatty compound, wherein the temperature of the oil phase is higher than a melting point of the high melting point fatty compound; and (2) preparing an aqueous phase comprising the aqueous carrier, wherein the temperature of the aqueous phase is below the melting point of the high melting point fatty compounds; and (3) mixing the oil phase and the aqueous phase to form an emulsion; wherein the mixing step (3) comprises the following detailed steps: (3-1) feeding either of the oil phase or the aqueous phase into a high shear field having an energy density of about 1.0×102 J/m3 or more; (3-2) feeding the other phase directly to the field; and (3-3) forming an emulsion; wherein the mixing step (3) is conducted by using a homogenizer having a rotating member; wherein the oil phase contains from 0 to about 50% of the aqueous carrier by weight of the oil phase; and wherein the composition further comprises a soluble salt. 2. The method of claim 1, wherein the mixing step (3) comprises the following detailed steps:
(3-1) feeding the aqueous phase into a high shear field having an energy density of about 1.0×102 J/m3 or more ; (3-2) feeding the oil phase directly to the field; and (3-3) forming an emulsion. 3. The method of claim 1, wherein the high shear field having an energy density of from about 1.0×103 J/m3. 4. The method of claim 1, the two phases reach to the high shear field within 0.52 seconds or less, after first meeting. 5. The method of claim 1, wherein the homogenizer having a rotating member is a rotor-stator homogenizer. 6. The method of claim 1, wherein the temperature of the emulsion is from about 2° C. to about 60° C. lower than the melting point of the high melting point fatty compound. 7. The method of claim 1, wherein the level of water in oil phase is up to about 40% by weight of the oil phase. 8. The method of claim 1, wherein the level of water in oil phase is up to about 25% by weight of the oil phase. 9. The method of claim 1, wherein the emulsion is a gel matrix comprising cationic surfactant, high melting point fatty compound, and aqueous carrier. 10. The method of claim 9 wherein the weight ratio of the cationic surfactant and the high melting point fatty compound is within the range of from about 1:1 to about 1:4. 11. The method of claim 1, wherein the mono-alkyl amine salt cationic surfactant is mono-alkyl amidoamine salt cationic surfactant. 12. The method of claim 1, wherein the soluble salt is selected from the group consisting of disodium EDTA, sodium chloride, sodium citrate, sodium carbonate, and mixtures thereof. 13. The method of claim 1, wherein the soluble salt is added to the water phase. 14. A composition made by the method of claim 1.
| 1,600 |
996 | 14,321,392 | 1,618 |
The invention relates to a process for preparing PCL-comprising microparticles, to microparticles obtainable by said process, to gel hence obtained and to several uses of the gel such as for the preparation of a medicament for treating a skin abnormality or disfigurement, and/or for controlling bladder function and/or controlling gastric reflux and/or for treating erectile dysfunction and/or for treating vocal cords. The gel may also be used for cosmetic applications.
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1-15. (canceled) 16. A process for preparing polycaprolactone (PCL)-comprising microparticles, wherein the process comprises:
(a) solubilizing a PCL polymer in a solvent to form a PCL polymer solution, (b) mixing the PCL polymer solution with a liquid comprising a surfactant, said liquid having a viscosity between about 20 and about 10,000 cP, (c) forming PCL-comprising microparticles from the solution. 17. The process according to claim 16, wherein the viscosity is between about 40 and about 1,000 cP. 18. The process according to claim 17, wherein the viscosity is between about 75 and about 300 cP. 19. The process according to claim 16, wherein the solvent comprises a halogen containing compound. 20. The process according to claim 19, wherein the solvent is dichloromethane. 21. The process according to claim 16, wherein the forming step comprises extracting the solvent from the PCL-comprising microparticles dispersed in the liquid by extraction evaporation. 22. The process according to claim 16, wherein the surfactant is methyl cellulose. 23. The process according to claim 22, wherein the methyl cellulose has a Mn between 41000 and 88000. 24. The process according to claim 22, wherein the methyl cellulose has a concentration between about 0.5 and about 2.5 w/w %. 25. The process according to claim 24, wherein the methyl cellulose has a concentration between about 0.8 and about 1.1 w/w %. 26. The process according to claim 16, wherein the PCL polymer is a linear polymer, a copolymer, a terpolymer or a blend of different types of homo/co/ter-polymers. 27. PCL-comprising microparticles having:
i) a diameter between 5 and 200 μm, ii) homogenous density, form and content, iii) essentially spherical and smooth surfaces, and iv) optionally, an active ingredient. 28. The microparticles according to claim 27, wherein the PCL-comprising polymer does not comprise a second monomer selected from the group consisting of glycolide, dioxanone, trimethylene carbonate and the lactides, and combinations thereof. 29. The microparticles according to claim 27, wherein the PCL-comprising polymer is a PCL homopolymer. 30. A biodegradable, injectable gel comprising microparticles according to claim 27. 31. The gel according to claim 30, comprising an anesthetic as the active ingredient. 32. The gel according to claim 30, which is an implant or a filler. 33. A medicament comprising (1) an active ingredient and (2) microparticles having:
i) a diameter between 5 and 200 μm, ii) homogenous density, form and content, iii) essentially spherical and smooth surfaces. 34. The medicament according to claim 33 which is a cosmetic. 35. A method of treating a skin abnormality or disfigurement, for controlling bladder function, for controlling gastric reflux, for treating erectile dysfunction, and/or for treating vocal cords, comprising administering to a patient in need thereof a biodegradable, injectable gel comprising microparticles according to claim 27.
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The invention relates to a process for preparing PCL-comprising microparticles, to microparticles obtainable by said process, to gel hence obtained and to several uses of the gel such as for the preparation of a medicament for treating a skin abnormality or disfigurement, and/or for controlling bladder function and/or controlling gastric reflux and/or for treating erectile dysfunction and/or for treating vocal cords. The gel may also be used for cosmetic applications.1-15. (canceled) 16. A process for preparing polycaprolactone (PCL)-comprising microparticles, wherein the process comprises:
(a) solubilizing a PCL polymer in a solvent to form a PCL polymer solution, (b) mixing the PCL polymer solution with a liquid comprising a surfactant, said liquid having a viscosity between about 20 and about 10,000 cP, (c) forming PCL-comprising microparticles from the solution. 17. The process according to claim 16, wherein the viscosity is between about 40 and about 1,000 cP. 18. The process according to claim 17, wherein the viscosity is between about 75 and about 300 cP. 19. The process according to claim 16, wherein the solvent comprises a halogen containing compound. 20. The process according to claim 19, wherein the solvent is dichloromethane. 21. The process according to claim 16, wherein the forming step comprises extracting the solvent from the PCL-comprising microparticles dispersed in the liquid by extraction evaporation. 22. The process according to claim 16, wherein the surfactant is methyl cellulose. 23. The process according to claim 22, wherein the methyl cellulose has a Mn between 41000 and 88000. 24. The process according to claim 22, wherein the methyl cellulose has a concentration between about 0.5 and about 2.5 w/w %. 25. The process according to claim 24, wherein the methyl cellulose has a concentration between about 0.8 and about 1.1 w/w %. 26. The process according to claim 16, wherein the PCL polymer is a linear polymer, a copolymer, a terpolymer or a blend of different types of homo/co/ter-polymers. 27. PCL-comprising microparticles having:
i) a diameter between 5 and 200 μm, ii) homogenous density, form and content, iii) essentially spherical and smooth surfaces, and iv) optionally, an active ingredient. 28. The microparticles according to claim 27, wherein the PCL-comprising polymer does not comprise a second monomer selected from the group consisting of glycolide, dioxanone, trimethylene carbonate and the lactides, and combinations thereof. 29. The microparticles according to claim 27, wherein the PCL-comprising polymer is a PCL homopolymer. 30. A biodegradable, injectable gel comprising microparticles according to claim 27. 31. The gel according to claim 30, comprising an anesthetic as the active ingredient. 32. The gel according to claim 30, which is an implant or a filler. 33. A medicament comprising (1) an active ingredient and (2) microparticles having:
i) a diameter between 5 and 200 μm, ii) homogenous density, form and content, iii) essentially spherical and smooth surfaces. 34. The medicament according to claim 33 which is a cosmetic. 35. A method of treating a skin abnormality or disfigurement, for controlling bladder function, for controlling gastric reflux, for treating erectile dysfunction, and/or for treating vocal cords, comprising administering to a patient in need thereof a biodegradable, injectable gel comprising microparticles according to claim 27.
| 1,600 |
997 | 15,686,919 | 1,628 |
The invention concerns the use of certain alpha 7 nicotinic acetylcholine receptor agonist for the facilitation of emergence from general anesthesia.
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1-48. (canceled) 49. A method comprising:
administering to a subject a therapeutically effective amount of an alpha 7 nicotinic acetylcholine receptor (α7 nAChR) agonist, in free base form or acid addition salt form, thereby promoting wakefulness in the subject, wherein the α7 nAChR agonist is a compound of formula (I)
wherein
L1 is —CH2—; L2 is —CH2—CH2—; and L3 is —CH2— or —CH(CH3)—; or
L1 is —CH2—CH2—; L2 is —CH2—; and L3 is —CH2—CH2—;
L4 is a group selected from
wherein the bond marked with the asterisk is attached to the azabicycloalkyl moiety;
R1 is methyl;
X1 is —O— or —NH—;
A2 is selected from
wherein the bond marked with the asterisk is attached to X1;
A1 is phenyl, indole or 1,3-dihydro-indol-2-one, which may be substituted once or more than once by R2, each R2 independently is C1-6alkyl, C1-6halogenalkyl or halogen. 50. The method of claim 49, wherein the α7 nAChR agonist of formula (I) is (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane. 51. The method of claim 49, wherein promoting wakefulness in the subject includes facilitating emergence of the subject from general anesthesia, wherein the subject has been treated with a general anesthetic agent. 52. The method of claim 51, wherein the general anesthetic agent is selected from an intravenous anesthetic, an inhalation anesthetic, and a combination thereof. 53. The method of claim 52, wherein the anesthetic agent is an intravenous anesthetic, and is selected from the group consisting of: propofol, etomidate, a barbiturate, a benzodiazepine, and ketamine. 54. The method of claim 52, wherein the anesthetic agent is an inhalation anesthetic, and is selected from the group consisting of: a halogenated ether, a halogenated ether in combination with nitrous oxide, halothane, and xenon. 55. The method of claim 51, wherein the general anesthetic agent is a combination of ketamine for an induction period and sevoflurane for a maintenance period. 56. The method of claim 51, further comprising:
intravenously administering the α7 nAChR agonist of formula (I) to the subject while concurrently administering the general anesthetic agent to the subject. 57. The method of claim 56, further comprising:
concurrently increasing a dose of the α7 nAChR agonist of formula (I) while reducing a dose of the general anesthetic agent. 58. The method of claim 51, further comprising:
administering the general anesthetic agent to the subject; and commencing intravenously administering the α7 nAChR agonist of formula (I) to the subject at or after a time at which the administering of the general anesthetic agent to the subject ceases. 59. The method of claim 51, further comprising:
intravenously administering the α7 nAChR agonist of formula (I) to the subject in an amount of 1 to 200 mg within 10 to 60 minutes. 60. The method of claim 49, wherein promoting wakefulness in the subject includes treating, preventing, or delaying progression of narcolepsy. 61. The method of claim 60, wherein the narcolepsy is one of: narcolepsy with cataplexy, narcolepsy without cataplexy, or narcolepsy due to a medical condition. 62. The method of claim 49, wherein promoting wakefulness in the subject includes treating, preventing, or delaying progression of a symptom of narcolepsy selected from: excessive daytime sleepiness, nocturnal sleep disruption, cataplexy, abnormal REM sleep, paralysis during sleep onset or during awakening, and hypnagogic hallucinations. 63. The method of claim 60, wherein the therapeutically effective amount of the α7 nAChR agonist is from 1 to 100 mg/day. 64. The method of claim 49, wherein promoting wakefulness in the subject includes treating, preventing, or delaying progression of fatigue. 65. The method of claim 64, wherein the fatigue is fatigue associated with multiple sclerosis, and is caused by (i) sleep deprivation, depression or general disabilities or (ii) lassitude. 66. The method of claim 64, wherein the fatigue is chronic fatigue syndrome. 67. The method of claim 64, wherein the fatigue is fatigue associated with an infectious disease, and wherein the fatigue is associated with HIV infection. 68. The method of claim 64, wherein the therapeutically effective amount of the α7 nAChR agonist is from 1 to 100 mg/day.
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The invention concerns the use of certain alpha 7 nicotinic acetylcholine receptor agonist for the facilitation of emergence from general anesthesia.1-48. (canceled) 49. A method comprising:
administering to a subject a therapeutically effective amount of an alpha 7 nicotinic acetylcholine receptor (α7 nAChR) agonist, in free base form or acid addition salt form, thereby promoting wakefulness in the subject, wherein the α7 nAChR agonist is a compound of formula (I)
wherein
L1 is —CH2—; L2 is —CH2—CH2—; and L3 is —CH2— or —CH(CH3)—; or
L1 is —CH2—CH2—; L2 is —CH2—; and L3 is —CH2—CH2—;
L4 is a group selected from
wherein the bond marked with the asterisk is attached to the azabicycloalkyl moiety;
R1 is methyl;
X1 is —O— or —NH—;
A2 is selected from
wherein the bond marked with the asterisk is attached to X1;
A1 is phenyl, indole or 1,3-dihydro-indol-2-one, which may be substituted once or more than once by R2, each R2 independently is C1-6alkyl, C1-6halogenalkyl or halogen. 50. The method of claim 49, wherein the α7 nAChR agonist of formula (I) is (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane. 51. The method of claim 49, wherein promoting wakefulness in the subject includes facilitating emergence of the subject from general anesthesia, wherein the subject has been treated with a general anesthetic agent. 52. The method of claim 51, wherein the general anesthetic agent is selected from an intravenous anesthetic, an inhalation anesthetic, and a combination thereof. 53. The method of claim 52, wherein the anesthetic agent is an intravenous anesthetic, and is selected from the group consisting of: propofol, etomidate, a barbiturate, a benzodiazepine, and ketamine. 54. The method of claim 52, wherein the anesthetic agent is an inhalation anesthetic, and is selected from the group consisting of: a halogenated ether, a halogenated ether in combination with nitrous oxide, halothane, and xenon. 55. The method of claim 51, wherein the general anesthetic agent is a combination of ketamine for an induction period and sevoflurane for a maintenance period. 56. The method of claim 51, further comprising:
intravenously administering the α7 nAChR agonist of formula (I) to the subject while concurrently administering the general anesthetic agent to the subject. 57. The method of claim 56, further comprising:
concurrently increasing a dose of the α7 nAChR agonist of formula (I) while reducing a dose of the general anesthetic agent. 58. The method of claim 51, further comprising:
administering the general anesthetic agent to the subject; and commencing intravenously administering the α7 nAChR agonist of formula (I) to the subject at or after a time at which the administering of the general anesthetic agent to the subject ceases. 59. The method of claim 51, further comprising:
intravenously administering the α7 nAChR agonist of formula (I) to the subject in an amount of 1 to 200 mg within 10 to 60 minutes. 60. The method of claim 49, wherein promoting wakefulness in the subject includes treating, preventing, or delaying progression of narcolepsy. 61. The method of claim 60, wherein the narcolepsy is one of: narcolepsy with cataplexy, narcolepsy without cataplexy, or narcolepsy due to a medical condition. 62. The method of claim 49, wherein promoting wakefulness in the subject includes treating, preventing, or delaying progression of a symptom of narcolepsy selected from: excessive daytime sleepiness, nocturnal sleep disruption, cataplexy, abnormal REM sleep, paralysis during sleep onset or during awakening, and hypnagogic hallucinations. 63. The method of claim 60, wherein the therapeutically effective amount of the α7 nAChR agonist is from 1 to 100 mg/day. 64. The method of claim 49, wherein promoting wakefulness in the subject includes treating, preventing, or delaying progression of fatigue. 65. The method of claim 64, wherein the fatigue is fatigue associated with multiple sclerosis, and is caused by (i) sleep deprivation, depression or general disabilities or (ii) lassitude. 66. The method of claim 64, wherein the fatigue is chronic fatigue syndrome. 67. The method of claim 64, wherein the fatigue is fatigue associated with an infectious disease, and wherein the fatigue is associated with HIV infection. 68. The method of claim 64, wherein the therapeutically effective amount of the α7 nAChR agonist is from 1 to 100 mg/day.
| 1,600 |
998 | 12,058,209 | 1,629 |
This invention relates to oral care compositions comprising an effective amount of a basic amino acid in free or salt form, together with an antibacterial agent, and to methods of using and of making such compositions.
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1. An oral care composition comprising
a. an effective amount of a basic amino acid, in free or salt form; b. an effective amount of an antibacterial agent. 2. The composition of claim 1 further comprising an anionic surfactant; an effective amount of a fluoride source; and/or an anionic polymer. 3. A composition according to claim 1 wherein the basic amino acid is arginine. 4. A composition according to claim 1 wherein the basic amino acid is in salt form and selected from arginine phosphate, arginine bicarbonate, and arginine hydrochloride. 5. A composition according to claim 1 wherein the antibacterial agent is triclosan. 6. A composition according to claim 1 wherein the antibacterial agent is selected from a stannous ion source and a zinc ion source. 7. A composition according claim 1 further comprising an anionic surfactant. 8. A composition according to claim 7 wherein the anionic surfactant is sodium lauryl sulfate. 9. A composition according to claim 1 further comprising an anionic polymer. 10. A composition according to claim 9 wherein the anionic polymer is a copolymer of methyl vinyl ether and maleic anhydride 11. A composition according to claim 1 which is a dentifrice comprising
a. an effective amount of a salt of a basic amino acid selected from arginine bicarbonate, arginine phosphate and arginine hydrochloride; b. an effective amount of triclosan; c. an effective amount of a soluble fluoride salt selected from sodium fluoride and sodium monofluophosphate; d. an anionic surfactant; and e. a copolymer of methyl vinyl ether and maleic anhydride. 12. A composition according to claim 1 further comprising xylitol. 13. A composition according to claim 1 further comprising a particulate material selected from silica and calcium carbonate. 14. A composition according to claim 1 wherein the radioactive dentin abrasion (RDA) is less than about 150. 15. The composition according to claim 1 in the form of a toothpaste further comprising one or more of water, abrasives, surfactants, foaming agents, vitamins, polymers, enzymes, humectants, thickeners, antimicrobial agents, preservatives, flavorings, colorings and/or combinations thereof. 16. A method comprising applying an effective amount of the oral composition of claim 1 to the oral cavity of a subject in need thereof to:
a. reduce or inhibit formation of dental caries, b. reduce, repair or inhibit early enamel lesions, c. reduce or inhibit demineralization and promote remineralization of the teeth, d. reduce hypersensitivity of the teeth, e. reduce or inhibit gingivitis, f. promote healing of sores or cuts in the mouth, g. reduce levels of acid producing bacteria, h. to increase relative levels of arginolytic bacteria, i. inhibit microbial biofilm formation in the oral cavity, j. raise and/or maintain plaque pH at levels of at least pH 5.5 following sugar challenge, k. reduce plaque accumulation, l. treat, relieve or reduce dry mouth, m. whiten teeth, n. enhance systemic health, including cardiovascular health, e.g., by reducing potential for systemic infection via the oral tissues, o. reduce erosion of the teeth, p. immunize or protect the teeth against cariogenic bacteria, and/or q. clean the teeth and oral cavity. 17. A method according to claim 16 to reduce or inhibit formation of dental caries or gingivitis. 18. An oral care composition comprising a basic amino acid, in free or salt form, and an antibacterial agent for use in the antibacterial treatment of an oral cavity of a subject. 19. An oral care composition according to claim 18 wherein the basic amino acid is present in an amount of from 0.1 to 20 wt % of the total composition weight. 20. An oral care composition according to claim 18 wherein the basic amino acid is present in an amount of from 1 to 10 wt % of the total composition weight. 21. An oral care composition according to 18 wherein the basic amino acid comprises arginine. 22. An oral care composition according to claim 18 wherein the antibacterial agent is present in an amount of from 0.01 to 5 wt % of the total composition weight. 23. An oral care composition according to claim 22 wherein the antibacterial agent is present in an amount of from 0.01 to 1 wt % of the total composition weight. 24. An oral care composition according to claim 18 wherein the antibacterial agent is triclosan. 25. An oral care composition according to claim 18 further comprising a soluble fluoride salt in an amount of from 0.01 to 2 wt % of the total composition weight. 26. An oral care composition according to claim 18 further comprising a source of fluoride ions in an amount to provide 50 to 25,000 ppm by weight of fluoride ions in the total composition weight. 27. An oral care composition according to claim 25 wherein the soluble fluoride salt is selected from sodium fluoride, sodium monofluorophosphate, and mixtures thereof. 28. An oral care composition according to claim 18 further comprising an anionic surfactant in an amount of from 0.01 to 10 wt % of the total composition weight. 29. An oral care composition according to claim 28 wherein the anionic surfactant is present in an amount of from 0.3 to 4.5 wt % of the total composition weight. 30. An oral care composition according to claim 28 wherein the anionic surfactant is selected from sodium lauryl sulfate, sodium laureth sulfate, and mixtures thereof. 31. An oral care composition according to claim 18 further comprising an abrasive material, the abrasive material including a small particle fraction comprising at least about 5 wt % of the total composition weight, wherein the particles of the small particle fraction have a d50 of less than 5 μm. 32. An oral care composition according to claim 31 wherein the small particle fraction comprises at least about 20 wt % of the total composition weight. 33. An oral care composition according to claim 31 wherein the abrasive material is selected from calcium carbonate, silica, and mixtures thereof. 34. An oral care composition according to claim 31 wherein the abrasive material comprises from 15 to 70 wt % of the total composition weight. 35. An oral care composition comprising an antibacterial agent and a basic amino acid, in free or salt form, for enhancing the delivery of the antibacterial agent to oral surfaces in an oral cavity of a subject. 36. An oral care composition according to claim 35 wherein the basic amino acid is present in an amount of from 0.1 to 20 wt % of the total composition weight. 37. An oral care composition according to claim 36 wherein the basic amino acid is present in an amount of from 1 to 10 wt % of the total composition weight. 38. An oral care composition according to claim 35 wherein the basic amino acid comprises arginine. 39. An oral care composition according to claim 35 wherein the antibacterial agent is present in an amount of from 0.01 to 5 wt % of the total composition weight. 40. An oral care composition according to claim 39 wherein the antibacterial agent is present in an amount of from 0.01 to 1 wt % of the total composition weight. 41. An oral care composition according to claim 35 wherein the antibacterial agent is triclosan. 42. Use of a basic amino acid, in free or salt form, in an oral care composition comprising an antibacterial agent for enhancing the delivery of the antibacterial agent to oral surfaces in an oral cavity of a subject. 43. Use according to claim 42 wherein the basic amino acid is present in an amount of from 0.1 to 20 wt % of the total composition weight. 44. Use according to claim 43 wherein the basic amino acid comprises arginine. 45. Use according to claim 42 wherein the antibacterial agent is present in an amount of from 0.01 to 5 wt % of the total composition weight. 46. Use according to claim 45 wherein the antibacterial agent is triclosan. 47. Use of a basic amino acid, in free or salt form, for the manufacture of a medicament which includes an antibacterial agent, for use in enhancing the delivery of the antibacterial agent to oral surfaces in an oral cavity of a subject. 48. A method of enhancing the delivery of an antibacterial agent in an oral care composition to oral surfaces in an oral cavity of a subject, the method comprising treating the oral cavity with an oral care composition comprising an antibacterial agent and a basic amino acid, in free or salt form.
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This invention relates to oral care compositions comprising an effective amount of a basic amino acid in free or salt form, together with an antibacterial agent, and to methods of using and of making such compositions.1. An oral care composition comprising
a. an effective amount of a basic amino acid, in free or salt form; b. an effective amount of an antibacterial agent. 2. The composition of claim 1 further comprising an anionic surfactant; an effective amount of a fluoride source; and/or an anionic polymer. 3. A composition according to claim 1 wherein the basic amino acid is arginine. 4. A composition according to claim 1 wherein the basic amino acid is in salt form and selected from arginine phosphate, arginine bicarbonate, and arginine hydrochloride. 5. A composition according to claim 1 wherein the antibacterial agent is triclosan. 6. A composition according to claim 1 wherein the antibacterial agent is selected from a stannous ion source and a zinc ion source. 7. A composition according claim 1 further comprising an anionic surfactant. 8. A composition according to claim 7 wherein the anionic surfactant is sodium lauryl sulfate. 9. A composition according to claim 1 further comprising an anionic polymer. 10. A composition according to claim 9 wherein the anionic polymer is a copolymer of methyl vinyl ether and maleic anhydride 11. A composition according to claim 1 which is a dentifrice comprising
a. an effective amount of a salt of a basic amino acid selected from arginine bicarbonate, arginine phosphate and arginine hydrochloride; b. an effective amount of triclosan; c. an effective amount of a soluble fluoride salt selected from sodium fluoride and sodium monofluophosphate; d. an anionic surfactant; and e. a copolymer of methyl vinyl ether and maleic anhydride. 12. A composition according to claim 1 further comprising xylitol. 13. A composition according to claim 1 further comprising a particulate material selected from silica and calcium carbonate. 14. A composition according to claim 1 wherein the radioactive dentin abrasion (RDA) is less than about 150. 15. The composition according to claim 1 in the form of a toothpaste further comprising one or more of water, abrasives, surfactants, foaming agents, vitamins, polymers, enzymes, humectants, thickeners, antimicrobial agents, preservatives, flavorings, colorings and/or combinations thereof. 16. A method comprising applying an effective amount of the oral composition of claim 1 to the oral cavity of a subject in need thereof to:
a. reduce or inhibit formation of dental caries, b. reduce, repair or inhibit early enamel lesions, c. reduce or inhibit demineralization and promote remineralization of the teeth, d. reduce hypersensitivity of the teeth, e. reduce or inhibit gingivitis, f. promote healing of sores or cuts in the mouth, g. reduce levels of acid producing bacteria, h. to increase relative levels of arginolytic bacteria, i. inhibit microbial biofilm formation in the oral cavity, j. raise and/or maintain plaque pH at levels of at least pH 5.5 following sugar challenge, k. reduce plaque accumulation, l. treat, relieve or reduce dry mouth, m. whiten teeth, n. enhance systemic health, including cardiovascular health, e.g., by reducing potential for systemic infection via the oral tissues, o. reduce erosion of the teeth, p. immunize or protect the teeth against cariogenic bacteria, and/or q. clean the teeth and oral cavity. 17. A method according to claim 16 to reduce or inhibit formation of dental caries or gingivitis. 18. An oral care composition comprising a basic amino acid, in free or salt form, and an antibacterial agent for use in the antibacterial treatment of an oral cavity of a subject. 19. An oral care composition according to claim 18 wherein the basic amino acid is present in an amount of from 0.1 to 20 wt % of the total composition weight. 20. An oral care composition according to claim 18 wherein the basic amino acid is present in an amount of from 1 to 10 wt % of the total composition weight. 21. An oral care composition according to 18 wherein the basic amino acid comprises arginine. 22. An oral care composition according to claim 18 wherein the antibacterial agent is present in an amount of from 0.01 to 5 wt % of the total composition weight. 23. An oral care composition according to claim 22 wherein the antibacterial agent is present in an amount of from 0.01 to 1 wt % of the total composition weight. 24. An oral care composition according to claim 18 wherein the antibacterial agent is triclosan. 25. An oral care composition according to claim 18 further comprising a soluble fluoride salt in an amount of from 0.01 to 2 wt % of the total composition weight. 26. An oral care composition according to claim 18 further comprising a source of fluoride ions in an amount to provide 50 to 25,000 ppm by weight of fluoride ions in the total composition weight. 27. An oral care composition according to claim 25 wherein the soluble fluoride salt is selected from sodium fluoride, sodium monofluorophosphate, and mixtures thereof. 28. An oral care composition according to claim 18 further comprising an anionic surfactant in an amount of from 0.01 to 10 wt % of the total composition weight. 29. An oral care composition according to claim 28 wherein the anionic surfactant is present in an amount of from 0.3 to 4.5 wt % of the total composition weight. 30. An oral care composition according to claim 28 wherein the anionic surfactant is selected from sodium lauryl sulfate, sodium laureth sulfate, and mixtures thereof. 31. An oral care composition according to claim 18 further comprising an abrasive material, the abrasive material including a small particle fraction comprising at least about 5 wt % of the total composition weight, wherein the particles of the small particle fraction have a d50 of less than 5 μm. 32. An oral care composition according to claim 31 wherein the small particle fraction comprises at least about 20 wt % of the total composition weight. 33. An oral care composition according to claim 31 wherein the abrasive material is selected from calcium carbonate, silica, and mixtures thereof. 34. An oral care composition according to claim 31 wherein the abrasive material comprises from 15 to 70 wt % of the total composition weight. 35. An oral care composition comprising an antibacterial agent and a basic amino acid, in free or salt form, for enhancing the delivery of the antibacterial agent to oral surfaces in an oral cavity of a subject. 36. An oral care composition according to claim 35 wherein the basic amino acid is present in an amount of from 0.1 to 20 wt % of the total composition weight. 37. An oral care composition according to claim 36 wherein the basic amino acid is present in an amount of from 1 to 10 wt % of the total composition weight. 38. An oral care composition according to claim 35 wherein the basic amino acid comprises arginine. 39. An oral care composition according to claim 35 wherein the antibacterial agent is present in an amount of from 0.01 to 5 wt % of the total composition weight. 40. An oral care composition according to claim 39 wherein the antibacterial agent is present in an amount of from 0.01 to 1 wt % of the total composition weight. 41. An oral care composition according to claim 35 wherein the antibacterial agent is triclosan. 42. Use of a basic amino acid, in free or salt form, in an oral care composition comprising an antibacterial agent for enhancing the delivery of the antibacterial agent to oral surfaces in an oral cavity of a subject. 43. Use according to claim 42 wherein the basic amino acid is present in an amount of from 0.1 to 20 wt % of the total composition weight. 44. Use according to claim 43 wherein the basic amino acid comprises arginine. 45. Use according to claim 42 wherein the antibacterial agent is present in an amount of from 0.01 to 5 wt % of the total composition weight. 46. Use according to claim 45 wherein the antibacterial agent is triclosan. 47. Use of a basic amino acid, in free or salt form, for the manufacture of a medicament which includes an antibacterial agent, for use in enhancing the delivery of the antibacterial agent to oral surfaces in an oral cavity of a subject. 48. A method of enhancing the delivery of an antibacterial agent in an oral care composition to oral surfaces in an oral cavity of a subject, the method comprising treating the oral cavity with an oral care composition comprising an antibacterial agent and a basic amino acid, in free or salt form.
| 1,600 |
999 | 15,532,185 | 1,699 |
The present invention relates to a method for detecting an aggregate form of an aggregate-forming polypeptide in a biosample, comprising the steps of: (a) spiking, in a biosample to be analyzed, (i) a monomeric or multimeric form of an aggregate-forming polypeptide, (ii) a hydrophobic deleted derivative of the aggregate-forming polypeptide, or (iii) a monomeric or multimeric form of the aggregate-forming polypeptide and a hydrophobic deleted derivative of the aggregate-forming polypeptide; (b) additionally forming the aggregate form of the aggregate-forming polypeptide by incubating the product of step (a); (c) making the product of step (b) come into contact with a binder-label in which a signal-generating label is coupled to a binder binding to the aggregate form of the aggregate-forming polypeptide; and (d) detecting a signal to be generated from the binder-label bound to the aggregate form of the aggregate-forming polypeptide.
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1. A method for detecting an aggregate form of an aggregate-forming polypeptide in a biosample, the method comprising the steps of:
(a) spiking, with a biosample to be analyzed, (i) a monomeric or multimeric form of the aggregate-forming polypeptide, (ii) a hydrophobic deleted derivative of the aggregate-forming polypeptide, or (iii) a monomeric or multimeric form of the aggregate-forming polypeptide and a hydrophobic deleted derivative of the aggregate-forming polypeptide; (b) additionally forming an aggregate form of the aggregate-forming polypeptide by incubating a product of step (a); (c) contacting, with a product of step (b), a binder-label in which a signal generation label is conjugated to a binder binding to the aggregate form of the aggregate-forming polypeptide; and (d) detecting a signal generated from the binder-label bound to the aggregate form of the aggregate-forming polypeptide, wherein the incubating in step (b) is carried out for a sufficient incubation time for multimerization of the spiked (i), (ii), or (iii) by the biosample. 2. The method of claim 1, wherein the biosample for performing the multimerization of the spiked (i), (ii), or (iii) is a biosample of a human being having a disease involving the multimeric form of the aggregate-forming polypeptide. 3. The method of claim 2, wherein the sufficient incubation time for the multimerization by the biosample is a time sufficient for a signal generated using the biosample of the human being having a disease involving the multimeric form of the aggregate-forming polypeptide to be 1.5-20 times greater than a signal generated using a biosample of a normal subject. 4. The method of claim 1, wherein the biosample is blood. 5. (canceled) 6. The method of claim 1, wherein the aggregate-forming polypeptide is selected from the group consisting of Aβ peptide, tau protein, prion, α-synuclein, Ig light chain, serum amyloid A, transthyretin, cystatin C, β2-microglobulin, huntingtin, superoxide dismutase, serpin, and amylin. 7. The method of claim 6, wherein the aggregate-forming polypeptide is Aβ peptide, tau protein, or α-synuclein. 8. The method of claim 1, wherein the monomeric form of the aggregate-forming polypeptide is Aβ peptide including the amino acid sequence of SEQ ID NO: 1 or α-synuclein including the amino acid sequence of SEQ ID NO: 2. 9. The method of claim 1, wherein the hydrophobic deleted derivative of the aggregate-forming polypeptide is Aβdelete peptide including the 37th amino acid residue to the 42nd amino acid residue in the amino acid sequence of SEQ ID NO: 1. 10. The method of claim 9, wherein the Aβdelete peptide is a peptide including the 29th amino acid residue to the 42nd amino acid residue in the amino acid sequence of SEQ ID NO: 1 11. The method of claim 10, wherein the Aβdelete peptide is a peptide including the 9th amino acid residue to the 42nd amino acid residue in the amino acid sequence of SEQ ID NO: 1 12. The method of claim 1, wherein a buffer is additionally added to the product of step (a). 13. The method of claim 12, wherein the buffer is added in an amount of 3-15 times (v/v) relative to an amount of the biosample. 14. The method of claim 12, wherein the buffer is a non-ionic surfactant-containing phosphate buffer. 15. The method of claim 1, wherein the additional forming of the aggregate form of aggregate-forming polypeptide in step (b) is conducted by incubating the product of step (a) at a temperature of 1-50° C. 16. The method of claim 1, wherein the additional forming of the aggregate form of the aggregate-forming polypeptide in step (b) is conducted by incubating the product of step (a) for 1 to 12 days. 17. The method of claim 1, wherein steps (c) and (d) are performed by comprising the following steps:
(c-1) contacting the product of step (b) with a capture antibody recognizing an epitope on the aggregate-forming polypeptide capturing the aggregate form; (c-2) contacting the captured aggregate form with a detection antibody recognizing an epitope on the aggregate-forming polypeptide; and (c-3) detecting an aggregate form-detection antibody complex. 18. The method of claim 17, wherein the detection antibody is a detection antibody recognizing an epitope identical to or overlapped with the epitope in step (c-1). 19. The method of claim 17, wherein the capture antibody is bound to a solid substrate. 20. The method of claim 17, wherein the detection antibody has a label generating a detectable signal. 21. The method of claim 20, wherein the label bound to the detection antibody includes a compound label, an enzyme label, a radioactive label, a fluorescent label, a luminescent label, a chemiluminescent label, and an FRET label. 22-37. (canceled)
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The present invention relates to a method for detecting an aggregate form of an aggregate-forming polypeptide in a biosample, comprising the steps of: (a) spiking, in a biosample to be analyzed, (i) a monomeric or multimeric form of an aggregate-forming polypeptide, (ii) a hydrophobic deleted derivative of the aggregate-forming polypeptide, or (iii) a monomeric or multimeric form of the aggregate-forming polypeptide and a hydrophobic deleted derivative of the aggregate-forming polypeptide; (b) additionally forming the aggregate form of the aggregate-forming polypeptide by incubating the product of step (a); (c) making the product of step (b) come into contact with a binder-label in which a signal-generating label is coupled to a binder binding to the aggregate form of the aggregate-forming polypeptide; and (d) detecting a signal to be generated from the binder-label bound to the aggregate form of the aggregate-forming polypeptide.1. A method for detecting an aggregate form of an aggregate-forming polypeptide in a biosample, the method comprising the steps of:
(a) spiking, with a biosample to be analyzed, (i) a monomeric or multimeric form of the aggregate-forming polypeptide, (ii) a hydrophobic deleted derivative of the aggregate-forming polypeptide, or (iii) a monomeric or multimeric form of the aggregate-forming polypeptide and a hydrophobic deleted derivative of the aggregate-forming polypeptide; (b) additionally forming an aggregate form of the aggregate-forming polypeptide by incubating a product of step (a); (c) contacting, with a product of step (b), a binder-label in which a signal generation label is conjugated to a binder binding to the aggregate form of the aggregate-forming polypeptide; and (d) detecting a signal generated from the binder-label bound to the aggregate form of the aggregate-forming polypeptide, wherein the incubating in step (b) is carried out for a sufficient incubation time for multimerization of the spiked (i), (ii), or (iii) by the biosample. 2. The method of claim 1, wherein the biosample for performing the multimerization of the spiked (i), (ii), or (iii) is a biosample of a human being having a disease involving the multimeric form of the aggregate-forming polypeptide. 3. The method of claim 2, wherein the sufficient incubation time for the multimerization by the biosample is a time sufficient for a signal generated using the biosample of the human being having a disease involving the multimeric form of the aggregate-forming polypeptide to be 1.5-20 times greater than a signal generated using a biosample of a normal subject. 4. The method of claim 1, wherein the biosample is blood. 5. (canceled) 6. The method of claim 1, wherein the aggregate-forming polypeptide is selected from the group consisting of Aβ peptide, tau protein, prion, α-synuclein, Ig light chain, serum amyloid A, transthyretin, cystatin C, β2-microglobulin, huntingtin, superoxide dismutase, serpin, and amylin. 7. The method of claim 6, wherein the aggregate-forming polypeptide is Aβ peptide, tau protein, or α-synuclein. 8. The method of claim 1, wherein the monomeric form of the aggregate-forming polypeptide is Aβ peptide including the amino acid sequence of SEQ ID NO: 1 or α-synuclein including the amino acid sequence of SEQ ID NO: 2. 9. The method of claim 1, wherein the hydrophobic deleted derivative of the aggregate-forming polypeptide is Aβdelete peptide including the 37th amino acid residue to the 42nd amino acid residue in the amino acid sequence of SEQ ID NO: 1. 10. The method of claim 9, wherein the Aβdelete peptide is a peptide including the 29th amino acid residue to the 42nd amino acid residue in the amino acid sequence of SEQ ID NO: 1 11. The method of claim 10, wherein the Aβdelete peptide is a peptide including the 9th amino acid residue to the 42nd amino acid residue in the amino acid sequence of SEQ ID NO: 1 12. The method of claim 1, wherein a buffer is additionally added to the product of step (a). 13. The method of claim 12, wherein the buffer is added in an amount of 3-15 times (v/v) relative to an amount of the biosample. 14. The method of claim 12, wherein the buffer is a non-ionic surfactant-containing phosphate buffer. 15. The method of claim 1, wherein the additional forming of the aggregate form of aggregate-forming polypeptide in step (b) is conducted by incubating the product of step (a) at a temperature of 1-50° C. 16. The method of claim 1, wherein the additional forming of the aggregate form of the aggregate-forming polypeptide in step (b) is conducted by incubating the product of step (a) for 1 to 12 days. 17. The method of claim 1, wherein steps (c) and (d) are performed by comprising the following steps:
(c-1) contacting the product of step (b) with a capture antibody recognizing an epitope on the aggregate-forming polypeptide capturing the aggregate form; (c-2) contacting the captured aggregate form with a detection antibody recognizing an epitope on the aggregate-forming polypeptide; and (c-3) detecting an aggregate form-detection antibody complex. 18. The method of claim 17, wherein the detection antibody is a detection antibody recognizing an epitope identical to or overlapped with the epitope in step (c-1). 19. The method of claim 17, wherein the capture antibody is bound to a solid substrate. 20. The method of claim 17, wherein the detection antibody has a label generating a detectable signal. 21. The method of claim 20, wherein the label bound to the detection antibody includes a compound label, an enzyme label, a radioactive label, a fluorescent label, a luminescent label, a chemiluminescent label, and an FRET label. 22-37. (canceled)
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