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800 | 14,089,517 | 1,633 | Disclosed is a method for amplifying RNA and/or DNA from immune cell populations and using the amplified products to produce an immune response profile and evaluate the possible correlation between a normal or abnormal immune response and the development of a disease such as an autoimmune disease, cancer, diabetes, or heart disease. | 1.-4. (canceled) 5. A composition, comprising:
(a) at least 2 V gene segment primers, and (b) at least 2 J gene segment primers,
each of said at least 2 V gene segment primers being capable of annealing to V gene segment sequence and amplifying V gene segment sequence, and each of said at least 2 J gene segment primers being capable of annealing to J gene segment sequence and amplifying J gene segment sequence,
wherein each of said V gene segment primers comprises a first sequence and a second sequence, wherein said first sequence is complementary to a portion of at least one V gene segment, wherein said first sequence is located 3′ to said second sequence on said V gene segment primer,
wherein each of said J gene segment primers comprises a first sequence and a second sequence, wherein said first sequence is complementary to a portion of a J gene segment, wherein said first sequence is located 3′ to said second sequence on said J gene segment primer, and
wherein one multiplex polymerase chain reaction (PCR) amplification of rearranged nucleic acid molecules from a sample comprising lymphocytes obtained from a human or animal subject, using said V gene segment and J gene segment primers produces non-identical amplicons sufficient to evaluate an immune response, the non-identical amplicons representing a diversity of rearranged TCR or IG sequences in the sample. 6. The composition of claim 5, wherein said first sequence of each V gene segment primer comprises sequence that is complementary to at least one or more of: a V Gamma gene segment, a V Delta gene segment, and a V Alpha gene segment, and wherein V gene segment primers allow amplification of at least one or more of: a TCR Gamma sequence, a TCR Delta sequence and a TCR Alpha sequence. 7. (canceled) 8. (canceled) 9. The composition of claim 5, wherein said first sequence of each V gene segment primer comprises a sequence that is complementary to a V Beta gene segment, and wherein the at least 2 V gene segment primers allow amplifying a TCR Beta sequence. 10. The composition of claim 5, wherein the V gene segment primers comprise SEQ ID NOS: 1-70, 73-135, 138-143, 146-155, 158-182, 190-198, and 201-223. 11. The composition of claim 5, further comprising a set of sequencing primers, wherein the sequencing primers are complementary to a region of the amplicons. 12. The composition of claim 5, wherein each of the amplicons span a VDJ rearrangement. 13. The composition of claim 5, wherein the at least two V gene segment primers comprise SEQ ID NO. 182, and the at least two J gene segment primers comprise SEQ ID NO: 183. 14. The composition of claim 5, further comprising a C segment primer for generating cDNA from mRNA. 15. The composition of claim 9, wherein the at least 2 V gene segment primers consist of at least 14 primers specific for 14 different V Beta genes. 16. The composition of claim 9, wherein each V-segment is complementary to at least one V gene segment primer. 17. The composition of claim 9, wherein the primers comprise SEQ ID NOS: 76 and 78. 18. A composition comprising:
(a) at least 2 V gene segment primers, and (b) at least 2 J gene segment primers,
each of said at least 2 V gene segment primers being capable of annealing to V gene segment sequence and amplifying V gene segment sequence, and each of said at least 2 J gene segment primers being capable of annealing to J gene segment sequence and amplifying J gene segment sequence,
wherein each of said V gene segment primers comprises a first sequence and a second sequence, wherein said first sequence is complementary to a portion of at least one V gene segment, wherein said first sequence is located 3′ to said second sequence on said V gene segment primer,
wherein each of said J gene segment primers has a first sequence and a second sequence, wherein said first sequence is complementary to a portion of a first region of a J gene segment, wherein said first sequence is located 3′ to said second sequence on said J gene segment primer, and
wherein one multiplex polymerase chain reaction (PCR) amplification of rearranged nucleic acid molecules of an immunoglobulin heavy chain (IGH) VH gene segment from a sample comprising lymphocytes obtained from a human or animal subject, using said V gene segment and J gene segment primers produces non-identical amplicons sufficient to evaluate an immune response, the non-identical amplicons representing a diversity of rearranged TCR or IG sequences in said sample. 19. A composition comprising:
(a) at least 2 V gene segment primers, and (b) at least 2 J gene segment primers,
each of said at least 2 V gene segment primers being capable of annealing to V gene segment sequence and amplifying V gene segment sequence, and each of said at least 2 J gene segment primers being capable of annealing to J gene segment sequence and amplifying J gene segment sequence,
wherein each of said V gene segment primers comprises a first sequence and a second sequence, wherein said first sequence is complementary to a portion of at least one V gene segment, wherein said first sequence is located 3′ to said second sequence on said V gene segment primer,
wherein each of said J gene segment primers comprises a first sequence and a second sequence, wherein said first sequence is complementary to a portion of a J gene segment, wherein said first sequence is located 3′ to said second sequence on said J gene segment primer, and wherein one multiplex polymerase chain reaction (PCR) amplification of rearranged nucleic acid molecules of an immunoglobulin light chain V gene segment from a sample comprising lymphocytes obtained from a human or animal subject, using said V gene segment primers and J gene segment primers produces non-identical amplicons sufficient to evaluate an immune response, the non-identical amplicons representing a diversity of rearranged immunoglobulin light chain sequences in the sample. 20. A method comprising:
(a) selecting at least 2 V gene segment primers of claim 5; and (b) selecting at least 2 J gene segment primers of claim 5; (c) combining the V gene segment and J gene segment primers with genomic DNA comprising rearranged nucleic acid molecules of a TCR region from lymphocytes obtained from a human or animal subject; (d) amplifying said rearranged nucleic acid molecules from said sample using said V gene segment and J gene segment primers, thereby producing non-identical amplicons sufficient to evaluate an immune response, the non-identical amplicons representing a diversity of TCR genes. 21. The method of claim 20, wherein said first sequence of each V gene segment primer comprises a sequence that is complementary to a V Beta gene segment. 22. The method of claim 20, further comprising sequencing the amplicons. 23. The method of claim 22, wherein sequencing utilizes a set of sequencing primers that are complementary to a defined region within the amplicons. 24. The method of claim 23, further comprising quantifying non-identical DNA sequences representing T-cell receptor Beta rearrangements among the amplicons. 25. The method of claim 24, wherein the method allows amplification of the entire immunorepertoire of a human. 26. A method of determining if a human subject lacks functional B or T cells to fight a disease, comprising:
(i) quantifying non-identical amplicons sufficient to evaluate an immune response, the non-identical amplicons representing a diversity of rearranged TCR sequences of the subject, wherein the quantifying non-identical amplicons sufficient to evaluate an immune response, the non-identical amplicons representing a diversity of rearranged TCR sequences comprises the steps of:
(a) selecting at least 2 V gene segment primers and at least 2 J gene segment primers of claim 5; and
(b) combining the V gene segment and J gene segment primers with a sample of genomic DNA comprising rearranged nucleic acid molecules of a TCR from lymphocytes obtained from the subject;
(c) amplifying said rearranged nucleic acid molecules from said sample using said V gene segment and J gene segment primers, thereby producing non-identical amplicons sufficient to evaluate an immune response, the non-identical amplicons representing a diversity of TCR genes in the sample;
(d) sequencing the amplicons;
(e) quantifying the diversity of TCR rearrangements among the amplicons for said subject to generate an immune status profile of TCR rearrangements; and
(ii) comparing the immune status profile of TCR rearrangements of said subject to an immune status profile of TCR rearrangements obtained from a normal subject. 27. The method of claim 26, wherein the immune status profile of at least two samples of genomic DNA are compared. 28. The method of claim 27, wherein one sample of genomic DNA is from a patient and the other sample is from a normal subject. 29. The method of claim 27, wherein one sample of genomic DNA is from a patient before a treatment and the other sample is from the patient after treatment. 30. The method of claim 27, wherein the two samples of genomic DNA are from the same patient at different times during treatment. 31. The method of claim 27, in which a disease is diagnosed based on the comparison of immune status profiles among the samples of genomic DNA. 32. (canceled) 33. The composition of claim 5, wherein the sample comprises genomic DNA, and/or cDNA transcribed from RNA, obtained from the human or animal subject. 34. (canceled) 35. The composition of claim 5, wherein the V gene segment and J gene segment primers are capable of amplifying TCR or IG sequences in the one multiplex polymerase chain reaction (PCR) to produce non-identical amplicons sufficient to evaluate an immune response, the non-identical amplicons representing a diversity of rearranged TCR or IG sequences in the sample. 36. The composition of claim 5, wherein said second sequence of each of said V gene and/or J gene segment primers comprises a sequencing primer sequence. 37. (canceled) 38. The composition of claim 5, wherein the at least two V gene segment primers comprise SEQ ID NOS: 160 and 173. 39. The composition claim 5, wherein the at least two J segment primers comprise SEQ ID NO: 183. 40-43. (canceled) | Disclosed is a method for amplifying RNA and/or DNA from immune cell populations and using the amplified products to produce an immune response profile and evaluate the possible correlation between a normal or abnormal immune response and the development of a disease such as an autoimmune disease, cancer, diabetes, or heart disease.1.-4. (canceled) 5. A composition, comprising:
(a) at least 2 V gene segment primers, and (b) at least 2 J gene segment primers,
each of said at least 2 V gene segment primers being capable of annealing to V gene segment sequence and amplifying V gene segment sequence, and each of said at least 2 J gene segment primers being capable of annealing to J gene segment sequence and amplifying J gene segment sequence,
wherein each of said V gene segment primers comprises a first sequence and a second sequence, wherein said first sequence is complementary to a portion of at least one V gene segment, wherein said first sequence is located 3′ to said second sequence on said V gene segment primer,
wherein each of said J gene segment primers comprises a first sequence and a second sequence, wherein said first sequence is complementary to a portion of a J gene segment, wherein said first sequence is located 3′ to said second sequence on said J gene segment primer, and
wherein one multiplex polymerase chain reaction (PCR) amplification of rearranged nucleic acid molecules from a sample comprising lymphocytes obtained from a human or animal subject, using said V gene segment and J gene segment primers produces non-identical amplicons sufficient to evaluate an immune response, the non-identical amplicons representing a diversity of rearranged TCR or IG sequences in the sample. 6. The composition of claim 5, wherein said first sequence of each V gene segment primer comprises sequence that is complementary to at least one or more of: a V Gamma gene segment, a V Delta gene segment, and a V Alpha gene segment, and wherein V gene segment primers allow amplification of at least one or more of: a TCR Gamma sequence, a TCR Delta sequence and a TCR Alpha sequence. 7. (canceled) 8. (canceled) 9. The composition of claim 5, wherein said first sequence of each V gene segment primer comprises a sequence that is complementary to a V Beta gene segment, and wherein the at least 2 V gene segment primers allow amplifying a TCR Beta sequence. 10. The composition of claim 5, wherein the V gene segment primers comprise SEQ ID NOS: 1-70, 73-135, 138-143, 146-155, 158-182, 190-198, and 201-223. 11. The composition of claim 5, further comprising a set of sequencing primers, wherein the sequencing primers are complementary to a region of the amplicons. 12. The composition of claim 5, wherein each of the amplicons span a VDJ rearrangement. 13. The composition of claim 5, wherein the at least two V gene segment primers comprise SEQ ID NO. 182, and the at least two J gene segment primers comprise SEQ ID NO: 183. 14. The composition of claim 5, further comprising a C segment primer for generating cDNA from mRNA. 15. The composition of claim 9, wherein the at least 2 V gene segment primers consist of at least 14 primers specific for 14 different V Beta genes. 16. The composition of claim 9, wherein each V-segment is complementary to at least one V gene segment primer. 17. The composition of claim 9, wherein the primers comprise SEQ ID NOS: 76 and 78. 18. A composition comprising:
(a) at least 2 V gene segment primers, and (b) at least 2 J gene segment primers,
each of said at least 2 V gene segment primers being capable of annealing to V gene segment sequence and amplifying V gene segment sequence, and each of said at least 2 J gene segment primers being capable of annealing to J gene segment sequence and amplifying J gene segment sequence,
wherein each of said V gene segment primers comprises a first sequence and a second sequence, wherein said first sequence is complementary to a portion of at least one V gene segment, wherein said first sequence is located 3′ to said second sequence on said V gene segment primer,
wherein each of said J gene segment primers has a first sequence and a second sequence, wherein said first sequence is complementary to a portion of a first region of a J gene segment, wherein said first sequence is located 3′ to said second sequence on said J gene segment primer, and
wherein one multiplex polymerase chain reaction (PCR) amplification of rearranged nucleic acid molecules of an immunoglobulin heavy chain (IGH) VH gene segment from a sample comprising lymphocytes obtained from a human or animal subject, using said V gene segment and J gene segment primers produces non-identical amplicons sufficient to evaluate an immune response, the non-identical amplicons representing a diversity of rearranged TCR or IG sequences in said sample. 19. A composition comprising:
(a) at least 2 V gene segment primers, and (b) at least 2 J gene segment primers,
each of said at least 2 V gene segment primers being capable of annealing to V gene segment sequence and amplifying V gene segment sequence, and each of said at least 2 J gene segment primers being capable of annealing to J gene segment sequence and amplifying J gene segment sequence,
wherein each of said V gene segment primers comprises a first sequence and a second sequence, wherein said first sequence is complementary to a portion of at least one V gene segment, wherein said first sequence is located 3′ to said second sequence on said V gene segment primer,
wherein each of said J gene segment primers comprises a first sequence and a second sequence, wherein said first sequence is complementary to a portion of a J gene segment, wherein said first sequence is located 3′ to said second sequence on said J gene segment primer, and wherein one multiplex polymerase chain reaction (PCR) amplification of rearranged nucleic acid molecules of an immunoglobulin light chain V gene segment from a sample comprising lymphocytes obtained from a human or animal subject, using said V gene segment primers and J gene segment primers produces non-identical amplicons sufficient to evaluate an immune response, the non-identical amplicons representing a diversity of rearranged immunoglobulin light chain sequences in the sample. 20. A method comprising:
(a) selecting at least 2 V gene segment primers of claim 5; and (b) selecting at least 2 J gene segment primers of claim 5; (c) combining the V gene segment and J gene segment primers with genomic DNA comprising rearranged nucleic acid molecules of a TCR region from lymphocytes obtained from a human or animal subject; (d) amplifying said rearranged nucleic acid molecules from said sample using said V gene segment and J gene segment primers, thereby producing non-identical amplicons sufficient to evaluate an immune response, the non-identical amplicons representing a diversity of TCR genes. 21. The method of claim 20, wherein said first sequence of each V gene segment primer comprises a sequence that is complementary to a V Beta gene segment. 22. The method of claim 20, further comprising sequencing the amplicons. 23. The method of claim 22, wherein sequencing utilizes a set of sequencing primers that are complementary to a defined region within the amplicons. 24. The method of claim 23, further comprising quantifying non-identical DNA sequences representing T-cell receptor Beta rearrangements among the amplicons. 25. The method of claim 24, wherein the method allows amplification of the entire immunorepertoire of a human. 26. A method of determining if a human subject lacks functional B or T cells to fight a disease, comprising:
(i) quantifying non-identical amplicons sufficient to evaluate an immune response, the non-identical amplicons representing a diversity of rearranged TCR sequences of the subject, wherein the quantifying non-identical amplicons sufficient to evaluate an immune response, the non-identical amplicons representing a diversity of rearranged TCR sequences comprises the steps of:
(a) selecting at least 2 V gene segment primers and at least 2 J gene segment primers of claim 5; and
(b) combining the V gene segment and J gene segment primers with a sample of genomic DNA comprising rearranged nucleic acid molecules of a TCR from lymphocytes obtained from the subject;
(c) amplifying said rearranged nucleic acid molecules from said sample using said V gene segment and J gene segment primers, thereby producing non-identical amplicons sufficient to evaluate an immune response, the non-identical amplicons representing a diversity of TCR genes in the sample;
(d) sequencing the amplicons;
(e) quantifying the diversity of TCR rearrangements among the amplicons for said subject to generate an immune status profile of TCR rearrangements; and
(ii) comparing the immune status profile of TCR rearrangements of said subject to an immune status profile of TCR rearrangements obtained from a normal subject. 27. The method of claim 26, wherein the immune status profile of at least two samples of genomic DNA are compared. 28. The method of claim 27, wherein one sample of genomic DNA is from a patient and the other sample is from a normal subject. 29. The method of claim 27, wherein one sample of genomic DNA is from a patient before a treatment and the other sample is from the patient after treatment. 30. The method of claim 27, wherein the two samples of genomic DNA are from the same patient at different times during treatment. 31. The method of claim 27, in which a disease is diagnosed based on the comparison of immune status profiles among the samples of genomic DNA. 32. (canceled) 33. The composition of claim 5, wherein the sample comprises genomic DNA, and/or cDNA transcribed from RNA, obtained from the human or animal subject. 34. (canceled) 35. The composition of claim 5, wherein the V gene segment and J gene segment primers are capable of amplifying TCR or IG sequences in the one multiplex polymerase chain reaction (PCR) to produce non-identical amplicons sufficient to evaluate an immune response, the non-identical amplicons representing a diversity of rearranged TCR or IG sequences in the sample. 36. The composition of claim 5, wherein said second sequence of each of said V gene and/or J gene segment primers comprises a sequencing primer sequence. 37. (canceled) 38. The composition of claim 5, wherein the at least two V gene segment primers comprise SEQ ID NOS: 160 and 173. 39. The composition claim 5, wherein the at least two J segment primers comprise SEQ ID NO: 183. 40-43. (canceled) | 1,600 |
801 | 14,915,517 | 1,617 | The invention relates to a cosmetic composition comprising, in a physiologically acceptable aqueous medium, a polysaccharide modified with hydrophobic chains; a polymer comprising sulfonic groups; a (meth)acrylic acid polymer, which is preferably crosslinked, and/or an oxyethylenated silicone surfactant.
Use for caring for and making up keratin materials. | 1. A composition, comprising, in a physiologically acceptable aqueous medium:
i) at least one polymer comprising a sulfonic group; ii) at least one polysaccharide modified with hydrophobic chains; and iii) at least one (meth)acrylic acid polymer, silicone surfactant which is an oxyethylenated polydimethylsiloxane, or both. 2. The composition of claim 1, wherein the polysaccharide is a fructan comprising hydrophobic chains. 3. The composition of claim 1, wherein the hydrophobic chains of the polysaccharide are
linear or branched, saturated or unsaturated hydrocarbon-based chains containing from 1 to 50 carbon atoms; divalent cycloaliphatic groups or organopolysiloxane chains comprising one or more ester, amide, urethane, carbamate, thiocarbamate, urea, thiourea and/or sulfonamide functions; or divalent aromatic groups. 4. The composition of claim 2, wherein the fructan comprises inulin having a degree of polymerization from 2 to about 1000 and a degree of substitution of less than 2 on the basis of one fructose unit. 5. The composition of claim 1, wherein the hydrophobic chains comprise at least one alkyl carbamate group of formula R—NH—CO— in which R is an alkyl group comprising from 1 to 22 carbon atoms. 6. The composition of claim 1, wherein the hydrophobic chains are lauryl carbamate groups. 7. The composition of claim 1, wherein the polysaccharide is present in a content ranging from 0.01% to 20% by weight, relative to the total weight of the composition. 8. The composition of claim 1, wherein the polymer comprising a sulfonic group is a 2-acrylamido-2-methylpropanesulfonic acid polymer. 9. The composition of claim 1, wherein the polymer comprising a sulfonic group is a crosslinked 2-acrylamido-2-methylpropanesulfonic acid homopolymer. 10. The composition of claim 1, wherein the polymer comprising sulfonic groups is present in a content ranging from 0.05% to 5% by weight, relative to the total weight of the composition. 11. The composition of claim 1, comprising the (meth)acrylic acid polymer which is an acrylic acid homopolymer. 12. The composition of claim 1, comprising an acrylic acid polymer is present in an amount ranging from 0.01% to 5% by weight relative to the total weight of the composition. 13. The composition of claim 1, comprising a silicone surfactant comprising from 2 to 50 mol of ethylene oxide. 14. The composition of claim 1, comprising the silicone surfactant in an amount ranging from 0.01% to 5% by weight relative to the total weight of the composition. 15. The composition of claim 1, comprising:
i) the at least one polymer comprising a sulfonic group; ii) the at least one polysaccharide modified with hydrophobic chains; iii) the at least one (meth)acrylic acid polymer; and iv) the at least one silicone surfactant which is an oxyethylenated polydimethylsiloxane. 16. The composition of claim 1, further comprising at least one active agent, pigment, nacre, filler, or mixture thereof. 17. The composition of claim 1, further comprising an active agent selected from the group consisting of a benzenediol derivative, a derivative, a mushroom extract, a peptide, salicylic, a salicylic acid derivative, a C-glycoside derivative, an algal extract, and a mixture thereof. 18. The composition of claim 1, further comprising a benzenediol derivative active agent which is a compound of formula (II):
wherein:
Y is H, an alkyl or alkenyl group comprising from 1 to 8 carbon atoms, a phenyl, Na+, K+ or NH4 +,
R1 is from H, a linear or branched, saturated or unsaturated alkyl group comprising from 1 to 18 carbon atoms, a —C(═O)—R2 group, in which R2 is a linear or branched, saturated or unsaturated alkyl group comprising from 1 to 17 carbon atoms or a —(CH2)n—COOX group in which n is between 0 and 17, and X is chosen from H, an alkyl or alkenyl group comprising from 1 to 8 carbon atoms, a phenyl, Na+, K+ or NH4 +,
or one of its salts of organic or inorganic bases, or one of its enantiomers. 19. The composition of claim 18, wherein R1 is a methyl and Y is H. 20. The composition of claim 1, further comprising a C-glycoside derivative active agent having formula (IV):
wherein:
R denotes an unsubstituted linear C1-C4 alkyl radical;
S represents a monosaccharide chosen from D-glucose, D-xylose, N-acetyl-D-glucosamine and L-fucose;
X represents a group chosen from —CO—, —CH(OH)—, —CH(NH2)—; and
isomers thereof and mixtures thereof. 21. The composition of claim 1, further comprising a salicylic acid derivative active agent having formula (III):
wherein:
the radical Ra denotes:
a linear, branched or cyclic, saturated aliphatic chain containing from 2 to 22 carbon atoms;
an unsaturated chain containing from 2 to 22 carbon atoms, containing one or more double bonds which may be conjugated;
an aromatic nucleus bonded to the carbonyl radical directly or by saturated or unsaturated aliphatic chains containing from 2 to 7 carbon atoms;
it being possible for said groups to be substituted with one or more identical or different substituents chosen from:
(i) halogen atoms,
(ii) trifluoromethyl group,
(iii) hydroxyl groups in free form or in a form esterified with an acid containing from 1 to 6 carbon atoms, or
(iv) a carboxyl function in free form or in a form esterified with a lower alcohol containing from 1 to 6 carbon atoms;
Rb is a hydroxyl group;
or a salt thereof derived from an inorganic or organic base. 22. The composition of claim 1, further comprising a mushroom extract active agent which is a Grifola frondosa extract. 23. The composition of claim 1, further comprising a peptide active agent. 24. The composition of claim 1, which is in the form of an oil-in-water emulsion. 25. The composition of claim 1, further comprising a cosmetic additive selected from the group consisting of an emulsifier, a gelling agent, an oil, a wax, a preserving agent, an antioxidant, water, a fragrance, a UV screen, a fiber, a chelating agent, an odor absorber, a colorant and a mixture thereof. 26. A non-therapeutic cosmetic treatment process, comprising applying the composition of claim 1 to a keratin material. | The invention relates to a cosmetic composition comprising, in a physiologically acceptable aqueous medium, a polysaccharide modified with hydrophobic chains; a polymer comprising sulfonic groups; a (meth)acrylic acid polymer, which is preferably crosslinked, and/or an oxyethylenated silicone surfactant.
Use for caring for and making up keratin materials.1. A composition, comprising, in a physiologically acceptable aqueous medium:
i) at least one polymer comprising a sulfonic group; ii) at least one polysaccharide modified with hydrophobic chains; and iii) at least one (meth)acrylic acid polymer, silicone surfactant which is an oxyethylenated polydimethylsiloxane, or both. 2. The composition of claim 1, wherein the polysaccharide is a fructan comprising hydrophobic chains. 3. The composition of claim 1, wherein the hydrophobic chains of the polysaccharide are
linear or branched, saturated or unsaturated hydrocarbon-based chains containing from 1 to 50 carbon atoms; divalent cycloaliphatic groups or organopolysiloxane chains comprising one or more ester, amide, urethane, carbamate, thiocarbamate, urea, thiourea and/or sulfonamide functions; or divalent aromatic groups. 4. The composition of claim 2, wherein the fructan comprises inulin having a degree of polymerization from 2 to about 1000 and a degree of substitution of less than 2 on the basis of one fructose unit. 5. The composition of claim 1, wherein the hydrophobic chains comprise at least one alkyl carbamate group of formula R—NH—CO— in which R is an alkyl group comprising from 1 to 22 carbon atoms. 6. The composition of claim 1, wherein the hydrophobic chains are lauryl carbamate groups. 7. The composition of claim 1, wherein the polysaccharide is present in a content ranging from 0.01% to 20% by weight, relative to the total weight of the composition. 8. The composition of claim 1, wherein the polymer comprising a sulfonic group is a 2-acrylamido-2-methylpropanesulfonic acid polymer. 9. The composition of claim 1, wherein the polymer comprising a sulfonic group is a crosslinked 2-acrylamido-2-methylpropanesulfonic acid homopolymer. 10. The composition of claim 1, wherein the polymer comprising sulfonic groups is present in a content ranging from 0.05% to 5% by weight, relative to the total weight of the composition. 11. The composition of claim 1, comprising the (meth)acrylic acid polymer which is an acrylic acid homopolymer. 12. The composition of claim 1, comprising an acrylic acid polymer is present in an amount ranging from 0.01% to 5% by weight relative to the total weight of the composition. 13. The composition of claim 1, comprising a silicone surfactant comprising from 2 to 50 mol of ethylene oxide. 14. The composition of claim 1, comprising the silicone surfactant in an amount ranging from 0.01% to 5% by weight relative to the total weight of the composition. 15. The composition of claim 1, comprising:
i) the at least one polymer comprising a sulfonic group; ii) the at least one polysaccharide modified with hydrophobic chains; iii) the at least one (meth)acrylic acid polymer; and iv) the at least one silicone surfactant which is an oxyethylenated polydimethylsiloxane. 16. The composition of claim 1, further comprising at least one active agent, pigment, nacre, filler, or mixture thereof. 17. The composition of claim 1, further comprising an active agent selected from the group consisting of a benzenediol derivative, a derivative, a mushroom extract, a peptide, salicylic, a salicylic acid derivative, a C-glycoside derivative, an algal extract, and a mixture thereof. 18. The composition of claim 1, further comprising a benzenediol derivative active agent which is a compound of formula (II):
wherein:
Y is H, an alkyl or alkenyl group comprising from 1 to 8 carbon atoms, a phenyl, Na+, K+ or NH4 +,
R1 is from H, a linear or branched, saturated or unsaturated alkyl group comprising from 1 to 18 carbon atoms, a —C(═O)—R2 group, in which R2 is a linear or branched, saturated or unsaturated alkyl group comprising from 1 to 17 carbon atoms or a —(CH2)n—COOX group in which n is between 0 and 17, and X is chosen from H, an alkyl or alkenyl group comprising from 1 to 8 carbon atoms, a phenyl, Na+, K+ or NH4 +,
or one of its salts of organic or inorganic bases, or one of its enantiomers. 19. The composition of claim 18, wherein R1 is a methyl and Y is H. 20. The composition of claim 1, further comprising a C-glycoside derivative active agent having formula (IV):
wherein:
R denotes an unsubstituted linear C1-C4 alkyl radical;
S represents a monosaccharide chosen from D-glucose, D-xylose, N-acetyl-D-glucosamine and L-fucose;
X represents a group chosen from —CO—, —CH(OH)—, —CH(NH2)—; and
isomers thereof and mixtures thereof. 21. The composition of claim 1, further comprising a salicylic acid derivative active agent having formula (III):
wherein:
the radical Ra denotes:
a linear, branched or cyclic, saturated aliphatic chain containing from 2 to 22 carbon atoms;
an unsaturated chain containing from 2 to 22 carbon atoms, containing one or more double bonds which may be conjugated;
an aromatic nucleus bonded to the carbonyl radical directly or by saturated or unsaturated aliphatic chains containing from 2 to 7 carbon atoms;
it being possible for said groups to be substituted with one or more identical or different substituents chosen from:
(i) halogen atoms,
(ii) trifluoromethyl group,
(iii) hydroxyl groups in free form or in a form esterified with an acid containing from 1 to 6 carbon atoms, or
(iv) a carboxyl function in free form or in a form esterified with a lower alcohol containing from 1 to 6 carbon atoms;
Rb is a hydroxyl group;
or a salt thereof derived from an inorganic or organic base. 22. The composition of claim 1, further comprising a mushroom extract active agent which is a Grifola frondosa extract. 23. The composition of claim 1, further comprising a peptide active agent. 24. The composition of claim 1, which is in the form of an oil-in-water emulsion. 25. The composition of claim 1, further comprising a cosmetic additive selected from the group consisting of an emulsifier, a gelling agent, an oil, a wax, a preserving agent, an antioxidant, water, a fragrance, a UV screen, a fiber, a chelating agent, an odor absorber, a colorant and a mixture thereof. 26. A non-therapeutic cosmetic treatment process, comprising applying the composition of claim 1 to a keratin material. | 1,600 |
802 | 13,700,175 | 1,615 | The present invention relates to balloon catheters with or without crimped stent, whose surface is coated with at least one antirestenotic agent and at least one transport promoting molecular dispersant, as well as a method for the preparation of these medical devices. | 1.-15. (canceled) 16. A catheter balloon with or without crimped stent, wherein the surface of the catheter balloon is coated at least partially with at least one antirestenotic agent and at least one transport promoting molecular dispersant, wherein the at least one transport promoting molecular dispersant is at least one compound of general formula (I):
wherein
X1 represents one of the following residues
-L1-R18, —C(R3)(R4)-L1-R18, -L1-C(R3)(R4)—R18, —C(R3)(R4)-L1-C(R5)(R6)—R18, -L1-Y—R18, —Y-L1-R18, —Y—C(R3)(R4)-L1-R18, —C(R3)(R4)—Y-L1-R18, —C(R3)(R4)-L1-Y—R18, —Y-L1-C(R3)(R4)—R18, -L1-Y—C(R3)(R4)—R18, -L1-C(R3)(R4)—Y—R18, —Y—C(R3)(R4)-L1-C(R5)(R6)—R18, —C(R3)(R4)—Y-L1-C(R5)(R6)—R18, —C(R3)(R4)-L1-Y—C(R5)(R6)—R18, —C(R3)(R4)-L1-C(R5)(R6)—Y—R18;
X2 represents one of the following residues
—R7, (—CH2—)p—R7, (—O—CH2—)p—R7;
X3 represents one of the following residues
-M1-R26, -M1-M2-R26, -M1-(M2)r-M3-R26, -M1-(M2)r-M3-(M4)s-R26;
X4 represents one of the following residues
-L2-R19, —C(R10)(R11)-L2-R19, -L2-C(R10)(R11)—R19, —C(R10)(R11)—C(R12)(R13)-L2-R19, —C(R10)(R11)-L2-C(R12)(R13)—R19, L2-C(R10)(R11)—C(R12)(R13)—R19;
L1 represents one of the following groups
L2 represents one of the following groups
—O—CO—, —NH—CO—, —CO—, —O—, —NH—, —CO—O—, —CO—NH—, —NH—CO—O—, —O—CO—NH—, —O—CO—O—, —NH—CO—NH—;
M1 represents one of the following groups
M2 represents one of the following groups
—CH2—, —CH2—CH2—, —CH2—CH2—CH2—, —CH2—CH2—CH2—CH2—, —O—, —O—CH2—, —O—CH2—CH2—, —O—CH2—CH2—CH2—, —O—CH2—CH2—CH2—CH2—, —O—CO—, —O—CO—CH2—, —O—CO—CH2—CH2—, —O—CO—CH2—CH2—CH2—, —O—CO—CH2—CH2—CH2—CH2—, —CO—, —CO—CH2—, —CO—CH2—CH2—, —CO—CH2—CH2—CH2—, —CO—CH2—CH2—CH2—CH2—;
M3 represents one of the following groups
a bond, —NH—, —NH—CO—, —NH—CO—NH—, —NH—CS—, —NH—CS—NH—, —NH—C(NH)—NH—;
M4 represents one of the following groups
(—CH2—O—CH2—)t, (—O—CH2—CH2—)t, (—CH2—CH2—O—)t;
Y represents (—CH2—)m, (—CH2—O—)m, (—O—CH2—)m, (—CH2—CH2—O—)m, or (—CH2—CH2—CH2—O—)m;
R1 to R13 represent independently of each other the following residues: —R14 to —R30, —OH, —OCH3, —OC2H5, —OC3H7, —O-cyclo-C3H5, —OCH(CH3)2, —OC(CH3)3, —OC4H9, —OPh, —OCH2-Ph, —OCPh3, —SH, —SCH3, —SC2H5, —SC3H7, —S-cyclo-C3H5, —SCH(CH3)2, —SC(CH3)3, —NO2, —F, —Cl, —Br, —I, —P(O)(OH)2, —P(O)(OCH3)2, —P(O)(OC2H5)2, —P(O)(OCH(CH3)2)2, —C(OH)[P(O)(OH)2]2, —Si(CH3)2(C(CH3)3), —Si(C2H5)3, —Si(CH3)3, —N3, —CN, —OCN, —NCO, —SCN, —NCS, —CHO, —COCH3, —COC2H5, —COC3H7, —CO-cyclo-C3H5, —COCH(CH3)2, —COC(CH3)3, —COOH, —COCN, —COOCH3, —COOC2H5, —COOC3H7, —COO-cyclo-C3H5, —COOCH(CH3)2, —COOC(CH3)3, —O—CO—R14, —CONH2, —CONHCH3, —CONHC2H5, —CONHC3H7, —CONH-cyclo-C3H5, —CONH[CH(CH3)2], —CONH[C(CH3)3], —CON(CH3)2, —CON(C2H5)2, —CON(C3H7)2, —CON(cyclo-C3H5)2, —CON[CH(CH3)2]2, —CON[C(CH3)3]2, —NHCOCH3, —NHCOC2H5, —NHCOC3H7, —NHCO-cyclo-C3H5, —NHCO—CH(CH3)2, —NHCO—C(CH3)3, —NHCO—OCH3, —NHCO—OC2H5, —NHCO—OC3H7, —NHCO—O-cyclo-C3H5, —NHCO—OCH(CH3)2, —NHCO—OC(CH3)3, —NH2, —NHCH3, —NHC2H5, —NHC3H7, —NH-cyclo-C3H5, —NHCH(CH3)2, —NHC(CH3)3, —N(CH3)2, —N(C2H5)2, —N(C3H7)2, —N(cyclo-C3H5)2, —N[CH(CH3)2]2, —N[C(CH3)3]2, —SOCH3, —SOC2H5, —SOC3H7, —SO-cyclo-C3H5, —SOCH(CH3)2, —SOC(CH3)3, —SO2CH3, —SO2C2H5, —SO2C3H7, —SO2-cyclo-C3H5, —SO2CH(CH3)2, —SO2C(CH3)3, —SO3H, —SO3CH3, —SO3C2H5, —SO3C3H7, —SO3-cyclo-C3H5, —SO3CH(CH3)2, —SO3C(CH3)3, —SO2NH2, —OCF3, —OC2F5, —O—COOCH3, —O—COOC2H5, —O—COOC3H7, —O—COO-cyclo-C3H5, —O—COOCH(CH3)2, —O—COOC(CH3)3, —NH—CO—NH2, —NH—CO—NHCH3, —NH—CO—NHC2H5, —NH—CO—NHC3H7, —NH—CO—NH-cyclo-C3H5, —NH—CO—NH[CH(CH3)2], —NH—CO—NH[C(CH3)3], —NH—CO—N(CH3)2, —NH—CO—N(C2H5)2, —NH—CO—N(C3H7)2, —NH—CO—N(cyclo-C3H5)2, —NH—CO—N[CH(CH3)2]2, —NH—CO—N[C(CH3)3]2, —NH—CS—NH2, —NH—CS—NHCH3, —NH—CS—NHC2H5, —NH—CS—NHC3H7, —NH—CS—NH-cyclo-C3H5, —NH—CS—NH[CH(CH3)2], —NH—CS—NH[C(CH3)3], —NH—CS—N(CH3)2, —NH—CS—N(C2H5)2, —NH—CS—N(C3H7)2, —NH—CS—N(cyclo-C3H5)2, —NH—CS—N[CH(CH3)2]2, —NH—CS—N[C(CH3)3]2, —NH—C(═NH)—NH2, —NH—C(═NH)—NHCH3, —NH—C(═NH)—NHC2H5, —NH—C(═NH)—NHC3H7, —NH—C(═NH)—NH-cyclo-C3H5, —NH—C(═NH)—NH[CH(CH3)2], —NH—C(═NH)—NH[C(CH3)3], —NH—C(═NH)—N(CH3)2, —NH—C(═NH)—N(C2H5)2, —NH—C(═NH)—N(C3H7)2, —NH—C(═NH)—N(cyclo-C3H5)2, —NH—C(═NH)—N[CH(CH3)2]2, —NH—C(═NH)—N[C(CH3)3]2, —O—CO—NH2, —O—CO—NHCH3, —O—CO—NHC2H5, —O—CO—NHC3H7, —O—CO—NH-cyclo-C3H5, —O—CO—NH[CH(CH3)2], —O—CO—NH[C(CH3)3], —O—CO—N(CH3)2, —O—CO—N(C2H5)2, —O—CO—N(C3H7)2, —O—CO—N(cyclo-C3H5)2, —O—CO—N[CH(CH3)2]2, —O—CO—N[C(CH3)3]2, —O—CO—OCH3, —O—CO—OC2H5, —O—CO—OC3H7, —O—CO—O-cyclo-C3H5, —O—CO—OCH(CH3)2, —O—CO—OC(CH3)3;
R14 to R30 represent independently of each other the following residues:
—CH2F, —CHF2, —CF3, —CH2Cl, —CH2Br, —CH2I, —CH2—CH2F, —CH2—CHF2, —CH2—CF3, —CH2—CH2Cl, —CH2—CH2Br, —CH2—CH2I, cyclo-C3H5, cyclo-C4H7, cyclo-C5H9, cyclo-C6H11, cyclo-C7H13, cyclo-C8H15, -Ph, —CH2-Ph, —CPh3, —H, —CH3, —C2H5, —C3H7, —CH(CH3)2, —C4H9, —CH2—CH(CH3)2, —CH(CH3)—C2H5, —C(CH3)3, —CH(CH3)—C3H7, —CH2—CH(CH3)—C2H5, —CH(CH3)—CH(CH3)2, —C(CH3)2—C2H5, —CH2—C(CH3)3, —CH(C2H5)2, —C2H4—CH(CH3)2, —C6H13, —C7H15, —C8H17, —C3H6—CH(CH3)2, —C2H4—CH(CH3)—C2H5, —CH(CH3)—C4H9, —CH2—CH(CH3)—C3H7, —CH(CH3)—CH2—CH(CH3)2, —CH(CH3)—CH(CH3)—C2H5, —CH2—CH(CH3)—CH(CH3)2, —CH2—C(CH3)2—C2H5, —C(CH3)2—C3H7, —C(CH3)2—CH(CH3)2, —C2H4—C(CH3)3, —CH(CH3)—C(CH3)3, —CH═CH2, —CH2—CH═CH2, —C(CH3)═CH2, —CH═CH—CH3, —C2H4—CH═CH2, —CH2—CH═CH—CH3, —CH═CH—C2H5, —CH2—C(CH3)═CH2, —CH(CH3)—CH═CH, —CH═C(CH3)2, —C(CH3)═CH—CH3, —CH═CH—CH═CH2, —C3H6—CH═CH2, —C2H4—CH═CH—CH3, —CH2—CH═CH—C2H5, —CH═CH—C3H7, —CH2—CH═CH—CH═CH2, —CH═CH—CH═CH—CH3, —CH═CH—CH2—CH═CH2, —C(CH3)═CH—CH═CH2, —CH═C(CH3)—CH═CH2, —CH═CH—C(CH3)═CH2, —C2H4—C(CH3)═CH2, —CH2—CH(CH3)—CH═CH2, —CH(CH3)—CH2—CH═CH2, —CH2—CH═C(CH3)2, —CH2—C(CH3)═CH—CH3, —CH(CH3)—CH═CH—CH3, —CH═CH—CH(CH3)2, —CH═C(CH3)—C2H5, —C(CH3)═CH—C2H5, —C(CH3)═C(CH3)2, —C(CH3)2—CH═CH2, —CH(CH3)—C(CH3)═CH2, —C(CH3)═CH—CH═CH2, —CH═C(CH3)—CH═CH2, —CH═CH—C(CH3)═CH2, —C4H8—CH═CH2, —C3H6—CH═CH—CH3, —C2H4—CH═CH—C2H5, —CH2—CH═CH—C3H7, —CH═CH—C4H9, —C3H6—C(CH3)═CH2, —C2H4—CH(CH3)—CH═CH2, —CH2—CH(CH3)—CH2—CH═CH2, —CH(CH3)—C2H4—CH═CH2, —C2H4—CH═C(CH3)2, —C2H4—C(CH3)═CH—CH3, —CH2—CH(CH3)—CH═CH—CH3, —CH(CH3)—CH2—CH═CH—CH3, —CH2—CH═CH—CH(CH3)2, —CH2—CH═C(CH3)—C2H5, —CH2—C(CH3)═CH—C2H5, —CH(CH3)—CH═CH—C2H5, —CH═CH—CH2—CH(CH3)2, —CH═CH—CH(CH3)—C2H5, —CH═C(CH3)—C3H7, —C(CH3)═CH—C3H7, —CH2—CH(CH3)—C(CH3)═CH2, —CH(CH3)—CH2—C(CH3)═CH2, —CH(CH3)—CH(CH3)—CH═CH2, —CH2—C(CH3)2—CH═CH2, —C(CH3)2—CH2—CH═CH2, —CH2—C(CH3)═C(CH3)2, —CH(CH3)—CH═C(CH3)2, —C(CH3)2—CH═CH—CH3, —CH(CH3)—C(CH3)═CH—CH3, —CH═C(CH3)—CH(CH3)2, —C(CH3)═CH—CH(CH3)2, —C(CH3)═C(CH3)—C2H5, —CH═CH—C(CH3)3, —C(CH3)2—C(CH3)═CH2, —CH(C2H5)—C(CH3)═CH2, —C(CH3)(C2H5)—CH═CH2, —CH(CH3)—C(C2H5)═CH2, —CH2—C(C3H7)═CH2, —CH2—C(C2H5)═CH—CH3, —CH(C2H5)—CH═CH—CH3, —C(C4H9)═CH2, —C(C3H7)═CH—CH3, —C(C2H5)═CH—C2H5, —C(C2H5)═C(CH3)2, —C[C(CH3)3]═CH2, —C[CH(CH3)(C2H5)]═CH2, —C[CH2—CH(CH3)2]═CH2, —C2H4—CH═CH—CH═CH2, —CH2—CH═CH—CH2—CH═CH2, —CH═CH—C2H4—CH═CH2, —CH2—CH═CH—CH═CH—CH3, —CH═CH—CH2—CH═CH—CH3, —CH═CH—CH═CH—C2H5, —CH2—CH═CH—C(CH3)═CH2, —CH2—CH═C(CH3)—CH═CH2, —CH2—C(CH3)═CH—CH═CH2, —CH(CH3)—CH═CH—CH═CH2, —CH═CH—CH2—C(CH3)═CH2, —CH═CH—CH(CH3)—CH═CH2, —CH═C(CH3)—CH2—CH═CH2, —C(CH3)═CH—CH2—CH═CH2, —CH═CH—CH═C(CH3)2, —CH═CH—C(CH3)═CH—CH3, —CH═C(CH3)—CH═CH—CH3, —C(CH3)═CH—CH═CH—CH3, —CH═C(CH3)—C(CH3)═CH2, —C(CH3)═CH—C(CH3)═CH2, —C(CH3)═C(CH3)—CH═CH2, —CH═CH—CH═CH—CH═CH2, —C≡CH, —C≡C—CH3, —CH2—C≡CH, —C2H4—C≡CH, —CH2—C≡C—CH3, —C≡C—C2H5, —C3H6—C≡CH, —C2H4—C≡C—CH3, —CH2—C≡C—C2H5, —C≡C—C3H7, —CH(CH3)—C≡CH, —CH2—CH(CH3)—C≡CH, —CH(CH3)—CH2—C≡CH, —CH(CH3)—C≡C—CH3, —C4H8—C≡CH, —C3H6—C≡C—CH3, —C2H4—C≡C—C2H5, —CH2—C≡C—C3H7, —C≡C—C4H9, —C2H4—CH(CH3)—C≡CH, —CH2—CH(CH3)—CH2—C≡CH, —CH(CH3)—C2H4—C≡CH, —CH2—CH(CH3)—C≡C—CH3, —CH(CH3)—CH2—C≡C—CH3, —CH(CH3)—C≡C—C2H5, —CH2—C≡C—CH(CH3)2, —C≡C—CH(CH3)—C2H5, —C≡C—CH2—CH(CH3)2, —C≡C—C(CH3)3, —CH(C2H5)—C≡C—CH3, —C(CH3)2—C≡C—CH3, —CH(C2H5)—CH2—C≡CH, —CH2—CH(C2H5)—C≡CH, —C(CH3)2—CH2—C≡CH, —CH2—C(CH3)2—C≡CH, —CH(CH3)—CH(CH3)—C≡CH, —CH(C3H7)—C≡CH, —C(CH3)(C2H5)—C≡CH, —C≡C—C≡CH, —CH2—C≡C—C≡CH, —C≡C—C≡C—CH3, —CH(C≡CH)2, —C2H4—C≡C—C≡CH, —CH2—C≡C—CH2—C≡CH, —C≡C—C2H4—C≡CH, —CH2—C≡C—C≡C—CH3, —C≡C—CH2—C≡C—CH3, —C≡C—C≡C—C2H5, —C≡C—CH(CH3)—C≡CH, —CH(CH3)—C≡C—C≡CH, —CH(C≡CH)—CH2—C≡CH, —C(C≡CH)2—CH3, —CH2—CH(C≡CH)2, —CH(C≡CH)—C≡C—CH3,
m is an integer from 1 to 10;
n is an integer from 0 to 5;
p is an integer from 0 to 3;
q is an integer from 0 to 4;
r represents 0 or 1;
s represents 0 or 1;
t is an integer from 1 to 10. 17. The catheter balloon according to claim 16, wherein the at least one antirestenotic agent is embedded or stored in the at least one transport promoting molecular dispersant. 18. The catheter balloon according to claim 16, wherein the amount ratio of the antirestenotic agent and the at least one transport promoting molecular dispersant is from 90 wt % antirestenotic agent to 10 wt % transport promoting molecular dispersant to 10 wt % antirestenotic agent to 90 wt % transport promoting molecular dispersant. 19. The catheter balloon according to claim 16, wherein the at least one antirestenotic agent is selected from the group comprising or consisting of: paclitaxel, docetaxel, sirolimus, biolimus A9, zotarolimus, everolimus, myolimus, novolimus, pimecrolimus, tacrolimus, ridaforolimus and temsirolimus. 20. The catheter balloon according to claim 19, wherein the at least one antirestenotic agent is paclitaxel. 21. The catheter balloon according to claim 19, wherein the at least one antirestenotic agent is sirolimus. 22. The catheter balloon according to claim 16, wherein the compound according to general formula (I) has a boiling point of at least 500° C. (at atmospheric pressure). 23. The catheter balloon according to claim 16, wherein the compound according to general formula (I) contains 7 to 9 oxygen atoms. 24. The catheter balloon according to claim 16, wherein the compound according to general formula (I) has a molar mass (molecular weight) of at least 500 g/mol. 25. The catheter balloon according to claim 16, wherein the compound according to general formula (I) has a melting point of above −60° C. 26. The catheter balloon according to claim 16, wherein the compound according to general formula (I) has a density from 0.95 g/cm3 to 1.05 g/cm3. 27. The catheter balloon according to claim 16, wherein the compound according to general formula (I) has a flash point of above 100° C. 28. The catheter balloon according to claim 16, wherein the compound according to general formula (I) has a refractive index nD 20 between 1.440 and 1.460. 29. A method for the preparation of a catheter balloon according to claim 16 comprising:
a) providing a catheter balloon of a balloon catheter;
b) providing a coating solution of the at least one antirestenotic agent and the at least one transport promoting molecular dispersant in a solvent or solvent mixture;
c) coating of the catheter balloon with the coating solution by means of dipping, spreading, spraying, brushing or pipetting procedure; and
d) drying the applied coating. | The present invention relates to balloon catheters with or without crimped stent, whose surface is coated with at least one antirestenotic agent and at least one transport promoting molecular dispersant, as well as a method for the preparation of these medical devices.1.-15. (canceled) 16. A catheter balloon with or without crimped stent, wherein the surface of the catheter balloon is coated at least partially with at least one antirestenotic agent and at least one transport promoting molecular dispersant, wherein the at least one transport promoting molecular dispersant is at least one compound of general formula (I):
wherein
X1 represents one of the following residues
-L1-R18, —C(R3)(R4)-L1-R18, -L1-C(R3)(R4)—R18, —C(R3)(R4)-L1-C(R5)(R6)—R18, -L1-Y—R18, —Y-L1-R18, —Y—C(R3)(R4)-L1-R18, —C(R3)(R4)—Y-L1-R18, —C(R3)(R4)-L1-Y—R18, —Y-L1-C(R3)(R4)—R18, -L1-Y—C(R3)(R4)—R18, -L1-C(R3)(R4)—Y—R18, —Y—C(R3)(R4)-L1-C(R5)(R6)—R18, —C(R3)(R4)—Y-L1-C(R5)(R6)—R18, —C(R3)(R4)-L1-Y—C(R5)(R6)—R18, —C(R3)(R4)-L1-C(R5)(R6)—Y—R18;
X2 represents one of the following residues
—R7, (—CH2—)p—R7, (—O—CH2—)p—R7;
X3 represents one of the following residues
-M1-R26, -M1-M2-R26, -M1-(M2)r-M3-R26, -M1-(M2)r-M3-(M4)s-R26;
X4 represents one of the following residues
-L2-R19, —C(R10)(R11)-L2-R19, -L2-C(R10)(R11)—R19, —C(R10)(R11)—C(R12)(R13)-L2-R19, —C(R10)(R11)-L2-C(R12)(R13)—R19, L2-C(R10)(R11)—C(R12)(R13)—R19;
L1 represents one of the following groups
L2 represents one of the following groups
—O—CO—, —NH—CO—, —CO—, —O—, —NH—, —CO—O—, —CO—NH—, —NH—CO—O—, —O—CO—NH—, —O—CO—O—, —NH—CO—NH—;
M1 represents one of the following groups
M2 represents one of the following groups
—CH2—, —CH2—CH2—, —CH2—CH2—CH2—, —CH2—CH2—CH2—CH2—, —O—, —O—CH2—, —O—CH2—CH2—, —O—CH2—CH2—CH2—, —O—CH2—CH2—CH2—CH2—, —O—CO—, —O—CO—CH2—, —O—CO—CH2—CH2—, —O—CO—CH2—CH2—CH2—, —O—CO—CH2—CH2—CH2—CH2—, —CO—, —CO—CH2—, —CO—CH2—CH2—, —CO—CH2—CH2—CH2—, —CO—CH2—CH2—CH2—CH2—;
M3 represents one of the following groups
a bond, —NH—, —NH—CO—, —NH—CO—NH—, —NH—CS—, —NH—CS—NH—, —NH—C(NH)—NH—;
M4 represents one of the following groups
(—CH2—O—CH2—)t, (—O—CH2—CH2—)t, (—CH2—CH2—O—)t;
Y represents (—CH2—)m, (—CH2—O—)m, (—O—CH2—)m, (—CH2—CH2—O—)m, or (—CH2—CH2—CH2—O—)m;
R1 to R13 represent independently of each other the following residues: —R14 to —R30, —OH, —OCH3, —OC2H5, —OC3H7, —O-cyclo-C3H5, —OCH(CH3)2, —OC(CH3)3, —OC4H9, —OPh, —OCH2-Ph, —OCPh3, —SH, —SCH3, —SC2H5, —SC3H7, —S-cyclo-C3H5, —SCH(CH3)2, —SC(CH3)3, —NO2, —F, —Cl, —Br, —I, —P(O)(OH)2, —P(O)(OCH3)2, —P(O)(OC2H5)2, —P(O)(OCH(CH3)2)2, —C(OH)[P(O)(OH)2]2, —Si(CH3)2(C(CH3)3), —Si(C2H5)3, —Si(CH3)3, —N3, —CN, —OCN, —NCO, —SCN, —NCS, —CHO, —COCH3, —COC2H5, —COC3H7, —CO-cyclo-C3H5, —COCH(CH3)2, —COC(CH3)3, —COOH, —COCN, —COOCH3, —COOC2H5, —COOC3H7, —COO-cyclo-C3H5, —COOCH(CH3)2, —COOC(CH3)3, —O—CO—R14, —CONH2, —CONHCH3, —CONHC2H5, —CONHC3H7, —CONH-cyclo-C3H5, —CONH[CH(CH3)2], —CONH[C(CH3)3], —CON(CH3)2, —CON(C2H5)2, —CON(C3H7)2, —CON(cyclo-C3H5)2, —CON[CH(CH3)2]2, —CON[C(CH3)3]2, —NHCOCH3, —NHCOC2H5, —NHCOC3H7, —NHCO-cyclo-C3H5, —NHCO—CH(CH3)2, —NHCO—C(CH3)3, —NHCO—OCH3, —NHCO—OC2H5, —NHCO—OC3H7, —NHCO—O-cyclo-C3H5, —NHCO—OCH(CH3)2, —NHCO—OC(CH3)3, —NH2, —NHCH3, —NHC2H5, —NHC3H7, —NH-cyclo-C3H5, —NHCH(CH3)2, —NHC(CH3)3, —N(CH3)2, —N(C2H5)2, —N(C3H7)2, —N(cyclo-C3H5)2, —N[CH(CH3)2]2, —N[C(CH3)3]2, —SOCH3, —SOC2H5, —SOC3H7, —SO-cyclo-C3H5, —SOCH(CH3)2, —SOC(CH3)3, —SO2CH3, —SO2C2H5, —SO2C3H7, —SO2-cyclo-C3H5, —SO2CH(CH3)2, —SO2C(CH3)3, —SO3H, —SO3CH3, —SO3C2H5, —SO3C3H7, —SO3-cyclo-C3H5, —SO3CH(CH3)2, —SO3C(CH3)3, —SO2NH2, —OCF3, —OC2F5, —O—COOCH3, —O—COOC2H5, —O—COOC3H7, —O—COO-cyclo-C3H5, —O—COOCH(CH3)2, —O—COOC(CH3)3, —NH—CO—NH2, —NH—CO—NHCH3, —NH—CO—NHC2H5, —NH—CO—NHC3H7, —NH—CO—NH-cyclo-C3H5, —NH—CO—NH[CH(CH3)2], —NH—CO—NH[C(CH3)3], —NH—CO—N(CH3)2, —NH—CO—N(C2H5)2, —NH—CO—N(C3H7)2, —NH—CO—N(cyclo-C3H5)2, —NH—CO—N[CH(CH3)2]2, —NH—CO—N[C(CH3)3]2, —NH—CS—NH2, —NH—CS—NHCH3, —NH—CS—NHC2H5, —NH—CS—NHC3H7, —NH—CS—NH-cyclo-C3H5, —NH—CS—NH[CH(CH3)2], —NH—CS—NH[C(CH3)3], —NH—CS—N(CH3)2, —NH—CS—N(C2H5)2, —NH—CS—N(C3H7)2, —NH—CS—N(cyclo-C3H5)2, —NH—CS—N[CH(CH3)2]2, —NH—CS—N[C(CH3)3]2, —NH—C(═NH)—NH2, —NH—C(═NH)—NHCH3, —NH—C(═NH)—NHC2H5, —NH—C(═NH)—NHC3H7, —NH—C(═NH)—NH-cyclo-C3H5, —NH—C(═NH)—NH[CH(CH3)2], —NH—C(═NH)—NH[C(CH3)3], —NH—C(═NH)—N(CH3)2, —NH—C(═NH)—N(C2H5)2, —NH—C(═NH)—N(C3H7)2, —NH—C(═NH)—N(cyclo-C3H5)2, —NH—C(═NH)—N[CH(CH3)2]2, —NH—C(═NH)—N[C(CH3)3]2, —O—CO—NH2, —O—CO—NHCH3, —O—CO—NHC2H5, —O—CO—NHC3H7, —O—CO—NH-cyclo-C3H5, —O—CO—NH[CH(CH3)2], —O—CO—NH[C(CH3)3], —O—CO—N(CH3)2, —O—CO—N(C2H5)2, —O—CO—N(C3H7)2, —O—CO—N(cyclo-C3H5)2, —O—CO—N[CH(CH3)2]2, —O—CO—N[C(CH3)3]2, —O—CO—OCH3, —O—CO—OC2H5, —O—CO—OC3H7, —O—CO—O-cyclo-C3H5, —O—CO—OCH(CH3)2, —O—CO—OC(CH3)3;
R14 to R30 represent independently of each other the following residues:
—CH2F, —CHF2, —CF3, —CH2Cl, —CH2Br, —CH2I, —CH2—CH2F, —CH2—CHF2, —CH2—CF3, —CH2—CH2Cl, —CH2—CH2Br, —CH2—CH2I, cyclo-C3H5, cyclo-C4H7, cyclo-C5H9, cyclo-C6H11, cyclo-C7H13, cyclo-C8H15, -Ph, —CH2-Ph, —CPh3, —H, —CH3, —C2H5, —C3H7, —CH(CH3)2, —C4H9, —CH2—CH(CH3)2, —CH(CH3)—C2H5, —C(CH3)3, —CH(CH3)—C3H7, —CH2—CH(CH3)—C2H5, —CH(CH3)—CH(CH3)2, —C(CH3)2—C2H5, —CH2—C(CH3)3, —CH(C2H5)2, —C2H4—CH(CH3)2, —C6H13, —C7H15, —C8H17, —C3H6—CH(CH3)2, —C2H4—CH(CH3)—C2H5, —CH(CH3)—C4H9, —CH2—CH(CH3)—C3H7, —CH(CH3)—CH2—CH(CH3)2, —CH(CH3)—CH(CH3)—C2H5, —CH2—CH(CH3)—CH(CH3)2, —CH2—C(CH3)2—C2H5, —C(CH3)2—C3H7, —C(CH3)2—CH(CH3)2, —C2H4—C(CH3)3, —CH(CH3)—C(CH3)3, —CH═CH2, —CH2—CH═CH2, —C(CH3)═CH2, —CH═CH—CH3, —C2H4—CH═CH2, —CH2—CH═CH—CH3, —CH═CH—C2H5, —CH2—C(CH3)═CH2, —CH(CH3)—CH═CH, —CH═C(CH3)2, —C(CH3)═CH—CH3, —CH═CH—CH═CH2, —C3H6—CH═CH2, —C2H4—CH═CH—CH3, —CH2—CH═CH—C2H5, —CH═CH—C3H7, —CH2—CH═CH—CH═CH2, —CH═CH—CH═CH—CH3, —CH═CH—CH2—CH═CH2, —C(CH3)═CH—CH═CH2, —CH═C(CH3)—CH═CH2, —CH═CH—C(CH3)═CH2, —C2H4—C(CH3)═CH2, —CH2—CH(CH3)—CH═CH2, —CH(CH3)—CH2—CH═CH2, —CH2—CH═C(CH3)2, —CH2—C(CH3)═CH—CH3, —CH(CH3)—CH═CH—CH3, —CH═CH—CH(CH3)2, —CH═C(CH3)—C2H5, —C(CH3)═CH—C2H5, —C(CH3)═C(CH3)2, —C(CH3)2—CH═CH2, —CH(CH3)—C(CH3)═CH2, —C(CH3)═CH—CH═CH2, —CH═C(CH3)—CH═CH2, —CH═CH—C(CH3)═CH2, —C4H8—CH═CH2, —C3H6—CH═CH—CH3, —C2H4—CH═CH—C2H5, —CH2—CH═CH—C3H7, —CH═CH—C4H9, —C3H6—C(CH3)═CH2, —C2H4—CH(CH3)—CH═CH2, —CH2—CH(CH3)—CH2—CH═CH2, —CH(CH3)—C2H4—CH═CH2, —C2H4—CH═C(CH3)2, —C2H4—C(CH3)═CH—CH3, —CH2—CH(CH3)—CH═CH—CH3, —CH(CH3)—CH2—CH═CH—CH3, —CH2—CH═CH—CH(CH3)2, —CH2—CH═C(CH3)—C2H5, —CH2—C(CH3)═CH—C2H5, —CH(CH3)—CH═CH—C2H5, —CH═CH—CH2—CH(CH3)2, —CH═CH—CH(CH3)—C2H5, —CH═C(CH3)—C3H7, —C(CH3)═CH—C3H7, —CH2—CH(CH3)—C(CH3)═CH2, —CH(CH3)—CH2—C(CH3)═CH2, —CH(CH3)—CH(CH3)—CH═CH2, —CH2—C(CH3)2—CH═CH2, —C(CH3)2—CH2—CH═CH2, —CH2—C(CH3)═C(CH3)2, —CH(CH3)—CH═C(CH3)2, —C(CH3)2—CH═CH—CH3, —CH(CH3)—C(CH3)═CH—CH3, —CH═C(CH3)—CH(CH3)2, —C(CH3)═CH—CH(CH3)2, —C(CH3)═C(CH3)—C2H5, —CH═CH—C(CH3)3, —C(CH3)2—C(CH3)═CH2, —CH(C2H5)—C(CH3)═CH2, —C(CH3)(C2H5)—CH═CH2, —CH(CH3)—C(C2H5)═CH2, —CH2—C(C3H7)═CH2, —CH2—C(C2H5)═CH—CH3, —CH(C2H5)—CH═CH—CH3, —C(C4H9)═CH2, —C(C3H7)═CH—CH3, —C(C2H5)═CH—C2H5, —C(C2H5)═C(CH3)2, —C[C(CH3)3]═CH2, —C[CH(CH3)(C2H5)]═CH2, —C[CH2—CH(CH3)2]═CH2, —C2H4—CH═CH—CH═CH2, —CH2—CH═CH—CH2—CH═CH2, —CH═CH—C2H4—CH═CH2, —CH2—CH═CH—CH═CH—CH3, —CH═CH—CH2—CH═CH—CH3, —CH═CH—CH═CH—C2H5, —CH2—CH═CH—C(CH3)═CH2, —CH2—CH═C(CH3)—CH═CH2, —CH2—C(CH3)═CH—CH═CH2, —CH(CH3)—CH═CH—CH═CH2, —CH═CH—CH2—C(CH3)═CH2, —CH═CH—CH(CH3)—CH═CH2, —CH═C(CH3)—CH2—CH═CH2, —C(CH3)═CH—CH2—CH═CH2, —CH═CH—CH═C(CH3)2, —CH═CH—C(CH3)═CH—CH3, —CH═C(CH3)—CH═CH—CH3, —C(CH3)═CH—CH═CH—CH3, —CH═C(CH3)—C(CH3)═CH2, —C(CH3)═CH—C(CH3)═CH2, —C(CH3)═C(CH3)—CH═CH2, —CH═CH—CH═CH—CH═CH2, —C≡CH, —C≡C—CH3, —CH2—C≡CH, —C2H4—C≡CH, —CH2—C≡C—CH3, —C≡C—C2H5, —C3H6—C≡CH, —C2H4—C≡C—CH3, —CH2—C≡C—C2H5, —C≡C—C3H7, —CH(CH3)—C≡CH, —CH2—CH(CH3)—C≡CH, —CH(CH3)—CH2—C≡CH, —CH(CH3)—C≡C—CH3, —C4H8—C≡CH, —C3H6—C≡C—CH3, —C2H4—C≡C—C2H5, —CH2—C≡C—C3H7, —C≡C—C4H9, —C2H4—CH(CH3)—C≡CH, —CH2—CH(CH3)—CH2—C≡CH, —CH(CH3)—C2H4—C≡CH, —CH2—CH(CH3)—C≡C—CH3, —CH(CH3)—CH2—C≡C—CH3, —CH(CH3)—C≡C—C2H5, —CH2—C≡C—CH(CH3)2, —C≡C—CH(CH3)—C2H5, —C≡C—CH2—CH(CH3)2, —C≡C—C(CH3)3, —CH(C2H5)—C≡C—CH3, —C(CH3)2—C≡C—CH3, —CH(C2H5)—CH2—C≡CH, —CH2—CH(C2H5)—C≡CH, —C(CH3)2—CH2—C≡CH, —CH2—C(CH3)2—C≡CH, —CH(CH3)—CH(CH3)—C≡CH, —CH(C3H7)—C≡CH, —C(CH3)(C2H5)—C≡CH, —C≡C—C≡CH, —CH2—C≡C—C≡CH, —C≡C—C≡C—CH3, —CH(C≡CH)2, —C2H4—C≡C—C≡CH, —CH2—C≡C—CH2—C≡CH, —C≡C—C2H4—C≡CH, —CH2—C≡C—C≡C—CH3, —C≡C—CH2—C≡C—CH3, —C≡C—C≡C—C2H5, —C≡C—CH(CH3)—C≡CH, —CH(CH3)—C≡C—C≡CH, —CH(C≡CH)—CH2—C≡CH, —C(C≡CH)2—CH3, —CH2—CH(C≡CH)2, —CH(C≡CH)—C≡C—CH3,
m is an integer from 1 to 10;
n is an integer from 0 to 5;
p is an integer from 0 to 3;
q is an integer from 0 to 4;
r represents 0 or 1;
s represents 0 or 1;
t is an integer from 1 to 10. 17. The catheter balloon according to claim 16, wherein the at least one antirestenotic agent is embedded or stored in the at least one transport promoting molecular dispersant. 18. The catheter balloon according to claim 16, wherein the amount ratio of the antirestenotic agent and the at least one transport promoting molecular dispersant is from 90 wt % antirestenotic agent to 10 wt % transport promoting molecular dispersant to 10 wt % antirestenotic agent to 90 wt % transport promoting molecular dispersant. 19. The catheter balloon according to claim 16, wherein the at least one antirestenotic agent is selected from the group comprising or consisting of: paclitaxel, docetaxel, sirolimus, biolimus A9, zotarolimus, everolimus, myolimus, novolimus, pimecrolimus, tacrolimus, ridaforolimus and temsirolimus. 20. The catheter balloon according to claim 19, wherein the at least one antirestenotic agent is paclitaxel. 21. The catheter balloon according to claim 19, wherein the at least one antirestenotic agent is sirolimus. 22. The catheter balloon according to claim 16, wherein the compound according to general formula (I) has a boiling point of at least 500° C. (at atmospheric pressure). 23. The catheter balloon according to claim 16, wherein the compound according to general formula (I) contains 7 to 9 oxygen atoms. 24. The catheter balloon according to claim 16, wherein the compound according to general formula (I) has a molar mass (molecular weight) of at least 500 g/mol. 25. The catheter balloon according to claim 16, wherein the compound according to general formula (I) has a melting point of above −60° C. 26. The catheter balloon according to claim 16, wherein the compound according to general formula (I) has a density from 0.95 g/cm3 to 1.05 g/cm3. 27. The catheter balloon according to claim 16, wherein the compound according to general formula (I) has a flash point of above 100° C. 28. The catheter balloon according to claim 16, wherein the compound according to general formula (I) has a refractive index nD 20 between 1.440 and 1.460. 29. A method for the preparation of a catheter balloon according to claim 16 comprising:
a) providing a catheter balloon of a balloon catheter;
b) providing a coating solution of the at least one antirestenotic agent and the at least one transport promoting molecular dispersant in a solvent or solvent mixture;
c) coating of the catheter balloon with the coating solution by means of dipping, spreading, spraying, brushing or pipetting procedure; and
d) drying the applied coating. | 1,600 |
803 | 14,912,776 | 1,631 | Automated methods of preparing patient samples for assays are disclosed. The methods include performing sample processing of multiple patient samples in multiple extraction wells of an extraction plate to prepare multiple eluded samples in at least some of the multiple extraction wells, and transferring, based upon an electronic plate map including multiple assay regions, one of the multiple eluded samples from a single extraction well of the multiple extraction wells into multiple test wells of the test plate, wherein each of the multiple test wells of the test plate are configured to carry out a different assay and receives a different master mix for a different assay type. Sample preparation apparatus configured to carry out the methods are described, as are other aspects | 1. A method of preparing samples for assaying on a test plate having a plurality of wells, comprising:
receiving, via a user interface, instructions to run a first assay type and a second assay type; determining sample identifications for a plurality of samples to be assayed; receiving assay orders corresponding to the sample identifications; defining, based on the assay orders and sample identifications, first and second assay regions of the plurality of wells, wherein each defined assay region includes at least one of the plurality of wells; and creating an electronic plate map including instructions to run a first assay type on samples contained within the first assay region, and to run a second assay type on samples contained within the second assay region. 2. The method of claim 1, comprising displaying a graphical representation of the test plate indicating the first assay region and the second assay region. 3. The method of claim 1, comprising three or more assay regions, and wherein a different assay type is prepared in each of the three or more assay regions. 4. The method of claim 3, comprising displaying a graphical representation of the test plate indicating the three or more assay regions. 5. The method of claim 1, comprising:
simultaneously including
one or more pre-processed control sample eluate from an extraction plate on one or more assay regions of the test plate, and
one or more post-processed control on one or more assay regions of the test plate. 6. The method of claim 1, comprising defining assay data sets for each of the first assay type and the second assay type being run in a particular batch, the assay data sets including at least an assay name, and a presence of pre-processed controls, a presence of post-processed controls, or both. 7. The method of claim 1, comprising displaying a graphical representation of at least some inventory requirements used to prepare the assays to be run on the test plate including the first assay region and the second assay region. 8. The method of claim 1, comprising defining the first and second assay regions based on the assay orders, the sample identifications, and controls. 9. The method of claim 1, comprising simultaneously including one or more pre-processed control samples and one or more post-processed control samples on the test plate. 10. The method of claim 1, comprising providing a list of at least some inventory requirements for processing of the first and second assays and the samples. 11. The method of claim 1, comprising generating an inventory image file based upon the electronic plate map. 12. The method of claim 1 further comprising transferring the electronic plate map to an amplification and detection device. 13. The method of claim 12, wherein the electronic plate map includes instructions to run a first assay type on eluted patient samples and a first master mix contained within the first assay region, and to run a second assay type on eluted patient samples and a second master mix contained within the second assay region. 14. A method of populating a test plate having multiple test plate wells, comprising:
performing sample processing of multiple patient samples in multiple extraction plate wells of an extraction plate to prepare multiple eluted samples in at least some of the multiple extraction plate wells; and transferring, based upon an electronic plate map including multiple assay regions, one of the multiple eluted samples from a single extraction plate well of the multiple extraction plate wells into multiple test wells of the test plate, wherein each of the multiple test wells of the test plate are in a different one of the multiple assay regions and each is configured to carry out a different assay type. 15. The method of claim 14, wherein the one of the multiple eluted samples from the single extraction well of the multiple wells is transferred to three or more of the multiple test wells of the test plate, wherein each of the three or more of the multiple test wells is in a different plate region. 16. The method of claim 14, wherein the one of the multiple eluted samples is transferred to between two and six of the multiple test wells of a test plate. 17. The method of claim 14, wherein each of the different assay types is provided in a different assay region of the test plate. 18. A method of preparing samples for assaying on a PCR plate having a plurality of PCR plate wells, comprising:
providing a plurality of patient samples to be assayed, the patient samples including sample identifications; receiving assay orders corresponding to the plurality of patient samples from an LIS; selecting, based upon the assay orders and sample identifications, a number and type of assays to perform on the PCR plate; dynamically defining assay data sets for each of the types of assays including types and numbers of pre-processed controls and post-processed controls; preparing the plurality of patient samples and the pre-processed controls through to patient sample eluate and control sample eluate on extraction plate wells of an extraction plate; defining, based on the types of assays, number of assays to perform, and a number of controls, an electronic plate map including multiple assay regions including a plurality of PCR plate wells, wherein each of the multiple assay regions includes at least one of the plurality of PCR plate wells; and dispensing patient sample eluate from an extraction plate well into the multiple assay regions wherein a number of the multiple assay regions on the PCR plate is two or more; and a different assay is to be performed in each of the multiple assay regions. 19. A sample preparation apparatus, comprising:
an extraction plate; a test plate; a memory operative to store at least patient sample identifications, assay orders for each patient sample, and number and type of assays; a processor coupled to the memory and operable to generate an electronic plate map including multiple assay regions based at least on a number of the patient samples, a number and type of assay orders for each of the patient samples, and number of controls; and one or more robots each including one or more coupled pipettes configured to patient sample eluate from an extraction plate well of the extraction plate and master mix to the multiple assay regions. 20. The sample preparation apparatus of claim 19, comprising a communication device configured to transfer an electronic data file including information from the electronic plate map to an amplification and detection device. 21. The sample preparation apparatus of claim 19, comprising sample preparation software including a required inventory module configured to be executed by the processor to prepare an image file or list of at least some of the inventory requirements for the multiple assays. 22. A machine-readable medium having non-transient instructions stored thereon, comprising:
a dynamic run setup module configured to define a plurality of assay data sets with desired run configurations based at least in part on a number and type of assays to run, and number and type of controls; and a work list and plate map display module configured to generate an electronic plate map including spatial information correlated to locations within multiple assay regions of a test plate of patient sample eluate and control eluate and optionally one or more post-processed controls. | Automated methods of preparing patient samples for assays are disclosed. The methods include performing sample processing of multiple patient samples in multiple extraction wells of an extraction plate to prepare multiple eluded samples in at least some of the multiple extraction wells, and transferring, based upon an electronic plate map including multiple assay regions, one of the multiple eluded samples from a single extraction well of the multiple extraction wells into multiple test wells of the test plate, wherein each of the multiple test wells of the test plate are configured to carry out a different assay and receives a different master mix for a different assay type. Sample preparation apparatus configured to carry out the methods are described, as are other aspects1. A method of preparing samples for assaying on a test plate having a plurality of wells, comprising:
receiving, via a user interface, instructions to run a first assay type and a second assay type; determining sample identifications for a plurality of samples to be assayed; receiving assay orders corresponding to the sample identifications; defining, based on the assay orders and sample identifications, first and second assay regions of the plurality of wells, wherein each defined assay region includes at least one of the plurality of wells; and creating an electronic plate map including instructions to run a first assay type on samples contained within the first assay region, and to run a second assay type on samples contained within the second assay region. 2. The method of claim 1, comprising displaying a graphical representation of the test plate indicating the first assay region and the second assay region. 3. The method of claim 1, comprising three or more assay regions, and wherein a different assay type is prepared in each of the three or more assay regions. 4. The method of claim 3, comprising displaying a graphical representation of the test plate indicating the three or more assay regions. 5. The method of claim 1, comprising:
simultaneously including
one or more pre-processed control sample eluate from an extraction plate on one or more assay regions of the test plate, and
one or more post-processed control on one or more assay regions of the test plate. 6. The method of claim 1, comprising defining assay data sets for each of the first assay type and the second assay type being run in a particular batch, the assay data sets including at least an assay name, and a presence of pre-processed controls, a presence of post-processed controls, or both. 7. The method of claim 1, comprising displaying a graphical representation of at least some inventory requirements used to prepare the assays to be run on the test plate including the first assay region and the second assay region. 8. The method of claim 1, comprising defining the first and second assay regions based on the assay orders, the sample identifications, and controls. 9. The method of claim 1, comprising simultaneously including one or more pre-processed control samples and one or more post-processed control samples on the test plate. 10. The method of claim 1, comprising providing a list of at least some inventory requirements for processing of the first and second assays and the samples. 11. The method of claim 1, comprising generating an inventory image file based upon the electronic plate map. 12. The method of claim 1 further comprising transferring the electronic plate map to an amplification and detection device. 13. The method of claim 12, wherein the electronic plate map includes instructions to run a first assay type on eluted patient samples and a first master mix contained within the first assay region, and to run a second assay type on eluted patient samples and a second master mix contained within the second assay region. 14. A method of populating a test plate having multiple test plate wells, comprising:
performing sample processing of multiple patient samples in multiple extraction plate wells of an extraction plate to prepare multiple eluted samples in at least some of the multiple extraction plate wells; and transferring, based upon an electronic plate map including multiple assay regions, one of the multiple eluted samples from a single extraction plate well of the multiple extraction plate wells into multiple test wells of the test plate, wherein each of the multiple test wells of the test plate are in a different one of the multiple assay regions and each is configured to carry out a different assay type. 15. The method of claim 14, wherein the one of the multiple eluted samples from the single extraction well of the multiple wells is transferred to three or more of the multiple test wells of the test plate, wherein each of the three or more of the multiple test wells is in a different plate region. 16. The method of claim 14, wherein the one of the multiple eluted samples is transferred to between two and six of the multiple test wells of a test plate. 17. The method of claim 14, wherein each of the different assay types is provided in a different assay region of the test plate. 18. A method of preparing samples for assaying on a PCR plate having a plurality of PCR plate wells, comprising:
providing a plurality of patient samples to be assayed, the patient samples including sample identifications; receiving assay orders corresponding to the plurality of patient samples from an LIS; selecting, based upon the assay orders and sample identifications, a number and type of assays to perform on the PCR plate; dynamically defining assay data sets for each of the types of assays including types and numbers of pre-processed controls and post-processed controls; preparing the plurality of patient samples and the pre-processed controls through to patient sample eluate and control sample eluate on extraction plate wells of an extraction plate; defining, based on the types of assays, number of assays to perform, and a number of controls, an electronic plate map including multiple assay regions including a plurality of PCR plate wells, wherein each of the multiple assay regions includes at least one of the plurality of PCR plate wells; and dispensing patient sample eluate from an extraction plate well into the multiple assay regions wherein a number of the multiple assay regions on the PCR plate is two or more; and a different assay is to be performed in each of the multiple assay regions. 19. A sample preparation apparatus, comprising:
an extraction plate; a test plate; a memory operative to store at least patient sample identifications, assay orders for each patient sample, and number and type of assays; a processor coupled to the memory and operable to generate an electronic plate map including multiple assay regions based at least on a number of the patient samples, a number and type of assay orders for each of the patient samples, and number of controls; and one or more robots each including one or more coupled pipettes configured to patient sample eluate from an extraction plate well of the extraction plate and master mix to the multiple assay regions. 20. The sample preparation apparatus of claim 19, comprising a communication device configured to transfer an electronic data file including information from the electronic plate map to an amplification and detection device. 21. The sample preparation apparatus of claim 19, comprising sample preparation software including a required inventory module configured to be executed by the processor to prepare an image file or list of at least some of the inventory requirements for the multiple assays. 22. A machine-readable medium having non-transient instructions stored thereon, comprising:
a dynamic run setup module configured to define a plurality of assay data sets with desired run configurations based at least in part on a number and type of assays to run, and number and type of controls; and a work list and plate map display module configured to generate an electronic plate map including spatial information correlated to locations within multiple assay regions of a test plate of patient sample eluate and control eluate and optionally one or more post-processed controls. | 1,600 |
804 | 14,281,638 | 1,618 | Various agents and additives for cross-linking treatments are identified in disclosed studies. The characteristics of the various agents and additives may be advantageously employed in formulations applied in cross-linking treatments of the eye. In some embodiments, riboflavin is combined with Iron(II) to enhance the cross-linking activity generated by the riboflavin. In other embodiments, cross-linking treatments employ an Iron(II) solution in combination with a hydrogen peroxide pre-soak. In yet other embodiments, 2,3-butanedione is employed to increase the efficacy of corneal cross-linking with a photosensitizer, such as riboflavin. In further embodiments, folic acid is employed in combination with a photosensitizer, such as riboflavin, to enhance cross-linking activity. In yet further embodiments, 2,3-butanedione, folic acid, a quinoxaline, a quinoline, dibucaine, Methotrexate, menadione, or a derivative thereof is applied as a cross-linking agent. | 1. A composition for applying therapy to a cornea of an eye, comprising:
a cross-linking agent that generates cross-linking activity in the cornea in response to exposure to a photo-activating light; and at least one additive different from the cross-linking agent and selected from the group consisting of iron, copper, manganese, chromium, vanadium, aluminum, cobalt, mercury, cadmium, nickel, arsenic, 2,3-butanedione, and folic acid, wherein the at least one additive enhances the cross-linking activity generated by the cross-linking agent. 2. The composition of claim 1, wherein the cross-linking agent is selected from the group consisting of riboflavin, 2,3-butanedione, folic acid, quinoxalines, quinolines, dibucaine, Methotrexate, menadione, and derivatives thereof. 3. The composition of claim 1, wherein the at least one additive is iron. 4. The composition of claim 3, wherein the iron is provided by FeSO4. 5. The composition of claim 1, wherein the at least one additive is 2,3-butanedione. 6. The composition of claim 1, wherein the at least one additive is folic acid. 7. A method for applying therapy to a cornea of an eye, comprising:
applying a composition to the cornea, the composition including
a cross-linking agent that generates cross-linking activity in the cornea in response to exposure to a photoactivating light; and
at least one additive different from the cross-linking agent and selected from the group consisting of iron, copper, manganese, chromium, vanadium, aluminum, cobalt, mercury, cadmium, nickel, arsenic, 2,3-butanedione, and folic acid; and
applying photoactivating light to the cornea to generate cross-linking activity in the cornea, wherein the at least one additive enhances the cross-linking activity generated by the cross-linking agent. 8. The method of claim 7, wherein the cross-linking agent is selected from the group consisting of riboflavin, 2,3-butanedione, folic acid, quinoxalines, quinolines, dibucaine, Methotrexate, menadione, and derivatives thereof. 9. The method of claim 7, wherein the at least one additive is iron. 10. The method of claim 9, wherein the iron is provided by FeSO4. 11. The method of claim 7, wherein the at least one additive is 2,3-butanedione. 12. The method of claim 7, wherein the at least one additive is folic acid. 13. The method of claim 7, wherein the photoactivating light is ultraviolet light. 14. The method of claim 7, wherein the photoactivating light is pulsed. 15. The method of claim 7, further comprising applying oxygen to the cornea. 16. A method for applying therapy to a cornea of an eye, comprising:
applying a cross-linking agent to the cornea, the cross-linking agent being selected from the group consisting of 2,3-butanedione, folic acid, quinoxalines, quinolines, dibucaine, Methotrexate, menadione, and derivatives thereof; and applying photoactivating light to the cornea to generate cross-linking activity in the cornea. 17. The method of claim 16, wherein the photoactivating light is ultraviolet light. 18. The method of claim 16, wherein the photoactivating light is pulsed. 19. The method of claim 16, further comprising applying oxygen to the cornea to control the cross-linking activity generated by the cross-linking agent. 20. A method for applying therapy to a cornea of an eye, comprising:
applying a hydrogen peroxide to the cornea; and applying an iron solution to the cornea after applying the hydrogen peroxide, the hydrogen peroxide and iron solution combining to generate cross-linking activity in the cornea. | Various agents and additives for cross-linking treatments are identified in disclosed studies. The characteristics of the various agents and additives may be advantageously employed in formulations applied in cross-linking treatments of the eye. In some embodiments, riboflavin is combined with Iron(II) to enhance the cross-linking activity generated by the riboflavin. In other embodiments, cross-linking treatments employ an Iron(II) solution in combination with a hydrogen peroxide pre-soak. In yet other embodiments, 2,3-butanedione is employed to increase the efficacy of corneal cross-linking with a photosensitizer, such as riboflavin. In further embodiments, folic acid is employed in combination with a photosensitizer, such as riboflavin, to enhance cross-linking activity. In yet further embodiments, 2,3-butanedione, folic acid, a quinoxaline, a quinoline, dibucaine, Methotrexate, menadione, or a derivative thereof is applied as a cross-linking agent.1. A composition for applying therapy to a cornea of an eye, comprising:
a cross-linking agent that generates cross-linking activity in the cornea in response to exposure to a photo-activating light; and at least one additive different from the cross-linking agent and selected from the group consisting of iron, copper, manganese, chromium, vanadium, aluminum, cobalt, mercury, cadmium, nickel, arsenic, 2,3-butanedione, and folic acid, wherein the at least one additive enhances the cross-linking activity generated by the cross-linking agent. 2. The composition of claim 1, wherein the cross-linking agent is selected from the group consisting of riboflavin, 2,3-butanedione, folic acid, quinoxalines, quinolines, dibucaine, Methotrexate, menadione, and derivatives thereof. 3. The composition of claim 1, wherein the at least one additive is iron. 4. The composition of claim 3, wherein the iron is provided by FeSO4. 5. The composition of claim 1, wherein the at least one additive is 2,3-butanedione. 6. The composition of claim 1, wherein the at least one additive is folic acid. 7. A method for applying therapy to a cornea of an eye, comprising:
applying a composition to the cornea, the composition including
a cross-linking agent that generates cross-linking activity in the cornea in response to exposure to a photoactivating light; and
at least one additive different from the cross-linking agent and selected from the group consisting of iron, copper, manganese, chromium, vanadium, aluminum, cobalt, mercury, cadmium, nickel, arsenic, 2,3-butanedione, and folic acid; and
applying photoactivating light to the cornea to generate cross-linking activity in the cornea, wherein the at least one additive enhances the cross-linking activity generated by the cross-linking agent. 8. The method of claim 7, wherein the cross-linking agent is selected from the group consisting of riboflavin, 2,3-butanedione, folic acid, quinoxalines, quinolines, dibucaine, Methotrexate, menadione, and derivatives thereof. 9. The method of claim 7, wherein the at least one additive is iron. 10. The method of claim 9, wherein the iron is provided by FeSO4. 11. The method of claim 7, wherein the at least one additive is 2,3-butanedione. 12. The method of claim 7, wherein the at least one additive is folic acid. 13. The method of claim 7, wherein the photoactivating light is ultraviolet light. 14. The method of claim 7, wherein the photoactivating light is pulsed. 15. The method of claim 7, further comprising applying oxygen to the cornea. 16. A method for applying therapy to a cornea of an eye, comprising:
applying a cross-linking agent to the cornea, the cross-linking agent being selected from the group consisting of 2,3-butanedione, folic acid, quinoxalines, quinolines, dibucaine, Methotrexate, menadione, and derivatives thereof; and applying photoactivating light to the cornea to generate cross-linking activity in the cornea. 17. The method of claim 16, wherein the photoactivating light is ultraviolet light. 18. The method of claim 16, wherein the photoactivating light is pulsed. 19. The method of claim 16, further comprising applying oxygen to the cornea to control the cross-linking activity generated by the cross-linking agent. 20. A method for applying therapy to a cornea of an eye, comprising:
applying a hydrogen peroxide to the cornea; and applying an iron solution to the cornea after applying the hydrogen peroxide, the hydrogen peroxide and iron solution combining to generate cross-linking activity in the cornea. | 1,600 |
805 | 15,121,944 | 1,651 | A method and system of preparing a sample for microbial testing by providing a sample in a sample bag, a dry sterile growth medium in a bag, and a source of pure (Type II) water heated to a temperature of about 25-50° C., homogenizing the sample, reconstituting the dry medium with the heated Type II water, mixing the medium and sample to a homogenous consistency and incubating the sample for a period of time sufficient to allow the growth of microbes. A tankless water heater or a heat exchanger can be used to heat the water to a desired temperature. The Type II water can be heated either before or after it is made. A blender can be used for the sample homogenization as well as the final mixing before incubation and may be a paddle or stationary blender. Microbes are detected by various methods well known in the art. | 1. A method of performing a microbiological test on a semi-solid and/or solid sample comprising the steps of:
a. providing a sample to be tested, b. providing dehydrated growth medium, c. providing a source of pure (Type II) water heated to a temperature of about 25-50° C. d. homogenizing the sample, e. reconstituting the medium into a liquid form with the heated Type II water by a method selected from the group consisting of
i. adding the heated Type II water to the medium and reconstituting it and then adding the reconstituted liquid medium to the homogenized sample in a container, or
ii. adding the heated Type II water, dehydrated medium and the homogenized sample in a container together,
f. mixing the heated Type II water, medium and homogenized sample to a homogenous consistency and g. incubating the container containing the water, medium and homogenized sample for a period of time sufficient to allow the growth of any microbes in the sample. 2. The method of claim 1 wherein the pure water is heated to a temperature between about 30-45° C., more preferably between 37 and 42° C. 3. The method of claim 1 wherein the water is heated by a heater upstream of the source of the water. 4. The method of claim 1 wherein the water is heated by a heater located downstream of the source of the water. 5. The method according to claim 1 further comprising the step (i) of examining the incubated sample to determine the presence or absence of microbes. 6. The method according to claim 1 further comprising the step (i) of examining the incubated sample to determine the presence or absence of microbes and enumerating the microbes if found. 7. The method according to claim 1 further comprising the step (j) of identifying any microbes which are present. 8. The method according to claim 1 wherein the microbes to be detected are selected from the group consisting of yeast, mold and bacteria. 9. The method according to claim 1 wherein the microbes to be detected are microbes known as food and beverage spoilage and food pathogenic microorganisms to cause issues with humans or animals that may ingest them. 10. The method according to claim 1 wherein the microbes to be detected are bacteria selected from the group consisting of coliform bacteria, Escherichia coli including pathogenic E. coli such as Shigatoxin producing E. coli (STEC), Salmonella, Listeria, Staphylococci, Shigella, Vibrio and the like. 11. The method according to claim 1 wherein the sample is incubated for a period of time to grow colony forming units that are detectable. 12. The method according to claim 1 wherein the sample is incubated for a period of time to grow colony forming units that are detectable by a detection method selected from the group consisting of visual detection, chemical detection (dyes, fluorescence), molecular detection (PCR, rPRC, TMA,) and electronic detection (laser topography, CCD camera, Camera/microscope) with or without the addition of chemical or molecular detection agents. 13. The method according to claim 1 wherein the sample is homogenized by a blender selected from the group consisting of a stationary blender and a paddle blender. 14. The method according to claim 1 wherein the dehydrated medium is in a form selected from the group consisting of powders and granules. 15. A system for detecting microbes in a sample comprising a bag of sterile granular growth medium, a system for producing pure (Type II) water, a system for heating the water, a blender for homogenizing a food sample and the combined sample, medium and water and an incubator for growing any microbes contained within the sample. 16. The method according to claim 1 wherein the water is heated to a temperature between about 25-50° C. by a heater and wherein the heater is selected from the group consisting of tankless water heaters and heat exchangers. 17. The method according to claim 1 wherein the sample is selected from the group consisting of food, environmental samples, cosmetics and pharmaceutical preparations. | A method and system of preparing a sample for microbial testing by providing a sample in a sample bag, a dry sterile growth medium in a bag, and a source of pure (Type II) water heated to a temperature of about 25-50° C., homogenizing the sample, reconstituting the dry medium with the heated Type II water, mixing the medium and sample to a homogenous consistency and incubating the sample for a period of time sufficient to allow the growth of microbes. A tankless water heater or a heat exchanger can be used to heat the water to a desired temperature. The Type II water can be heated either before or after it is made. A blender can be used for the sample homogenization as well as the final mixing before incubation and may be a paddle or stationary blender. Microbes are detected by various methods well known in the art.1. A method of performing a microbiological test on a semi-solid and/or solid sample comprising the steps of:
a. providing a sample to be tested, b. providing dehydrated growth medium, c. providing a source of pure (Type II) water heated to a temperature of about 25-50° C. d. homogenizing the sample, e. reconstituting the medium into a liquid form with the heated Type II water by a method selected from the group consisting of
i. adding the heated Type II water to the medium and reconstituting it and then adding the reconstituted liquid medium to the homogenized sample in a container, or
ii. adding the heated Type II water, dehydrated medium and the homogenized sample in a container together,
f. mixing the heated Type II water, medium and homogenized sample to a homogenous consistency and g. incubating the container containing the water, medium and homogenized sample for a period of time sufficient to allow the growth of any microbes in the sample. 2. The method of claim 1 wherein the pure water is heated to a temperature between about 30-45° C., more preferably between 37 and 42° C. 3. The method of claim 1 wherein the water is heated by a heater upstream of the source of the water. 4. The method of claim 1 wherein the water is heated by a heater located downstream of the source of the water. 5. The method according to claim 1 further comprising the step (i) of examining the incubated sample to determine the presence or absence of microbes. 6. The method according to claim 1 further comprising the step (i) of examining the incubated sample to determine the presence or absence of microbes and enumerating the microbes if found. 7. The method according to claim 1 further comprising the step (j) of identifying any microbes which are present. 8. The method according to claim 1 wherein the microbes to be detected are selected from the group consisting of yeast, mold and bacteria. 9. The method according to claim 1 wherein the microbes to be detected are microbes known as food and beverage spoilage and food pathogenic microorganisms to cause issues with humans or animals that may ingest them. 10. The method according to claim 1 wherein the microbes to be detected are bacteria selected from the group consisting of coliform bacteria, Escherichia coli including pathogenic E. coli such as Shigatoxin producing E. coli (STEC), Salmonella, Listeria, Staphylococci, Shigella, Vibrio and the like. 11. The method according to claim 1 wherein the sample is incubated for a period of time to grow colony forming units that are detectable. 12. The method according to claim 1 wherein the sample is incubated for a period of time to grow colony forming units that are detectable by a detection method selected from the group consisting of visual detection, chemical detection (dyes, fluorescence), molecular detection (PCR, rPRC, TMA,) and electronic detection (laser topography, CCD camera, Camera/microscope) with or without the addition of chemical or molecular detection agents. 13. The method according to claim 1 wherein the sample is homogenized by a blender selected from the group consisting of a stationary blender and a paddle blender. 14. The method according to claim 1 wherein the dehydrated medium is in a form selected from the group consisting of powders and granules. 15. A system for detecting microbes in a sample comprising a bag of sterile granular growth medium, a system for producing pure (Type II) water, a system for heating the water, a blender for homogenizing a food sample and the combined sample, medium and water and an incubator for growing any microbes contained within the sample. 16. The method according to claim 1 wherein the water is heated to a temperature between about 25-50° C. by a heater and wherein the heater is selected from the group consisting of tankless water heaters and heat exchangers. 17. The method according to claim 1 wherein the sample is selected from the group consisting of food, environmental samples, cosmetics and pharmaceutical preparations. | 1,600 |
806 | 13,863,001 | 1,611 | A concentrated liquid sanitizing and rinse composition containing peroxycarboxylic acid(s) and compatible rinse aid surfactants is disclosed. The sanitizing and rinsing compositions are formulated in a single liquid concentrate, replacing a traditional dual product of a sanitizer and rinse aid. The sanitizing and rinsing chemistries are particularly effective at neutral pHs against gram negative organisms at elevated temperatures. Methods of using the concentrated liquid sanitizing and rinse composition are also disclosed. | 1. A sanitizing rinse additive composition comprising:
a C1-C22 peroxycarboxylic acid; a C1-C22 carboxylic acid; hydrogen peroxide; and a nonionic defoaming and wetting surfactant(s); wherein the composition is a low odor concentrate having less than about 2 wt-% peroxyacetic and peracid acid, and wherein the composition when diluted from about 0.01% weight/volume to about 2% weight/volume provides at least a 5 log reduction in pathogenic organisms at a temperature of at least about 100° F. 2. The composition of claim 1, wherein the nonionic defoaming surfactant is an alkyl-ethylene oxide-propylene oxide copolymer surfactant and wherein the nonionic wetting surfactant is an alcohol ethoxylate according to the following structure R—O—(CH2CH2O)n—H, wherein R is a C1-C12 alkyl group and n is an integer in the range of 1 to 100. 3. The composition of claim 2, wherein the alkyl-ethylene oxide-propylene oxide copolymer surfactant has a single hydroxyl functional group per molecule according to the following structure Alkyl-(EO)m-(PO)n-POH, wherein m is an integer in the range from 1 to 20 and n is an integer in the range from 1 to 20. 4. The composition of claim 1, wherein the ratio of the nonionic defoaming surfactant to the nonionic wetting surfactant is from about 1.5:1 to about 10:1 5. The composition of claim 1, wherein the C1-C22 peroxycarboxylic acid is a C2-C20 peroxycarboxylic acid and wherein the C1-C22 carboxylic acid is a C2-C20 carboxylic acid. 6. The composition of claim 1, further comprising at least one additional agent selected from the group consisting of a hydrotrope or coupling agent, a solvent, a stabilizing agent and combinations thereof. 7. The composition of claim 1, wherein the C1-C22 peroxycarboxylic acid comprises from about 1 wt-% to about 40 wt-%, the C1-C22 carboxylic acid comprises from about 1 wt-% to about 80 wt-%, the hydrogen peroxide comprises from about 1 wt-% to about 80 wt-%, and the nonionic surfactants comprise from about 1 wt-% to about 50 wt-% of the composition. 8. The composition of claim 1, wherein the composition when diluted from about 0.01% weight/volume to about 0.05% weight/volume provides at least a 5 log reduction in pathogenic organisms in 30 seconds or less at a temperature of at least about 120° F. 9. The composition of claim 1, wherein peroxycarboxylic acid in the concentrate contains less than about 1 wt-% peroxyacetic acid. 10. A concentrated sanitizing rinse additive composition comprising:
from about 1 wt-% to about 40 wt-% C1-C22 peroxycarboxylic acid; from about 1 wt-% to about 80 wt-% C1-C22 carboxylic acid; from about 1 wt-% to about 75 wt-% hydrogen peroxide; from about 1 wt-% to about 25 wt-% alkyl-ethylene oxide-propylene oxide type nonionic surfactant; and from about 1 wt-% to about 20 wt-% alcohol ethoxylate nonionic surfactant; wherein the concentrate composition has low odor, and wherein the composition when diluted from about 0.01% weight/volume to about 1% weight/volume provides at least a 5 log reduction in pathogenic organisms at a temperature of at least about 100° F., and wherein the diluted composition has a pH of about 5 or greater. 11. The composition of claim 10, wherein the C1-C22 peroxycarboxylic acid is a C2-C20 peroxycarboxylic acid selected from the group consisting of peroxyacetic acid, peroxyoctanoic acid, peroxysulfonated oleic acid and combinations thereof, wherein the C1-C22 carboxylic acid is a C2-C20 carboxylic acid selected from the group consisting of acetic acid, octanoic acid, sulfonated oleic acid and combinations thereof, and wherein the composition comprises less than about 2 wt-% peroxyacetic acid. 12. The composition of claim 10, wherein the nonionic defoaming surfactant is an alkyl-ethylene oxide-propylene oxide copolymer surfactant according to the following structure Alkyl-(EO)m-(PO)n-POH, wherein m is an integer in the range from 1 to 20 and n is an integer in the range from 1 to 20, and wherein the nonionic wetting surfactant is an alcohol ethoxylate according to the following structure R—O—(CH2CH2O)n—H, wherein R is a C1-C12 alkyl group and n is an integer in the range of 1 to 100. 13. The composition of claim 10, further comprising at least one additional agent selected from the group consisting of a hydrotrope or coupling agent, a solvent, a stabilizing agent and combinations thereof. 14. The composition of claim 13, wherein the stabilizing agent is a phosphate peroxycarboxylic acid stabilizer and/or dipicolinic acid peroxycarboxylic acid stabilizer. 15. A method of sanitizing and rinsing comprising:
providing a low odor, liquid concentrate, equilibrium peroxycarboxylic acid sanitizing rinse aid composition, wherein the composition comprises: a C1-C22 peroxycarboxylic acid; a C1-C22 carboxylic acid; hydrogen peroxide; an alkyl-ethylene oxide-propylene oxide type nonionic surfactant; and an alcohol ethoxylate nonionic surfactant; and sanitizing a surface in need thereof without an additional rinsing step; wherein the composition when diluted from about 0.01% weight/volume to about 1% weight/volume provides at least a 5 log reduction in pathogenic organisms at a temperature of at least about 100° F. 16. The method of claim 15, wherein the composition is diluted from about 0.01% weight/volume to about 0.2% weight/volume with a diluent. 17. The method of claim 16, wherein the composition is diluted from about 0.01% weight/volume to about 0.05% weight/volume with a diluent. 18. The method of claim 16, wherein the sanitized surface is spot-free and film-free. 19. The method of claim 18, wherein the sanitizing is a low or no odor application of use. 20. The method of claim 15, wherein the utilities for a warewashing machine employing the sanitizing are substantially similar to or less than a low temperature ware wash machine employed for chlorine-based sanitizing. | A concentrated liquid sanitizing and rinse composition containing peroxycarboxylic acid(s) and compatible rinse aid surfactants is disclosed. The sanitizing and rinsing compositions are formulated in a single liquid concentrate, replacing a traditional dual product of a sanitizer and rinse aid. The sanitizing and rinsing chemistries are particularly effective at neutral pHs against gram negative organisms at elevated temperatures. Methods of using the concentrated liquid sanitizing and rinse composition are also disclosed.1. A sanitizing rinse additive composition comprising:
a C1-C22 peroxycarboxylic acid; a C1-C22 carboxylic acid; hydrogen peroxide; and a nonionic defoaming and wetting surfactant(s); wherein the composition is a low odor concentrate having less than about 2 wt-% peroxyacetic and peracid acid, and wherein the composition when diluted from about 0.01% weight/volume to about 2% weight/volume provides at least a 5 log reduction in pathogenic organisms at a temperature of at least about 100° F. 2. The composition of claim 1, wherein the nonionic defoaming surfactant is an alkyl-ethylene oxide-propylene oxide copolymer surfactant and wherein the nonionic wetting surfactant is an alcohol ethoxylate according to the following structure R—O—(CH2CH2O)n—H, wherein R is a C1-C12 alkyl group and n is an integer in the range of 1 to 100. 3. The composition of claim 2, wherein the alkyl-ethylene oxide-propylene oxide copolymer surfactant has a single hydroxyl functional group per molecule according to the following structure Alkyl-(EO)m-(PO)n-POH, wherein m is an integer in the range from 1 to 20 and n is an integer in the range from 1 to 20. 4. The composition of claim 1, wherein the ratio of the nonionic defoaming surfactant to the nonionic wetting surfactant is from about 1.5:1 to about 10:1 5. The composition of claim 1, wherein the C1-C22 peroxycarboxylic acid is a C2-C20 peroxycarboxylic acid and wherein the C1-C22 carboxylic acid is a C2-C20 carboxylic acid. 6. The composition of claim 1, further comprising at least one additional agent selected from the group consisting of a hydrotrope or coupling agent, a solvent, a stabilizing agent and combinations thereof. 7. The composition of claim 1, wherein the C1-C22 peroxycarboxylic acid comprises from about 1 wt-% to about 40 wt-%, the C1-C22 carboxylic acid comprises from about 1 wt-% to about 80 wt-%, the hydrogen peroxide comprises from about 1 wt-% to about 80 wt-%, and the nonionic surfactants comprise from about 1 wt-% to about 50 wt-% of the composition. 8. The composition of claim 1, wherein the composition when diluted from about 0.01% weight/volume to about 0.05% weight/volume provides at least a 5 log reduction in pathogenic organisms in 30 seconds or less at a temperature of at least about 120° F. 9. The composition of claim 1, wherein peroxycarboxylic acid in the concentrate contains less than about 1 wt-% peroxyacetic acid. 10. A concentrated sanitizing rinse additive composition comprising:
from about 1 wt-% to about 40 wt-% C1-C22 peroxycarboxylic acid; from about 1 wt-% to about 80 wt-% C1-C22 carboxylic acid; from about 1 wt-% to about 75 wt-% hydrogen peroxide; from about 1 wt-% to about 25 wt-% alkyl-ethylene oxide-propylene oxide type nonionic surfactant; and from about 1 wt-% to about 20 wt-% alcohol ethoxylate nonionic surfactant; wherein the concentrate composition has low odor, and wherein the composition when diluted from about 0.01% weight/volume to about 1% weight/volume provides at least a 5 log reduction in pathogenic organisms at a temperature of at least about 100° F., and wherein the diluted composition has a pH of about 5 or greater. 11. The composition of claim 10, wherein the C1-C22 peroxycarboxylic acid is a C2-C20 peroxycarboxylic acid selected from the group consisting of peroxyacetic acid, peroxyoctanoic acid, peroxysulfonated oleic acid and combinations thereof, wherein the C1-C22 carboxylic acid is a C2-C20 carboxylic acid selected from the group consisting of acetic acid, octanoic acid, sulfonated oleic acid and combinations thereof, and wherein the composition comprises less than about 2 wt-% peroxyacetic acid. 12. The composition of claim 10, wherein the nonionic defoaming surfactant is an alkyl-ethylene oxide-propylene oxide copolymer surfactant according to the following structure Alkyl-(EO)m-(PO)n-POH, wherein m is an integer in the range from 1 to 20 and n is an integer in the range from 1 to 20, and wherein the nonionic wetting surfactant is an alcohol ethoxylate according to the following structure R—O—(CH2CH2O)n—H, wherein R is a C1-C12 alkyl group and n is an integer in the range of 1 to 100. 13. The composition of claim 10, further comprising at least one additional agent selected from the group consisting of a hydrotrope or coupling agent, a solvent, a stabilizing agent and combinations thereof. 14. The composition of claim 13, wherein the stabilizing agent is a phosphate peroxycarboxylic acid stabilizer and/or dipicolinic acid peroxycarboxylic acid stabilizer. 15. A method of sanitizing and rinsing comprising:
providing a low odor, liquid concentrate, equilibrium peroxycarboxylic acid sanitizing rinse aid composition, wherein the composition comprises: a C1-C22 peroxycarboxylic acid; a C1-C22 carboxylic acid; hydrogen peroxide; an alkyl-ethylene oxide-propylene oxide type nonionic surfactant; and an alcohol ethoxylate nonionic surfactant; and sanitizing a surface in need thereof without an additional rinsing step; wherein the composition when diluted from about 0.01% weight/volume to about 1% weight/volume provides at least a 5 log reduction in pathogenic organisms at a temperature of at least about 100° F. 16. The method of claim 15, wherein the composition is diluted from about 0.01% weight/volume to about 0.2% weight/volume with a diluent. 17. The method of claim 16, wherein the composition is diluted from about 0.01% weight/volume to about 0.05% weight/volume with a diluent. 18. The method of claim 16, wherein the sanitized surface is spot-free and film-free. 19. The method of claim 18, wherein the sanitizing is a low or no odor application of use. 20. The method of claim 15, wherein the utilities for a warewashing machine employing the sanitizing are substantially similar to or less than a low temperature ware wash machine employed for chlorine-based sanitizing. | 1,600 |
807 | 16,013,552 | 1,649 | Formulations and methods of treatment are disclosed for prevention and/or treatment of visual loss from age-related macular degeneration. The disclosed formulations include botulinum neurotoxin (e.g., botulinum neurotoxin or a fragment thereof, either in pure form or with one or more peptide fragments and/or neurotoxin associated proteins. In some embodiments, the disclosed formulations are applied to the para orbital or periorbital region of a patient to delay or stop the progression of dry macular degeneration. The methods described herein do not involve a direct injection into the eye or subconjunctival region, thus significantly easing both comfort and administration related complications and further preserving barrier functions of retinal layers while also delaying or ceasing the degenerative process to wet conversion. | 1. A method of treating and/or retarding progression of dry macular degeneration in a patient, the method comprising:
identifying a patient with dry macular degeneration; and injecting a botulinum neurotoxin into a periorbital or a para orbital region of the patient, but not into an intra-ocular or a subconjunctival region of the patient, wherein the botulinum neurotoxin injected conforms with conventional dosing. 2. The method of claim 1, wherein the patient has one or more of the following risk factors:
presence of geographic atrophy near fovea; high numbers and volume of drusen; presence of soft drusen or drusenoids; cyst formation; hyper reflective foci in the neuro retina; pigmentation in the macula; disorganization of continuity of the IS-OS line; genetic polymorphisms associated with severe macular degeneration; polymorphisms involving complement; geographic atrophy in contralateral eye; and a genetic evaluation indicating elevated risk factors. 3. The method of claim 1, wherein the progression of dry macular degeneration involves conversion of dry macular degeneration to wet macular degeneration. 4. The method of claim 3, wherein wet macular degeneration is determined by OCT, OCT-A, and/or fluorescein angiography. 5. The method of claim 1, wherein the botulinum neurotoxin is injected into the para orbital region and targets the pterygopalatine fossa. 6. The method of claim 1, wherein injecting the botulinum neurotoxin avoids diplopia and ptosis. 7. The method of claim 1, wherein the conventional dosing ranges between 5-400 units. 8. The method of claim 1 further comprising one or more repeated injections of botulinum neurotoxin into the periorbital or the para orbital region of the patient. 9. The method of claim 1, wherein treating and/or retarding the progression of dry macular degeneration comprises delaying degeneration of the retinal pigment epithelium, preserving photoreceptors, preventing cell apoptosis, preventing retinal pigment epithelial activation and migration, reducing sheet distortion, preventing geographic atrophy, preventing retinal atrophy, and/or preventing loss of rods and cones. 10. The method of claim 9, wherein alterations in cytoskeleton assembly within the retinal pigment epithelium occur so that barriers in the retinal pigment epithelium are maintained with attachments to basement membrane and rejuvenation of an apical portion of the retinal pigment epithelium occurs, causing cessation of degeneration within the choroid. | Formulations and methods of treatment are disclosed for prevention and/or treatment of visual loss from age-related macular degeneration. The disclosed formulations include botulinum neurotoxin (e.g., botulinum neurotoxin or a fragment thereof, either in pure form or with one or more peptide fragments and/or neurotoxin associated proteins. In some embodiments, the disclosed formulations are applied to the para orbital or periorbital region of a patient to delay or stop the progression of dry macular degeneration. The methods described herein do not involve a direct injection into the eye or subconjunctival region, thus significantly easing both comfort and administration related complications and further preserving barrier functions of retinal layers while also delaying or ceasing the degenerative process to wet conversion.1. A method of treating and/or retarding progression of dry macular degeneration in a patient, the method comprising:
identifying a patient with dry macular degeneration; and injecting a botulinum neurotoxin into a periorbital or a para orbital region of the patient, but not into an intra-ocular or a subconjunctival region of the patient, wherein the botulinum neurotoxin injected conforms with conventional dosing. 2. The method of claim 1, wherein the patient has one or more of the following risk factors:
presence of geographic atrophy near fovea; high numbers and volume of drusen; presence of soft drusen or drusenoids; cyst formation; hyper reflective foci in the neuro retina; pigmentation in the macula; disorganization of continuity of the IS-OS line; genetic polymorphisms associated with severe macular degeneration; polymorphisms involving complement; geographic atrophy in contralateral eye; and a genetic evaluation indicating elevated risk factors. 3. The method of claim 1, wherein the progression of dry macular degeneration involves conversion of dry macular degeneration to wet macular degeneration. 4. The method of claim 3, wherein wet macular degeneration is determined by OCT, OCT-A, and/or fluorescein angiography. 5. The method of claim 1, wherein the botulinum neurotoxin is injected into the para orbital region and targets the pterygopalatine fossa. 6. The method of claim 1, wherein injecting the botulinum neurotoxin avoids diplopia and ptosis. 7. The method of claim 1, wherein the conventional dosing ranges between 5-400 units. 8. The method of claim 1 further comprising one or more repeated injections of botulinum neurotoxin into the periorbital or the para orbital region of the patient. 9. The method of claim 1, wherein treating and/or retarding the progression of dry macular degeneration comprises delaying degeneration of the retinal pigment epithelium, preserving photoreceptors, preventing cell apoptosis, preventing retinal pigment epithelial activation and migration, reducing sheet distortion, preventing geographic atrophy, preventing retinal atrophy, and/or preventing loss of rods and cones. 10. The method of claim 9, wherein alterations in cytoskeleton assembly within the retinal pigment epithelium occur so that barriers in the retinal pigment epithelium are maintained with attachments to basement membrane and rejuvenation of an apical portion of the retinal pigment epithelium occurs, causing cessation of degeneration within the choroid. | 1,600 |
808 | 14,698,698 | 1,658 | Protein supplements that include proteins from animal products, such as whey and eggs, are disclosed. Such a protein supplement may also include one or more immune modulators, such as transfer factor and/or nanofraction immune modulators. | 1. A protein supplement, including:
an animal-based protein hydrolysate; and an immune modulator. 2. The protein supplement of claim 1, wherein the immune modulator is from a source other than the animal-based protein hydrolysate. 3. The protein supplement of claim 1, wherein the animal-based protein hydrolysate comprises a hydrolysate of milk proteins. 4. The protein supplement of claim 3, wherein the animal-based protein hydrolysate comprises a hydrolysate of whey proteins. 5. The protein supplement of claim 1, wherein the animal-based protein-hydrolysate comprises a hydrolysate of egg proteins. 7. The protein supplement of claim 1, wherein the immune modulator comprises nanofraction immune modulators. 8. The protein supplement of claim 7, wherein the immune modulator has an upper molecular weight cutoff of about 5 KD or less. 9. The protein supplement of claim 8, wherein the immune modulator substantially lacks transfer factor. 10. The protein supplement of claim 1, wherein the immune modulator comprises transfer factor. 11. The protein supplement of claim 10, wherein the immune modulator has an upper molecular weight cutoff of about 12 KD or less. 12. The protein supplement of claim 10, wherein the immune modulator has an upper molecular weight cutoff of about 10 KD or less. 13. A protein supplement, including:
a whey hydrolysate; and a fraction of at least one of colostrum and egg, each fraction having an upper molecular weight cutoff of about 12 KD or less. 14. The protein supplement of claim 13, consisting essentially of the whey hydrolysate and the fraction of at least one of colostrum and egg. 15. The protein supplement of claim 13, consisting of the whey hydrolysate and the fraction at least one of colostrum and egg. 16. The protein supplement of claim 13, wherein each fraction has a molecular weight cutoff of about 10 KD or less. 17. The protein supplement of claim 13, wherein each fraction has a molecular weight cutoff of about 5 KD or less. 18. The protein supplement of claim 13, wherein the whey hydrolysate is a hydrolysate of standard whey. 19. The protein supplement of claim 13, wherein the whey hydrolysate is a hydrolysate of a whey protein concentrate. 20. The protein supplement of claim 13, wherein the whey hydrolysate is a hydrolysate of a whey protein isolate. 21. A protein supplement, including:
egg protein from avian eggs; milk protein. 22. The protein supplement of claim 21, wherein the egg protein comprises albumin. 23. The protein supplement of claim 21, wherein the egg protein comprises a whole egg hydrolysate. 24. The protein supplement of claim 21, wherein the milk protein comprises whey protein. 25. The protein supplement of claim 24, wherein the whey protein comprises a whey protein concentrate. 26. The protein supplement of claim 24, wherein the whey protein comprises a whey protein isolate. 27. The protein supplement of claim 24, wherein the whey protein comprises a hydrolysate of whey, a hydrolysate of a whey protein concentrate or a hydrolysate of a whey protein isolate. 28. The protein supplement of claim 21, wherein the milk protein comprises a milk protein hydrolysate. 29. The protein supplement of claim 21, consisting essentially of the egg protein and the milk protein. 30. The protein supplement of claim 21, further comprising:
an immune modulator. 31. The protein supplement of claim 30, wherein the immune modulator includes transfer factor. 32. The protein supplement of claim 31, wherein at least about 80% of all proteins of the immune modulator are proteins having molecular weights of less than 5,000 Da. 33. The protein supplement of claim 32, wherein at least about 50% of all proteins of the immune modulator are proteins having molecular weights of less than 3,000 Da. 34. The protein supplement of claim 33, wherein the immune modulator comprises colostrum or a fraction of colostrum. 35. The protein supplement of claim 34, further comprising: another immune modulator. 36. The protein supplement of claim 35, wherein the another immune modulator comprises avian transfer factor. 37. The protein supplement of claim 36, consisting essentially of the egg protein, the milk protein, the immune modulator and the another immune modulator. 38. The protein supplement of claim 21, lacking protein from a plant source. 39. The protein supplement of claim 21, lacking soy protein. 40. The protein supplement of claim 21, wherein:
the milk protein makes up about 70% of a combined weight of the milk protein and the egg protein; and the egg protein makes up about 30% of the combined weight. 41. The protein supplement of claim 21, wherein:
the milk protein makes up about 60% of a combined weight of the milk protein and the egg protein; and the egg protein makes up about 40% of the combined weight. 42. The protein supplement of claim 21, wherein:
the milk protein makes up about 50% of a combined weight of the milk protein and the egg protein; and the egg protein makes up about 50% of the combined weight. 43. The protein supplement of claim 21, wherein:
the milk protein makes up about 40% of a combined weight of the milk protein and the egg protein; and the egg protein makes up about 60% of the combined weight. 44. The protein supplement of claim 21, wherein:
the milk protein makes up about 30% of a combined weight of the milk protein and the egg protein; and the egg protein makes up about 70% of the combined weight. 45. A food product including the protein supplement of claim 1. 46. The food product of claim 45, comprising an energy bar. 47. A baby formula including the protein supplement of claim 1. 48. A method for reducing inflammation in a body of a subject, comprising administering a composition according to claim 1 to the subject. 49. A method for supplementing a diet of a subject, comprising replacing at least a portion of the subject's diet with a composition according to claim 1. 50. The method of claim 49, wherein administering comprises administering the composition in place of breakfast. 51. The method of claim 49, comprising reducing body fat in the subject's body. 52. A method for increasing at least one of muscle mass and muscle strength of a subject, comprising administering a composition according to claim 1 to the subject. 53. The method of claim 52, wherein administering comprises administering the composition to the subject within an hour of increased physical activity. 54. A method for reducing muscle catabolism in a subject, comprising administering a composition according to claim 1 to the subject. | Protein supplements that include proteins from animal products, such as whey and eggs, are disclosed. Such a protein supplement may also include one or more immune modulators, such as transfer factor and/or nanofraction immune modulators.1. A protein supplement, including:
an animal-based protein hydrolysate; and an immune modulator. 2. The protein supplement of claim 1, wherein the immune modulator is from a source other than the animal-based protein hydrolysate. 3. The protein supplement of claim 1, wherein the animal-based protein hydrolysate comprises a hydrolysate of milk proteins. 4. The protein supplement of claim 3, wherein the animal-based protein hydrolysate comprises a hydrolysate of whey proteins. 5. The protein supplement of claim 1, wherein the animal-based protein-hydrolysate comprises a hydrolysate of egg proteins. 7. The protein supplement of claim 1, wherein the immune modulator comprises nanofraction immune modulators. 8. The protein supplement of claim 7, wherein the immune modulator has an upper molecular weight cutoff of about 5 KD or less. 9. The protein supplement of claim 8, wherein the immune modulator substantially lacks transfer factor. 10. The protein supplement of claim 1, wherein the immune modulator comprises transfer factor. 11. The protein supplement of claim 10, wherein the immune modulator has an upper molecular weight cutoff of about 12 KD or less. 12. The protein supplement of claim 10, wherein the immune modulator has an upper molecular weight cutoff of about 10 KD or less. 13. A protein supplement, including:
a whey hydrolysate; and a fraction of at least one of colostrum and egg, each fraction having an upper molecular weight cutoff of about 12 KD or less. 14. The protein supplement of claim 13, consisting essentially of the whey hydrolysate and the fraction of at least one of colostrum and egg. 15. The protein supplement of claim 13, consisting of the whey hydrolysate and the fraction at least one of colostrum and egg. 16. The protein supplement of claim 13, wherein each fraction has a molecular weight cutoff of about 10 KD or less. 17. The protein supplement of claim 13, wherein each fraction has a molecular weight cutoff of about 5 KD or less. 18. The protein supplement of claim 13, wherein the whey hydrolysate is a hydrolysate of standard whey. 19. The protein supplement of claim 13, wherein the whey hydrolysate is a hydrolysate of a whey protein concentrate. 20. The protein supplement of claim 13, wherein the whey hydrolysate is a hydrolysate of a whey protein isolate. 21. A protein supplement, including:
egg protein from avian eggs; milk protein. 22. The protein supplement of claim 21, wherein the egg protein comprises albumin. 23. The protein supplement of claim 21, wherein the egg protein comprises a whole egg hydrolysate. 24. The protein supplement of claim 21, wherein the milk protein comprises whey protein. 25. The protein supplement of claim 24, wherein the whey protein comprises a whey protein concentrate. 26. The protein supplement of claim 24, wherein the whey protein comprises a whey protein isolate. 27. The protein supplement of claim 24, wherein the whey protein comprises a hydrolysate of whey, a hydrolysate of a whey protein concentrate or a hydrolysate of a whey protein isolate. 28. The protein supplement of claim 21, wherein the milk protein comprises a milk protein hydrolysate. 29. The protein supplement of claim 21, consisting essentially of the egg protein and the milk protein. 30. The protein supplement of claim 21, further comprising:
an immune modulator. 31. The protein supplement of claim 30, wherein the immune modulator includes transfer factor. 32. The protein supplement of claim 31, wherein at least about 80% of all proteins of the immune modulator are proteins having molecular weights of less than 5,000 Da. 33. The protein supplement of claim 32, wherein at least about 50% of all proteins of the immune modulator are proteins having molecular weights of less than 3,000 Da. 34. The protein supplement of claim 33, wherein the immune modulator comprises colostrum or a fraction of colostrum. 35. The protein supplement of claim 34, further comprising: another immune modulator. 36. The protein supplement of claim 35, wherein the another immune modulator comprises avian transfer factor. 37. The protein supplement of claim 36, consisting essentially of the egg protein, the milk protein, the immune modulator and the another immune modulator. 38. The protein supplement of claim 21, lacking protein from a plant source. 39. The protein supplement of claim 21, lacking soy protein. 40. The protein supplement of claim 21, wherein:
the milk protein makes up about 70% of a combined weight of the milk protein and the egg protein; and the egg protein makes up about 30% of the combined weight. 41. The protein supplement of claim 21, wherein:
the milk protein makes up about 60% of a combined weight of the milk protein and the egg protein; and the egg protein makes up about 40% of the combined weight. 42. The protein supplement of claim 21, wherein:
the milk protein makes up about 50% of a combined weight of the milk protein and the egg protein; and the egg protein makes up about 50% of the combined weight. 43. The protein supplement of claim 21, wherein:
the milk protein makes up about 40% of a combined weight of the milk protein and the egg protein; and the egg protein makes up about 60% of the combined weight. 44. The protein supplement of claim 21, wherein:
the milk protein makes up about 30% of a combined weight of the milk protein and the egg protein; and the egg protein makes up about 70% of the combined weight. 45. A food product including the protein supplement of claim 1. 46. The food product of claim 45, comprising an energy bar. 47. A baby formula including the protein supplement of claim 1. 48. A method for reducing inflammation in a body of a subject, comprising administering a composition according to claim 1 to the subject. 49. A method for supplementing a diet of a subject, comprising replacing at least a portion of the subject's diet with a composition according to claim 1. 50. The method of claim 49, wherein administering comprises administering the composition in place of breakfast. 51. The method of claim 49, comprising reducing body fat in the subject's body. 52. A method for increasing at least one of muscle mass and muscle strength of a subject, comprising administering a composition according to claim 1 to the subject. 53. The method of claim 52, wherein administering comprises administering the composition to the subject within an hour of increased physical activity. 54. A method for reducing muscle catabolism in a subject, comprising administering a composition according to claim 1 to the subject. | 1,600 |
809 | 15,050,343 | 1,642 | The present invention provides assays and methods for determining an individual's risk of developing colorectal cancer (CRC) by analyzing a pre-cancerous polyp tissue sample. The present invention also provides assay and methods for selecting an anti-cancer therapeutic drug for an individual diagnosed as having early stage CRC. | 1. A method for diagnosing the risk of developing colorectal cancer (CRC) in a subject, the method comprising:
a) lysing a cell from a polyp sample taken from the subject to form a cell lysate; b) measuring the activation and/or expression level of the at least one signal transduction analyte in the cell lysate; c) indicating whether the subject is at risk of developing CRC based upon the activation and/or expression level of the at least one signal transduction analyte compared to that of a control; and d) if the polyp sample is pre-cancerous, optionally treating the subject with a therapeutic drug or a polypectomy. 2. The method of claim 1, wherein at least one signal transduction analyte is selected from the group consisting of HER1, HER2, HER3, cMET, PI3K, IGF1R, SHC, CK, AKT, ERK, MEK, RSK, PRAS, RPS6, and a combination thereof. 3. The method of claim 1, wherein the subject is at risk of developing CRC when the measured activation and/or expression level of the at least one signal transduction analyte is higher compared to that of a control. 4. The method of claim 1, wherein step (b) comprises measuring the activation and/or expression level of any combination of two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen of said signal transduction analyte. 5. The method of claim 1, wherein step (b) is performed with a proximity dual detection assay. 6. The method of claim 1, wherein the proximity dual detection assay is a Collaborative Enzyme Enhanced Reactive ImmunoAssay (CEER). 7. The method of claim 1, wherein the activation level of the at least one signal transduction analyte corresponds to the phosphorylation level thereof. 8. The method of claim 1, wherein the activation level of the at least one signal transduction analyte corresponds to the phosphorylation level of HER1, HER2, HER3, cMET, PI3K, IGF1R, SHC, CK, AKT, ERK, MEK, RSK, PRAS, or RPS6. 9. The method of claim 1, wherein the activation level of the at least one signal transduction analyte corresponds to a level of a PI3K complex. 10. The method of claim 1, wherein the control is from a non-adenomatous tissue. 11. The method of claim 1, wherein the polyp sample is an adenomatous polyp. 12. The method of claim 1, wherein the control is from a healthy subject. 13. The method of claim 1, wherein the control is from a CRC subject. 14. The method of claim 1, wherein the polyp sample is from a polypectomy. 15. The method of claim 14, wherein the polypectomy is a polypectomy of the colon and/or rectum. 16. The method of claim 1, further comprising selecting a suitable anticancer drug for the treatment of colorectal cancer based upon the activation and/or expression level of the at least one signal transduction analyte determined in step (b). 17. The method of claim 16, wherein the anticancer drug is selected from the group consisting of a monoclonal antibody, tyrosine kinase inhibitor, anti-proliferative agent, chemotherapeutic agent, and combinations thereof. 18. The method of claim 1, further comprising recommending a polypectomy. 19. A method for identifying a subject as likely to develop colorectal cancer (CRC), the method comprising:
a) measuring the activation and/or expression level of at least one signal transduction analyte in a cell lysate obtained from a polyp sample taken from the subject; b) indicating whether the subject is likely to develop CRC based upon the activation and/or expression level of the at least one signal transduction analyte compared to that of a control; and c) determining if the polyp sample is pre-cancerous, and optionally treating the subject with a therapeutic drug or a polypectomy. 20. A method for identifying a subject as likely to develop colorectal cancer (CRC), the method comprising:
measuring the activation and/or expression level of at least one signal transduction analyte in a cell lysate obtained from a polyp sample taken from the subject, wherein the subject is likely to develop CRC when the measured activation and/or expression level of the at least one signal transduction analyte is higher compared to that of a control. 21. The method of claim 19, wherein at least one signal transduction analyte is selected from the group consisting of HER1, HER2, HER3, cMET, PI3K, IGF1R, SHC, CK, AKT, ERK, MEK, RSK, PRAS, RPS6, and a combination thereof. 22. The method of claim 19, wherein the activation level of the at least one signal transduction analyte corresponds to a level of a PI3K complex. | The present invention provides assays and methods for determining an individual's risk of developing colorectal cancer (CRC) by analyzing a pre-cancerous polyp tissue sample. The present invention also provides assay and methods for selecting an anti-cancer therapeutic drug for an individual diagnosed as having early stage CRC.1. A method for diagnosing the risk of developing colorectal cancer (CRC) in a subject, the method comprising:
a) lysing a cell from a polyp sample taken from the subject to form a cell lysate; b) measuring the activation and/or expression level of the at least one signal transduction analyte in the cell lysate; c) indicating whether the subject is at risk of developing CRC based upon the activation and/or expression level of the at least one signal transduction analyte compared to that of a control; and d) if the polyp sample is pre-cancerous, optionally treating the subject with a therapeutic drug or a polypectomy. 2. The method of claim 1, wherein at least one signal transduction analyte is selected from the group consisting of HER1, HER2, HER3, cMET, PI3K, IGF1R, SHC, CK, AKT, ERK, MEK, RSK, PRAS, RPS6, and a combination thereof. 3. The method of claim 1, wherein the subject is at risk of developing CRC when the measured activation and/or expression level of the at least one signal transduction analyte is higher compared to that of a control. 4. The method of claim 1, wherein step (b) comprises measuring the activation and/or expression level of any combination of two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen of said signal transduction analyte. 5. The method of claim 1, wherein step (b) is performed with a proximity dual detection assay. 6. The method of claim 1, wherein the proximity dual detection assay is a Collaborative Enzyme Enhanced Reactive ImmunoAssay (CEER). 7. The method of claim 1, wherein the activation level of the at least one signal transduction analyte corresponds to the phosphorylation level thereof. 8. The method of claim 1, wherein the activation level of the at least one signal transduction analyte corresponds to the phosphorylation level of HER1, HER2, HER3, cMET, PI3K, IGF1R, SHC, CK, AKT, ERK, MEK, RSK, PRAS, or RPS6. 9. The method of claim 1, wherein the activation level of the at least one signal transduction analyte corresponds to a level of a PI3K complex. 10. The method of claim 1, wherein the control is from a non-adenomatous tissue. 11. The method of claim 1, wherein the polyp sample is an adenomatous polyp. 12. The method of claim 1, wherein the control is from a healthy subject. 13. The method of claim 1, wherein the control is from a CRC subject. 14. The method of claim 1, wherein the polyp sample is from a polypectomy. 15. The method of claim 14, wherein the polypectomy is a polypectomy of the colon and/or rectum. 16. The method of claim 1, further comprising selecting a suitable anticancer drug for the treatment of colorectal cancer based upon the activation and/or expression level of the at least one signal transduction analyte determined in step (b). 17. The method of claim 16, wherein the anticancer drug is selected from the group consisting of a monoclonal antibody, tyrosine kinase inhibitor, anti-proliferative agent, chemotherapeutic agent, and combinations thereof. 18. The method of claim 1, further comprising recommending a polypectomy. 19. A method for identifying a subject as likely to develop colorectal cancer (CRC), the method comprising:
a) measuring the activation and/or expression level of at least one signal transduction analyte in a cell lysate obtained from a polyp sample taken from the subject; b) indicating whether the subject is likely to develop CRC based upon the activation and/or expression level of the at least one signal transduction analyte compared to that of a control; and c) determining if the polyp sample is pre-cancerous, and optionally treating the subject with a therapeutic drug or a polypectomy. 20. A method for identifying a subject as likely to develop colorectal cancer (CRC), the method comprising:
measuring the activation and/or expression level of at least one signal transduction analyte in a cell lysate obtained from a polyp sample taken from the subject, wherein the subject is likely to develop CRC when the measured activation and/or expression level of the at least one signal transduction analyte is higher compared to that of a control. 21. The method of claim 19, wherein at least one signal transduction analyte is selected from the group consisting of HER1, HER2, HER3, cMET, PI3K, IGF1R, SHC, CK, AKT, ERK, MEK, RSK, PRAS, RPS6, and a combination thereof. 22. The method of claim 19, wherein the activation level of the at least one signal transduction analyte corresponds to a level of a PI3K complex. | 1,600 |
810 | 13,203,365 | 1,613 | Compounds that inhibit phosphodiesterase 1 (PDE1) are useful to treat glaucoma or elevated intraocular pressure. The PDE1 inhibitors may be administered as monotherapy or in combination with additional intraocular-pressure lowering agents. In addition, the invention provides ophthalmic compositions comprising PDE 1 inhibitors and optionally one or more additional intraocular pressure-lowering agents. Topical and systemic therapy may be used. | 1. A method of treatment or prophylaxis of a glaucoma or elevated intraocular pressure comprising administering an effective amount of a PDE 1 inhibitor, or a combination of the PDE 1 inhibitor and an intraocular pressure-lowering agent, to a patient in need thereof. 2. The method of claim 1 wherein the PDE 1 inhibitor is a compound of the formula (I):
wherein
(i) R1 is H or C1-4 alkyl;
(ii) R4 is H or C1-4 alkyl and R2 and R3 are, independently, H or C1-4 alkyl, aryl, heteroaryl, heteroarylalkoxy, arylalkoxy, heteroarylaklyl, or arylalkyl;
or R2 is H and R3 and R4 together form a di-, tri-, or tetra-methylene bridge;
(iii) R5 is attached to one of the nitrogens on the pyrazolo portion of Formula I and is a substituted heteroarylalkyl or is a moiety of Formula Q
wherein X, Y and Z are, independently, N or C; R8, R9, R11 and R12 are independently H or halogen; and R10 is halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or thiadiazolyl, diazolyl, triazolyl, tetrazolyl, arylcarbonyl, alkylsulfonyl, heteroarylcarbonyl, or alkoxycarbonyl; provided that when X, Y, or Z is nitrogen, R8, R9, or R10, respectively, is not present;
(iv) R6 is H, alkyl, aryl, heteroaryl, arylalkyl, arylamino, heterarylamino, N,N-dialkylamino, N,N-diarylamino, or N-aryl-N-(arylakyl)amino; and
(v) n=0 or 1;
(vi) when n=1, A is —C(R13R14)—
wherein R13 and R14, are, independently, H or C1-4 alkyl, aryl, heteroaryl, heteroarylalkoxy, arylalkoxy, heteroarylalkyl or arylalkyl;
in free, salt or prodrug form. 3. The method according to claim lwherein the PDE 1 inhibitor is a compound of Formula II:
wherein
Ra and Rb are, independently, H or C1-4 alkyl;
R6 is phenylamino or benzylamino;
R10 is phenyl, pyridyl, or thiadiazolyl;
in free or salt form. 4. The method according to claim 1 wherein the PDE 1 inhibitor is a compound of Formula III:
wherein
R2 is H and R3 and R4 together form a tri- or tetra-methylene bridge; or at least one of R2 and R3 is methyl, isopropyl or arylalkoxy and R4 is H; or R2 and R3 are H and R4 is a C1-4 alkyl;
R6 is phenylamino or benzylamino;
R10 is haloalkyl, phenyl, pyridyl (for example pyrid-2-yl), or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl);
in free or salt form. 5. The method according to claim 1 wherein the PDE 1 inhibitor is a compound of Formula IV:
wherein
R2 is H and R3 and R1 together form a tri- or tetra-methylene bridge; or at least one of R2 and R3 is methyl, isopropyl or arylalkoxy and R4 is H; or R2 and R3 are H and R4 is a C1-4 alkyl;
R6 is phenylamino or benzylamino;
R10 is phenyl, pyridyl, or thiadiazolyl;
in free or salt form. 6. The method according to claim 1 wherein the PDE 1 inhibitor is a compound of formula Ia:
wherein
(i) R1 is H or C1-4 alkyl;
(ii) R4 is H and R2 and R3 are, independently, H or C1-4 alkyl, aryl, or arylalkyl;
or R2 is H and R3 and R4 together form a di-, tri- or tetramethylene bridge;
(iii) R5 is attached to one of the nitrogens on the pyrazolo portion of formula Ia and is a substituted benzyl of formula B
wherein R8, R9, R11 and R12 are independently H or halogen; and R10 is halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, arylcarbonyl, or heteroarylcarbonyl, and (iv) R6 is H, alkyl, aryl, heteroaryl, arylalkyl, arylamino, heteroarylamino, arylalkylamino, N,N-dialkylamino, N,N-diarylamino, or N-aryl-N-(arylalkyl)amino;
in free, salt or prodrug form. 7. The method according to claim 1 wherein the PDE 1 inhibitor is a compound of Formula VI:
wherein
R2 is H and R3 and R4 together form a tri- or tetra-methylene bridge; or R2 and R3 are each methyl and R4 is H; or R2 and R4 are H and R3 is isopropyl [pref. the carbon carrying R3 having the R configuration];
R6 is phenylamino or benzylamino;
R10 is phenyl, pyridyl, or thiadiazolyl;
in free or salt form. 8. The method of claim 1 wherein the PDE 1 inhibitor is a compound of the Formula (V):
wherein
Ra is methyl or C2-C6 alkyl;
R1 is H or C1-C4 alkyl;
each of R2 and R3 is independently selected from H and C1-C4 alkyl, or R2 is H or C1-C4 alkyl and R3 is OH, C2-C4 alkanoyloxy or fluoro, or R2 and R3 when taken together represent C2-C6 alkylene, or R2 and R3 when taken together with the carbon atom to which they are attached represent a carbonyl group;
Ar is either (a)
wherein
each of R4, R5 and R6 is independently selected from
H
C1-C4 alkyl,
C1-C4 alkoxy,
C1-C4 alkoxy-Z—,
halo,
halo(C1-C4)alkyl,
phenoxy, optionally substituted by up to three substitutents each of which substitutent is independently selected from halo, C1-4 alkyl, and C1-C4 alkoxy,
nitro,
hydroxy,
hydroxy-Z—,
C2-C4 alkanoyl,
amino,
amino-Z—,
(C1-C4 alkyl)NH,
(C1-C4 alkyl)2N—,
(C1-C4 alkyl)NH—Z—,
(C1-C4 alkyl)2N—Z—,
—COOH,
—Z—COOH,
—COO(C1-C4 alkyl),
—Z—COO(C1-C4 alkyl)
C1-C4 alkanesulphonamido,
C1-C4 alkanesulphonamido-Z—,
halo(C1-C4)alkanesulphonamido,
halo(C1-C4)alkanesulphonamido-Z—,
C1-C4 alkanamido,
C1-C4 alkanamido-Z—,
HOOC—Z—NH—,
HOOC—Z—NH—Z—,
(C1-C4 alkyl)OOC—Z—NH—,
(C1-C4 alkyl)OOC—Z—NH—Z—,
C1-C4 alkyl-NH—SO2—NH—,
C1-C4 alkyl-NH—SO2—NH—Z—,
(C1-C4 alkyl)2—N—SO2—NH—,
(C1-C4 alkyl)2—N—SO2—NH—Z—,
C1-C4 alkoxy CH═CH—Z—CONH—,
C1-C4 alkoxy CH═CHCONH
C1-C4 alkyl-SO2—N(C1-C4 alkyl)-,
C1-C4 alkyl-SO2—N(C1-C4 alkyl)-Z—,
(C1-C4 alkyl)NH—Z—SO2—NH—,
(C1-C4 alkyl)2N—Z—SO2—NH—,
(C1-C4 alkyl)NH—Z—SO2—NH—Z—,
(C1-C4 alkyl)2N—Z—SO2—NH—Z—,
benzenesulphonamido, optionally ring substituted by up to three substitutents each of which is independently selected from halo, C1-4 alkyl, and C1-C4 alkoxy,
C1-C4 alkanoyl-N(C1-C4 alkyl)-,
C1-C4 alkanoyl-N(C1-C4 alkyl)-Z—,
C1-C4 alkoxycarbonyl-CH(CH2OH)NHSO2—,
—SO3H,
—SO2NH2,
H2NOC—CH(CH2OH)—NHSO2—, HOOC—Z—O—, and
(C1-C4 alkyl)OOC—Z—O—,
or optionally one of R4, R5 and R6 is a G-Het group and wherein the others of R4, R5 and R6 are independently selected from the R4, R5 and R6 substitutents listed above;
Z is C1-C4 alkylene,
G is a direct link, Z, O, —SO2NH—, SO2, or —Z—N(C1-C4 alkyl)SO2—,
Het is a 5- or 6-membered heterocyclic group containing 1, 2, 3 or 4 nitrogen heteroatoms; or 1 or 2 nitrogen heteroatoms and 1 sulphur heteroatom or 1 oxygen heteroatom; or the heterocyclic group is furanyl or thiophenyl; wherein the Het group is saturated or partially or fully unsaturated and optionally substituted by up to 3 substitutents, wherein each substitutent is independently selected from C1-C4 alkyl, oxo, hydroxy, halo, and halo(C1-C4)alkyl;
or
(b) any one of the following bicyclic groups:
benzodioxolanyl,
benzodioxanyl,
benzimidazolyl,
quinolinyl,
indolyl,
quinazolinyl,
isoquinolinyl,
benzotriazolyl,
benzofuranyl,
benzothiophenyl,
quinoxalinyl, or
phthalizinyl,
wherein said bicyclic Ar groups are linked to the neighbouring —C(R2R3)— group
via the benzo ring portion,
and wherein the heterocyclic portion of said bicyclic Ar group is optionally partially or fully saturated, said group being optionally substituted by one or more of C1-C4 alkyl, halo, hydroxy, oxo, amino, and C1-C4 alkoxy;
in free or pharmaceutically acceptable salt form.s 9. The method according to claim 1 wherein the PDE 1 inhibitor is selected from the following:
in free or pharmaceutically acceptable salt form. 10. The method according to claim 1 wherein the compound is
in free or pharmaceutically acceptable salt form. 11. The method according to claim 1 wherein the PDE 1 inhibitor is a compound of the Formula VIIa or VIIb:
in free or salt form, wherein:
i) q=0, 1 or 2;
ii) R1, Ra, Rb, Rc and Rd are each independently H, alkyl, aryl, heteroaryl, 10 cycloalkyl or heterocycloalkyl groups,
wherein each alkyl group of R1, Ra, Rb, Rc and Rd is independently unsubstituted or substituted with 1 to 5 independently selected R3 moieties which can be the same or different, each R3 moiety being independently selected from the group consisting of hydroxy, alkoxy, cycloalkoxy, aryloxy, alkylthio, arylthio, aryl, haloaryl, heteroaryl, cycloalkyl, heterocycloalkyl, amino, alkylamino, dialkylamino, cycloalkylamino and heterocycloalkylamino groups;
wherein each of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups of R1, Ra, Rb, Rc and Rd is independently unsubstituted or substituted with 1 to 5 independently selected R4 moieties which can be the same or different, each R4 moiety being independently selected from the group consisting of: halo, optionally substituted aryl, heteroaryl, nitro, cyano, haloalkyl, haloalkoxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, amino, alkylamino, dialkylamino, —OCF3, acyloxy, —OR8, —C(O)R9, —C(O)OR8, —NR10C(O)R9, —NR10C(O)OR8, —NR10S(O)2R9, —S(O)0-2R9 groups, carbonyl when two hydrogens attached to the same carbon atom of the cycloalkyl or heterocycloalkyl group of R′ are substituted, and ═CR8R9 when two hydrogens attached to the same carbon atom of the cycloalkyl or heterocycloalkyl groups of R1 are substituted,
wherein each of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups of the R3and R4 moieties above is independently unsubstituted or substituted with 1 to 5 independently selected R12 moieties which can be the same or different, each R12 moiety being independently selected from the group consisting of: halo, phenyl, nitro, cyano, haloalkyl, haloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl, amino, alkylamino, —OCF3, acyloxy, —OR8, C(O)R9, —C(O)OR8, —NR10C(O)R9, —NR10C(O)OR8, —NR10S(O)2R9, —S(O)0-2R9 groups, carbonyl when two hydrogens attached to the same carbon atom of the cycloalkyl or heterocycloalkyl group of R3 or R4 are substituted, and ═CR8R9 when two hydrogens attached to the same carbon atom of the cycloalkyl or heterocycloalkyl group of R3 or R4 are substituted; or
iii) Ra and Rb, together with the carbon to which they are both attached, form a 4- to 7-membered cycloalkyl or heterocycloalkyl ring, and Rc and Rd are each independently H or an alkyl group; or
iv) Ra and Rc, together with the respective carbons to which they are attached, form a 4- to 7-membered cycloalkyl or heterocycloalkyl ring, and Rb and Rd are each independently H or an alkyl group, preferably Ra and Rc together have the cis configuration, e.g., where the carbons carrying Ra and Rc have the R and S configurations, respectively;
v) R2 is H, halo, alkyl, haloalkyl, alkoxy, alkylthio, amino, aminosulfonyl, monoalkylamino, dialkylamino, hydroxyalkylamino, aminoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl or alkylaminocarbonyl group,
wherein each alkyl group of R2 is independently unsubstituted or substituted with 1 to 5 independently selected R13 moieties which can be the same or different, each R13 moiety being independently selected from the group consisting of halo, hydroxy, alkoxy, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, amino, monoalkylamino or dialkylamino group,
wherein each aryl group of R13 is independently unsubstituted or substituted with 1 to 5 independently selected R4 moieties which can be the same or different;
vi) Y is H or an alkyl group substituted with (i) an aryl, heteroaryl, cycloalkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino group, or (ii) an aryl group substituted with from one to three moieties each independently selected from the group consisting of: halo, alkyl, phenyl, hydroxy, alkoxy, phenoxy, amino, monoalkylamino and dialkylamino group;
vii) each R8 is independently H, alkyl or aryl;
viii) each R9 is independently H, alkyl, aryl or —NR10R11;
ix) each R10 is independently H, alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein each alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of R10 is unsubstituted or independently substituted with 1 to 5R14 moieties which can be the same or different, each R14 moiety being independently selected from the group consisting of: halo, alkyl, aryl, cycloalkyl, —CF3, —OCF3, —CN, —OR8, —CH2OR8, —C(O)OR8 and —C(O)NR8R8; and
x) each R11 is independently H, alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein each alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of R11 is unsubstituted or independently substituted with 1 to 5 R14 moieties which can be the same or different. 12.-21. (canceled) 22. The method according to claim 1, wherein the PDE 1 inhibitor is selected from the following:
in free or salt form. 23. The method according to claim 1, wherein the PDE 1 inhibitor is
in free or salt form. 24. The method according to claim 1, wherein the PDE I inhibitor is Compounds of Formula VIIIa or VIIIb:
in free or salt form, wherein:
R1 is hydrogen, alkyl or alkyl substituted with aryl or hydroxy;
R2 is hydrogen, aryl, heteroaryl, cycloalkyl, alkyl or alkyl substituted with aryl, heteroaryl, hydroxy, alkoxy, amino, monoalkyl amino or dialkylamino, or —(CH2)m TCOR20 wherein m is an integer from 1 to 6, T is oxygen or —NH— and R20 is hydrogen, aryl, heteroaryl, alkyl or alkyl substituted with aryl or heteroaryl;
R3 is hydrogen, halo, trifluoromethyl, alkoxy, alkylthio, alkyl, cycloalkyl, aryl, aminosulfonyl, amino, monoalkylamino, dialkylamino, hydroxyalkylamino, aminoalkylamino, carboxy, alkoxycarbonyl or aminocarbonyl or alkyl substituted with aryl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino;
Ra, Rb, Rc and Rd independently represent hydrogen, alkyl, cycloalkyl or aryl; or (Ra and Rb) or (Rc and Rd) or (Rb and Rc) can complete a saturated ring of 5- to 7-carbon atoms, or (Ra and Rb) taken together and (Rb and Rc) taken together, each complete a saturated ring of 5- to 7-carbon atoms, wherein each ring optionally can contain a sulfur or oxygen atom and whose carbon atoms may be optionally substituted with one or more or the following: alkenyl, alkynyl, hydroxy, carboxy, alkoxycarbonyl, alkyl or alkyl substituted with hydroxy, carboxy or alkoxycarbonyl; or such saturated ring can have two adjacent carbon atoms which are shared with an adjoining aryl ring; and
n is zero or one. 25. The method according to claim 1, wherein the PDE 1 inhibitor is a Compound of Formula IXa or IXb:
or a pharmaceutically acceptable salt thereof, wherein,
q=0 or 1;
R1 is H, cycloalkyl, alkyl, R23-alkyl- or R26;
Ra, Rb and Rc are, independently of one another, each H, alkyl, cyoloalkyl, aryl, R22-aryl- or R24-alkyl-; or
Ra and Rb, together with the carbon to which they are both attached, form a 4- to 7-membered ring, and Rc is H or alkyl; or
Ra and Rc, together with the respective carbons to which they are attached, form a 4- to 7-membered ring, and Rb is H or alkyl;
(i) X is a bond;
Y is aryl-alkyl or R22-aryl-alkyl-; and
R2 is monohaloalkyl, polyhaloalkyl, provided that it is not trifluoromethyl, azido, cyano, oximino, cycloalkenyl, heteroaryl, R22-heteroaryl- or R27-alkyl-;
(ii) X is a bond;
Y is aryl-alkyl or R22-aryl-alkyl-; and
R2 is H, halo, —CONHR6, —CONR6R7, —CO2R6, monohaloalkyl, polyhaloalkyl, azido, cyano, —C═N—OR6, cycloalkyl, cycloalkylalkyl, R26, aminosulfonyl, alkyl or R23-alkyl-
(iii) X is —O— or —S—;
Y is aryl-alkyl or R22-aryl-alkyl-; and
R2 is R26, cycloalkyl cycloalkylalkyl, heterocycloalkyl, cycloalkenyl or R26-alkyl-;
(iv) X is —O— or —S—;
Y is aryl-alkyl or R22-aryl-alkyl-; and
R2 is alkyl, R26, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, cycloalkenyl or R28-alkyl-;
(v) X is —SO— or —SO2—;
Y is aryl-alkyl or R22-aryl-alkyl-; and
R2 is alkyl, R26, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, cycloalkenyl or R28-alkyl-;
(vi) X is —NR8—;
Y is aryl-alkyl or R22-aryl-alkyl-; and
R2 is (R29)p-alkyl-, cycloalkyl, (R30)p-cycloalkyl-, cycloalkenyl, (R30)p-cycloalkenyl-, heterocycloalkyl or (R30)p-heterocycloalkyl-:
(vii) X is —NR8—;
Y is aryl-alkyl or R22-aryl-alkyl-; and
R2 is alkyl, R26, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, cycloalkenyl or R31-alkyl-; or
(viii) X is —C≡C—;
Y is aryl-alkyl or R22-aryl-alkyl-; and
R2 is alkyl, R26, cycloalkyl, cycloalkylalkyl or R23-alkyl-;
where,
R6 is H or R7;
R7 is alkyl, cycloalkyl or cycloalkylalkyl;
R8 is heterocycloalkyl or R6;
R21 is 1-6 substituents each independently selected from the group consisting of halo, hydroxy, alkoxy, phenoxy, phenyl, nitro, aminosulfonyl, cyano, monohaloalkyl, polyhaloalkyl, thiol, alkylthio, cyoloalkyl, cycloalkylalkyl, amino, alkylamino, acylamino, carboxyl, —C(O)OR34, carboxamido, —OCF3 and acyloxy;
R22 is 1-6 substituents each independently selected from the group consisting of alkyl and R21,
R23 is cycloalkoxy aryloxy, alkylthio, arylthio, cycloalkyl or R28;
R24 is cycloalkyl or R26;
R25 is hydroxy, alkoxy, amino, monoalkylamino, dialkylamino or R26;
R26 is aryl, R22-aryl-, heteroaryl or R22-heteroaryl-;
R27 is cycloalkoxy, aryloxy, alkylthio, arylthio, heteroaryl, R22-heteroaryl-, cycloalkyl, heterocycloalkyl, cycloalkenyl, cycloalkylamino or heterocycloalkylamino;
R28 is cycloalkylamino, heterocycloalkylamino or R25;
R29 is alkoxy, cycloalkylamino, heterocycloalkylamino or R26;
R30 is halo, hydroxy, alkoxy, amino, aminosulfonyl, cyano, monohaloalkyl, polyhaloalkyl, thiol, alkylthio, alkyl, cyoloalkyl, cycloalkylalkyl or acyloxy;
R31 is cycloalkyl or R28;
R34 is alkyl, aryl, aralkyl and heteroaryl; and
p is 1 to 4. 26. The method according to claim 1, wherein the PDE 1 inhibitor is a compound of Formula X:
in free or a pharmaceutically acceptable salt thereof, wherein:
R1, R2 and R3 are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, hydroxy, (di-lower alkyl)amino, 4-morpholinyl, 1-pyrrolidinyl, 1-pyrrolyl, —CF3, —OCF3, phenyl and methoxyphenyl; or R1 and R2 together are methylenedioxy; or R1 and R2 together with the carbon atoms to which they are attached form a benzene ring; and
Ra is hydrogen and Rb and Rc, together with the carbon atoms to which they are attached, form a saturated ring of 5 carbons; or Ra is lower alkyl, Rb is hydrogen or lower alkyl, and Rc is hydrogen; or Ra, Rb and the carbon atom to which they are attached form a saturated ring of 5-7 carbons, and Rc is hydrogen; or Ra is hydrogen, and Rb, Rc and the carbon atoms to which they are attached form a tetrahydrofuran ring; or Ra and Rb, together with the carbon atom to which they are attached, and Rb and Rc, together with the carbon atoms to which they are attached, each form a saturated ring of 5-7 carbons. 27. The method according to claim 1, wherein the PDE 1 Inhibitor is selected from the following:
in free or salt form. 28. The method according to claim 1, wherein the PDE 1 inhibitor is a 2-(optionally hetero) arylmethyl-3-(optionally hetero) arylamino-[2H]-pyrazolo[3,4-d]pyrimidine-4,6 (5H,7H)-dione in free, salt, or prodrug form 29. The method according to claim 28, wherein the PDE 1 inhibitor is a compound of formula (XII):
(i) R1 is H or alkyl;
(ii) R2 is H, alkyl, cycloalkyl, haloalkyl, alkylaminoalkyl, hydroxyalkyl, arylalkyl, heteroarylalkyl, or alkoxyarylalkyl;
(iii) R3 is heteroarylmethyl or a substituted benzyl of formula A
wherein R8, R9, R11 and R12 are independently H or halogen; and R10 is halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, arylcarbonyl, or heteroarylcarbonyl, alkoxycarbonyl, aminocarbonyl;
(iv) R4 is aryl or heteroaryl; and
(v) R5 is H, alkyl, cycloalkyl, heteroaryl, aryl, p-benzylaryl;
wherein “alk” or “alkyl” refers to C1-6 alkyl and “cycloalkyl” refers to C3-6 cycloalkyl; in free, salt or prodrug form. 30. The method according to claim 1, wherein the PDE 1 inhibitor is a compound of formula (XIII):
wherein
R1 is methyl;
R2 is H, alkyl, cycloalkyl, heteroaryl, aryl, haloalkyl, alkylaminoalkyl, hydroxyalkyl, arylalkyl, or alkoxyarylalkyl;
R4 is phenyl;
R5 is H; and
R10 is phenyl, pyridyl; pyrimidinyl, pyrazolyl, thiadiazolyl, haloalkyl, alkylsulfonyl, oxadiazolyl, aminocarbonyl, or triazolyl;
wherein “alk” or “alkyl” refers to C1-6 alkyl;
in free, salt or prodrug form. 31.-55. (canceled) | Compounds that inhibit phosphodiesterase 1 (PDE1) are useful to treat glaucoma or elevated intraocular pressure. The PDE1 inhibitors may be administered as monotherapy or in combination with additional intraocular-pressure lowering agents. In addition, the invention provides ophthalmic compositions comprising PDE 1 inhibitors and optionally one or more additional intraocular pressure-lowering agents. Topical and systemic therapy may be used.1. A method of treatment or prophylaxis of a glaucoma or elevated intraocular pressure comprising administering an effective amount of a PDE 1 inhibitor, or a combination of the PDE 1 inhibitor and an intraocular pressure-lowering agent, to a patient in need thereof. 2. The method of claim 1 wherein the PDE 1 inhibitor is a compound of the formula (I):
wherein
(i) R1 is H or C1-4 alkyl;
(ii) R4 is H or C1-4 alkyl and R2 and R3 are, independently, H or C1-4 alkyl, aryl, heteroaryl, heteroarylalkoxy, arylalkoxy, heteroarylaklyl, or arylalkyl;
or R2 is H and R3 and R4 together form a di-, tri-, or tetra-methylene bridge;
(iii) R5 is attached to one of the nitrogens on the pyrazolo portion of Formula I and is a substituted heteroarylalkyl or is a moiety of Formula Q
wherein X, Y and Z are, independently, N or C; R8, R9, R11 and R12 are independently H or halogen; and R10 is halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or thiadiazolyl, diazolyl, triazolyl, tetrazolyl, arylcarbonyl, alkylsulfonyl, heteroarylcarbonyl, or alkoxycarbonyl; provided that when X, Y, or Z is nitrogen, R8, R9, or R10, respectively, is not present;
(iv) R6 is H, alkyl, aryl, heteroaryl, arylalkyl, arylamino, heterarylamino, N,N-dialkylamino, N,N-diarylamino, or N-aryl-N-(arylakyl)amino; and
(v) n=0 or 1;
(vi) when n=1, A is —C(R13R14)—
wherein R13 and R14, are, independently, H or C1-4 alkyl, aryl, heteroaryl, heteroarylalkoxy, arylalkoxy, heteroarylalkyl or arylalkyl;
in free, salt or prodrug form. 3. The method according to claim lwherein the PDE 1 inhibitor is a compound of Formula II:
wherein
Ra and Rb are, independently, H or C1-4 alkyl;
R6 is phenylamino or benzylamino;
R10 is phenyl, pyridyl, or thiadiazolyl;
in free or salt form. 4. The method according to claim 1 wherein the PDE 1 inhibitor is a compound of Formula III:
wherein
R2 is H and R3 and R4 together form a tri- or tetra-methylene bridge; or at least one of R2 and R3 is methyl, isopropyl or arylalkoxy and R4 is H; or R2 and R3 are H and R4 is a C1-4 alkyl;
R6 is phenylamino or benzylamino;
R10 is haloalkyl, phenyl, pyridyl (for example pyrid-2-yl), or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl);
in free or salt form. 5. The method according to claim 1 wherein the PDE 1 inhibitor is a compound of Formula IV:
wherein
R2 is H and R3 and R1 together form a tri- or tetra-methylene bridge; or at least one of R2 and R3 is methyl, isopropyl or arylalkoxy and R4 is H; or R2 and R3 are H and R4 is a C1-4 alkyl;
R6 is phenylamino or benzylamino;
R10 is phenyl, pyridyl, or thiadiazolyl;
in free or salt form. 6. The method according to claim 1 wherein the PDE 1 inhibitor is a compound of formula Ia:
wherein
(i) R1 is H or C1-4 alkyl;
(ii) R4 is H and R2 and R3 are, independently, H or C1-4 alkyl, aryl, or arylalkyl;
or R2 is H and R3 and R4 together form a di-, tri- or tetramethylene bridge;
(iii) R5 is attached to one of the nitrogens on the pyrazolo portion of formula Ia and is a substituted benzyl of formula B
wherein R8, R9, R11 and R12 are independently H or halogen; and R10 is halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, arylcarbonyl, or heteroarylcarbonyl, and (iv) R6 is H, alkyl, aryl, heteroaryl, arylalkyl, arylamino, heteroarylamino, arylalkylamino, N,N-dialkylamino, N,N-diarylamino, or N-aryl-N-(arylalkyl)amino;
in free, salt or prodrug form. 7. The method according to claim 1 wherein the PDE 1 inhibitor is a compound of Formula VI:
wherein
R2 is H and R3 and R4 together form a tri- or tetra-methylene bridge; or R2 and R3 are each methyl and R4 is H; or R2 and R4 are H and R3 is isopropyl [pref. the carbon carrying R3 having the R configuration];
R6 is phenylamino or benzylamino;
R10 is phenyl, pyridyl, or thiadiazolyl;
in free or salt form. 8. The method of claim 1 wherein the PDE 1 inhibitor is a compound of the Formula (V):
wherein
Ra is methyl or C2-C6 alkyl;
R1 is H or C1-C4 alkyl;
each of R2 and R3 is independently selected from H and C1-C4 alkyl, or R2 is H or C1-C4 alkyl and R3 is OH, C2-C4 alkanoyloxy or fluoro, or R2 and R3 when taken together represent C2-C6 alkylene, or R2 and R3 when taken together with the carbon atom to which they are attached represent a carbonyl group;
Ar is either (a)
wherein
each of R4, R5 and R6 is independently selected from
H
C1-C4 alkyl,
C1-C4 alkoxy,
C1-C4 alkoxy-Z—,
halo,
halo(C1-C4)alkyl,
phenoxy, optionally substituted by up to three substitutents each of which substitutent is independently selected from halo, C1-4 alkyl, and C1-C4 alkoxy,
nitro,
hydroxy,
hydroxy-Z—,
C2-C4 alkanoyl,
amino,
amino-Z—,
(C1-C4 alkyl)NH,
(C1-C4 alkyl)2N—,
(C1-C4 alkyl)NH—Z—,
(C1-C4 alkyl)2N—Z—,
—COOH,
—Z—COOH,
—COO(C1-C4 alkyl),
—Z—COO(C1-C4 alkyl)
C1-C4 alkanesulphonamido,
C1-C4 alkanesulphonamido-Z—,
halo(C1-C4)alkanesulphonamido,
halo(C1-C4)alkanesulphonamido-Z—,
C1-C4 alkanamido,
C1-C4 alkanamido-Z—,
HOOC—Z—NH—,
HOOC—Z—NH—Z—,
(C1-C4 alkyl)OOC—Z—NH—,
(C1-C4 alkyl)OOC—Z—NH—Z—,
C1-C4 alkyl-NH—SO2—NH—,
C1-C4 alkyl-NH—SO2—NH—Z—,
(C1-C4 alkyl)2—N—SO2—NH—,
(C1-C4 alkyl)2—N—SO2—NH—Z—,
C1-C4 alkoxy CH═CH—Z—CONH—,
C1-C4 alkoxy CH═CHCONH
C1-C4 alkyl-SO2—N(C1-C4 alkyl)-,
C1-C4 alkyl-SO2—N(C1-C4 alkyl)-Z—,
(C1-C4 alkyl)NH—Z—SO2—NH—,
(C1-C4 alkyl)2N—Z—SO2—NH—,
(C1-C4 alkyl)NH—Z—SO2—NH—Z—,
(C1-C4 alkyl)2N—Z—SO2—NH—Z—,
benzenesulphonamido, optionally ring substituted by up to three substitutents each of which is independently selected from halo, C1-4 alkyl, and C1-C4 alkoxy,
C1-C4 alkanoyl-N(C1-C4 alkyl)-,
C1-C4 alkanoyl-N(C1-C4 alkyl)-Z—,
C1-C4 alkoxycarbonyl-CH(CH2OH)NHSO2—,
—SO3H,
—SO2NH2,
H2NOC—CH(CH2OH)—NHSO2—, HOOC—Z—O—, and
(C1-C4 alkyl)OOC—Z—O—,
or optionally one of R4, R5 and R6 is a G-Het group and wherein the others of R4, R5 and R6 are independently selected from the R4, R5 and R6 substitutents listed above;
Z is C1-C4 alkylene,
G is a direct link, Z, O, —SO2NH—, SO2, or —Z—N(C1-C4 alkyl)SO2—,
Het is a 5- or 6-membered heterocyclic group containing 1, 2, 3 or 4 nitrogen heteroatoms; or 1 or 2 nitrogen heteroatoms and 1 sulphur heteroatom or 1 oxygen heteroatom; or the heterocyclic group is furanyl or thiophenyl; wherein the Het group is saturated or partially or fully unsaturated and optionally substituted by up to 3 substitutents, wherein each substitutent is independently selected from C1-C4 alkyl, oxo, hydroxy, halo, and halo(C1-C4)alkyl;
or
(b) any one of the following bicyclic groups:
benzodioxolanyl,
benzodioxanyl,
benzimidazolyl,
quinolinyl,
indolyl,
quinazolinyl,
isoquinolinyl,
benzotriazolyl,
benzofuranyl,
benzothiophenyl,
quinoxalinyl, or
phthalizinyl,
wherein said bicyclic Ar groups are linked to the neighbouring —C(R2R3)— group
via the benzo ring portion,
and wherein the heterocyclic portion of said bicyclic Ar group is optionally partially or fully saturated, said group being optionally substituted by one or more of C1-C4 alkyl, halo, hydroxy, oxo, amino, and C1-C4 alkoxy;
in free or pharmaceutically acceptable salt form.s 9. The method according to claim 1 wherein the PDE 1 inhibitor is selected from the following:
in free or pharmaceutically acceptable salt form. 10. The method according to claim 1 wherein the compound is
in free or pharmaceutically acceptable salt form. 11. The method according to claim 1 wherein the PDE 1 inhibitor is a compound of the Formula VIIa or VIIb:
in free or salt form, wherein:
i) q=0, 1 or 2;
ii) R1, Ra, Rb, Rc and Rd are each independently H, alkyl, aryl, heteroaryl, 10 cycloalkyl or heterocycloalkyl groups,
wherein each alkyl group of R1, Ra, Rb, Rc and Rd is independently unsubstituted or substituted with 1 to 5 independently selected R3 moieties which can be the same or different, each R3 moiety being independently selected from the group consisting of hydroxy, alkoxy, cycloalkoxy, aryloxy, alkylthio, arylthio, aryl, haloaryl, heteroaryl, cycloalkyl, heterocycloalkyl, amino, alkylamino, dialkylamino, cycloalkylamino and heterocycloalkylamino groups;
wherein each of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups of R1, Ra, Rb, Rc and Rd is independently unsubstituted or substituted with 1 to 5 independently selected R4 moieties which can be the same or different, each R4 moiety being independently selected from the group consisting of: halo, optionally substituted aryl, heteroaryl, nitro, cyano, haloalkyl, haloalkoxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, amino, alkylamino, dialkylamino, —OCF3, acyloxy, —OR8, —C(O)R9, —C(O)OR8, —NR10C(O)R9, —NR10C(O)OR8, —NR10S(O)2R9, —S(O)0-2R9 groups, carbonyl when two hydrogens attached to the same carbon atom of the cycloalkyl or heterocycloalkyl group of R′ are substituted, and ═CR8R9 when two hydrogens attached to the same carbon atom of the cycloalkyl or heterocycloalkyl groups of R1 are substituted,
wherein each of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups of the R3and R4 moieties above is independently unsubstituted or substituted with 1 to 5 independently selected R12 moieties which can be the same or different, each R12 moiety being independently selected from the group consisting of: halo, phenyl, nitro, cyano, haloalkyl, haloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl, amino, alkylamino, —OCF3, acyloxy, —OR8, C(O)R9, —C(O)OR8, —NR10C(O)R9, —NR10C(O)OR8, —NR10S(O)2R9, —S(O)0-2R9 groups, carbonyl when two hydrogens attached to the same carbon atom of the cycloalkyl or heterocycloalkyl group of R3 or R4 are substituted, and ═CR8R9 when two hydrogens attached to the same carbon atom of the cycloalkyl or heterocycloalkyl group of R3 or R4 are substituted; or
iii) Ra and Rb, together with the carbon to which they are both attached, form a 4- to 7-membered cycloalkyl or heterocycloalkyl ring, and Rc and Rd are each independently H or an alkyl group; or
iv) Ra and Rc, together with the respective carbons to which they are attached, form a 4- to 7-membered cycloalkyl or heterocycloalkyl ring, and Rb and Rd are each independently H or an alkyl group, preferably Ra and Rc together have the cis configuration, e.g., where the carbons carrying Ra and Rc have the R and S configurations, respectively;
v) R2 is H, halo, alkyl, haloalkyl, alkoxy, alkylthio, amino, aminosulfonyl, monoalkylamino, dialkylamino, hydroxyalkylamino, aminoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl or alkylaminocarbonyl group,
wherein each alkyl group of R2 is independently unsubstituted or substituted with 1 to 5 independently selected R13 moieties which can be the same or different, each R13 moiety being independently selected from the group consisting of halo, hydroxy, alkoxy, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, amino, monoalkylamino or dialkylamino group,
wherein each aryl group of R13 is independently unsubstituted or substituted with 1 to 5 independently selected R4 moieties which can be the same or different;
vi) Y is H or an alkyl group substituted with (i) an aryl, heteroaryl, cycloalkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino group, or (ii) an aryl group substituted with from one to three moieties each independently selected from the group consisting of: halo, alkyl, phenyl, hydroxy, alkoxy, phenoxy, amino, monoalkylamino and dialkylamino group;
vii) each R8 is independently H, alkyl or aryl;
viii) each R9 is independently H, alkyl, aryl or —NR10R11;
ix) each R10 is independently H, alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein each alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of R10 is unsubstituted or independently substituted with 1 to 5R14 moieties which can be the same or different, each R14 moiety being independently selected from the group consisting of: halo, alkyl, aryl, cycloalkyl, —CF3, —OCF3, —CN, —OR8, —CH2OR8, —C(O)OR8 and —C(O)NR8R8; and
x) each R11 is independently H, alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein each alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of R11 is unsubstituted or independently substituted with 1 to 5 R14 moieties which can be the same or different. 12.-21. (canceled) 22. The method according to claim 1, wherein the PDE 1 inhibitor is selected from the following:
in free or salt form. 23. The method according to claim 1, wherein the PDE 1 inhibitor is
in free or salt form. 24. The method according to claim 1, wherein the PDE I inhibitor is Compounds of Formula VIIIa or VIIIb:
in free or salt form, wherein:
R1 is hydrogen, alkyl or alkyl substituted with aryl or hydroxy;
R2 is hydrogen, aryl, heteroaryl, cycloalkyl, alkyl or alkyl substituted with aryl, heteroaryl, hydroxy, alkoxy, amino, monoalkyl amino or dialkylamino, or —(CH2)m TCOR20 wherein m is an integer from 1 to 6, T is oxygen or —NH— and R20 is hydrogen, aryl, heteroaryl, alkyl or alkyl substituted with aryl or heteroaryl;
R3 is hydrogen, halo, trifluoromethyl, alkoxy, alkylthio, alkyl, cycloalkyl, aryl, aminosulfonyl, amino, monoalkylamino, dialkylamino, hydroxyalkylamino, aminoalkylamino, carboxy, alkoxycarbonyl or aminocarbonyl or alkyl substituted with aryl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino;
Ra, Rb, Rc and Rd independently represent hydrogen, alkyl, cycloalkyl or aryl; or (Ra and Rb) or (Rc and Rd) or (Rb and Rc) can complete a saturated ring of 5- to 7-carbon atoms, or (Ra and Rb) taken together and (Rb and Rc) taken together, each complete a saturated ring of 5- to 7-carbon atoms, wherein each ring optionally can contain a sulfur or oxygen atom and whose carbon atoms may be optionally substituted with one or more or the following: alkenyl, alkynyl, hydroxy, carboxy, alkoxycarbonyl, alkyl or alkyl substituted with hydroxy, carboxy or alkoxycarbonyl; or such saturated ring can have two adjacent carbon atoms which are shared with an adjoining aryl ring; and
n is zero or one. 25. The method according to claim 1, wherein the PDE 1 inhibitor is a Compound of Formula IXa or IXb:
or a pharmaceutically acceptable salt thereof, wherein,
q=0 or 1;
R1 is H, cycloalkyl, alkyl, R23-alkyl- or R26;
Ra, Rb and Rc are, independently of one another, each H, alkyl, cyoloalkyl, aryl, R22-aryl- or R24-alkyl-; or
Ra and Rb, together with the carbon to which they are both attached, form a 4- to 7-membered ring, and Rc is H or alkyl; or
Ra and Rc, together with the respective carbons to which they are attached, form a 4- to 7-membered ring, and Rb is H or alkyl;
(i) X is a bond;
Y is aryl-alkyl or R22-aryl-alkyl-; and
R2 is monohaloalkyl, polyhaloalkyl, provided that it is not trifluoromethyl, azido, cyano, oximino, cycloalkenyl, heteroaryl, R22-heteroaryl- or R27-alkyl-;
(ii) X is a bond;
Y is aryl-alkyl or R22-aryl-alkyl-; and
R2 is H, halo, —CONHR6, —CONR6R7, —CO2R6, monohaloalkyl, polyhaloalkyl, azido, cyano, —C═N—OR6, cycloalkyl, cycloalkylalkyl, R26, aminosulfonyl, alkyl or R23-alkyl-
(iii) X is —O— or —S—;
Y is aryl-alkyl or R22-aryl-alkyl-; and
R2 is R26, cycloalkyl cycloalkylalkyl, heterocycloalkyl, cycloalkenyl or R26-alkyl-;
(iv) X is —O— or —S—;
Y is aryl-alkyl or R22-aryl-alkyl-; and
R2 is alkyl, R26, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, cycloalkenyl or R28-alkyl-;
(v) X is —SO— or —SO2—;
Y is aryl-alkyl or R22-aryl-alkyl-; and
R2 is alkyl, R26, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, cycloalkenyl or R28-alkyl-;
(vi) X is —NR8—;
Y is aryl-alkyl or R22-aryl-alkyl-; and
R2 is (R29)p-alkyl-, cycloalkyl, (R30)p-cycloalkyl-, cycloalkenyl, (R30)p-cycloalkenyl-, heterocycloalkyl or (R30)p-heterocycloalkyl-:
(vii) X is —NR8—;
Y is aryl-alkyl or R22-aryl-alkyl-; and
R2 is alkyl, R26, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, cycloalkenyl or R31-alkyl-; or
(viii) X is —C≡C—;
Y is aryl-alkyl or R22-aryl-alkyl-; and
R2 is alkyl, R26, cycloalkyl, cycloalkylalkyl or R23-alkyl-;
where,
R6 is H or R7;
R7 is alkyl, cycloalkyl or cycloalkylalkyl;
R8 is heterocycloalkyl or R6;
R21 is 1-6 substituents each independently selected from the group consisting of halo, hydroxy, alkoxy, phenoxy, phenyl, nitro, aminosulfonyl, cyano, monohaloalkyl, polyhaloalkyl, thiol, alkylthio, cyoloalkyl, cycloalkylalkyl, amino, alkylamino, acylamino, carboxyl, —C(O)OR34, carboxamido, —OCF3 and acyloxy;
R22 is 1-6 substituents each independently selected from the group consisting of alkyl and R21,
R23 is cycloalkoxy aryloxy, alkylthio, arylthio, cycloalkyl or R28;
R24 is cycloalkyl or R26;
R25 is hydroxy, alkoxy, amino, monoalkylamino, dialkylamino or R26;
R26 is aryl, R22-aryl-, heteroaryl or R22-heteroaryl-;
R27 is cycloalkoxy, aryloxy, alkylthio, arylthio, heteroaryl, R22-heteroaryl-, cycloalkyl, heterocycloalkyl, cycloalkenyl, cycloalkylamino or heterocycloalkylamino;
R28 is cycloalkylamino, heterocycloalkylamino or R25;
R29 is alkoxy, cycloalkylamino, heterocycloalkylamino or R26;
R30 is halo, hydroxy, alkoxy, amino, aminosulfonyl, cyano, monohaloalkyl, polyhaloalkyl, thiol, alkylthio, alkyl, cyoloalkyl, cycloalkylalkyl or acyloxy;
R31 is cycloalkyl or R28;
R34 is alkyl, aryl, aralkyl and heteroaryl; and
p is 1 to 4. 26. The method according to claim 1, wherein the PDE 1 inhibitor is a compound of Formula X:
in free or a pharmaceutically acceptable salt thereof, wherein:
R1, R2 and R3 are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, hydroxy, (di-lower alkyl)amino, 4-morpholinyl, 1-pyrrolidinyl, 1-pyrrolyl, —CF3, —OCF3, phenyl and methoxyphenyl; or R1 and R2 together are methylenedioxy; or R1 and R2 together with the carbon atoms to which they are attached form a benzene ring; and
Ra is hydrogen and Rb and Rc, together with the carbon atoms to which they are attached, form a saturated ring of 5 carbons; or Ra is lower alkyl, Rb is hydrogen or lower alkyl, and Rc is hydrogen; or Ra, Rb and the carbon atom to which they are attached form a saturated ring of 5-7 carbons, and Rc is hydrogen; or Ra is hydrogen, and Rb, Rc and the carbon atoms to which they are attached form a tetrahydrofuran ring; or Ra and Rb, together with the carbon atom to which they are attached, and Rb and Rc, together with the carbon atoms to which they are attached, each form a saturated ring of 5-7 carbons. 27. The method according to claim 1, wherein the PDE 1 Inhibitor is selected from the following:
in free or salt form. 28. The method according to claim 1, wherein the PDE 1 inhibitor is a 2-(optionally hetero) arylmethyl-3-(optionally hetero) arylamino-[2H]-pyrazolo[3,4-d]pyrimidine-4,6 (5H,7H)-dione in free, salt, or prodrug form 29. The method according to claim 28, wherein the PDE 1 inhibitor is a compound of formula (XII):
(i) R1 is H or alkyl;
(ii) R2 is H, alkyl, cycloalkyl, haloalkyl, alkylaminoalkyl, hydroxyalkyl, arylalkyl, heteroarylalkyl, or alkoxyarylalkyl;
(iii) R3 is heteroarylmethyl or a substituted benzyl of formula A
wherein R8, R9, R11 and R12 are independently H or halogen; and R10 is halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, arylcarbonyl, or heteroarylcarbonyl, alkoxycarbonyl, aminocarbonyl;
(iv) R4 is aryl or heteroaryl; and
(v) R5 is H, alkyl, cycloalkyl, heteroaryl, aryl, p-benzylaryl;
wherein “alk” or “alkyl” refers to C1-6 alkyl and “cycloalkyl” refers to C3-6 cycloalkyl; in free, salt or prodrug form. 30. The method according to claim 1, wherein the PDE 1 inhibitor is a compound of formula (XIII):
wherein
R1 is methyl;
R2 is H, alkyl, cycloalkyl, heteroaryl, aryl, haloalkyl, alkylaminoalkyl, hydroxyalkyl, arylalkyl, or alkoxyarylalkyl;
R4 is phenyl;
R5 is H; and
R10 is phenyl, pyridyl; pyrimidinyl, pyrazolyl, thiadiazolyl, haloalkyl, alkylsulfonyl, oxadiazolyl, aminocarbonyl, or triazolyl;
wherein “alk” or “alkyl” refers to C1-6 alkyl;
in free, salt or prodrug form. 31.-55. (canceled) | 1,600 |
811 | 15,834,491 | 1,649 | Formulations and methods of treatment are disclosed for prevention and/or treatment of visual loss from age-related macular degeneration. The disclosed formulations include botulinum neurotoxin (e.g., botulinum neurotoxin or a fragment thereof, either in pure form or with one or more peptide fragments and/or neurotoxin associated proteins). In some embodiments, the disclosed formulations also include one or more anti-VEGF agents. The disclosed formulations may be applied to an intraocular or extraocular region of a patient. If applied to an extra ocular region of a patient, the botulinum-based pharmaceutical formulation may be transported to the intra-ocular region of the patient via axoplasmic transport, thereby allowing the active ingredient(s) to penetrate into the choroid, neuro-retina, and/or retinal pigment epithelium without direct injection into the eye, allowing for improved therapeutic safety by eliminating risk of retinal detachment, retinal break, retinal hemorrhage, and blindness associated with direct injection into the eye. | 1. A method of treating age-related macular degeneration, the method comprising:
administering a botulinum neurotoxin or a fragment thereof to a human or mammalian patient suffering from or at risk for macular degeneration. 2. The method of claim 1, wherein the administration of the botulinum neurotoxin mitigates wet and exudative macular degeneration by reducing sub-retinal leakage, intra retinal leakage, choroidal leakage, and restores and prevents loss of vision. 3. The method of claim 1, wherein the botulinum neurotoxin is injected into or near one or more of: a forehead of the patient, a periocular region of the patient, a nasal region of the patient, a neck of the patient, a nasal mucosa of the patient, a sinus of the patient, a para-orbital region of the patient, and a pterygopalatine fossa of the patient, and the botulinum neurotoxin is not injected into an intra-ocular region of the patient. 4. The method of claim 3, wherein the administration of the botulinum neurotoxin avoids complications from intra-ocular injection, including but not limited to intra-ocular hemorrhage, endophthalmitis, retinal detachment, retinal breaks, lens dislocations, cataract formation, and increases in intra-ocular pressure. 5. The method of claim 4, wherein the botulinum neurotoxin is administered as a dose of from 0.5 to 25,000 LD 50 units. 6. The method of claim 3, wherein the botulinum neurotoxin is administered as a dose that conforms with conventional dosing. 7. The method of claim 1, wherein the botulinum neurotoxin is injected into a vitreous or aqueous humor of an eye of the patient. 8. The method of claim 7, wherein the botulinum neurotoxin is administered as a dose of from 0.01 to 3,000 LD 50 units. 9. The method of claim 7, wherein the botulinum neurotoxin is administered as a dose that conforms with conventional dosing. 10. The method of claim 1, wherein the botulinum neurotoxin is administered via epibulbar injection or topical administration to the patient. 11. The method of claim 1, wherein the administration of the botulinum neurotoxin improves and/or preserves vision of the patient. 12. The method of claim 1, wherein the botulinum neurotoxin or fragment thereof is selected from the group consisting of: botulinum toxin A1-A5, B, C1-3, D, E, F, G and H. 13. The method of claim 1, wherein the botulinum neurotoxin is administered with a polycationic protein or a macromolecule. 14. The method of claim 1, wherein the macular degeneration is dry and not exudative as determined by OCT or fluorescein angiography. 15. The method of claim 14, wherein the macular degeneration is assessed by analysis of choroid, retinal pigment epithelium, and neuro-retina by OCT and/or fundus photography. 16. The method of claim 1, wherein the botulinum neurotoxin is administered with one or more accessory proteins. 17. The method of claim 1, wherein the botulinum neurotoxin is administered as a pure neurotoxin. 18. A method of treating age-related macular degeneration, the method comprising:
administering a formulation to a patient, wherein the formulation comprises a botulinum toxin-derived complexing protein devoid of neurotoxin and containing one or more isolated hemagglutinin proteins or fragments thereof, wherein the hemagglutinin is present in a quantity that corresponds to a specific botulinum neurotoxin dosing activity. 19. The method of claim 18, wherein the formulation is administered by injection or by topical administration. 20. An injectable formulation comprising:
a botulinum neurotoxin or a fragment thereof; a fusion protein addition of an anti-VEGF agent; and a stabilizing excipient. 21. The injectable formulation of claim 20, wherein the botulinum toxin or fragment thereof is selected from the group consisting of: botulinum toxin A1-A5, B, C1-3, D, E, F, G, and H. 22. The injectable formulation of claim 20, wherein the fusion protein addition is ranibizumab, abicipar, bevacizumab, or aflibercept. 23. An injectable formulation comprising:
a botulinum toxin or a fragment thereof; a non-covalent addition of an anti-VEGF agent; and a stabilizing agent. 24. The injectable formulation of claim 23, wherein the botulinum toxin or fragment thereof is selected from the group consisting of: botulinum toxin A1-A5, B, C1-3, D, E, F, G, and H. 25. The injectable formulation of claim 23, wherein the anti-VEGF agent is ranibizumab, abicipar, bevacizumab, or aflibercept. | Formulations and methods of treatment are disclosed for prevention and/or treatment of visual loss from age-related macular degeneration. The disclosed formulations include botulinum neurotoxin (e.g., botulinum neurotoxin or a fragment thereof, either in pure form or with one or more peptide fragments and/or neurotoxin associated proteins). In some embodiments, the disclosed formulations also include one or more anti-VEGF agents. The disclosed formulations may be applied to an intraocular or extraocular region of a patient. If applied to an extra ocular region of a patient, the botulinum-based pharmaceutical formulation may be transported to the intra-ocular region of the patient via axoplasmic transport, thereby allowing the active ingredient(s) to penetrate into the choroid, neuro-retina, and/or retinal pigment epithelium without direct injection into the eye, allowing for improved therapeutic safety by eliminating risk of retinal detachment, retinal break, retinal hemorrhage, and blindness associated with direct injection into the eye.1. A method of treating age-related macular degeneration, the method comprising:
administering a botulinum neurotoxin or a fragment thereof to a human or mammalian patient suffering from or at risk for macular degeneration. 2. The method of claim 1, wherein the administration of the botulinum neurotoxin mitigates wet and exudative macular degeneration by reducing sub-retinal leakage, intra retinal leakage, choroidal leakage, and restores and prevents loss of vision. 3. The method of claim 1, wherein the botulinum neurotoxin is injected into or near one or more of: a forehead of the patient, a periocular region of the patient, a nasal region of the patient, a neck of the patient, a nasal mucosa of the patient, a sinus of the patient, a para-orbital region of the patient, and a pterygopalatine fossa of the patient, and the botulinum neurotoxin is not injected into an intra-ocular region of the patient. 4. The method of claim 3, wherein the administration of the botulinum neurotoxin avoids complications from intra-ocular injection, including but not limited to intra-ocular hemorrhage, endophthalmitis, retinal detachment, retinal breaks, lens dislocations, cataract formation, and increases in intra-ocular pressure. 5. The method of claim 4, wherein the botulinum neurotoxin is administered as a dose of from 0.5 to 25,000 LD 50 units. 6. The method of claim 3, wherein the botulinum neurotoxin is administered as a dose that conforms with conventional dosing. 7. The method of claim 1, wherein the botulinum neurotoxin is injected into a vitreous or aqueous humor of an eye of the patient. 8. The method of claim 7, wherein the botulinum neurotoxin is administered as a dose of from 0.01 to 3,000 LD 50 units. 9. The method of claim 7, wherein the botulinum neurotoxin is administered as a dose that conforms with conventional dosing. 10. The method of claim 1, wherein the botulinum neurotoxin is administered via epibulbar injection or topical administration to the patient. 11. The method of claim 1, wherein the administration of the botulinum neurotoxin improves and/or preserves vision of the patient. 12. The method of claim 1, wherein the botulinum neurotoxin or fragment thereof is selected from the group consisting of: botulinum toxin A1-A5, B, C1-3, D, E, F, G and H. 13. The method of claim 1, wherein the botulinum neurotoxin is administered with a polycationic protein or a macromolecule. 14. The method of claim 1, wherein the macular degeneration is dry and not exudative as determined by OCT or fluorescein angiography. 15. The method of claim 14, wherein the macular degeneration is assessed by analysis of choroid, retinal pigment epithelium, and neuro-retina by OCT and/or fundus photography. 16. The method of claim 1, wherein the botulinum neurotoxin is administered with one or more accessory proteins. 17. The method of claim 1, wherein the botulinum neurotoxin is administered as a pure neurotoxin. 18. A method of treating age-related macular degeneration, the method comprising:
administering a formulation to a patient, wherein the formulation comprises a botulinum toxin-derived complexing protein devoid of neurotoxin and containing one or more isolated hemagglutinin proteins or fragments thereof, wherein the hemagglutinin is present in a quantity that corresponds to a specific botulinum neurotoxin dosing activity. 19. The method of claim 18, wherein the formulation is administered by injection or by topical administration. 20. An injectable formulation comprising:
a botulinum neurotoxin or a fragment thereof; a fusion protein addition of an anti-VEGF agent; and a stabilizing excipient. 21. The injectable formulation of claim 20, wherein the botulinum toxin or fragment thereof is selected from the group consisting of: botulinum toxin A1-A5, B, C1-3, D, E, F, G, and H. 22. The injectable formulation of claim 20, wherein the fusion protein addition is ranibizumab, abicipar, bevacizumab, or aflibercept. 23. An injectable formulation comprising:
a botulinum toxin or a fragment thereof; a non-covalent addition of an anti-VEGF agent; and a stabilizing agent. 24. The injectable formulation of claim 23, wherein the botulinum toxin or fragment thereof is selected from the group consisting of: botulinum toxin A1-A5, B, C1-3, D, E, F, G, and H. 25. The injectable formulation of claim 23, wherein the anti-VEGF agent is ranibizumab, abicipar, bevacizumab, or aflibercept. | 1,600 |
812 | 14,898,810 | 1,611 | A synergistic preservative composition comprises sorbic acid or a salt thereof, benzyl alcohol, and a mixture of (i) 1,2-propanediol and/or 1,3-propanediol, and (ii), 4-butanediol and/or 1,3-butanediol. The composition is particularly suited for the preservation of cosmetics and personal care products. | 1. A preservative composition comprising
(a) from 1 to 20 wt. % of sorbic acid or a salt thenqgf hereof; (b) from 10 to 89 wt. % of benzyl alcohol; (c) from 10 to 89 wt. % of a mixture of
(i) 1,2-propanediol, 1,3-propanediol, or a mixture thereof; and
(ii) 1,4-butanediol, 1,3-butanediol, or a mixture thereof
in a weight ratio of (i) to (ii) of 1:4 to 4:1,
based on the total weight of (a), (b) and (c). 2. The preservative composition of claim 1, comprising
(a) from 1 to 10 wt. % of sorbic acid or a salt thereof, (b) from 20 to 70 wt. % of benzyl alcohol, (c) from 20 to 70 wt. % of a mixture of
(i) 1,2-propanediol, 1,3-propanediol, or a mixture thereof; and
(ii) 1,4-butanediol, 1,3-butanediol, or a mixture thereof,
in a weight ratio of (i) to (ii) of 1:4 to 4:1,
based on the total weight of (a), (b) and (c). 3. The preservative composition of claim 2, comprising
(a) from 2 to 10 wt. % of sorbic acid or a salt thereof, (b) from 20 to 50 wt. % of benzyl alcohol, (c) from 40 to 70 wt. % of a mixture of
(i) 1,2-propanediol, 1,3-propanediol, or a mixture thereof; and
(ii) 1,4-butanediol, 1,3-butanediol, or a mixture thereof,
in a weight ratio of (i) to (ii) of 1:4 to 4:1,
based on the total weight of (a), (b) and (c). 4. The preservative composition of claim 3, comprising
(a) from 4 to 10 wt. % of sorbic acid or a salt thereof, (b) from 20 to 45 wt. % of benzyl alcohol, (c) from 50 to 70 wt. % of a mixture of
(i) 1,2-propanediol, 1,3-propanediol, or a mixture thereof; and
(ii) 1,4-butanediol, 1,3-butanediol, or a mixture thereof,
in a weight ratio of (i) to (ii) of 1:4 to 2:1,
based on the total weight of (a), (b) and (c). 5. The preservative composition of claim 1, wherein component (c) is a mixture of (i) 1,2-propanediol and (ii) 1,4-butanedial. 6. The preservative composition of claim 5, comprising
(a) from 4 to 10 wt. % of sorbic acid, (b) from 20 to 45 wt. % of benzyl alcohol, (c) from 50 to 70 wt. % of a mixture of
(i) 1,2-propanediol: and
(ii) 1,4-butanediol,
in a weight ratio of (i) to (ii) of 1:4 to 2:1,
based on the total weight of (a), (b) and (c). 7. The preservative composition of claim 1, wherein component (c) is a mixture of (i) 1,3-propanediol and (ii) 1,3-butanediol. 8. The preservative composition of claim 7, comprising
(a) from 4 to 10 wt. % of sorbic acid, (b) from 20 to 45 wt. % of benzyl alcohol, (c) from 50 to 70 wt. % of a mixture of
(i) 1,3-propanediol; and
(ii) 1,3-butanediol,
in a weight ratio of 0) to (ii) of 1:4 to 2:1,
based on the total weight of (a), (b) and (c). 9. A method for preventing or inhibiting microbial growth in a cosmetic or personal care product, comprising the step of adding to said product a preservative composition according to claim 1 in an amount of 0.1 to 10,0 wt. %, calculated as sum of components (a), (b) and (c), and based on 100% total weight of said product. 10. The method of claim 9, wherein the preservative composition is added to the cosmetic or personal care product in an amount of 0.5 to 5.0 wt. %, calculated as sum of components (a), (b) and (c), and based on t00% total weight of said product. 11. The method of claim 9 or 10, wherein the cosmetic or personal care product is selected from the group consisting of shampoos, lotions, shower gels, bubble baths, bath oils, creams, baby products, liquid soaps, hair gels, make-up, and sunscreens. 12. A preserved cosmetic or personal care product obtained by the method of claim 9. 13. The preservative composition of claim 2, wherein component (c) is a mixture of (i) 1,2-propanediol and (ii) 1,4-butanediol. 14. The preservative composition of claim 3, wherein component (c) is a mixture of (i) 1,2 propanediol and (ii) 1 4-butanediol. 15. The preservative composition of claim 2, wherein component (c) is a mixture of (i) 1,3-propanediol and (ii) 1,3-butanediol. 16. The preservative composition of claim 3, wherein component (c) is a mixture of (i) 1,3-propanediol and (ii) 1,3-butanediol. 17. A method for preventing or inhibiting microbial growth in a cosmetic or personal care product, comprising the step of adding to said product a preservative composition according to claim 4 in an amount of 0.1 to 10.0 wt. %, calculated as sum of components (a), (b) and (c), and based on 100% total weight of said product. 18. The method of claim 17, wherein the preservative composition is added to the cosmetic or personal care product in an amount of 0.5 to 5.0 wt. %, calculated as sum of components (a), (b) and (c), and based on 100% total weight of said product. 19. The method of claim 17, wherein the cosmetic or personal care product is selected from the group consisting of shampoos, lotions, shower gels, bubble baths, bath oils, creams, baby products, liquid soaps, hair gels, make-up, and sunscreens. 20. A preserved cosmetic or personal care product obtained by the method of claim 17. | A synergistic preservative composition comprises sorbic acid or a salt thereof, benzyl alcohol, and a mixture of (i) 1,2-propanediol and/or 1,3-propanediol, and (ii), 4-butanediol and/or 1,3-butanediol. The composition is particularly suited for the preservation of cosmetics and personal care products.1. A preservative composition comprising
(a) from 1 to 20 wt. % of sorbic acid or a salt thenqgf hereof; (b) from 10 to 89 wt. % of benzyl alcohol; (c) from 10 to 89 wt. % of a mixture of
(i) 1,2-propanediol, 1,3-propanediol, or a mixture thereof; and
(ii) 1,4-butanediol, 1,3-butanediol, or a mixture thereof
in a weight ratio of (i) to (ii) of 1:4 to 4:1,
based on the total weight of (a), (b) and (c). 2. The preservative composition of claim 1, comprising
(a) from 1 to 10 wt. % of sorbic acid or a salt thereof, (b) from 20 to 70 wt. % of benzyl alcohol, (c) from 20 to 70 wt. % of a mixture of
(i) 1,2-propanediol, 1,3-propanediol, or a mixture thereof; and
(ii) 1,4-butanediol, 1,3-butanediol, or a mixture thereof,
in a weight ratio of (i) to (ii) of 1:4 to 4:1,
based on the total weight of (a), (b) and (c). 3. The preservative composition of claim 2, comprising
(a) from 2 to 10 wt. % of sorbic acid or a salt thereof, (b) from 20 to 50 wt. % of benzyl alcohol, (c) from 40 to 70 wt. % of a mixture of
(i) 1,2-propanediol, 1,3-propanediol, or a mixture thereof; and
(ii) 1,4-butanediol, 1,3-butanediol, or a mixture thereof,
in a weight ratio of (i) to (ii) of 1:4 to 4:1,
based on the total weight of (a), (b) and (c). 4. The preservative composition of claim 3, comprising
(a) from 4 to 10 wt. % of sorbic acid or a salt thereof, (b) from 20 to 45 wt. % of benzyl alcohol, (c) from 50 to 70 wt. % of a mixture of
(i) 1,2-propanediol, 1,3-propanediol, or a mixture thereof; and
(ii) 1,4-butanediol, 1,3-butanediol, or a mixture thereof,
in a weight ratio of (i) to (ii) of 1:4 to 2:1,
based on the total weight of (a), (b) and (c). 5. The preservative composition of claim 1, wherein component (c) is a mixture of (i) 1,2-propanediol and (ii) 1,4-butanedial. 6. The preservative composition of claim 5, comprising
(a) from 4 to 10 wt. % of sorbic acid, (b) from 20 to 45 wt. % of benzyl alcohol, (c) from 50 to 70 wt. % of a mixture of
(i) 1,2-propanediol: and
(ii) 1,4-butanediol,
in a weight ratio of (i) to (ii) of 1:4 to 2:1,
based on the total weight of (a), (b) and (c). 7. The preservative composition of claim 1, wherein component (c) is a mixture of (i) 1,3-propanediol and (ii) 1,3-butanediol. 8. The preservative composition of claim 7, comprising
(a) from 4 to 10 wt. % of sorbic acid, (b) from 20 to 45 wt. % of benzyl alcohol, (c) from 50 to 70 wt. % of a mixture of
(i) 1,3-propanediol; and
(ii) 1,3-butanediol,
in a weight ratio of 0) to (ii) of 1:4 to 2:1,
based on the total weight of (a), (b) and (c). 9. A method for preventing or inhibiting microbial growth in a cosmetic or personal care product, comprising the step of adding to said product a preservative composition according to claim 1 in an amount of 0.1 to 10,0 wt. %, calculated as sum of components (a), (b) and (c), and based on 100% total weight of said product. 10. The method of claim 9, wherein the preservative composition is added to the cosmetic or personal care product in an amount of 0.5 to 5.0 wt. %, calculated as sum of components (a), (b) and (c), and based on t00% total weight of said product. 11. The method of claim 9 or 10, wherein the cosmetic or personal care product is selected from the group consisting of shampoos, lotions, shower gels, bubble baths, bath oils, creams, baby products, liquid soaps, hair gels, make-up, and sunscreens. 12. A preserved cosmetic or personal care product obtained by the method of claim 9. 13. The preservative composition of claim 2, wherein component (c) is a mixture of (i) 1,2-propanediol and (ii) 1,4-butanediol. 14. The preservative composition of claim 3, wherein component (c) is a mixture of (i) 1,2 propanediol and (ii) 1 4-butanediol. 15. The preservative composition of claim 2, wherein component (c) is a mixture of (i) 1,3-propanediol and (ii) 1,3-butanediol. 16. The preservative composition of claim 3, wherein component (c) is a mixture of (i) 1,3-propanediol and (ii) 1,3-butanediol. 17. A method for preventing or inhibiting microbial growth in a cosmetic or personal care product, comprising the step of adding to said product a preservative composition according to claim 4 in an amount of 0.1 to 10.0 wt. %, calculated as sum of components (a), (b) and (c), and based on 100% total weight of said product. 18. The method of claim 17, wherein the preservative composition is added to the cosmetic or personal care product in an amount of 0.5 to 5.0 wt. %, calculated as sum of components (a), (b) and (c), and based on 100% total weight of said product. 19. The method of claim 17, wherein the cosmetic or personal care product is selected from the group consisting of shampoos, lotions, shower gels, bubble baths, bath oils, creams, baby products, liquid soaps, hair gels, make-up, and sunscreens. 20. A preserved cosmetic or personal care product obtained by the method of claim 17. | 1,600 |
813 | 16,012,961 | 1,618 | Described herein are oral pharmaceutical compositions comprising liquid dosage forms of sodium naproxen in soft gel capsules. In one embodiment, the pharmaceutical composition comprises sodium naproxen, 0.2-1.0 mole equivalents of a de-ionizing agent per mole of naproxen, polyethylene glycol, and one or more solubilizers such as propylene glycol, polyvinyl pyrrolidone or a combination thereof. | 1. A soft gelatin capsule comprising a fill material comprising:
(a) a naproxen salt; (b) a deionizing agent comprising lactic acid in an amount of from 0.2 to 1.0 mole equivalents per mole of naproxen salt; (c) polyethylene glycol; and (d) one or more solubilizers. 2. The capsule of claim 1, wherein the naproxen salt is naproxen sodium. 3. The capsule of claim 1, wherein the fill material further comprises water in an amount from 1% to 18% by weight. 4. The capsule of claim 1, wherein polyethylene glycol is present in an amount from 10% to 80% by weight. 5. The capsule of claim 1, wherein the polyethylene glycol comprises one or more polyethylene glycols with a molecular weight between 300 and 1500. 6. The capsule of claim 1, wherein the solubilizer is present in amount from 1% to 10% by weight. 7. The capsule of claim 1, wherein the one or more solubilizers comprise glycerin, polyvinylpyrrolidone, propylene glycol, or combinations thereof. 8. The capsule of claim 1, further comprising one or more excipients comprising plasticizers, crystallization inhibitors, wetting agents, bulk filling agents, bioavailability enhancers, solvents, dyes, preservatives, surfactants, or combinations thereof. 9. The capsule of claim 1, wherein the fill material is liquid. 10. A method for treating pain, inflammation, or fever comprising administering the capsule of claim 1 to a patient in need thereof. 11. A method of making the capsule of claim 1 comprising
(a) mixing components (a), (b), (c), and (d) as defined in claim 1; and
(b) encapsulating the mixture in a softgel capsule. 12. The method of claim 11, wherein step (a) is conducted at a temperature of from 50° C. to 70° C. 13. A soft gelatin capsule comprising a fill material comprising:
(a) naproxen sodium; (b) a deionizing agent comprising lactic acid in an amount of from 0.2 to 1.0 mole equivalents per mole of naproxen sodium; (c) polyethylene glycol; and (d) a solubilizer comprising glycerin, polyvinylpyrrolidone, propylene glycol, or combinations thereof. 14. The capsule of claim 13, wherein polyethylene glycol is present in an amount from 10% to 80% by weight. 15. The capsule of claim 13, wherein the polyethylene glycol comprises one or more polyethylene glycols with a molecular weight between 300 and 1500. 16. The capsule of claim 13, wherein the fill material further comprises water in an amount from 1% to 18% by weight. 17. The capsule of claim 13, further comprising one or more excipients comprising plasticizers, crystallization inhibitors, wetting agents, bulk filling agents, bioavailability enhancers, solvents, dyes, preservatives, surfactants, or combinations thereof. 18. The capsule of claim 13, wherein the solubilizer is present in amount from 1% to 10% by weight. 19. The capsule of claim 13, wherein the fill material is liquid. 20. A method for treating pain, inflammation, or fever comprising administering the capsule of claim 13 to a patient in need thereof. | Described herein are oral pharmaceutical compositions comprising liquid dosage forms of sodium naproxen in soft gel capsules. In one embodiment, the pharmaceutical composition comprises sodium naproxen, 0.2-1.0 mole equivalents of a de-ionizing agent per mole of naproxen, polyethylene glycol, and one or more solubilizers such as propylene glycol, polyvinyl pyrrolidone or a combination thereof.1. A soft gelatin capsule comprising a fill material comprising:
(a) a naproxen salt; (b) a deionizing agent comprising lactic acid in an amount of from 0.2 to 1.0 mole equivalents per mole of naproxen salt; (c) polyethylene glycol; and (d) one or more solubilizers. 2. The capsule of claim 1, wherein the naproxen salt is naproxen sodium. 3. The capsule of claim 1, wherein the fill material further comprises water in an amount from 1% to 18% by weight. 4. The capsule of claim 1, wherein polyethylene glycol is present in an amount from 10% to 80% by weight. 5. The capsule of claim 1, wherein the polyethylene glycol comprises one or more polyethylene glycols with a molecular weight between 300 and 1500. 6. The capsule of claim 1, wherein the solubilizer is present in amount from 1% to 10% by weight. 7. The capsule of claim 1, wherein the one or more solubilizers comprise glycerin, polyvinylpyrrolidone, propylene glycol, or combinations thereof. 8. The capsule of claim 1, further comprising one or more excipients comprising plasticizers, crystallization inhibitors, wetting agents, bulk filling agents, bioavailability enhancers, solvents, dyes, preservatives, surfactants, or combinations thereof. 9. The capsule of claim 1, wherein the fill material is liquid. 10. A method for treating pain, inflammation, or fever comprising administering the capsule of claim 1 to a patient in need thereof. 11. A method of making the capsule of claim 1 comprising
(a) mixing components (a), (b), (c), and (d) as defined in claim 1; and
(b) encapsulating the mixture in a softgel capsule. 12. The method of claim 11, wherein step (a) is conducted at a temperature of from 50° C. to 70° C. 13. A soft gelatin capsule comprising a fill material comprising:
(a) naproxen sodium; (b) a deionizing agent comprising lactic acid in an amount of from 0.2 to 1.0 mole equivalents per mole of naproxen sodium; (c) polyethylene glycol; and (d) a solubilizer comprising glycerin, polyvinylpyrrolidone, propylene glycol, or combinations thereof. 14. The capsule of claim 13, wherein polyethylene glycol is present in an amount from 10% to 80% by weight. 15. The capsule of claim 13, wherein the polyethylene glycol comprises one or more polyethylene glycols with a molecular weight between 300 and 1500. 16. The capsule of claim 13, wherein the fill material further comprises water in an amount from 1% to 18% by weight. 17. The capsule of claim 13, further comprising one or more excipients comprising plasticizers, crystallization inhibitors, wetting agents, bulk filling agents, bioavailability enhancers, solvents, dyes, preservatives, surfactants, or combinations thereof. 18. The capsule of claim 13, wherein the solubilizer is present in amount from 1% to 10% by weight. 19. The capsule of claim 13, wherein the fill material is liquid. 20. A method for treating pain, inflammation, or fever comprising administering the capsule of claim 13 to a patient in need thereof. | 1,600 |
814 | 14,851,352 | 1,619 | The present invention relates to the use of at least one 2-methylsuccinic acid diester derivative of formula (I) below:
in a composition comprising, in a cosmetically acceptable medium, at least one liquid fatty phase and at least one lipophilic active agent, for dissolving the said active agent in the said liquid fatty phase and/or for improving the solubility of the said active agent in the said solid fatty phase. The present invention relates especially to a composition comprising, in a cosmetically acceptable medium, at least one liquid fatty phase, characterized in that it contains at least one 2-methylsuccinic acid ester derivative of formula (I) and at least one lipophilic active agent. | 1. A composition comprising, in a cosmetically acceptable medium, at least one liquid fatty phase, characterized in that it contains at least one 2-methylsuccinic acid diester derivative of formula (I) and/or an optical isomer and/or solvate thereof of formula (I) below:
in which:
R1 and R2, which may be identical or different, denote a linear or branched C1-C20 alkyl radical or a C5-C6 cycloalkyl radical optionally substituted with C1-C3 alkyl radicals, R1 and R2 not simultaneously denoting a methyl radical, and at least one lipophilic active agent, wherein said at least one 2-methylsuccinic acid diester derivative of formula (I) and/or an optical isomer and/or solvate thereof of formula (I) is present in an amount effective to dissolve the active agent in the liquid fatty phase and/or to improve the solubility of the active agent in the fatty phase. 2. The composition according to claim 1, in which the compound of formula (I) is chosen from those for which R1 and R2 represent, independently of each other, a linear or branched C1-C12 alkyl radical, R1 and R2 not simultaneously denoting a methyl radical. 3. The composition according to claim 1, in which the compound of formula (I) is chosen from compounds (a) to (ab) below: 4. The composition according to claim 3, in which the compound of formula (I) is chosen from compounds (g), (j), (k), (l), (o), (q), (s), (u), (v), (w), (x(Previously Presented)), (z). 5. The composition according to claim 1, in which the compound(s) of formula (I) in accordance with the invention constitute(s) the sole solvent for the lipophilic active agent(s). 6. The composition according to claim 1, in which the lipophilic active agent is chosen from lipophilic organic UV-screening agents selected from the group consisting of para-aminobenzoic acid derivatives, salicylic derivatives, cinnamic derivatives, benzophenone and aminobenzophenone derivatives, anthranilic derivatives, dibenzoylmethane derivatives, β,β-diphenylacrylate derivatives, benzylidenecamphor derivatives, benzotriazole derivatives, triazine derivatives, bis-resorcinyl triazine derivatives, imidazoline derivatives, benzalmalonate derivatives, 4,4-diarylbutadiene derivatives, benzoxazole derivatives, merocyanin derivatives, diphenyl butadiene malonate or malononitrile derivatives, chalcone derivatives and merocyanin derivatives, and mixtures. 7. The composition according to claim 1, in which the lipophilic active agent is chosen from aminophenol derivatives, salicylic acid derivatives, N,N′-di(arylmethylene)ethylenediaminetriacetate derivatives, 2-amino-4-alkylaminopyrimidine 3-oxide derivatives, flavonoids, retinoids, carotenoids such as lycopene, DHEA, derivatives thereof and chemical or metabolic precursors thereof and also fragrances, essential oils, hormones, vitamins, in particular vitamin E, and ceramides, or mixtures thereof. 8. A method for improving the efficacy of an active agent and/or the cosmetic qualities and/or the stability of a composition which comprises providing at least one 2-methylsuccinic acid diester derivative of formula (I) and/or an optical isomer and/or solvate thereof:
in which:
R1 and R2, which may be identical or different, denote a linear or branched C1-C20 alkyl radical or a C5-C6 cycloalkyl radical optionally substituted with C1-C3 alkyl radicals, R1 and R2 not simultaneously denoting a methyl radical,
in a composition comprising, in a cosmetically acceptable medium, at least one liquid fatty phase and at least one lipophilic active agent. 9. A method for improving sun protection factor which comprises providing at least one 2-methylsuccinic acid diester derivative of formula (I) and/or an optical isomer and/or solvate thereof:
in which:
R1 and R2, which may be identical or different, denote a linear or branched C1-C20 alkyl radical or a C5-C6 cycloalkyl radical optionally substituted with C1-C3 alkyl radicals, R1 and R2 not simultaneously denoting a methyl radical, in a composition comprising, in a cosmetically acceptable medium, at least one liquid fatty phase and at least one lipophilic organic UV-screening agent. 10. A compound selected from the group consisting of formulae (y), (z) and (ab) as follows: 11. The composition according to claim 2, in which the compound(s) of formula (I) in accordance with the invention constitute(s) the sole solvent for the lipophilic active agent(s). 12. The composition according to claim 3, in which the compound(s) of formula (I) in accordance with the invention constitute(s) the sole solvent for the lipophilic active agent(s). 13. The composition according to claim 4, in which the compound(s) of formula (I) in accordance with the invention constitute(s) the sole solvent for the lipophilic active agent(s). 14. The composition according to claim 2, in which the lipophilic active agent is chosen from lipophilic organic UV-screening agents. 15. The composition according to claim 3, in which the lipophilic active agent is chosen from lipophilic organic UV-screening agents. 16. A method for dissolving an active agent in a liquid fatty phase and/or for improving the solubility of the said active agent in the said fatty phase of a composition which comprises providing at least one 2-methylsuccinic acid diester derivative of formula (I) below and/or an optical isomer thereof and/or solvate thereof:
in which:
R1 and R2, which may be identical or different, denote a linear or branched C1-C20 alkyl radical or a C5-C6 cycloalkyl radical optionally substituted with C1-C3 alkyl radicals, R1 and R2 not simultaneously denoting a methyl radical,
in a composition comprising, in a cosmetically acceptable medium, at least one liquid fatty phase and at least one lipophilic active agent. 17. The method according to claim 16, in which the lipophilic active agent is chosen from lipophilic organic UV-screening agents. 18. The method according to claim 17, in which the lipophilic organic UV-screening agent is chosen from para-aminobenzoic acid derivatives, salicylic derivatives, cinnamic derivatives, benzophenone and aminobenzophenone derivatives, anthranilic derivatives, dibenzoylmethane derivatives, β,β-diphenylacrylate derivatives, benzylidenecamphor derivatives, benzotriazole derivatives, triazine derivatives, bis-resorcinyl triazine derivatives, imidazoline derivatives, benzalmalonate derivatives, 4,4-diarylbutadiene derivatives, benzoxazole derivatives, merocyanin derivatives, diphenyl butadiene malonate or malononitrile derivatives, chalcone derivatives and merocyanin derivatives, and mixtures thereof. 19. The method according to claim 18, in which the lipophilic organic UV-screening agent is chosen from dibenzoylmethane derivatives, triazine derivatives, bis-resorcinyl triazine derivatives, benzotriazole derivatives, chalcone derivatives, benzophenone or aminobenzophenone derivatives, and derivatives of the diphenylbutadiene malonate or malononitrile family, or mixtures thereof. 20. The method according to claim 16, in which the lipophilic active agent is chosen from aminophenol derivatives, salicylic acid derivatives, N,N′-di(arylmethylene)ethylenediaminetriacetate derivatives, 2-amino-4-alkylaminopyrimidine 3-oxide derivatives, flavonoids, retinoids, carotenoids such as lycopene, DHEA, derivatives thereof and chemical or metabolic precursors thereof and also fragrances, essential oils, hormones, vitamins, in particular vitamin E, and ceramides, or mixtures thereof. | The present invention relates to the use of at least one 2-methylsuccinic acid diester derivative of formula (I) below:
in a composition comprising, in a cosmetically acceptable medium, at least one liquid fatty phase and at least one lipophilic active agent, for dissolving the said active agent in the said liquid fatty phase and/or for improving the solubility of the said active agent in the said solid fatty phase. The present invention relates especially to a composition comprising, in a cosmetically acceptable medium, at least one liquid fatty phase, characterized in that it contains at least one 2-methylsuccinic acid ester derivative of formula (I) and at least one lipophilic active agent.1. A composition comprising, in a cosmetically acceptable medium, at least one liquid fatty phase, characterized in that it contains at least one 2-methylsuccinic acid diester derivative of formula (I) and/or an optical isomer and/or solvate thereof of formula (I) below:
in which:
R1 and R2, which may be identical or different, denote a linear or branched C1-C20 alkyl radical or a C5-C6 cycloalkyl radical optionally substituted with C1-C3 alkyl radicals, R1 and R2 not simultaneously denoting a methyl radical, and at least one lipophilic active agent, wherein said at least one 2-methylsuccinic acid diester derivative of formula (I) and/or an optical isomer and/or solvate thereof of formula (I) is present in an amount effective to dissolve the active agent in the liquid fatty phase and/or to improve the solubility of the active agent in the fatty phase. 2. The composition according to claim 1, in which the compound of formula (I) is chosen from those for which R1 and R2 represent, independently of each other, a linear or branched C1-C12 alkyl radical, R1 and R2 not simultaneously denoting a methyl radical. 3. The composition according to claim 1, in which the compound of formula (I) is chosen from compounds (a) to (ab) below: 4. The composition according to claim 3, in which the compound of formula (I) is chosen from compounds (g), (j), (k), (l), (o), (q), (s), (u), (v), (w), (x(Previously Presented)), (z). 5. The composition according to claim 1, in which the compound(s) of formula (I) in accordance with the invention constitute(s) the sole solvent for the lipophilic active agent(s). 6. The composition according to claim 1, in which the lipophilic active agent is chosen from lipophilic organic UV-screening agents selected from the group consisting of para-aminobenzoic acid derivatives, salicylic derivatives, cinnamic derivatives, benzophenone and aminobenzophenone derivatives, anthranilic derivatives, dibenzoylmethane derivatives, β,β-diphenylacrylate derivatives, benzylidenecamphor derivatives, benzotriazole derivatives, triazine derivatives, bis-resorcinyl triazine derivatives, imidazoline derivatives, benzalmalonate derivatives, 4,4-diarylbutadiene derivatives, benzoxazole derivatives, merocyanin derivatives, diphenyl butadiene malonate or malononitrile derivatives, chalcone derivatives and merocyanin derivatives, and mixtures. 7. The composition according to claim 1, in which the lipophilic active agent is chosen from aminophenol derivatives, salicylic acid derivatives, N,N′-di(arylmethylene)ethylenediaminetriacetate derivatives, 2-amino-4-alkylaminopyrimidine 3-oxide derivatives, flavonoids, retinoids, carotenoids such as lycopene, DHEA, derivatives thereof and chemical or metabolic precursors thereof and also fragrances, essential oils, hormones, vitamins, in particular vitamin E, and ceramides, or mixtures thereof. 8. A method for improving the efficacy of an active agent and/or the cosmetic qualities and/or the stability of a composition which comprises providing at least one 2-methylsuccinic acid diester derivative of formula (I) and/or an optical isomer and/or solvate thereof:
in which:
R1 and R2, which may be identical or different, denote a linear or branched C1-C20 alkyl radical or a C5-C6 cycloalkyl radical optionally substituted with C1-C3 alkyl radicals, R1 and R2 not simultaneously denoting a methyl radical,
in a composition comprising, in a cosmetically acceptable medium, at least one liquid fatty phase and at least one lipophilic active agent. 9. A method for improving sun protection factor which comprises providing at least one 2-methylsuccinic acid diester derivative of formula (I) and/or an optical isomer and/or solvate thereof:
in which:
R1 and R2, which may be identical or different, denote a linear or branched C1-C20 alkyl radical or a C5-C6 cycloalkyl radical optionally substituted with C1-C3 alkyl radicals, R1 and R2 not simultaneously denoting a methyl radical, in a composition comprising, in a cosmetically acceptable medium, at least one liquid fatty phase and at least one lipophilic organic UV-screening agent. 10. A compound selected from the group consisting of formulae (y), (z) and (ab) as follows: 11. The composition according to claim 2, in which the compound(s) of formula (I) in accordance with the invention constitute(s) the sole solvent for the lipophilic active agent(s). 12. The composition according to claim 3, in which the compound(s) of formula (I) in accordance with the invention constitute(s) the sole solvent for the lipophilic active agent(s). 13. The composition according to claim 4, in which the compound(s) of formula (I) in accordance with the invention constitute(s) the sole solvent for the lipophilic active agent(s). 14. The composition according to claim 2, in which the lipophilic active agent is chosen from lipophilic organic UV-screening agents. 15. The composition according to claim 3, in which the lipophilic active agent is chosen from lipophilic organic UV-screening agents. 16. A method for dissolving an active agent in a liquid fatty phase and/or for improving the solubility of the said active agent in the said fatty phase of a composition which comprises providing at least one 2-methylsuccinic acid diester derivative of formula (I) below and/or an optical isomer thereof and/or solvate thereof:
in which:
R1 and R2, which may be identical or different, denote a linear or branched C1-C20 alkyl radical or a C5-C6 cycloalkyl radical optionally substituted with C1-C3 alkyl radicals, R1 and R2 not simultaneously denoting a methyl radical,
in a composition comprising, in a cosmetically acceptable medium, at least one liquid fatty phase and at least one lipophilic active agent. 17. The method according to claim 16, in which the lipophilic active agent is chosen from lipophilic organic UV-screening agents. 18. The method according to claim 17, in which the lipophilic organic UV-screening agent is chosen from para-aminobenzoic acid derivatives, salicylic derivatives, cinnamic derivatives, benzophenone and aminobenzophenone derivatives, anthranilic derivatives, dibenzoylmethane derivatives, β,β-diphenylacrylate derivatives, benzylidenecamphor derivatives, benzotriazole derivatives, triazine derivatives, bis-resorcinyl triazine derivatives, imidazoline derivatives, benzalmalonate derivatives, 4,4-diarylbutadiene derivatives, benzoxazole derivatives, merocyanin derivatives, diphenyl butadiene malonate or malononitrile derivatives, chalcone derivatives and merocyanin derivatives, and mixtures thereof. 19. The method according to claim 18, in which the lipophilic organic UV-screening agent is chosen from dibenzoylmethane derivatives, triazine derivatives, bis-resorcinyl triazine derivatives, benzotriazole derivatives, chalcone derivatives, benzophenone or aminobenzophenone derivatives, and derivatives of the diphenylbutadiene malonate or malononitrile family, or mixtures thereof. 20. The method according to claim 16, in which the lipophilic active agent is chosen from aminophenol derivatives, salicylic acid derivatives, N,N′-di(arylmethylene)ethylenediaminetriacetate derivatives, 2-amino-4-alkylaminopyrimidine 3-oxide derivatives, flavonoids, retinoids, carotenoids such as lycopene, DHEA, derivatives thereof and chemical or metabolic precursors thereof and also fragrances, essential oils, hormones, vitamins, in particular vitamin E, and ceramides, or mixtures thereof. | 1,600 |
815 | 15,167,730 | 1,657 | Bioprosthetic tissues and methods for making same, comprising fixing bioprosthetic implant tissue by treatment with 0.1 to 10 wt. % glutaraldehyde at elevated temperature, capping said fixed tissue by treatment with a diamine crosslinking agent, and treating said capped tissue with about 0.6 wt. % glutaraldehyde. | 1. A packaged bioprosthetic device comprising:
a dry collagenous tissue comprising at least first and second sets of crosslinkages, wherein the first set of crosslinkages is provided between free amine functional groups on the collagenous tissue, wherein the second set of crosslinkages is provided between free aldehyde functional groups, and wherein at least a portion of the water initially present in the dry collagenous tissue has been replaced with glycerol; and a packaging containing the dry collagenous tissue. 2. The packaged bioprosthetic device of claim 1, wherein the first set of crosslinkages is provided by reaction of a first dialdehyde with the free amine functional groups. 3. The packaged bioprosthetic device of claim 2, wherein the first dialdehyde is glutaraldehyde. 4. The packaged bioprosthetic device of claim 1, wherein the second set of crosslinkages is provided by reaction of a diamine with the free aldehyde functional groups. 5. The packaged bioprosthetic device of claim 4, wherein the diamine is one or more selected from the group consisting of: a polyetheramine and a lysine. 6. The packaged bioprosthetic device of claim 4, wherein the second set of crosslinkages includes Schiff bases. 7. The packaged bioprosthetic device of claim 6, wherein the Schiff bases are reduced by a reducing agent. 8. The packaged bioprosthetic device of claim 7, wherein the reducing agent is a borohydride. 9. The packaged bioprosthetic device of claim 8, wherein the borohydride is one or more selected from the group consisting of: sodium borohydride, potassium borohydride and cyanoborohydride. 10. The packaged bioprosthetic device of claim 4, further comprising a third set of crosslinkages. 11. The packaged bioprosthetic device of claim 10, wherein the third set of crosslinkages is provided between free amine functional groups on the collagenous tissue, free amine functional groups of the diamine, or free amine functional groups on the collagenous tissue and the diamine. 12. The packaged bioprosthetic device of claim 11, wherein the third set of crosslinkages is provided by reaction of a second dialdehyde with the free amine functional groups on the collagenous tissue, the free amine functional groups of the diamine, or both. 13. The packaged bioprosthetic device of claim 12, wherein the second dialdehyde is glutaraldehyde. 14. The packaged bioprosthetic device of claim 1, wherein the second set of crosslinkages is provided between free aldehyde functional groups on the collagenous tissue. 15. The packaged bioprosthetic device of claim 1, wherein the collagenous tissue is selected from the group consisting of bovine pericardium, porcine tissue, blood vessels, skin, dura mater, pericardium, small intestinal submucosa, tissue heart valves, ligaments, and tendons. 16. The packaged bioprosthetic device of claim 1, wherein the collagenous tissue is a native valve treated and mounted as a whole valve. 17. The packaged bioprosthetic device of claim 1, wherein the bioprosthetic device is a bioprosthetic heart valve and the dry collagenous tissue form leaflets of the bioprosthetic heart valve. 18. The packaged bioprosthetic device of claim 17, wherein the packaged dry collagenous tissue is sterilized. 19. The packaged bioprosthetic device of claim 18, wherein the packaged dry collagenous tissue is sterilized with ethylene oxide. 20. The packaged bioprosthetic device of claim 19, wherein the packaging comprises a double sterile barrier packaging. | Bioprosthetic tissues and methods for making same, comprising fixing bioprosthetic implant tissue by treatment with 0.1 to 10 wt. % glutaraldehyde at elevated temperature, capping said fixed tissue by treatment with a diamine crosslinking agent, and treating said capped tissue with about 0.6 wt. % glutaraldehyde.1. A packaged bioprosthetic device comprising:
a dry collagenous tissue comprising at least first and second sets of crosslinkages, wherein the first set of crosslinkages is provided between free amine functional groups on the collagenous tissue, wherein the second set of crosslinkages is provided between free aldehyde functional groups, and wherein at least a portion of the water initially present in the dry collagenous tissue has been replaced with glycerol; and a packaging containing the dry collagenous tissue. 2. The packaged bioprosthetic device of claim 1, wherein the first set of crosslinkages is provided by reaction of a first dialdehyde with the free amine functional groups. 3. The packaged bioprosthetic device of claim 2, wherein the first dialdehyde is glutaraldehyde. 4. The packaged bioprosthetic device of claim 1, wherein the second set of crosslinkages is provided by reaction of a diamine with the free aldehyde functional groups. 5. The packaged bioprosthetic device of claim 4, wherein the diamine is one or more selected from the group consisting of: a polyetheramine and a lysine. 6. The packaged bioprosthetic device of claim 4, wherein the second set of crosslinkages includes Schiff bases. 7. The packaged bioprosthetic device of claim 6, wherein the Schiff bases are reduced by a reducing agent. 8. The packaged bioprosthetic device of claim 7, wherein the reducing agent is a borohydride. 9. The packaged bioprosthetic device of claim 8, wherein the borohydride is one or more selected from the group consisting of: sodium borohydride, potassium borohydride and cyanoborohydride. 10. The packaged bioprosthetic device of claim 4, further comprising a third set of crosslinkages. 11. The packaged bioprosthetic device of claim 10, wherein the third set of crosslinkages is provided between free amine functional groups on the collagenous tissue, free amine functional groups of the diamine, or free amine functional groups on the collagenous tissue and the diamine. 12. The packaged bioprosthetic device of claim 11, wherein the third set of crosslinkages is provided by reaction of a second dialdehyde with the free amine functional groups on the collagenous tissue, the free amine functional groups of the diamine, or both. 13. The packaged bioprosthetic device of claim 12, wherein the second dialdehyde is glutaraldehyde. 14. The packaged bioprosthetic device of claim 1, wherein the second set of crosslinkages is provided between free aldehyde functional groups on the collagenous tissue. 15. The packaged bioprosthetic device of claim 1, wherein the collagenous tissue is selected from the group consisting of bovine pericardium, porcine tissue, blood vessels, skin, dura mater, pericardium, small intestinal submucosa, tissue heart valves, ligaments, and tendons. 16. The packaged bioprosthetic device of claim 1, wherein the collagenous tissue is a native valve treated and mounted as a whole valve. 17. The packaged bioprosthetic device of claim 1, wherein the bioprosthetic device is a bioprosthetic heart valve and the dry collagenous tissue form leaflets of the bioprosthetic heart valve. 18. The packaged bioprosthetic device of claim 17, wherein the packaged dry collagenous tissue is sterilized. 19. The packaged bioprosthetic device of claim 18, wherein the packaged dry collagenous tissue is sterilized with ethylene oxide. 20. The packaged bioprosthetic device of claim 19, wherein the packaging comprises a double sterile barrier packaging. | 1,600 |
816 | 14,173,461 | 1,641 | A system and method of quantitating the concentration of a molecule of interest in one embodiment includes establishing a plurality of test environments at a plurality of test sites, each of the plurality of test environments associated with one of a plurality of response curves, each of the plurality of response curves different from the other of the plurality of response curves, storing a combined response curve resulting from a summation of the plurality of response curves, exposing the plurality of test sites to a sample having a concentration of a molecule of interest, obtaining a plurality of quantitation signals, each of the plurality of quantitation signals associated with one of the plurality of test sites, associating a summation of the plurality of quantitation signals with the stored combined response curve, and generating a signal related to the concentration of the molecule of interest based upon the association. | 1. A method of quantitating the concentration of a molecule of interest comprising:
establishing a plurality of test environments at a plurality of test sites, each of the plurality of test environments associated with one of a plurality of response curves, each of the plurality of response curves different from the other of the plurality of response curves; storing a combined response curve resulting from a summation of the plurality of response curves; exposing the plurality of test sites to a sample having a concentration of a molecule of interest; obtaining a plurality of quantitation signals, each of the plurality of quantitation signals associated with one of the plurality of test sites; associating a summation of the plurality of quantitation signals with the stored combined response curve; and generating a signal related to the concentration of the molecule of interest based upon the association. 2. The method of claim 1, wherein each of the plurality of response curves overlaps at least one of the other of the plurality of response curves. 3. The method of claim 1, wherein establishing a plurality of test environments comprises:
controlling at least one environmental factor of a group of environmental factors consisting of temperature, electric field, magnetic field, pH, and buffer type for each of the plurality of test sites, such that the controlled at least one environmental factor is different between at least two of the plurality of test sites. 4. The method of claim 3, wherein controlling at least one environmental factor comprises:
controlling the at least one environmental factor such that the controlled at least one environmental factor at each of the plurality of sites is different from each of the other of the plurality of test sites. 5. The method of claim 1, wherein establishing a plurality of test environments comprises:
providing at least one capturing agent; identifying, for each of the plurality of test sites, a respective capturing agent recipe, wherein the capturing agent recipe for each of the plurality of test sites is different from the capturing agent recipe for each of the other of the plurality of test sites; and immobilizing, in each of the plurality of test sites, the at least one capturing agent in accordance with the identified recipe. 6. The method of claim 5, wherein the at least one capturing agent comprises a plurality of capturing agents, each of the plurality of capturing agents exhibiting an affinity to the molecule of interest that is different from the affinity to the molecule of interest of another of the plurality of capturing agents. 7. The method of claim 6, wherein the capturing agent recipe for each of the plurality of test sites includes a selected one of the at least one capturing agent that is different from the at least one capturing agent in the other of the plurality of test sites. 8. The method of claim 5, wherein the capturing agent recipe for a first of the plurality of test sites includes a selected one of the at least one capturing agent that is the same as the at least one capturing agent in a second of the plurality of test sites. 9. The method of claim 8, wherein the concentration of the selected one of the at least one capturing agent in the first of the plurality of test sites is greater than the concentration of the selected one of the at least one capturing agent in the second of the plurality of test sites. 10. The method of claim 1, further comprising:
forming each of the plurality of test sites in a respective well of a multi-well plate. 11. The method of claim 1, further comprising:
forming each of the plurality of test sites on a CMOS substrate. 12. A method of quantitating the concentration of a molecule of interest comprising:
establishing a first test environment at a first test site; establishing a second test environment at a second test site such that a response curve for the second site is different from a response curve of the first site; storing a combined response curve resulting from a summation of the response curve for the second site and the response curve of the first site; exposing the first test site and the second test site to a sample having a concentration of a molecule of interest; obtaining a first quantitation signal from the first test site; obtaining a second quantitation signal from the second test site; combining the first quantitation signal and the second quantitation signal; associating the combined first quantitation signal and second quantitation signal with the stored response curve; and generating a signal related to the concentration of the molecule of interest based upon the association. 13. The method of claim 12, wherein each of the plurality of response curves overlaps at least one of the other of the plurality of response curves. 14. The method of claim 12, wherein:
establishing a first test environment includes controlling at least one environmental factor of a group of environmental factors consisting of temperature, electric field, magnetic field, and pH, for the first test site; and establishing a second test environment includes controlling the at least one environmental factor for the second test site, such that the controlled at least one environmental factor is different between the first test site and the second test site. 15. The method of claim 12, further comprising:
providing at least one capturing agent; identifying, for each of the first and the second test sites, a respective capturing agent recipe, wherein the capturing agent recipe for each of the first and the second test sites is different from the capturing agent recipe for the other of the first and the second test sites; and immobilizing, in each of the first and the second test sites, the at least one capturing agent in accordance with the identified recipe. 16. The method of claim 15, wherein the at least one capturing agent comprises a plurality of capturing agents, each of the plurality of capturing agents exhibiting an affinity to the molecule of interest that is different from the affinity to the molecule of interest of another of the plurality of capturing agents. 17. The method of claim 12, further comprising:
forming each of the first and the second test sites in a respective well of a multi-well plate. 18. The method of claim 12, further comprising:
forming each of the first and the second test sites on a CMOS substrate. | A system and method of quantitating the concentration of a molecule of interest in one embodiment includes establishing a plurality of test environments at a plurality of test sites, each of the plurality of test environments associated with one of a plurality of response curves, each of the plurality of response curves different from the other of the plurality of response curves, storing a combined response curve resulting from a summation of the plurality of response curves, exposing the plurality of test sites to a sample having a concentration of a molecule of interest, obtaining a plurality of quantitation signals, each of the plurality of quantitation signals associated with one of the plurality of test sites, associating a summation of the plurality of quantitation signals with the stored combined response curve, and generating a signal related to the concentration of the molecule of interest based upon the association.1. A method of quantitating the concentration of a molecule of interest comprising:
establishing a plurality of test environments at a plurality of test sites, each of the plurality of test environments associated with one of a plurality of response curves, each of the plurality of response curves different from the other of the plurality of response curves; storing a combined response curve resulting from a summation of the plurality of response curves; exposing the plurality of test sites to a sample having a concentration of a molecule of interest; obtaining a plurality of quantitation signals, each of the plurality of quantitation signals associated with one of the plurality of test sites; associating a summation of the plurality of quantitation signals with the stored combined response curve; and generating a signal related to the concentration of the molecule of interest based upon the association. 2. The method of claim 1, wherein each of the plurality of response curves overlaps at least one of the other of the plurality of response curves. 3. The method of claim 1, wherein establishing a plurality of test environments comprises:
controlling at least one environmental factor of a group of environmental factors consisting of temperature, electric field, magnetic field, pH, and buffer type for each of the plurality of test sites, such that the controlled at least one environmental factor is different between at least two of the plurality of test sites. 4. The method of claim 3, wherein controlling at least one environmental factor comprises:
controlling the at least one environmental factor such that the controlled at least one environmental factor at each of the plurality of sites is different from each of the other of the plurality of test sites. 5. The method of claim 1, wherein establishing a plurality of test environments comprises:
providing at least one capturing agent; identifying, for each of the plurality of test sites, a respective capturing agent recipe, wherein the capturing agent recipe for each of the plurality of test sites is different from the capturing agent recipe for each of the other of the plurality of test sites; and immobilizing, in each of the plurality of test sites, the at least one capturing agent in accordance with the identified recipe. 6. The method of claim 5, wherein the at least one capturing agent comprises a plurality of capturing agents, each of the plurality of capturing agents exhibiting an affinity to the molecule of interest that is different from the affinity to the molecule of interest of another of the plurality of capturing agents. 7. The method of claim 6, wherein the capturing agent recipe for each of the plurality of test sites includes a selected one of the at least one capturing agent that is different from the at least one capturing agent in the other of the plurality of test sites. 8. The method of claim 5, wherein the capturing agent recipe for a first of the plurality of test sites includes a selected one of the at least one capturing agent that is the same as the at least one capturing agent in a second of the plurality of test sites. 9. The method of claim 8, wherein the concentration of the selected one of the at least one capturing agent in the first of the plurality of test sites is greater than the concentration of the selected one of the at least one capturing agent in the second of the plurality of test sites. 10. The method of claim 1, further comprising:
forming each of the plurality of test sites in a respective well of a multi-well plate. 11. The method of claim 1, further comprising:
forming each of the plurality of test sites on a CMOS substrate. 12. A method of quantitating the concentration of a molecule of interest comprising:
establishing a first test environment at a first test site; establishing a second test environment at a second test site such that a response curve for the second site is different from a response curve of the first site; storing a combined response curve resulting from a summation of the response curve for the second site and the response curve of the first site; exposing the first test site and the second test site to a sample having a concentration of a molecule of interest; obtaining a first quantitation signal from the first test site; obtaining a second quantitation signal from the second test site; combining the first quantitation signal and the second quantitation signal; associating the combined first quantitation signal and second quantitation signal with the stored response curve; and generating a signal related to the concentration of the molecule of interest based upon the association. 13. The method of claim 12, wherein each of the plurality of response curves overlaps at least one of the other of the plurality of response curves. 14. The method of claim 12, wherein:
establishing a first test environment includes controlling at least one environmental factor of a group of environmental factors consisting of temperature, electric field, magnetic field, and pH, for the first test site; and establishing a second test environment includes controlling the at least one environmental factor for the second test site, such that the controlled at least one environmental factor is different between the first test site and the second test site. 15. The method of claim 12, further comprising:
providing at least one capturing agent; identifying, for each of the first and the second test sites, a respective capturing agent recipe, wherein the capturing agent recipe for each of the first and the second test sites is different from the capturing agent recipe for the other of the first and the second test sites; and immobilizing, in each of the first and the second test sites, the at least one capturing agent in accordance with the identified recipe. 16. The method of claim 15, wherein the at least one capturing agent comprises a plurality of capturing agents, each of the plurality of capturing agents exhibiting an affinity to the molecule of interest that is different from the affinity to the molecule of interest of another of the plurality of capturing agents. 17. The method of claim 12, further comprising:
forming each of the first and the second test sites in a respective well of a multi-well plate. 18. The method of claim 12, further comprising:
forming each of the first and the second test sites on a CMOS substrate. | 1,600 |
817 | 15,440,628 | 1,641 | Methods include determining in a sample an amount of a first isomeric analyte and a second isomeric analyte. A first measurement value and a second measurement value are determined. The first measurement value represents a total amount of the first isomeric analyte and the second isomeric analyte. The second measurement value represents an amount of the second isomeric analyte only. The second measurement value is subtracted from the first measurement value to obtain a resulting value and the resulting value is equated to an amount of the first isomeric analyte in the sample. | 1-20. (canceled) 21. A method of determining in a sample an amount of non-epi-25-hydroxy vitamin D3 and 3-epi 25-hydroxy vitamin D3, the method comprising:
(a) conducting an assay on a first portion of the sample using an assay protocol wherein assay reagents utilized in the assay protocol of this step (a) comprise vitamin D3 conjugated to a label and a first antibody having a binding affinity for each of non-epi-25-hydroxy vitamin D3 and 3-epi 25-hydroxy vitamin D3 of 108 to 1014 liters/mole to form a first complex comprising the first antibody and non-epi-25-hydroxy vitamin D3 and a second complex comprising the first antibody and 3-epi 25-hydroxy vitamin D3 wherein the first complex and the second complex include vitamin D3 conjugated to a label wherein an amount of signal from the first complex and the second complex is related to a total amount non-epi-25-hydroxy vitamin D3 and 3-epi 25-hydroxy vitamin D3 in the sample to obtain a first measurement value; and (b) conducting the assay on a second portion of the sample using the same assay protocol as in step (a) wherein assay reagents utilized in the assay protocol in this step (b) comprise the vitamin D3 conjugated to a label and the first antibody, wherein a second antibody having a binding affinity for the non-epi-25-hydroxy vitamin D3 of 106 to 108 liters/mole and a binding affinity for the 3-epi 25-hydroxy vitamin D3 of less than about 104 liters/mole is employed in an amount of about 5 to about 200 times the amount of the first antibody, wherein the binding affinity of the second antibody for non-epi-25-hydroxy vitamin D3 is less than the binding affinity of the first antibody for non-epi-25-hydroxy vitamin D3 by a factor of at least about 10, wherein the second antibody binds the non-epi-25-hydroxy vitamin D3 such that the non-epi-25-hydroxy vitamin D3 does not bind to the first antibody, and wherein a complex is formed comprising the first antibody and the epi-25-hydroxy vitamin D3, wherein the complex includes the vitamin D3 conjugated to a label wherein an amount of signal from the complex is related to an amount of the 3-epi 25-hydroxy vitamin D3 in the sample to obtain a second measurement value;
wherein an amount of the non-epi-25-hydroxy vitamin D3 in the sample is determined by subtracting the second measurement value from the first measurement value. 22. The method according to claim 21, wherein the assay protocol is a competitive homogeneous assay protocol. 23. The method according to claim 21, wherein the assay protocol employs reagents that comprise a particle. 24. The method according to claim 21, wherein the assay protocol employs reagents that comprise a photosensitizer reagent and a chemiluminescent particle. 25. The method according to claim 24, wherein the photosensitizer reagent comprises a particle. | Methods include determining in a sample an amount of a first isomeric analyte and a second isomeric analyte. A first measurement value and a second measurement value are determined. The first measurement value represents a total amount of the first isomeric analyte and the second isomeric analyte. The second measurement value represents an amount of the second isomeric analyte only. The second measurement value is subtracted from the first measurement value to obtain a resulting value and the resulting value is equated to an amount of the first isomeric analyte in the sample.1-20. (canceled) 21. A method of determining in a sample an amount of non-epi-25-hydroxy vitamin D3 and 3-epi 25-hydroxy vitamin D3, the method comprising:
(a) conducting an assay on a first portion of the sample using an assay protocol wherein assay reagents utilized in the assay protocol of this step (a) comprise vitamin D3 conjugated to a label and a first antibody having a binding affinity for each of non-epi-25-hydroxy vitamin D3 and 3-epi 25-hydroxy vitamin D3 of 108 to 1014 liters/mole to form a first complex comprising the first antibody and non-epi-25-hydroxy vitamin D3 and a second complex comprising the first antibody and 3-epi 25-hydroxy vitamin D3 wherein the first complex and the second complex include vitamin D3 conjugated to a label wherein an amount of signal from the first complex and the second complex is related to a total amount non-epi-25-hydroxy vitamin D3 and 3-epi 25-hydroxy vitamin D3 in the sample to obtain a first measurement value; and (b) conducting the assay on a second portion of the sample using the same assay protocol as in step (a) wherein assay reagents utilized in the assay protocol in this step (b) comprise the vitamin D3 conjugated to a label and the first antibody, wherein a second antibody having a binding affinity for the non-epi-25-hydroxy vitamin D3 of 106 to 108 liters/mole and a binding affinity for the 3-epi 25-hydroxy vitamin D3 of less than about 104 liters/mole is employed in an amount of about 5 to about 200 times the amount of the first antibody, wherein the binding affinity of the second antibody for non-epi-25-hydroxy vitamin D3 is less than the binding affinity of the first antibody for non-epi-25-hydroxy vitamin D3 by a factor of at least about 10, wherein the second antibody binds the non-epi-25-hydroxy vitamin D3 such that the non-epi-25-hydroxy vitamin D3 does not bind to the first antibody, and wherein a complex is formed comprising the first antibody and the epi-25-hydroxy vitamin D3, wherein the complex includes the vitamin D3 conjugated to a label wherein an amount of signal from the complex is related to an amount of the 3-epi 25-hydroxy vitamin D3 in the sample to obtain a second measurement value;
wherein an amount of the non-epi-25-hydroxy vitamin D3 in the sample is determined by subtracting the second measurement value from the first measurement value. 22. The method according to claim 21, wherein the assay protocol is a competitive homogeneous assay protocol. 23. The method according to claim 21, wherein the assay protocol employs reagents that comprise a particle. 24. The method according to claim 21, wherein the assay protocol employs reagents that comprise a photosensitizer reagent and a chemiluminescent particle. 25. The method according to claim 24, wherein the photosensitizer reagent comprises a particle. | 1,600 |
818 | 14,029,376 | 1,617 | Ready-to-use foamable pesticide compositions that contain a particulate pesticide suspended therein and applicators for dispensing such compositions. Methods for treating pests such as arthropods by contacting pests with such compositions are also provided. | 1. A ready-to-use foamable pesticide composition comprising:
a diluent; a particulate pesticide suspended in the diluent; a thickening agent; and a surfactant system comprising at least one fatty acid soap. 2. A ready-to-use foamable pesticide composition as set forth in claim 1 wherein the particulate pesticide is an arthropodicide selected from the group consisting of (M1) organo(thio)phosphate compounds selected from the group consisting of acephate, azamethiphos, azinphos-ethyl, azinphos-methyl, chlorethoxyfos, chlorfenvinphos, chlormephos, chlorpyrifos, chlorpyrifos-methyl, coumaphos, cyanophos, demeton-S-methyl, diazinon, dichlorvos/DDVP, dicrotophos, dimethoate, dimethylvinphos, disulfoton, EPN, ethion, ethoprophos, famphur, fenamiphos, fenitrothion, fenthion, flupyrazophos, fosthiazate, heptenophos, isoxathion, malathion, mecarbam, methamidophos, methidathion, mevinphos, monocrotophos, omethoate, oxydemeton-methyl, parathion, parathion-methyl, phenthoate, phorate, phosalone, phosmet, phosphamidon, phoxim, pirimiphos-methyl, profenofos, propetamphos, prothiofos, pyraclofos, pyridaphenthion, quinalphos, sulfotep, tebupirimfos, temephos, terbufos, tetrachlorvinphos, thiometon, triazophos, trichlorfon and vamidothion; (M2) carbamate compounds selected from the group consisting of aldicarb, alanycarb, bendiocarb, benfuracarb, butocarboxim, butoxycarboxim, carbaryl, carbofuran, carbosulfan, ethiofencarb, fenobucarb, formetanate, furathiocarb, isoprocarb, methiocarb, methomyl, metolcarb, oxamyl, pirimicarb, propoxur, thiodicarb, thiofanox, trimethacarb, XMC, xylylcarb and triazamate; (M3) pyrethroid compounds selected from the group consisting of acrinathrin, allethrin, d-cis-trans allethrin, d-trans allethrin, bifenthrin, bioallethrin, bioallethrin S-cylclopentenyl, bioresmethrin, cycloprothrin, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, gamma-cyhalothrin, cypermethrin, alpha-cypermethrin, beta-cypermethrin, theta-cypermethrin, zeta-cypermethrin, cyphenothrin, deltamethrin, empenthrin, esfenvalerate, etofenprox, fenpropathrin, fenvalerate, flucythrinate, flumethrin, tau-fluvalinate, halfenprox, imiprothrin, metofluthrin, permethrin, phenothrin, prallethrin, profluthrin, pyrethrin (pyrethrum), resmethrin, silafluofen, tefluthrin, tetramethrin, tralomethrin and transfluthrin; (M4) juvenile hormone mimics selected from the group consisting of hydroprene, kinoprene, methoprene, fenoxycarb and pyriproxyfen; (M5) nicotinic receptor agonists/antagonists compounds selected from the group consisting of acetamiprid, bensultap, cartap hydrochloride, clothianidin, dinotefuran, imidacloprid, thiamethoxam, nitenpyram, nicotine, spinosad (allosteric agonist), spinetoram (allosteric agonist), thiacloprid, thiocyclam, thiosultap-sodium and AKD1022; (M6) GABA gated chloride channel antagonist compounds selected from the group consisting of chlordane, endosulfan, gamma-HCH (lindane); ethiprole, fipronil, pyrafluprole and pyriprole; (M7) chloride channel activators selected from the group consisting of abamectin, emamectin benzoate, milbemectin and lepimectin; (M8) METI I compounds selected from the group consisting of fenazaquin, fenpyroximate, pyrimidifen, pyridaben, tebufenpyrad, tolfenpyrad, flufenerim and rotenone; (M9) METI II and III compounds selected from the group consisting of acequinocyl, fluacyprim, hydramethylnon; (M10) uncouplers of oxidative phosphorylation selected from the group consisting of chlorfenapyr and DNOC; (M11) inhibitors of oxidative phosphorylation selected from the group consisting of azocyclotin, cyhexatin, diafenthiuron, fenbutatin oxide, propargite, tetradifon; (M12) moulting disruptors selected from the group consisting of cyromazine, chromafenozide, halofenozide, methoxyfenozide, tebufenozide; synergists selected from the group consisting of piperonyl butoxideand tribufos; (M14) sodium channel blocker compounds selected from the group consisting of indoxacarb, metaflumizone; (M15) selective feeding blockers selected from the group consisting of crylotie, pymetrozine and flonicamid; (M16) mite growth inhibitors selected from the group consisting of clofentezine, hexythiazox and etoxazole; (M17) chitin synthesis inhibitors selected from the group consisting of buprofezin, bistrifluoron, chlorfluazuron, diflubenzuron, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron, noviflumuron, teflubenzuron and triflumuron; (M18) lipid biosynthesis inhibitors selected from the group consisting of spirodiclofen, spiromesifen, spirotetramat; (M19) octapaminergic agonsits selected from amitraz; (M20) ryanodine receptor modulators selected from the group consisting of flubendiamide and the phtalamid compound (R)—, (S)-3-Chlor-N1-{2-methyl-4-[1,2,2,2-tetrafluor-1-(trifluormethyl)ethyl]phenyl}-N2-(1-methyl-2-methylsulfonylethyl)phthalamid (M20.1); (M21) isoxazoline compounds selected from the group consisting of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-pyridin-2-ylmethyl-benzamide (M21.1), 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-(2,2,2-trifluoro-ethyl)-benzamide (M21.2), 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (M21.3), 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalene-1-carboxylic acid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide (M21.4), 4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-[(methoxyimino)methyl]-2-methylbenzamide (M21.5) 4-[5-(3-Chloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (M21.6), 4-[5-(3-Chloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalene-1-carboxylic acid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide (M21.7) and 5-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-[1,2,4]triazol-1-yl-benzonitrile (M21.8); (M22) anthranilamide compounds selected from the group consisting of chloranthraniliprole, cyantraniliprole, 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [4-cyano-2-(1-cyclopropyl-ethylcarbamoyl)-6-methyl-phenyl]-amide (M22.1), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [2-chloro-4-cyano-6-(1-cyclopropyl-ethylcarbamoyl)-phenyl]-amide (M22.2), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [2-bromo-4-cyano-6-(1-cyclopropyl-ethylcarbamoyl)-phenyl]-amide (M22.3), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [2-bromo-4-chloro-6-(1-cyclopropyl-ethylcarbamoyl)-phenyl]-amide (M22.4), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [2,4-dichloro-6-(1-cyclopropyl-ethylcarbamoyl)-phenyl]-amide (M22.5), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [4-chloro-2-(1-cyclopropyl-ethylcarbamoyl)-6-methyl-phenyl]-amide (M22.6), N′-(2-{[5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-5-chloro-3-methyl-benzoyl)-hydrazinecarboxylic acid methyl ester (M22.7), N′-(2-{[5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-5-chloro-3-methyl-benzoyl)-N′-methyl-hydrazinecarboxylic acid methyl ester (M22.8), N′-(2-{[5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-5-chloro-3-methyl-benzoyl)-N,N′-dimethyl-hydrazinecarboxylic acid methyl ester (M22.9), N′-(3,5-Dibromo-2-{[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-benzoyl)-hydrazinecarboxylic acid methyl ester (M22.10), N′-(3,5-Dibromo-2-{[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-benzoyl)-N′-methyl-hydrazinecarboxylic acid methyl ester (M22.11) and N′-(3,5-Dibromo-2-{[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-benzoyl)-N,N′-dimethyl-hydrazinecarboxylic acid methyl ester (M22.12); (M23) malononitrile compounds selected from the group consisting of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(3,3,3-trifluoro-propyl)malononitrile (CF2H—CF2-CF2-CF2-CH2-C(CN)2-CH2-CH2-CF3) (M23.1) and 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(3,3,4,4,4-pentafluorobutyl)-malonodinitrile (CF2H—CF2-CF2-CF2-CH2-C(CN)2-CH2-CH2-CF2-CF3) (M23.2); (M24) microbial disruptors selected from the group consisting of Bacillus thuringiensis subsp. Israelensi, Bacillus sphaericus, Bacillus thuringiensis subsp. Aizawai, Bacillus thuringiensis subsp. Kurstaki and Bacillus thuringiensis subsp. Tenebrionis; (M25) aminofuranone compounds selected from the group consisting of 4-{[(6-Bromopyrid-3-yl)methyl](2-fluoroethyl)amino}furan-2(5H)-on (M25.1), 4-{[(6-Fluoropyrid-3-yl)methyl](2,2-difluoroethyl)amino}furan-2(5H)-on (M25.2), 4-{[(2-Chloro-1,3-thiazolo-5-yl)methyl] (2-fluoro ethyl)amino}furan-2(5H)—on (M25.3), 4-{[(6-Chloropyrid-3-yl)methyl](2-fluoroethyl)amino}furan-2(5H)-on (M25.4), 4-{[(6-Chloropyrid-3-yl)methyl](2,2-difluoroethyl)amino}furan-2(5H)-on (M25.5), 4-{[(6-Chloro-5-fluoropyrid-3-yl)methyl](methyl)amino}furan-2(5H)-on (M25.6), 4-{[(5,6-Dichloropyrid-3-yl)methyl](2-fluoroethyl)amino}furan-2(5H)-on (M25.7), 4-{[(6-Chloro-5-fluoropyrid-3-yl)methyl](cyclopropyl)amino}furan-2(5H)—on (M25.8), 4-{[(6-Chloropyrid-3-yl)methyl](cyclopropyl)amino}furan-2(5H)-on (M25.9) and 4-{[(6-Chloropyrid-3-yl)methyl](methyl)amino}furan-2(5H)-on (M25.10); (M26) various other compounds selected from the group consisting of amidoflumet, benclothiaz, benzoximate, bifenazate, borax, bromopropylate, cyenopyrafen, cyflumetofen, chinomethionate, dicofol, fluoroacetate, pyridalyl, pyrifluquinazon, tartar emetic, sulfoxaflor, N—R′-2,2-dihalo-1-R″cyclo-propanecarboxamide-2-(2,6-dichloro-α,α,α-trifluoro-p-tolyl)hydrazone or N—R′-2,2-di(R″)propionamide-2-(2,6-dichloro-α,α,α-trifluoro-p-tolyl)-hydrazone, wherein R′ is methyl or ethyl, halo is chloro or bromo, R″ is hydrogen or methyl and R′ is methyl or ethyl, 4-But-2-ynyloxy-6-(3,5-dimethyl-piperidin-1-yl)-2-fluoro-pyrimidine (M26.1), Cyclopropaneacetic acid, 1,1′-[(3S,4R,4aR,6S,6aS,12R,12aS,12bS)-4-[[(2-cyclopropylacetyl)oxy]methyl]-1,3,4,4a,5,6,6a,12,12a,12b-decahydro-12-hydroxy-4,6a,12b-trimethyl-11-oxo-9-(3-pyridinyl)-2H,11H-naphtho[2,1-b]pyrano[3,4-e]pyran-3,6-diyl]ester(M26.2) and 8-(2-Cyclopropylmethoxy-4-trifluoromethyl-phenoxy)-3-(6-trifluoromethyl-pyridazin-3-yl)-3-aza-bicyclo[3.2.1]octane (M26.3). 3. A ready-to-use foamable pesticide composition as set forth in claim 1 wherein the particulate pesticide is a fungicide selected from the group consisting of respiration inhibitors selected from the group consisting of azoxystrobin, dimoxystrobin, enestroburin, fluoxastro-bin, kresoxim-methyl, meto-minostrobin, orysastrobin, picoxy-strobin, pyraclostrobin, pyrametostrobin, pyraoxystrobin, pyribencarb, trifloxystrobin, methyl (2-chloro-5 [1-(3-methylbenzyl-oxy-imino)-ethyl]benzyl)-carba-mate and 2 (2-(3-(2,6-di-chlorophenyl)-1-methyl-allylidene-aminooxy-methyl)-phenyl)-2-methoxyimino-N methyl-acetamide, famoxadone, fenamidone, benodanil, bixafen, boscalid, carboxin, fen-furam, fenhexamid, fluopyram, flutolanil, furametpyr, isopyrazam, isotianil, mepronil, oxycarboxin, penflufen, penthiopyrad, sedaxane, tecloftalam, thifluz-amide, tiadinil, 2-amino-4 methyl-thiazole-5-carbox-anilide, N-(3′,4′,5′ tri-fluoro-bi-phenyl-2 yl)-3-difluoro-methyl-1-methyl-1H-pyrazole-4 carboxamide, N-(4′-tri-fluoro-methyl-thiobi-phenyl-2-yl)-3 difluoromethyl-1-methyl-1H pyrazole-4-carbox-amide and N-(2-(1,3,3-trimethyl-butyl)-phenyl)-1,3-dimethyl-5 fluoro-1H-pyrazole-4 carbox-amide, cyazofamid, amisulbrom, diflumetorim, binapacryl, dinobuton, dinocap, fluazinam, nitrthal-isopropyl, tecnazen, ferimzone, fentin salts, ametoctradin, silthiofam; sterol biosynthesis inhibitors (SBI fungicides) selected from the group consisting of azaconazole, bitertanol, bromuconazole, cyproconazole, difenoconazole, diniconazole, diniconazole-M, epoxiconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imibenconazole, ipconazole, metconazole, myclobutanil, paclobutrazole, penconazole, propiconazole, prothio-conazole, simeconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole, uniconazole, imazalil, pefurazoate, oxpoconazole, prochloraz, triflumizole, fenarimol, nuarimol, pyrifenox, triforine, aldimorph, dodemorph, dodemorph-acetate, fenpropimorph, tridemorph, fenpropidin, piperalin, spiroxamine, fenhexamid, benalaxyl, benalaxyl-M, kiralaxyl, metalaxyl, metalaxyl-M (mefenoxam), ofurace, oxadixyl, hymexazole, octhilinone, oxolinic acid, bupirimate, benomyl, carbendazim, fuberidazole, thiabendazole, thiophanate-methyl, 5-chloro-7 (4-methyl-piperidin-1-yl)-6-(2,4,6-trifluorophenyl)-[1,2,4]tri-azolo-[1,5a]pyrimidine, diethofencarb, ethaboxam, pencycuron, fluopicolide, zoxamide, metrafenone, cyprodinil, mepanipyrim, nitrapyrin, pyrimethanil, blasticidin-S, kasugamycin, kasugamycin hydrochloride-hydrate, mildiomycin, streptomycin, oxytetracyclin, polyoxine, validamycin A, fluoroimid, iprodione, procymidone, vinclozolin, fenpiclonil, fludioxonil, quinoxyfen, edifenphos, iprobenfos, pyrazophos, isoprothiolane, dicloran, quintozene, tecnazene, tolclofos-methyl, biphenyl, chloroneb, etridiazole, dimethomorph, flumorph, mandiproamid, pyrimorph, benthiavalicarb, iprovalicarb, pyribencarb, valifenalate and N-(1-(1-(4-cyano-phenyl)-ethanesulfonyl)-but-2-yl) carbamic acid-(4-fluorophenyl) ester, propamocarb, propamo-carb-hydrochlorid, Bordeaux mixture, copper acetate, copper hydroxide, copper oxychloride, basic copper sulfate, sulfur, ferbam, mancozeb, maneb, metam, methasulphocarb, metiram, propineb, thiram, zineb, ziram, anilazine, chlorothalonil, captafol, captan, folpet, dichlofluanid, dichlorophen, flusulfamide, hexachlorobenzene, pentachlorphenole and its salts, phthalide, tolylfluanid, N-(4-chloro-2-nitro-phenyl)-N-ethyl-4-methyl-benzenesulfonamide, guanidine, dodine, dodine free base, guazatine, guazatine-acetate, iminoctadine, iminoctadine-triacetate, iminoctadine-tris(albesilate), dithianon, validamycin, polyoxin B, pyroquilon, tricyclazole, carpropamide, dicyclomet, fenoxanil, acibenzolar-S-methyl, probenazole, isotianil, tiadinil, prohexadione-calcium, fosetyl, fosetyl-aluminum, phosphorous acid and its salts, bronopol, chinomethionat, cyflufenamid, cymoxanil, dazomet, debacarb, diclomezine, difenzoquat, difenzoquat-methylsulfate, diphenylamin, flumetover, flusulfamide, flutianil, methasulfocarb, oxin-copper, proquinazid, tebufloquin, tecloftalam, triazoxide, 2-butoxy-6-iodo-3-propylchromen-4-one, N-(cyclo-propylmethoxyimino-(6-difluoro-methoxy-2,3-difluoro-phenyl)-methyl)-2-phenyl acetamide, N′-(4-(4-chloro-3-trifluoromethyl-phenoxy)-2,5-dimethyl-phenyl)-N-ethyl-N methyl formamidine, N′ (4-(4-fluoro-3-trifluoromethyl-phenoxy)-2,5-dimethyl-phenyl)-N-ethyl-N-methyl formamidine, N′-(2-methyl-5-trifluoromethyl-4-(3-trimethyl-silanyl-prop-oxy)-phenyl)-N-ethyl-N-methyl formamidine, N′-(5-difluoromethyl-2 methyl-4-(3-tri-methylsilanyl-propoxy)-phenyl)-N-ethyl-N-methyl formamidine, 2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazole-1-yl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide, 2-{1-[2-(5-meth-yl-3-trifluoromethyl-pyrazole-1-yl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid methyl-(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-amide, methoxy-acetic acid 6-tert-butyl-8-fluoro-2,3-dimethyl-quinolin-4-yl ester and N-Methyl-2-{1-[(S-methyl-3-trifluoro-methyl-1H-pyr-azol-1-yl)-acetyl]-piperi-din-4-yl}-N-[(1R)-1,2,3,4-tetrahydro-naphthalen-1-yl]-4-thi-azolecarboxamide, 3-[5-(4-chloro-phenyl)-2,3-dimethyl-isoxazolidin-3-yl]-pyridine, 3-[5-(4-methyl-phenyl)-2,3-dimethyl-isoxazolidin-3-yl]-pyridine, 5-amino-2-iso-propyl-3-oxo-4-ortho-tolyl-2,3-dihydro-pyrazole-1 carbo-thioic acid S-allyl ester, N-(6-methoxy-pyridin-3-yl) cyclopropanecarboxylic acid amide, 5-chloro-1 (4,6-dimethoxy-pyrimidin-2-yl)-2-methyl-1H-benzoimidazole, 2-(4-chloro-phenyl)-N-[4-(3,4-dimeth-oxy-phenyl)-isoxazol-5-yl]-2-prop-2-ynyloxy-acetamide, abscisic acid, amidochlor, ancymidol, 6-benzylaminopurine, brassinolide, butralin, chlormequat (chlormequat chloride), choline chloride, cyclanilide, daminozide, dike-gulac, dimethipin, 2,6-dimethylpuridine, ethephon, flumetralin, flurprimidol, fluthi-acet, forchlorfenuron, gibberellic acid, inabenfide, indole-3-acetic acid, maleic hydrazide, mefluidide, mepiquat (mepiquat chloride), naphthaleneacetic acid, N 6 benzyladenine, paclobutrazol, prohexadione (prohexadione-calcium), prohydrojasmon, thidiazuron, triapenthenol, tributyl phosphorotrithioate, 2,3,5 tri iodobenzoic acid, trinexapac-ethyl and uniconazole and antifungal biocontrol agents. 4. A ready-to-use foamable pesticide composition as set forth in claim 1 wherein the particulate pesticide is a herbicide selected from the group consisting of acetochlor, alachlor, butachlor, dimethachlor, dimethenamid, flufenacet, mefenacet, metolachlor, metazachlor, napropamide, naproanilide, pethoxamid, pretilachlor, propachlor, thenylchlor, bilanafos, glyphosate, glufosinate, sulfosate, clodinafop, cyhalofop-butyl, fenoxaprop, fluazifop, haloxyfop, metamifop, propaquizafop, quizalofop, quizalofop-P-tefuryl, diquat, paraquat, asulam, butylate, carbetamide, desmedipham, dimepiperate, eptam (EPTC), esprocarb, molinate, orbencarb, phenmedipham, prosulfocarb, pyributicarb, thiobencarb, triallate, butroxydim, clethodim, cycloxydim, profoxydim, sethoxydim, tepraloxydim, tralkoxydim, benfluralin, ethalfluralin, oryzalin, pendimethalin, prodiamine, trifluralin, acifluorfen, aclonifen, bifenox, diclofop, ethoxyfen, fomesafen, lactofen, oxyfluorfen, bomoxynil, dichlobenil, ioxynil, imazamethabenz, imazamox, imazapic, imazapyr, imazaquin, imazethapyr, clomeprop, 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4-DB, dichlorprop, MCPA, MCPA-thioethyl, MCPB, Mecoprop, chloridazon, flufenpyr-ethyl, fluthiacet, norflurazon, pyridate, aminopyralid, clopyralid, diflufenican, dithiopyr, fluridone, fluoroxypyr, picloram, picolinafen, thiazopyr, amidosulfuron, azimsulfuron, bensulfuron, chlorimuron-ethyl, chlorsulfuron, cinosulfuron, cyclosulfamuron, ethoxysulfuron, flazasulfuron, flucetosulfuron, flupyrsulfuron, foramsulfuron, halosulfuron, imazosulfuron, iodosulfuron, mesosulfuron, metazosulfuron, metsulfuron-methyl, nicosulfuron, oxasulfuron, primisulfuron, prosulfuron, pyrazosulfuron, rimsulfuron, sulfometuron, sulfosulfuron, thifensulfuron, triasulfuron, tribenuron, trifloxysulfuron, triflusulfuron, tritosulfuron, 1 ((2-chloro-6-propyl-imidazo[1,2-b]pyridazin-3-yl)sulfonyl)-3-(4,6-dimethoxy-pyrimidin-2-yl)urea, triazines: ametryn, atrazine, cyanazine, dimethametryn, ethiozin, hexazinone, metamitron, metribuzin, prometryn, simazine, terbuthylazine, terbutryn, triaziflam, chlorotoluron, daimuron, diuron, fluometuron, isoproturon, linuron, metha-benzthiazuron, tebuthiuron, bispyribac-sodium, cloransulam-methyl, diclosulam, florasulam, flucarbazone, flumetsulam, metosulam, ortho-sulfamuron, penoxsulam, propoxycarbazone, pyribambenz-propyl, pyribenzoxim, pyriftalid, pyriminobac-methyl, pyrimisulfan, pyrithiobac, pyroxasulfone, pyroxsulam, amicarbazone, aminotriazole, anilofos, beflubutamid, benazolin, bencarbazone, benfluresate, benzofenap, bentazone, benzobicyclon, bicyclopyrone, bromacil, bromobutide, butafenacil, butamifos, cafenstrole, carfentrazone, cinidon-ethlyl, chlorthal, cinmethylin, clomazone, cumyluron, cyprosulfamide, dicamba, difenzoquat, diflufenzopyr, Drechslera monoceras, endothal, ethofumesate, etobenzanid, fenoxasulfone, fentrazamide, flumiclorac-pentyl, flumioxazin, flupoxam, fluorochloridone, flurtamone, indanofan, isoxaben, isoxaflutole, lenacil, propanil, propyzamide, quinclorac, quinmerac, mesotrione, methyl arsonic acid, naptalam, oxadiargyl, oxadiazon, oxaziclomefone, pentoxazone, pinoxaden, pyraclonil, pyraflufen-ethyl, pyrasulfotole, pyrazoxyfen, pyrazolynate, quinoclamine, saflufenacil, sulcotrione, sulfentrazone, terbacil, tefuryltrione, tembotrione, thiencarbazone, topramezone, (3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydro-2H-pyrimidin-1-yl)-phenoxy]-pyridin-2-yloxy)-acetic acid ethyl ester, 6-amino-5-chloro-2-cyclopropyl-pyrimidine-4-carboxylic acid methyl ester, 6-chloro-3-(2-cyclopropyl-6-methyl-phenoxy)-pyridazin-4-ol, 4-amino-3-chloro-6-(4-chloro-phenyl)-5-fluoro-pyridine-2-carboxylic acid and 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxy-phenyl)-pyridine-2-carboxylic acid methyl ester, and 4-amino-3-chloro-6-(4-chloro-3-dimethylamino-2-fluoro-phenyl)-pyridine-2-carboxylic acid methyl ester. 5. A ready-to-use foamable pesticide composition as set forth in claim 1 wherein the thickening agent is selected from the group consisting of bentonite clay, xantham gum, guar gum, gum arabic, alginin, gum tragacanth and sodium alginate. 6. A ready-to-use foamable pesticide composition as set forth in claim 1 comprising a foam stabilizer. 7. A ready-to-use foamable pesticide composition as set forth in claim 6 wherein the thickening agent is also the foam stabilizer. 8. A ready-to-use foamable pesticide composition as set forth in claim 1 wherein the composition is capable of remaining in a foam phase for less than about 2 minutes after application. 9. A ready-to-use foamable pesticide composition as set forth in claim 1 wherein the composition comprises a propellant and the total amount of propellants in the pesticide composition is at least about 1% by weight of the composition. 10. A ready-to-use foamable pesticide composition as set forth in claim 1 comprising at least about 0.005% by weight particulate pesticide. 11. A pesticide applicator for applying pesticide to pests, the applicator comprising:
a container; and a pesticide composition within the container, the pesticide composition comprising a diluent, a particulate pesticide suspended in the diluent, a thickening agent and a surfactant system comprising at least one fatty acid soap. 12. A pesticide applicator as set forth in claim 11 wherein the particulate pesticide is an arthropodicide selected from the group consisting of (M1) organo(thio)phosphate compounds selected from the group consisting of acephate, azamethiphos, azinphos-ethyl, azinphos-methyl, chlorethoxyfos, chlorfenvinphos, chlormephos, chlorpyrifos, chlorpyrifos-methyl, coumaphos, cyanophos, demeton-S-methyl, diazinon, dichlorvos/DDVP, dicrotophos, dimethoate, dimethylvinphos, disulfoton, EPN, ethion, ethoprophos, famphur, fenamiphos, fenitrothion, fenthion, flupyrazophos, fosthiazate, heptenophos, isoxathion, malathion, mecarbam, methamidophos, methidathion, mevinphos, monocrotophos, omethoate, oxydemeton-methyl, parathion, parathion-methyl, phenthoate, phorate, phosalone, phosmet, phosphamidon, phoxim, pirimiphos-methyl, profenofos, propetamphos, prothiofos, pyraclofos, pyridaphenthion, quinalphos, sulfotep, tebupirimfos, temephos, terbufos, tetrachlorvinphos, thiometon, triazophos, trichlorfon and vamidothion; (M2) carbamate compounds selected from the group consisting of aldicarb, alanycarb, bendiocarb, benfuracarb, butocarboxim, butoxycarboxim, carbaryl, carbofuran, carbosulfan, ethiofencarb, fenobucarb, formetanate, furathiocarb, isoprocarb, methiocarb, methomyl, metolcarb, oxamyl, pirimicarb, propoxur, thiodicarb, thiofanox, trimethacarb, XMC, xylylcarb and triazamate; (M3) pyrethroid compounds selected from the group consisting of acrinathrin, allethrin, d-cis-trans allethrin, d-trans allethrin, bifenthrin, bioallethrin, bioallethrin S-cylclopentenyl, bioresmethrin, cycloprothrin, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, gamma-cyhalothrin, cypermethrin, alpha-cypermethrin, beta-cypermethrin, theta-cypermethrin, zeta-cypermethrin, cyphenothrin, deltamethrin, empenthrin, esfenvalerate, etofenprox, fenpropathrin, fenvalerate, flucythrinate, flumethrin, tau-fluvalinate, halfenprox, imiprothrin, metofluthrin, permethrin, phenothrin, prallethrin, profluthrin, pyrethrin (pyrethrum), resmethrin, silafluofen, tefluthrin, tetramethrin, tralomethrin and transfluthrin; (M4) juvenile hormone mimics selected from the group consisting of hydroprene, kinoprene, methoprene, fenoxycarb and pyriproxyfen; (M5) nicotinic receptor agonists/antagonists compounds selected from the group consisting of acetamiprid, bensultap, cartap hydrochloride, clothianidin, dinotefuran, imidacloprid, thiamethoxam, nitenpyram, nicotine, spinosad (allosteric agonist), spinetoram (allosteric agonist), thiacloprid, thiocyclam, thiosultap-sodium and AKD 1022; (M6) GABA gated chloride channel antagonist compounds selected from the group consisting of chlordane, endosulfan, gamma-HCH (lindane); ethiprole, fipronil, pyrafluprole and pyriprole; (M7) chloride channel activators selected from the group consisting of abamectin, emamectin benzoate, milbemectin and lepimectin; (M8) METI I compounds selected from the group consisting of fenazaquin, fenpyroximate, pyrimidifen, pyridaben, tebufenpyrad, tolfenpyrad, flufenerim and rotenone; (M9) METI II and III compounds selected from the group consisting of acequinocyl, fluacyprim, hydramethylnon; (M10) uncouplers of oxidative phosphorylation selected from the group consisting of chlorfenapyr and DNOC; (M11) inhibitors of oxidative phosphorylation selected from the group consisting of azocyclotin, cyhexatin, diafenthiuron, fenbutatin oxide, propargite, tetradifon; (M12) moulting disruptors selected from the group consisting of cyromazine, chromafenozide, halofenozide, methoxyfenozide, tebufenozide; synergists selected from the group consisting of piperonyl butoxideand tribufos; (M14) sodium channel blocker compounds selected from the group consisting of indoxacarb, metaflumizone; (M15) selective feeding blockers selected from the group consisting of crylotie, pymetrozine and flonicamid; (M16) mite growth inhibitors selected from the group consisting of clofentezine, hexythiazox and etoxazole; (M17) chitin synthesis inhibitors selected from the group consisting of buprofezin, bistrifluoron, chlorfluazuron, diflubenzuron, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron, noviflumuron, teflubenzuron and triflumuron; (M18) lipid biosynthesis inhibitors selected from the group consisting of spirodiclofen, spiromesifen, spirotetramat; (M19) octapaminergic agonsits selected from amitraz; (M20) ryanodine receptor modulators selected from the group consisting of flubendiamide and the phtalamid compound (R)—, (S)-3-Chlor-N-1-{2-methyl-4-[1,2,2,2-tetrafluor-1-(trifluormethyl)ethyl]phenyl}-N2-(1-methyl-2-methylsulfonylethyl)phthalamid (M20.1); (M21) isoxazoline compounds selected from the group consisting of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-pyridin-2-ylmethyl-benzamide (M21.1), 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-(2,2,2-trifluoro-ethyl)-benzamide (M21.2), 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (M21.3), 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalene-1-carboxylic acid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide (M21.4), 4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-[(methoxyimino)methyl]-2-methylbenzamide (M21.5) 4-[5-(3-Chloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (M21.6), 4-[5-(3-Chloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalene-1-carboxylic acid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide (M21.7) and 5-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-[1,2,4]triazol-1-yl-benzonitrile (M21.8); (M22) anthranilamide compounds selected from the group consisting of chloranthraniliprole, cyantraniliprole, 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [4-cyano-2-(1-cyclopropyl-ethylcarbamoyl)-6-methyl-phenyl]-amide (M22.1), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [2-chloro-4-cyano-6-(1-cyclopropyl-ethylcarbamoyl)-phenyl]-amide (M22.2), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [2-bromo-4-cyano-6-(1-cyclopropyl-ethylcarbamoyl)-phenyl]-amide (M22.3), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [2-bromo-4-chloro-6-(1-cyclopropyl-ethylcarbamoyl)-phenyl]-amide (M22.4), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [2,4-dichloro-6-(1-cyclopropyl-ethylcarbamoyl)-phenyl]-amide (M22.5), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [4-chloro-2-(1-cyclopropyl-ethylcarbamoyl)-6-methyl-phenyl]-amide (M22.6), N′-(2-{[5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-5-chloro-3-methyl-benzoyl)-hydrazinecarboxylic acid methyl ester (M22.7), N′-(2-{[5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-5-chloro-3-methyl-benzoyl)-N′-methyl-hydrazinecarboxylic acid methyl ester (M22.8), N′-(2-{[5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-5-chloro-3-methyl-benzoyl)-N,N′-dimethyl-hydrazines arb oxylic acid methyl ester (M22.9), N′-(3,5-Dibromo-2-{[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-benzoyl)-hydrazinecarboxylic acid methyl ester (M22.10), N′-(3,5-Dibromo-2-{[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-benzoyl)-N′-methyl-hydrazinecarboxylic acid methyl ester (M22.11) and N′-(3,5-Dibromo-2-{[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-benzoyl)-N,N′-dimethyl-hydrazinecarboxylic acid methyl ester (M22.12); (M23) malononitrile compounds selected from the group consisting of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(3,3,3-trifluoro-propyl)malononitrile (CF2H—CF2-CF2-CF2-CH2-C(CN)2-CH2-CH2-CF3) (M23.1) and 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(3,3,4,4,4-pentafluorobutyl)-malonodinitrile (CF2H—CF2-CF2-CF2-CH2-C(CN)2-CH2-CH2-CF2-CF3) (M23.2); (M24) microbial disruptors selected from the group consisting of Bacillus thuringiensis subsp. Israelensi, Bacillus sphaericus, Bacillus thuringiensis subsp. Aizawai, Bacillus thuringiensis subsp. Kurstaki and Bacillus thuringiensis subsp. Tenebrionis; (M25) aminofuranone compounds selected from the group consisting of 4-{[(6-Bromopyrid-3-yl)methyl](2-fluoroethyl)amino}furan-2(5H)-on (M25.1), 4-{[(6-Fluoropyrid-3-yl)methyl] (2,2-difluoroethyl)amino}furan-2(5H)-on (M25.2), 4-{[(2-Chloro-1,3-thiazolo-5-yl)methyl](2-fluoroethyl)amino}furan-2(5H)-on (M25.3), 4-{[(6-Chloropyrid-3-yl)methyl](2-fluoroethyl)amino}furan-2(5H)-on (M25.4), 4-{[(6-Chloropyrid-3-yl)methyl](2,2-difluoroethyl)amino}furan-2(5H)-on (M25.5), 4-{[(6-Chloro-5-fluoropyrid-3-yl)methyl](methyl)amino}furan-2(5H)-on (M25.6), 4-{[(5,6-Dichloropyrid-3-yl)methyl](2-fluoroethyl)amino}furan-2(5H)-on (M25.7), 4-{[(6-Chloro-5-fluoropyrid-3-yl)methyl](cyclopropyl)amino}furan-2(5H)-on (M25.8), 4-{[(6-Chloropyrid-3-yl)methyl](cyclopropyl)amino}furan-2(5H)-on (M25.9) and 4-{[(6-Chloropyrid-3-yl)methyl](methyl)amino}furan-2(5H)-on (M25.10); (M26) various other compounds selected from the group consisting of amidoflumet, benclothiaz, benzoximate, bifenazate, borax, bromopropylate, cyenopyrafen, cyflumetofen, chinomethionate, dicofol, fluoroacetate, pyridalyl, pyrifluquinazon, tartar emetic, sulfoxaflor, N—R′-2,2-dihalo-1-R″cyclo-propanecarboxamide-2-(2,6-dichloro-α,α,α-trifluoro-p-tolyl)hydrazone or N—R′-2,2-di(R′″)propionamide-2-(2,6-dichloro-α,α,α-trifluoro-p-tolyl)-hydrazone, wherein R′ is methyl or ethyl, halo is chloro or bromo, R″ is hydrogen or methyl and R′″ is methyl or ethyl, 4-But-2-ynyloxy-6-(3,5-dimethyl-piperidin-1-yl)-2-fluoro-pyrimidine (M26.1), Cyclopropaneacetic acid, 1,1′-[(3S,4R,4aR,6S,6aS,12R,12aS,12bS)-4-[[(2-cyclopropylacetyl)oxy]methyl]-1,3,4,4a,5,6,6a,12,12a,12b-decahydro-12-hydroxy-4,6a,12b-trimethyl-11-oxo-9-(3-pyridinyl)-2H,11H-naphtho[2,1-b]pyrano[3,4-e]pyran-3,6-diyl]ester (M26.2) and 8-(2-Cyclopropylmethoxy-4-trifluoromethyl-phenoxy)-3-(6-trifluoromethyl-pyridazin-3-yl)-3-aza-bicyclo[3.2.1]octane (M26.3). 13. A pesticide applicator as set forth in claim 11 wherein the particulate pesticide is a fungicide selected from the group consisting of respiration inhibitors selected from the group consisting of azoxystrobin, dimoxystrobin, enestroburin, fluoxastro-bin, kresoxim-methyl, meto-minostrobin, orysastrobin, picoxy-strobin, pyraclostrobin, pyrametostrobin, pyraoxystrobin, pyribencarb, trifloxystrobin, methyl (2-chloro-5 [1-(3-methylbenzyl-oxy-imino)-ethyl]benzyl)-carba-mate and 2 (2-(3-(2,6-di-chlorophenyl)-1-methyl-allylidene-aminooxy-methyl)-phenyl)-2-methoxyimino-N methyl-acetamide, famoxadone, fenamidone, benodanil, bixafen, boscalid, carboxin, fen-furam, fenhexamid, fluopyram, flutolanil, furametpyr, isopyrazam, isotianil, mepronil, oxycarboxin, penflufen, penthiopyrad, sedaxane, tecloftalam, thifluz-amide, tiadinil, 2-amino-4 methyl-thiazole-5-carbox-anilide, N-(3′,4′,5′ tri-fluoro-bi-phenyl-2 yl)-3-difluoro-methyl-1-methyl-1H-pyrazole-4 carboxamide, N-(4′-tri-fluoro-methyl-thiobi-phenyl-2-yl)-3 difluoromethyl-1-methyl-1H pyrazole-4-carbox-amide and N-(2-(1,3,3-trimethyl-butyl)-phenyl)-1,3-dimethyl-5 fluoro-1H-pyrazole-4 carbox-amide, cyazofamid, amisulbrom, diflumetorim, binapacryl, dinobuton, dinocap, fluazinam, nitrthal-isopropyl, tecnazen, ferimzone, fentin salts, ametoctradin, silthiofam; sterol biosynthesis inhibitors (SBI fungicides) selected from the group consisting of azaconazole, bitertanol, bromuconazole, cyproconazole, difenoconazole, diniconazole, diniconazole-M, epoxiconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imibenconazole, ipconazole, metconazole, myclobutanil, paclobutrazole, penconazole, propiconazole, prothio-conazole, simeconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole, uniconazole, imazalil, pefurazoate, oxpoconazole, prochloraz, triflumizole, fenarimol, nuarimol, pyrifenox, triforine, aldimorph, dodemorph, dodemorph-acetate, fenpropimorph, tridemorph, fenpropidin, piperalin, spiroxamine, fenhexamid, benalaxyl, benalaxyl-M, kiralaxyl, metalaxyl, metalaxyl-M (mefenoxam), ofurace, oxadixyl, hymexazole, octhilinone, oxolinic acid, bupirimate, benomyl, carbendazim, fuberidazole, thiabendazole, thiophanate-methyl, 5-chloro-7 (4-methyl-piperidin-1-yl)-6-(2,4,6-trifluorophenyl)-[1,2,4]tri-azolo-[1,5a]pyrimidine, diethofencarb, ethaboxam, pencycuron, fluopicolide, zoxamide, metrafenone, cyprodinil, mepanipyrim, nitrapyrin, pyrimethanil, blasticidin-S, kasugamycin, kasugamycin hydrochloride-hydrate, mildiomycin, streptomycin, oxytetracyclin, polyoxine, validamycin A, fluoroimid, iprodione, procymidone, vinclozolin, fenpiclonil, fludioxonil, quinoxyfen, edifenphos, iprobenfos, pyrazophos, isoprothiolane, dicloran, quintozene, tecnazene, tolclofos-methyl, biphenyl, chloroneb, etridiazole, dimethomorph, flumorph, mandiproamid, pyrimorph, benthiavalicarb, iprovalicarb, pyribencarb, valifenalate and N-(1-(1-(4-cyano-phenyl)-ethanesulfonyl)-but-2-yl) carbamic acid-(4-fluorophenyl) ester, propamocarb, propamo-carb-hydrochlorid, Bordeaux mixture, copper acetate, copper hydroxide, copper oxychloride, basic copper sulfate, sulfur, ferbam, mancozeb, maneb, metam, methasulphocarb, metiram, propineb, thiram, zineb, ziram, anilazine, chlorothalonil, captafol, captan, folpet, dichlofluanid, dichlorophen, flusulfamide, hexachlorobenzene, pentachlorphenole and its salts, phthalide, tolylfluanid, N-(4-chloro-2-nitro-phenyl)-N-ethyl-4-methyl-benzenesulfonamide, guanidine, dodine, dodine free base, guazatine, guazatine-acetate, iminoctadine, iminoctadine-triacetate, iminoctadine-tris(albesilate), dithianon, validamycin, polyoxin B, pyroquilon, tricyclazole, carpropamide, dicyclomet, fenoxanil, acibenzolar-S-methyl, probenazole, isotianil, tiadinil, prohexadione-calcium, fosetyl, fosetyl-aluminum, phosphorous acid and its salts, bronopol, chinomethionat, cyflufenamid, cymoxanil, dazomet, debacarb, diclomezine, difenzoquat, difenzoquat-methylsulfate, diphenylamin, flumetover, flusulfamide, flutianil, methasulfocarb, oxin-copper, proquinazid, tebufloquin, tecloftalam, triazoxide, 2-butoxy-6-iodo-3-propylchromen-4-one, N-(cyclo-propylmethoxyimino-(6-difluoro-methoxy-2,3-difluoro-phenyl)-methyl)-2-phenyl acetamide, N′-(4-(4-chloro-3-trifluoromethyl-phenoxy)-2,5-dimethyl-phenyl)-N-ethyl-N methyl formamidine, N′ (4-(4-fluoro-3-trifluoromethyl-phenoxy)-2,5-dimethyl-phenyl)-N-ethyl-N-methyl formamidine, N′-(2-methyl-5-trifluoromethyl-4-(3-trimethyl-silanyl-prop-oxy)-phenyl)-N-ethyl-N-methyl formamidine, N′-(5-difluoromethyl-2 methyl-4-(3-tri-methylsilanyl-propoxy)-phenyl)-N-ethyl-N-methyl formamidine, 2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazole-1-yl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide, 2-{1-[2-(5-meth-yl-3-trifluoromethyl-pyrazole-1-yl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid methyl-(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-amide, methoxy-acetic acid 6-tert-butyl-8-fluoro-2,3-dimethyl-quinolin-4-yl ester and N-Methyl-2-{1-[(5-methyl-3-trifluoro-methyl-1H-pyr-azol-1-yl)-acetyl]-piperi-din-4-yl}-N-[(1R)-1,2,3,4-tetrahydro-naphthalen-1-yl]-4-thi-azolecarboxamide, 3-[5-(4-chloro-phenyl)-2,3-dimethyl-isoxazolidin-3 yl]-pyridine, 3-[5-(4-methyl-phenyl)-2,3-dimethyl-isoxazolidin-3-yl]-pyridine, 5-amino-2-iso-propyl-3-oxo-4-ortho-tolyl-2,3-dihydro-pyrazole-1 carbo-thioic acid S-allyl ester, N-(6-methoxy-pyridin-3-yl)cyclopropanecarboxylic acid amide, 5-chloro-1 (4,6-dimethoxy-pyrimidin-2-yl)-2-methyl-1H-benzoimidazole, 2-(4-chloro-phenyl)-N-[4-(3,4-dimeth-oxy-phenyl)-isoxazol-5-yl]-2-prop-2-ynyloxy-acetamide, abscisic acid, amidochlor, ancymidol, 6-benzylaminopurine, brassinolide, butralin, chlormequat (chlormequat chloride), choline chloride, cyclanilide, daminozide, dike-gulac, dimethipin, 2,6-dimethylpuridine, ethephon, flumetralin, flurprimidol, fluthi-acet, forchlorfenuron, gibberellic acid, inabenfide, indole-3-acetic acid, maleic hydrazide, mefluidide, mepiquat (mepiquat chloride), naphthaleneacetic acid, N 6 benzyladenine, paclobutrazol, prohexadione (prohexadione-calcium), prohydrojasmon, thidiazuron, triapenthenol, tributyl phosphorotrithioate, 2,3,5 tri iodobenzoic acid, trinexapac-ethyl and uniconazole and antifungal biocontrol agents. 14. A pesticide applicator as set forth in claim 11 wherein the particulate pesticide is a herbicide selected from the group consisting of acetochlor, alachlor, butachlor, dimethachlor, dimethenamid, flufenacet, mefenacet, metolachlor, metazachlor, napropamide, naproanilide, pethoxamid, pretilachlor, propachlor, thenylchlor, bilanafos, glyphosate, glufosinate, sulfosate, clodinafop, cyhalofop-butyl, fenoxaprop, fluazifop, haloxyfop, metamifop, propaquizafop, quizalofop, quizalofop-P-tefuryl, diquat, paraquat, asulam, butylate, carbetamide, desmedipham, dimepiperate, eptam (EPTC), esprocarb, molinate, orbencarb, phenmedipham, prosulfocarb, pyributicarb, thiobencarb, triallate, butroxydim, clethodim, cycloxydim, profoxydim, sethoxydim, tepraloxydim, tralkoxydim, benfluralin, ethalfluralin, oryzalin, pendimethalin, prodiamine, trifluralin, acifluorfen, aclonifen, bifenox, diclofop, ethoxyfen, fomesafen, lactofen, oxyfluorfen, bomoxynil, dichlobenil, ioxynil, imazamethabenz, imazamox, imazapic, imazapyr, imazaquin, imazethapyr, clomeprop, 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4-DB, dichlorprop, MCPA, MCPA-thioethyl, MCPB, Mecoprop, chloridazon, flufenpyr-ethyl, fluthiacet, norflurazon, pyridate, aminopyralid, clopyralid, diflufenican, dithiopyr, fluridone, fluoroxypyr, picloram, picolinafen, thiazopyr, amidosulfuron, azimsulfuron, bensulfuron, chlorimuron-ethyl, chlorsulfuron, cinosulfuron, cyclosulfamuron, ethoxysulfuron, flazasulfuron, flucetosulfuron, flupyrsulfuron, foramsulfuron, halosulfuron, imazosulfuron, iodosulfuron, mesosulfuron, metazosulfuron, metsulfuron-methyl, nicosulfuron, oxasulfuron, primisulfuron, prosulfuron, pyrazosulfuron, rimsulfuron, sulfometuron, sulfosulfuron, thifensulfuron, triasulfuron, tribenuron, trifloxysulfuron, triflusulfuron, tritosulfuron, 1 ((2-chloro-6-propyl-imidazo[1,2-b]pyridazin-3-yl)sulfonyl)-3-(4,6-dimethoxy-pyrimidin-2-yl)urea, triazines: ametryn, atrazine, cyanazine, dimethametryn, ethiozin, hexazinone, metamitron, metribuzin, prometryn, simazine, terbuthylazine, terbutryn, triaziflam, chlorotoluron, daimuron, diuron, fluometuron, isoproturon, linuron, metha-benzthiazuron, tebuthiuron, bispyribac-sodium, cloransulam-methyl, diclosulam, florasulam, flucarbazone, flumetsulam, metosulam, ortho-sulfamuron, penoxsulam, propoxycarbazone, pyribambenz-propyl, pyribenzoxim, pyriftalid, pyriminobac-methyl, pyrimisulfan, pyrithiobac, pyroxasulfone, pyroxsulam, amicarbazone, aminotriazole, anilofos, beflubutamid, benazolin, bencarbazone, benfluresate, benzofenap, bentazone, benzobicyclon, bicyclopyrone, bromacil, bromobutide, butafenacil, butamifos, cafenstrole, carfentrazone, cinidon-ethlyl, chlorthal, cinmethylin, clomazone, cumyluron, cyprosulfamide, dicamba, difenzoquat, diflufenzopyr, Drechslera monoceras, endothal, ethofumesate, etobenzanid, fenoxasulfone, fentrazamide, flumiclorac-pentyl, flumioxazin, flupoxam, fluorochloridone, flurtamone, indanofan, isoxaben, isoxaflutole, lenacil, propanil, propyzamide, quinclorac, quinmerac, mesotrione, methyl arsonic acid, naptalam, oxadiargyl, oxadiazon, oxaziclomefone, pentoxazone, pinoxaden, pyraclonil, pyraflufen-ethyl, pyrasulfotole, pyrazoxyfen, pyrazolynate, quinoclamine, saflufenacil, sulcotrione, sulfentrazone, terbacil, tefuryltrione, tembotrione, thiencarbazone, topramezone, (3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydro-2H-pyrimidin-1-yl)-phenoxy]-pyridin-2-yloxy)-acetic acid ethyl ester, 6-amino-5-chloro-2-cyclopropyl-pyrimidine-4-carboxylic acid methyl ester, 6-chloro-3-(2-cyclopropyl-6-methyl-phenoxy)-pyridazin-4-ol, 4-amino-3-chloro-6-(4-chloro-phenyl)-5-fluoro-pyridine-2-carboxylic acid and 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxy-phenyl)-pyridine-2-carboxylic acid methyl ester, and 4-amino-3-chloro-6-(4-chloro-3-dimethylamino-2-fluoro-phenyl)-pyridine-2-carboxylic acid methyl ester. 15. A pesticide applicator as set forth in claim 11 wherein the pesticide composition comprises a propellant to pressurize the composition within the container. 16. A pesticide applicator as set forth in claim 15 wherein the total amount of propellants in the pesticide composition is at least about 1% by weight of the composition. 17. A pesticide applicator as set forth in claim 15 wherein the propellant is selected from the group consisting of propane, isobutane, carbon dioxide and mixtures thereof. 18. A pesticide applicator as set forth in claim 15 wherein the composition comprises propane and isobutane as propellants. 19. A pesticide applicator as set forth in claim 11 comprising a valve and an actuator connected to the valve for regulating the flow of the pesticide composition from the container. 20. A pesticide applicator as set forth in claim 11 wherein the applicator further comprises a delivery system and an adaptor clamp for connecting the delivery system. 21. A pesticide applicator as set forth in claim 20 wherein the delivery system comprises a wand and an exhaust port fluidly connected to a hose. 22. A pesticide applicator as set forth in claim 11 wherein the thickening agent is selected from the group consisting of bentonite clay, xantham gum, guar gum, gum arabic, alginin, gum tragacanth and sodium alginate. 23. A pesticide applicator as set forth in claim 11 comprising a foam stabilizer. 24. A pesticide applicator as set forth in claim 23 wherein the thickening agent is also the foam stabilizer. 25. A pesticide applicator as set forth in claim 11 wherein the composition comprises at least about 0.005% by weight particulate pesticide. | Ready-to-use foamable pesticide compositions that contain a particulate pesticide suspended therein and applicators for dispensing such compositions. Methods for treating pests such as arthropods by contacting pests with such compositions are also provided.1. A ready-to-use foamable pesticide composition comprising:
a diluent; a particulate pesticide suspended in the diluent; a thickening agent; and a surfactant system comprising at least one fatty acid soap. 2. A ready-to-use foamable pesticide composition as set forth in claim 1 wherein the particulate pesticide is an arthropodicide selected from the group consisting of (M1) organo(thio)phosphate compounds selected from the group consisting of acephate, azamethiphos, azinphos-ethyl, azinphos-methyl, chlorethoxyfos, chlorfenvinphos, chlormephos, chlorpyrifos, chlorpyrifos-methyl, coumaphos, cyanophos, demeton-S-methyl, diazinon, dichlorvos/DDVP, dicrotophos, dimethoate, dimethylvinphos, disulfoton, EPN, ethion, ethoprophos, famphur, fenamiphos, fenitrothion, fenthion, flupyrazophos, fosthiazate, heptenophos, isoxathion, malathion, mecarbam, methamidophos, methidathion, mevinphos, monocrotophos, omethoate, oxydemeton-methyl, parathion, parathion-methyl, phenthoate, phorate, phosalone, phosmet, phosphamidon, phoxim, pirimiphos-methyl, profenofos, propetamphos, prothiofos, pyraclofos, pyridaphenthion, quinalphos, sulfotep, tebupirimfos, temephos, terbufos, tetrachlorvinphos, thiometon, triazophos, trichlorfon and vamidothion; (M2) carbamate compounds selected from the group consisting of aldicarb, alanycarb, bendiocarb, benfuracarb, butocarboxim, butoxycarboxim, carbaryl, carbofuran, carbosulfan, ethiofencarb, fenobucarb, formetanate, furathiocarb, isoprocarb, methiocarb, methomyl, metolcarb, oxamyl, pirimicarb, propoxur, thiodicarb, thiofanox, trimethacarb, XMC, xylylcarb and triazamate; (M3) pyrethroid compounds selected from the group consisting of acrinathrin, allethrin, d-cis-trans allethrin, d-trans allethrin, bifenthrin, bioallethrin, bioallethrin S-cylclopentenyl, bioresmethrin, cycloprothrin, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, gamma-cyhalothrin, cypermethrin, alpha-cypermethrin, beta-cypermethrin, theta-cypermethrin, zeta-cypermethrin, cyphenothrin, deltamethrin, empenthrin, esfenvalerate, etofenprox, fenpropathrin, fenvalerate, flucythrinate, flumethrin, tau-fluvalinate, halfenprox, imiprothrin, metofluthrin, permethrin, phenothrin, prallethrin, profluthrin, pyrethrin (pyrethrum), resmethrin, silafluofen, tefluthrin, tetramethrin, tralomethrin and transfluthrin; (M4) juvenile hormone mimics selected from the group consisting of hydroprene, kinoprene, methoprene, fenoxycarb and pyriproxyfen; (M5) nicotinic receptor agonists/antagonists compounds selected from the group consisting of acetamiprid, bensultap, cartap hydrochloride, clothianidin, dinotefuran, imidacloprid, thiamethoxam, nitenpyram, nicotine, spinosad (allosteric agonist), spinetoram (allosteric agonist), thiacloprid, thiocyclam, thiosultap-sodium and AKD1022; (M6) GABA gated chloride channel antagonist compounds selected from the group consisting of chlordane, endosulfan, gamma-HCH (lindane); ethiprole, fipronil, pyrafluprole and pyriprole; (M7) chloride channel activators selected from the group consisting of abamectin, emamectin benzoate, milbemectin and lepimectin; (M8) METI I compounds selected from the group consisting of fenazaquin, fenpyroximate, pyrimidifen, pyridaben, tebufenpyrad, tolfenpyrad, flufenerim and rotenone; (M9) METI II and III compounds selected from the group consisting of acequinocyl, fluacyprim, hydramethylnon; (M10) uncouplers of oxidative phosphorylation selected from the group consisting of chlorfenapyr and DNOC; (M11) inhibitors of oxidative phosphorylation selected from the group consisting of azocyclotin, cyhexatin, diafenthiuron, fenbutatin oxide, propargite, tetradifon; (M12) moulting disruptors selected from the group consisting of cyromazine, chromafenozide, halofenozide, methoxyfenozide, tebufenozide; synergists selected from the group consisting of piperonyl butoxideand tribufos; (M14) sodium channel blocker compounds selected from the group consisting of indoxacarb, metaflumizone; (M15) selective feeding blockers selected from the group consisting of crylotie, pymetrozine and flonicamid; (M16) mite growth inhibitors selected from the group consisting of clofentezine, hexythiazox and etoxazole; (M17) chitin synthesis inhibitors selected from the group consisting of buprofezin, bistrifluoron, chlorfluazuron, diflubenzuron, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron, noviflumuron, teflubenzuron and triflumuron; (M18) lipid biosynthesis inhibitors selected from the group consisting of spirodiclofen, spiromesifen, spirotetramat; (M19) octapaminergic agonsits selected from amitraz; (M20) ryanodine receptor modulators selected from the group consisting of flubendiamide and the phtalamid compound (R)—, (S)-3-Chlor-N1-{2-methyl-4-[1,2,2,2-tetrafluor-1-(trifluormethyl)ethyl]phenyl}-N2-(1-methyl-2-methylsulfonylethyl)phthalamid (M20.1); (M21) isoxazoline compounds selected from the group consisting of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-pyridin-2-ylmethyl-benzamide (M21.1), 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-(2,2,2-trifluoro-ethyl)-benzamide (M21.2), 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (M21.3), 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalene-1-carboxylic acid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide (M21.4), 4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-[(methoxyimino)methyl]-2-methylbenzamide (M21.5) 4-[5-(3-Chloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (M21.6), 4-[5-(3-Chloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalene-1-carboxylic acid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide (M21.7) and 5-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-[1,2,4]triazol-1-yl-benzonitrile (M21.8); (M22) anthranilamide compounds selected from the group consisting of chloranthraniliprole, cyantraniliprole, 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [4-cyano-2-(1-cyclopropyl-ethylcarbamoyl)-6-methyl-phenyl]-amide (M22.1), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [2-chloro-4-cyano-6-(1-cyclopropyl-ethylcarbamoyl)-phenyl]-amide (M22.2), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [2-bromo-4-cyano-6-(1-cyclopropyl-ethylcarbamoyl)-phenyl]-amide (M22.3), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [2-bromo-4-chloro-6-(1-cyclopropyl-ethylcarbamoyl)-phenyl]-amide (M22.4), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [2,4-dichloro-6-(1-cyclopropyl-ethylcarbamoyl)-phenyl]-amide (M22.5), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [4-chloro-2-(1-cyclopropyl-ethylcarbamoyl)-6-methyl-phenyl]-amide (M22.6), N′-(2-{[5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-5-chloro-3-methyl-benzoyl)-hydrazinecarboxylic acid methyl ester (M22.7), N′-(2-{[5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-5-chloro-3-methyl-benzoyl)-N′-methyl-hydrazinecarboxylic acid methyl ester (M22.8), N′-(2-{[5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-5-chloro-3-methyl-benzoyl)-N,N′-dimethyl-hydrazinecarboxylic acid methyl ester (M22.9), N′-(3,5-Dibromo-2-{[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-benzoyl)-hydrazinecarboxylic acid methyl ester (M22.10), N′-(3,5-Dibromo-2-{[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-benzoyl)-N′-methyl-hydrazinecarboxylic acid methyl ester (M22.11) and N′-(3,5-Dibromo-2-{[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-benzoyl)-N,N′-dimethyl-hydrazinecarboxylic acid methyl ester (M22.12); (M23) malononitrile compounds selected from the group consisting of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(3,3,3-trifluoro-propyl)malononitrile (CF2H—CF2-CF2-CF2-CH2-C(CN)2-CH2-CH2-CF3) (M23.1) and 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(3,3,4,4,4-pentafluorobutyl)-malonodinitrile (CF2H—CF2-CF2-CF2-CH2-C(CN)2-CH2-CH2-CF2-CF3) (M23.2); (M24) microbial disruptors selected from the group consisting of Bacillus thuringiensis subsp. Israelensi, Bacillus sphaericus, Bacillus thuringiensis subsp. Aizawai, Bacillus thuringiensis subsp. Kurstaki and Bacillus thuringiensis subsp. Tenebrionis; (M25) aminofuranone compounds selected from the group consisting of 4-{[(6-Bromopyrid-3-yl)methyl](2-fluoroethyl)amino}furan-2(5H)-on (M25.1), 4-{[(6-Fluoropyrid-3-yl)methyl](2,2-difluoroethyl)amino}furan-2(5H)-on (M25.2), 4-{[(2-Chloro-1,3-thiazolo-5-yl)methyl] (2-fluoro ethyl)amino}furan-2(5H)—on (M25.3), 4-{[(6-Chloropyrid-3-yl)methyl](2-fluoroethyl)amino}furan-2(5H)-on (M25.4), 4-{[(6-Chloropyrid-3-yl)methyl](2,2-difluoroethyl)amino}furan-2(5H)-on (M25.5), 4-{[(6-Chloro-5-fluoropyrid-3-yl)methyl](methyl)amino}furan-2(5H)-on (M25.6), 4-{[(5,6-Dichloropyrid-3-yl)methyl](2-fluoroethyl)amino}furan-2(5H)-on (M25.7), 4-{[(6-Chloro-5-fluoropyrid-3-yl)methyl](cyclopropyl)amino}furan-2(5H)—on (M25.8), 4-{[(6-Chloropyrid-3-yl)methyl](cyclopropyl)amino}furan-2(5H)-on (M25.9) and 4-{[(6-Chloropyrid-3-yl)methyl](methyl)amino}furan-2(5H)-on (M25.10); (M26) various other compounds selected from the group consisting of amidoflumet, benclothiaz, benzoximate, bifenazate, borax, bromopropylate, cyenopyrafen, cyflumetofen, chinomethionate, dicofol, fluoroacetate, pyridalyl, pyrifluquinazon, tartar emetic, sulfoxaflor, N—R′-2,2-dihalo-1-R″cyclo-propanecarboxamide-2-(2,6-dichloro-α,α,α-trifluoro-p-tolyl)hydrazone or N—R′-2,2-di(R″)propionamide-2-(2,6-dichloro-α,α,α-trifluoro-p-tolyl)-hydrazone, wherein R′ is methyl or ethyl, halo is chloro or bromo, R″ is hydrogen or methyl and R′ is methyl or ethyl, 4-But-2-ynyloxy-6-(3,5-dimethyl-piperidin-1-yl)-2-fluoro-pyrimidine (M26.1), Cyclopropaneacetic acid, 1,1′-[(3S,4R,4aR,6S,6aS,12R,12aS,12bS)-4-[[(2-cyclopropylacetyl)oxy]methyl]-1,3,4,4a,5,6,6a,12,12a,12b-decahydro-12-hydroxy-4,6a,12b-trimethyl-11-oxo-9-(3-pyridinyl)-2H,11H-naphtho[2,1-b]pyrano[3,4-e]pyran-3,6-diyl]ester(M26.2) and 8-(2-Cyclopropylmethoxy-4-trifluoromethyl-phenoxy)-3-(6-trifluoromethyl-pyridazin-3-yl)-3-aza-bicyclo[3.2.1]octane (M26.3). 3. A ready-to-use foamable pesticide composition as set forth in claim 1 wherein the particulate pesticide is a fungicide selected from the group consisting of respiration inhibitors selected from the group consisting of azoxystrobin, dimoxystrobin, enestroburin, fluoxastro-bin, kresoxim-methyl, meto-minostrobin, orysastrobin, picoxy-strobin, pyraclostrobin, pyrametostrobin, pyraoxystrobin, pyribencarb, trifloxystrobin, methyl (2-chloro-5 [1-(3-methylbenzyl-oxy-imino)-ethyl]benzyl)-carba-mate and 2 (2-(3-(2,6-di-chlorophenyl)-1-methyl-allylidene-aminooxy-methyl)-phenyl)-2-methoxyimino-N methyl-acetamide, famoxadone, fenamidone, benodanil, bixafen, boscalid, carboxin, fen-furam, fenhexamid, fluopyram, flutolanil, furametpyr, isopyrazam, isotianil, mepronil, oxycarboxin, penflufen, penthiopyrad, sedaxane, tecloftalam, thifluz-amide, tiadinil, 2-amino-4 methyl-thiazole-5-carbox-anilide, N-(3′,4′,5′ tri-fluoro-bi-phenyl-2 yl)-3-difluoro-methyl-1-methyl-1H-pyrazole-4 carboxamide, N-(4′-tri-fluoro-methyl-thiobi-phenyl-2-yl)-3 difluoromethyl-1-methyl-1H pyrazole-4-carbox-amide and N-(2-(1,3,3-trimethyl-butyl)-phenyl)-1,3-dimethyl-5 fluoro-1H-pyrazole-4 carbox-amide, cyazofamid, amisulbrom, diflumetorim, binapacryl, dinobuton, dinocap, fluazinam, nitrthal-isopropyl, tecnazen, ferimzone, fentin salts, ametoctradin, silthiofam; sterol biosynthesis inhibitors (SBI fungicides) selected from the group consisting of azaconazole, bitertanol, bromuconazole, cyproconazole, difenoconazole, diniconazole, diniconazole-M, epoxiconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imibenconazole, ipconazole, metconazole, myclobutanil, paclobutrazole, penconazole, propiconazole, prothio-conazole, simeconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole, uniconazole, imazalil, pefurazoate, oxpoconazole, prochloraz, triflumizole, fenarimol, nuarimol, pyrifenox, triforine, aldimorph, dodemorph, dodemorph-acetate, fenpropimorph, tridemorph, fenpropidin, piperalin, spiroxamine, fenhexamid, benalaxyl, benalaxyl-M, kiralaxyl, metalaxyl, metalaxyl-M (mefenoxam), ofurace, oxadixyl, hymexazole, octhilinone, oxolinic acid, bupirimate, benomyl, carbendazim, fuberidazole, thiabendazole, thiophanate-methyl, 5-chloro-7 (4-methyl-piperidin-1-yl)-6-(2,4,6-trifluorophenyl)-[1,2,4]tri-azolo-[1,5a]pyrimidine, diethofencarb, ethaboxam, pencycuron, fluopicolide, zoxamide, metrafenone, cyprodinil, mepanipyrim, nitrapyrin, pyrimethanil, blasticidin-S, kasugamycin, kasugamycin hydrochloride-hydrate, mildiomycin, streptomycin, oxytetracyclin, polyoxine, validamycin A, fluoroimid, iprodione, procymidone, vinclozolin, fenpiclonil, fludioxonil, quinoxyfen, edifenphos, iprobenfos, pyrazophos, isoprothiolane, dicloran, quintozene, tecnazene, tolclofos-methyl, biphenyl, chloroneb, etridiazole, dimethomorph, flumorph, mandiproamid, pyrimorph, benthiavalicarb, iprovalicarb, pyribencarb, valifenalate and N-(1-(1-(4-cyano-phenyl)-ethanesulfonyl)-but-2-yl) carbamic acid-(4-fluorophenyl) ester, propamocarb, propamo-carb-hydrochlorid, Bordeaux mixture, copper acetate, copper hydroxide, copper oxychloride, basic copper sulfate, sulfur, ferbam, mancozeb, maneb, metam, methasulphocarb, metiram, propineb, thiram, zineb, ziram, anilazine, chlorothalonil, captafol, captan, folpet, dichlofluanid, dichlorophen, flusulfamide, hexachlorobenzene, pentachlorphenole and its salts, phthalide, tolylfluanid, N-(4-chloro-2-nitro-phenyl)-N-ethyl-4-methyl-benzenesulfonamide, guanidine, dodine, dodine free base, guazatine, guazatine-acetate, iminoctadine, iminoctadine-triacetate, iminoctadine-tris(albesilate), dithianon, validamycin, polyoxin B, pyroquilon, tricyclazole, carpropamide, dicyclomet, fenoxanil, acibenzolar-S-methyl, probenazole, isotianil, tiadinil, prohexadione-calcium, fosetyl, fosetyl-aluminum, phosphorous acid and its salts, bronopol, chinomethionat, cyflufenamid, cymoxanil, dazomet, debacarb, diclomezine, difenzoquat, difenzoquat-methylsulfate, diphenylamin, flumetover, flusulfamide, flutianil, methasulfocarb, oxin-copper, proquinazid, tebufloquin, tecloftalam, triazoxide, 2-butoxy-6-iodo-3-propylchromen-4-one, N-(cyclo-propylmethoxyimino-(6-difluoro-methoxy-2,3-difluoro-phenyl)-methyl)-2-phenyl acetamide, N′-(4-(4-chloro-3-trifluoromethyl-phenoxy)-2,5-dimethyl-phenyl)-N-ethyl-N methyl formamidine, N′ (4-(4-fluoro-3-trifluoromethyl-phenoxy)-2,5-dimethyl-phenyl)-N-ethyl-N-methyl formamidine, N′-(2-methyl-5-trifluoromethyl-4-(3-trimethyl-silanyl-prop-oxy)-phenyl)-N-ethyl-N-methyl formamidine, N′-(5-difluoromethyl-2 methyl-4-(3-tri-methylsilanyl-propoxy)-phenyl)-N-ethyl-N-methyl formamidine, 2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazole-1-yl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide, 2-{1-[2-(5-meth-yl-3-trifluoromethyl-pyrazole-1-yl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid methyl-(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-amide, methoxy-acetic acid 6-tert-butyl-8-fluoro-2,3-dimethyl-quinolin-4-yl ester and N-Methyl-2-{1-[(S-methyl-3-trifluoro-methyl-1H-pyr-azol-1-yl)-acetyl]-piperi-din-4-yl}-N-[(1R)-1,2,3,4-tetrahydro-naphthalen-1-yl]-4-thi-azolecarboxamide, 3-[5-(4-chloro-phenyl)-2,3-dimethyl-isoxazolidin-3-yl]-pyridine, 3-[5-(4-methyl-phenyl)-2,3-dimethyl-isoxazolidin-3-yl]-pyridine, 5-amino-2-iso-propyl-3-oxo-4-ortho-tolyl-2,3-dihydro-pyrazole-1 carbo-thioic acid S-allyl ester, N-(6-methoxy-pyridin-3-yl) cyclopropanecarboxylic acid amide, 5-chloro-1 (4,6-dimethoxy-pyrimidin-2-yl)-2-methyl-1H-benzoimidazole, 2-(4-chloro-phenyl)-N-[4-(3,4-dimeth-oxy-phenyl)-isoxazol-5-yl]-2-prop-2-ynyloxy-acetamide, abscisic acid, amidochlor, ancymidol, 6-benzylaminopurine, brassinolide, butralin, chlormequat (chlormequat chloride), choline chloride, cyclanilide, daminozide, dike-gulac, dimethipin, 2,6-dimethylpuridine, ethephon, flumetralin, flurprimidol, fluthi-acet, forchlorfenuron, gibberellic acid, inabenfide, indole-3-acetic acid, maleic hydrazide, mefluidide, mepiquat (mepiquat chloride), naphthaleneacetic acid, N 6 benzyladenine, paclobutrazol, prohexadione (prohexadione-calcium), prohydrojasmon, thidiazuron, triapenthenol, tributyl phosphorotrithioate, 2,3,5 tri iodobenzoic acid, trinexapac-ethyl and uniconazole and antifungal biocontrol agents. 4. A ready-to-use foamable pesticide composition as set forth in claim 1 wherein the particulate pesticide is a herbicide selected from the group consisting of acetochlor, alachlor, butachlor, dimethachlor, dimethenamid, flufenacet, mefenacet, metolachlor, metazachlor, napropamide, naproanilide, pethoxamid, pretilachlor, propachlor, thenylchlor, bilanafos, glyphosate, glufosinate, sulfosate, clodinafop, cyhalofop-butyl, fenoxaprop, fluazifop, haloxyfop, metamifop, propaquizafop, quizalofop, quizalofop-P-tefuryl, diquat, paraquat, asulam, butylate, carbetamide, desmedipham, dimepiperate, eptam (EPTC), esprocarb, molinate, orbencarb, phenmedipham, prosulfocarb, pyributicarb, thiobencarb, triallate, butroxydim, clethodim, cycloxydim, profoxydim, sethoxydim, tepraloxydim, tralkoxydim, benfluralin, ethalfluralin, oryzalin, pendimethalin, prodiamine, trifluralin, acifluorfen, aclonifen, bifenox, diclofop, ethoxyfen, fomesafen, lactofen, oxyfluorfen, bomoxynil, dichlobenil, ioxynil, imazamethabenz, imazamox, imazapic, imazapyr, imazaquin, imazethapyr, clomeprop, 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4-DB, dichlorprop, MCPA, MCPA-thioethyl, MCPB, Mecoprop, chloridazon, flufenpyr-ethyl, fluthiacet, norflurazon, pyridate, aminopyralid, clopyralid, diflufenican, dithiopyr, fluridone, fluoroxypyr, picloram, picolinafen, thiazopyr, amidosulfuron, azimsulfuron, bensulfuron, chlorimuron-ethyl, chlorsulfuron, cinosulfuron, cyclosulfamuron, ethoxysulfuron, flazasulfuron, flucetosulfuron, flupyrsulfuron, foramsulfuron, halosulfuron, imazosulfuron, iodosulfuron, mesosulfuron, metazosulfuron, metsulfuron-methyl, nicosulfuron, oxasulfuron, primisulfuron, prosulfuron, pyrazosulfuron, rimsulfuron, sulfometuron, sulfosulfuron, thifensulfuron, triasulfuron, tribenuron, trifloxysulfuron, triflusulfuron, tritosulfuron, 1 ((2-chloro-6-propyl-imidazo[1,2-b]pyridazin-3-yl)sulfonyl)-3-(4,6-dimethoxy-pyrimidin-2-yl)urea, triazines: ametryn, atrazine, cyanazine, dimethametryn, ethiozin, hexazinone, metamitron, metribuzin, prometryn, simazine, terbuthylazine, terbutryn, triaziflam, chlorotoluron, daimuron, diuron, fluometuron, isoproturon, linuron, metha-benzthiazuron, tebuthiuron, bispyribac-sodium, cloransulam-methyl, diclosulam, florasulam, flucarbazone, flumetsulam, metosulam, ortho-sulfamuron, penoxsulam, propoxycarbazone, pyribambenz-propyl, pyribenzoxim, pyriftalid, pyriminobac-methyl, pyrimisulfan, pyrithiobac, pyroxasulfone, pyroxsulam, amicarbazone, aminotriazole, anilofos, beflubutamid, benazolin, bencarbazone, benfluresate, benzofenap, bentazone, benzobicyclon, bicyclopyrone, bromacil, bromobutide, butafenacil, butamifos, cafenstrole, carfentrazone, cinidon-ethlyl, chlorthal, cinmethylin, clomazone, cumyluron, cyprosulfamide, dicamba, difenzoquat, diflufenzopyr, Drechslera monoceras, endothal, ethofumesate, etobenzanid, fenoxasulfone, fentrazamide, flumiclorac-pentyl, flumioxazin, flupoxam, fluorochloridone, flurtamone, indanofan, isoxaben, isoxaflutole, lenacil, propanil, propyzamide, quinclorac, quinmerac, mesotrione, methyl arsonic acid, naptalam, oxadiargyl, oxadiazon, oxaziclomefone, pentoxazone, pinoxaden, pyraclonil, pyraflufen-ethyl, pyrasulfotole, pyrazoxyfen, pyrazolynate, quinoclamine, saflufenacil, sulcotrione, sulfentrazone, terbacil, tefuryltrione, tembotrione, thiencarbazone, topramezone, (3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydro-2H-pyrimidin-1-yl)-phenoxy]-pyridin-2-yloxy)-acetic acid ethyl ester, 6-amino-5-chloro-2-cyclopropyl-pyrimidine-4-carboxylic acid methyl ester, 6-chloro-3-(2-cyclopropyl-6-methyl-phenoxy)-pyridazin-4-ol, 4-amino-3-chloro-6-(4-chloro-phenyl)-5-fluoro-pyridine-2-carboxylic acid and 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxy-phenyl)-pyridine-2-carboxylic acid methyl ester, and 4-amino-3-chloro-6-(4-chloro-3-dimethylamino-2-fluoro-phenyl)-pyridine-2-carboxylic acid methyl ester. 5. A ready-to-use foamable pesticide composition as set forth in claim 1 wherein the thickening agent is selected from the group consisting of bentonite clay, xantham gum, guar gum, gum arabic, alginin, gum tragacanth and sodium alginate. 6. A ready-to-use foamable pesticide composition as set forth in claim 1 comprising a foam stabilizer. 7. A ready-to-use foamable pesticide composition as set forth in claim 6 wherein the thickening agent is also the foam stabilizer. 8. A ready-to-use foamable pesticide composition as set forth in claim 1 wherein the composition is capable of remaining in a foam phase for less than about 2 minutes after application. 9. A ready-to-use foamable pesticide composition as set forth in claim 1 wherein the composition comprises a propellant and the total amount of propellants in the pesticide composition is at least about 1% by weight of the composition. 10. A ready-to-use foamable pesticide composition as set forth in claim 1 comprising at least about 0.005% by weight particulate pesticide. 11. A pesticide applicator for applying pesticide to pests, the applicator comprising:
a container; and a pesticide composition within the container, the pesticide composition comprising a diluent, a particulate pesticide suspended in the diluent, a thickening agent and a surfactant system comprising at least one fatty acid soap. 12. A pesticide applicator as set forth in claim 11 wherein the particulate pesticide is an arthropodicide selected from the group consisting of (M1) organo(thio)phosphate compounds selected from the group consisting of acephate, azamethiphos, azinphos-ethyl, azinphos-methyl, chlorethoxyfos, chlorfenvinphos, chlormephos, chlorpyrifos, chlorpyrifos-methyl, coumaphos, cyanophos, demeton-S-methyl, diazinon, dichlorvos/DDVP, dicrotophos, dimethoate, dimethylvinphos, disulfoton, EPN, ethion, ethoprophos, famphur, fenamiphos, fenitrothion, fenthion, flupyrazophos, fosthiazate, heptenophos, isoxathion, malathion, mecarbam, methamidophos, methidathion, mevinphos, monocrotophos, omethoate, oxydemeton-methyl, parathion, parathion-methyl, phenthoate, phorate, phosalone, phosmet, phosphamidon, phoxim, pirimiphos-methyl, profenofos, propetamphos, prothiofos, pyraclofos, pyridaphenthion, quinalphos, sulfotep, tebupirimfos, temephos, terbufos, tetrachlorvinphos, thiometon, triazophos, trichlorfon and vamidothion; (M2) carbamate compounds selected from the group consisting of aldicarb, alanycarb, bendiocarb, benfuracarb, butocarboxim, butoxycarboxim, carbaryl, carbofuran, carbosulfan, ethiofencarb, fenobucarb, formetanate, furathiocarb, isoprocarb, methiocarb, methomyl, metolcarb, oxamyl, pirimicarb, propoxur, thiodicarb, thiofanox, trimethacarb, XMC, xylylcarb and triazamate; (M3) pyrethroid compounds selected from the group consisting of acrinathrin, allethrin, d-cis-trans allethrin, d-trans allethrin, bifenthrin, bioallethrin, bioallethrin S-cylclopentenyl, bioresmethrin, cycloprothrin, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, gamma-cyhalothrin, cypermethrin, alpha-cypermethrin, beta-cypermethrin, theta-cypermethrin, zeta-cypermethrin, cyphenothrin, deltamethrin, empenthrin, esfenvalerate, etofenprox, fenpropathrin, fenvalerate, flucythrinate, flumethrin, tau-fluvalinate, halfenprox, imiprothrin, metofluthrin, permethrin, phenothrin, prallethrin, profluthrin, pyrethrin (pyrethrum), resmethrin, silafluofen, tefluthrin, tetramethrin, tralomethrin and transfluthrin; (M4) juvenile hormone mimics selected from the group consisting of hydroprene, kinoprene, methoprene, fenoxycarb and pyriproxyfen; (M5) nicotinic receptor agonists/antagonists compounds selected from the group consisting of acetamiprid, bensultap, cartap hydrochloride, clothianidin, dinotefuran, imidacloprid, thiamethoxam, nitenpyram, nicotine, spinosad (allosteric agonist), spinetoram (allosteric agonist), thiacloprid, thiocyclam, thiosultap-sodium and AKD 1022; (M6) GABA gated chloride channel antagonist compounds selected from the group consisting of chlordane, endosulfan, gamma-HCH (lindane); ethiprole, fipronil, pyrafluprole and pyriprole; (M7) chloride channel activators selected from the group consisting of abamectin, emamectin benzoate, milbemectin and lepimectin; (M8) METI I compounds selected from the group consisting of fenazaquin, fenpyroximate, pyrimidifen, pyridaben, tebufenpyrad, tolfenpyrad, flufenerim and rotenone; (M9) METI II and III compounds selected from the group consisting of acequinocyl, fluacyprim, hydramethylnon; (M10) uncouplers of oxidative phosphorylation selected from the group consisting of chlorfenapyr and DNOC; (M11) inhibitors of oxidative phosphorylation selected from the group consisting of azocyclotin, cyhexatin, diafenthiuron, fenbutatin oxide, propargite, tetradifon; (M12) moulting disruptors selected from the group consisting of cyromazine, chromafenozide, halofenozide, methoxyfenozide, tebufenozide; synergists selected from the group consisting of piperonyl butoxideand tribufos; (M14) sodium channel blocker compounds selected from the group consisting of indoxacarb, metaflumizone; (M15) selective feeding blockers selected from the group consisting of crylotie, pymetrozine and flonicamid; (M16) mite growth inhibitors selected from the group consisting of clofentezine, hexythiazox and etoxazole; (M17) chitin synthesis inhibitors selected from the group consisting of buprofezin, bistrifluoron, chlorfluazuron, diflubenzuron, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron, noviflumuron, teflubenzuron and triflumuron; (M18) lipid biosynthesis inhibitors selected from the group consisting of spirodiclofen, spiromesifen, spirotetramat; (M19) octapaminergic agonsits selected from amitraz; (M20) ryanodine receptor modulators selected from the group consisting of flubendiamide and the phtalamid compound (R)—, (S)-3-Chlor-N-1-{2-methyl-4-[1,2,2,2-tetrafluor-1-(trifluormethyl)ethyl]phenyl}-N2-(1-methyl-2-methylsulfonylethyl)phthalamid (M20.1); (M21) isoxazoline compounds selected from the group consisting of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-pyridin-2-ylmethyl-benzamide (M21.1), 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-(2,2,2-trifluoro-ethyl)-benzamide (M21.2), 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (M21.3), 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalene-1-carboxylic acid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide (M21.4), 4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-[(methoxyimino)methyl]-2-methylbenzamide (M21.5) 4-[5-(3-Chloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (M21.6), 4-[5-(3-Chloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalene-1-carboxylic acid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide (M21.7) and 5-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-[1,2,4]triazol-1-yl-benzonitrile (M21.8); (M22) anthranilamide compounds selected from the group consisting of chloranthraniliprole, cyantraniliprole, 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [4-cyano-2-(1-cyclopropyl-ethylcarbamoyl)-6-methyl-phenyl]-amide (M22.1), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [2-chloro-4-cyano-6-(1-cyclopropyl-ethylcarbamoyl)-phenyl]-amide (M22.2), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [2-bromo-4-cyano-6-(1-cyclopropyl-ethylcarbamoyl)-phenyl]-amide (M22.3), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [2-bromo-4-chloro-6-(1-cyclopropyl-ethylcarbamoyl)-phenyl]-amide (M22.4), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [2,4-dichloro-6-(1-cyclopropyl-ethylcarbamoyl)-phenyl]-amide (M22.5), 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [4-chloro-2-(1-cyclopropyl-ethylcarbamoyl)-6-methyl-phenyl]-amide (M22.6), N′-(2-{[5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-5-chloro-3-methyl-benzoyl)-hydrazinecarboxylic acid methyl ester (M22.7), N′-(2-{[5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-5-chloro-3-methyl-benzoyl)-N′-methyl-hydrazinecarboxylic acid methyl ester (M22.8), N′-(2-{[5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-5-chloro-3-methyl-benzoyl)-N,N′-dimethyl-hydrazines arb oxylic acid methyl ester (M22.9), N′-(3,5-Dibromo-2-{[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-benzoyl)-hydrazinecarboxylic acid methyl ester (M22.10), N′-(3,5-Dibromo-2-{[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-benzoyl)-N′-methyl-hydrazinecarboxylic acid methyl ester (M22.11) and N′-(3,5-Dibromo-2-{[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-benzoyl)-N,N′-dimethyl-hydrazinecarboxylic acid methyl ester (M22.12); (M23) malononitrile compounds selected from the group consisting of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(3,3,3-trifluoro-propyl)malononitrile (CF2H—CF2-CF2-CF2-CH2-C(CN)2-CH2-CH2-CF3) (M23.1) and 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(3,3,4,4,4-pentafluorobutyl)-malonodinitrile (CF2H—CF2-CF2-CF2-CH2-C(CN)2-CH2-CH2-CF2-CF3) (M23.2); (M24) microbial disruptors selected from the group consisting of Bacillus thuringiensis subsp. Israelensi, Bacillus sphaericus, Bacillus thuringiensis subsp. Aizawai, Bacillus thuringiensis subsp. Kurstaki and Bacillus thuringiensis subsp. Tenebrionis; (M25) aminofuranone compounds selected from the group consisting of 4-{[(6-Bromopyrid-3-yl)methyl](2-fluoroethyl)amino}furan-2(5H)-on (M25.1), 4-{[(6-Fluoropyrid-3-yl)methyl] (2,2-difluoroethyl)amino}furan-2(5H)-on (M25.2), 4-{[(2-Chloro-1,3-thiazolo-5-yl)methyl](2-fluoroethyl)amino}furan-2(5H)-on (M25.3), 4-{[(6-Chloropyrid-3-yl)methyl](2-fluoroethyl)amino}furan-2(5H)-on (M25.4), 4-{[(6-Chloropyrid-3-yl)methyl](2,2-difluoroethyl)amino}furan-2(5H)-on (M25.5), 4-{[(6-Chloro-5-fluoropyrid-3-yl)methyl](methyl)amino}furan-2(5H)-on (M25.6), 4-{[(5,6-Dichloropyrid-3-yl)methyl](2-fluoroethyl)amino}furan-2(5H)-on (M25.7), 4-{[(6-Chloro-5-fluoropyrid-3-yl)methyl](cyclopropyl)amino}furan-2(5H)-on (M25.8), 4-{[(6-Chloropyrid-3-yl)methyl](cyclopropyl)amino}furan-2(5H)-on (M25.9) and 4-{[(6-Chloropyrid-3-yl)methyl](methyl)amino}furan-2(5H)-on (M25.10); (M26) various other compounds selected from the group consisting of amidoflumet, benclothiaz, benzoximate, bifenazate, borax, bromopropylate, cyenopyrafen, cyflumetofen, chinomethionate, dicofol, fluoroacetate, pyridalyl, pyrifluquinazon, tartar emetic, sulfoxaflor, N—R′-2,2-dihalo-1-R″cyclo-propanecarboxamide-2-(2,6-dichloro-α,α,α-trifluoro-p-tolyl)hydrazone or N—R′-2,2-di(R′″)propionamide-2-(2,6-dichloro-α,α,α-trifluoro-p-tolyl)-hydrazone, wherein R′ is methyl or ethyl, halo is chloro or bromo, R″ is hydrogen or methyl and R′″ is methyl or ethyl, 4-But-2-ynyloxy-6-(3,5-dimethyl-piperidin-1-yl)-2-fluoro-pyrimidine (M26.1), Cyclopropaneacetic acid, 1,1′-[(3S,4R,4aR,6S,6aS,12R,12aS,12bS)-4-[[(2-cyclopropylacetyl)oxy]methyl]-1,3,4,4a,5,6,6a,12,12a,12b-decahydro-12-hydroxy-4,6a,12b-trimethyl-11-oxo-9-(3-pyridinyl)-2H,11H-naphtho[2,1-b]pyrano[3,4-e]pyran-3,6-diyl]ester (M26.2) and 8-(2-Cyclopropylmethoxy-4-trifluoromethyl-phenoxy)-3-(6-trifluoromethyl-pyridazin-3-yl)-3-aza-bicyclo[3.2.1]octane (M26.3). 13. A pesticide applicator as set forth in claim 11 wherein the particulate pesticide is a fungicide selected from the group consisting of respiration inhibitors selected from the group consisting of azoxystrobin, dimoxystrobin, enestroburin, fluoxastro-bin, kresoxim-methyl, meto-minostrobin, orysastrobin, picoxy-strobin, pyraclostrobin, pyrametostrobin, pyraoxystrobin, pyribencarb, trifloxystrobin, methyl (2-chloro-5 [1-(3-methylbenzyl-oxy-imino)-ethyl]benzyl)-carba-mate and 2 (2-(3-(2,6-di-chlorophenyl)-1-methyl-allylidene-aminooxy-methyl)-phenyl)-2-methoxyimino-N methyl-acetamide, famoxadone, fenamidone, benodanil, bixafen, boscalid, carboxin, fen-furam, fenhexamid, fluopyram, flutolanil, furametpyr, isopyrazam, isotianil, mepronil, oxycarboxin, penflufen, penthiopyrad, sedaxane, tecloftalam, thifluz-amide, tiadinil, 2-amino-4 methyl-thiazole-5-carbox-anilide, N-(3′,4′,5′ tri-fluoro-bi-phenyl-2 yl)-3-difluoro-methyl-1-methyl-1H-pyrazole-4 carboxamide, N-(4′-tri-fluoro-methyl-thiobi-phenyl-2-yl)-3 difluoromethyl-1-methyl-1H pyrazole-4-carbox-amide and N-(2-(1,3,3-trimethyl-butyl)-phenyl)-1,3-dimethyl-5 fluoro-1H-pyrazole-4 carbox-amide, cyazofamid, amisulbrom, diflumetorim, binapacryl, dinobuton, dinocap, fluazinam, nitrthal-isopropyl, tecnazen, ferimzone, fentin salts, ametoctradin, silthiofam; sterol biosynthesis inhibitors (SBI fungicides) selected from the group consisting of azaconazole, bitertanol, bromuconazole, cyproconazole, difenoconazole, diniconazole, diniconazole-M, epoxiconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imibenconazole, ipconazole, metconazole, myclobutanil, paclobutrazole, penconazole, propiconazole, prothio-conazole, simeconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole, uniconazole, imazalil, pefurazoate, oxpoconazole, prochloraz, triflumizole, fenarimol, nuarimol, pyrifenox, triforine, aldimorph, dodemorph, dodemorph-acetate, fenpropimorph, tridemorph, fenpropidin, piperalin, spiroxamine, fenhexamid, benalaxyl, benalaxyl-M, kiralaxyl, metalaxyl, metalaxyl-M (mefenoxam), ofurace, oxadixyl, hymexazole, octhilinone, oxolinic acid, bupirimate, benomyl, carbendazim, fuberidazole, thiabendazole, thiophanate-methyl, 5-chloro-7 (4-methyl-piperidin-1-yl)-6-(2,4,6-trifluorophenyl)-[1,2,4]tri-azolo-[1,5a]pyrimidine, diethofencarb, ethaboxam, pencycuron, fluopicolide, zoxamide, metrafenone, cyprodinil, mepanipyrim, nitrapyrin, pyrimethanil, blasticidin-S, kasugamycin, kasugamycin hydrochloride-hydrate, mildiomycin, streptomycin, oxytetracyclin, polyoxine, validamycin A, fluoroimid, iprodione, procymidone, vinclozolin, fenpiclonil, fludioxonil, quinoxyfen, edifenphos, iprobenfos, pyrazophos, isoprothiolane, dicloran, quintozene, tecnazene, tolclofos-methyl, biphenyl, chloroneb, etridiazole, dimethomorph, flumorph, mandiproamid, pyrimorph, benthiavalicarb, iprovalicarb, pyribencarb, valifenalate and N-(1-(1-(4-cyano-phenyl)-ethanesulfonyl)-but-2-yl) carbamic acid-(4-fluorophenyl) ester, propamocarb, propamo-carb-hydrochlorid, Bordeaux mixture, copper acetate, copper hydroxide, copper oxychloride, basic copper sulfate, sulfur, ferbam, mancozeb, maneb, metam, methasulphocarb, metiram, propineb, thiram, zineb, ziram, anilazine, chlorothalonil, captafol, captan, folpet, dichlofluanid, dichlorophen, flusulfamide, hexachlorobenzene, pentachlorphenole and its salts, phthalide, tolylfluanid, N-(4-chloro-2-nitro-phenyl)-N-ethyl-4-methyl-benzenesulfonamide, guanidine, dodine, dodine free base, guazatine, guazatine-acetate, iminoctadine, iminoctadine-triacetate, iminoctadine-tris(albesilate), dithianon, validamycin, polyoxin B, pyroquilon, tricyclazole, carpropamide, dicyclomet, fenoxanil, acibenzolar-S-methyl, probenazole, isotianil, tiadinil, prohexadione-calcium, fosetyl, fosetyl-aluminum, phosphorous acid and its salts, bronopol, chinomethionat, cyflufenamid, cymoxanil, dazomet, debacarb, diclomezine, difenzoquat, difenzoquat-methylsulfate, diphenylamin, flumetover, flusulfamide, flutianil, methasulfocarb, oxin-copper, proquinazid, tebufloquin, tecloftalam, triazoxide, 2-butoxy-6-iodo-3-propylchromen-4-one, N-(cyclo-propylmethoxyimino-(6-difluoro-methoxy-2,3-difluoro-phenyl)-methyl)-2-phenyl acetamide, N′-(4-(4-chloro-3-trifluoromethyl-phenoxy)-2,5-dimethyl-phenyl)-N-ethyl-N methyl formamidine, N′ (4-(4-fluoro-3-trifluoromethyl-phenoxy)-2,5-dimethyl-phenyl)-N-ethyl-N-methyl formamidine, N′-(2-methyl-5-trifluoromethyl-4-(3-trimethyl-silanyl-prop-oxy)-phenyl)-N-ethyl-N-methyl formamidine, N′-(5-difluoromethyl-2 methyl-4-(3-tri-methylsilanyl-propoxy)-phenyl)-N-ethyl-N-methyl formamidine, 2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazole-1-yl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide, 2-{1-[2-(5-meth-yl-3-trifluoromethyl-pyrazole-1-yl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid methyl-(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-amide, methoxy-acetic acid 6-tert-butyl-8-fluoro-2,3-dimethyl-quinolin-4-yl ester and N-Methyl-2-{1-[(5-methyl-3-trifluoro-methyl-1H-pyr-azol-1-yl)-acetyl]-piperi-din-4-yl}-N-[(1R)-1,2,3,4-tetrahydro-naphthalen-1-yl]-4-thi-azolecarboxamide, 3-[5-(4-chloro-phenyl)-2,3-dimethyl-isoxazolidin-3 yl]-pyridine, 3-[5-(4-methyl-phenyl)-2,3-dimethyl-isoxazolidin-3-yl]-pyridine, 5-amino-2-iso-propyl-3-oxo-4-ortho-tolyl-2,3-dihydro-pyrazole-1 carbo-thioic acid S-allyl ester, N-(6-methoxy-pyridin-3-yl)cyclopropanecarboxylic acid amide, 5-chloro-1 (4,6-dimethoxy-pyrimidin-2-yl)-2-methyl-1H-benzoimidazole, 2-(4-chloro-phenyl)-N-[4-(3,4-dimeth-oxy-phenyl)-isoxazol-5-yl]-2-prop-2-ynyloxy-acetamide, abscisic acid, amidochlor, ancymidol, 6-benzylaminopurine, brassinolide, butralin, chlormequat (chlormequat chloride), choline chloride, cyclanilide, daminozide, dike-gulac, dimethipin, 2,6-dimethylpuridine, ethephon, flumetralin, flurprimidol, fluthi-acet, forchlorfenuron, gibberellic acid, inabenfide, indole-3-acetic acid, maleic hydrazide, mefluidide, mepiquat (mepiquat chloride), naphthaleneacetic acid, N 6 benzyladenine, paclobutrazol, prohexadione (prohexadione-calcium), prohydrojasmon, thidiazuron, triapenthenol, tributyl phosphorotrithioate, 2,3,5 tri iodobenzoic acid, trinexapac-ethyl and uniconazole and antifungal biocontrol agents. 14. A pesticide applicator as set forth in claim 11 wherein the particulate pesticide is a herbicide selected from the group consisting of acetochlor, alachlor, butachlor, dimethachlor, dimethenamid, flufenacet, mefenacet, metolachlor, metazachlor, napropamide, naproanilide, pethoxamid, pretilachlor, propachlor, thenylchlor, bilanafos, glyphosate, glufosinate, sulfosate, clodinafop, cyhalofop-butyl, fenoxaprop, fluazifop, haloxyfop, metamifop, propaquizafop, quizalofop, quizalofop-P-tefuryl, diquat, paraquat, asulam, butylate, carbetamide, desmedipham, dimepiperate, eptam (EPTC), esprocarb, molinate, orbencarb, phenmedipham, prosulfocarb, pyributicarb, thiobencarb, triallate, butroxydim, clethodim, cycloxydim, profoxydim, sethoxydim, tepraloxydim, tralkoxydim, benfluralin, ethalfluralin, oryzalin, pendimethalin, prodiamine, trifluralin, acifluorfen, aclonifen, bifenox, diclofop, ethoxyfen, fomesafen, lactofen, oxyfluorfen, bomoxynil, dichlobenil, ioxynil, imazamethabenz, imazamox, imazapic, imazapyr, imazaquin, imazethapyr, clomeprop, 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4-DB, dichlorprop, MCPA, MCPA-thioethyl, MCPB, Mecoprop, chloridazon, flufenpyr-ethyl, fluthiacet, norflurazon, pyridate, aminopyralid, clopyralid, diflufenican, dithiopyr, fluridone, fluoroxypyr, picloram, picolinafen, thiazopyr, amidosulfuron, azimsulfuron, bensulfuron, chlorimuron-ethyl, chlorsulfuron, cinosulfuron, cyclosulfamuron, ethoxysulfuron, flazasulfuron, flucetosulfuron, flupyrsulfuron, foramsulfuron, halosulfuron, imazosulfuron, iodosulfuron, mesosulfuron, metazosulfuron, metsulfuron-methyl, nicosulfuron, oxasulfuron, primisulfuron, prosulfuron, pyrazosulfuron, rimsulfuron, sulfometuron, sulfosulfuron, thifensulfuron, triasulfuron, tribenuron, trifloxysulfuron, triflusulfuron, tritosulfuron, 1 ((2-chloro-6-propyl-imidazo[1,2-b]pyridazin-3-yl)sulfonyl)-3-(4,6-dimethoxy-pyrimidin-2-yl)urea, triazines: ametryn, atrazine, cyanazine, dimethametryn, ethiozin, hexazinone, metamitron, metribuzin, prometryn, simazine, terbuthylazine, terbutryn, triaziflam, chlorotoluron, daimuron, diuron, fluometuron, isoproturon, linuron, metha-benzthiazuron, tebuthiuron, bispyribac-sodium, cloransulam-methyl, diclosulam, florasulam, flucarbazone, flumetsulam, metosulam, ortho-sulfamuron, penoxsulam, propoxycarbazone, pyribambenz-propyl, pyribenzoxim, pyriftalid, pyriminobac-methyl, pyrimisulfan, pyrithiobac, pyroxasulfone, pyroxsulam, amicarbazone, aminotriazole, anilofos, beflubutamid, benazolin, bencarbazone, benfluresate, benzofenap, bentazone, benzobicyclon, bicyclopyrone, bromacil, bromobutide, butafenacil, butamifos, cafenstrole, carfentrazone, cinidon-ethlyl, chlorthal, cinmethylin, clomazone, cumyluron, cyprosulfamide, dicamba, difenzoquat, diflufenzopyr, Drechslera monoceras, endothal, ethofumesate, etobenzanid, fenoxasulfone, fentrazamide, flumiclorac-pentyl, flumioxazin, flupoxam, fluorochloridone, flurtamone, indanofan, isoxaben, isoxaflutole, lenacil, propanil, propyzamide, quinclorac, quinmerac, mesotrione, methyl arsonic acid, naptalam, oxadiargyl, oxadiazon, oxaziclomefone, pentoxazone, pinoxaden, pyraclonil, pyraflufen-ethyl, pyrasulfotole, pyrazoxyfen, pyrazolynate, quinoclamine, saflufenacil, sulcotrione, sulfentrazone, terbacil, tefuryltrione, tembotrione, thiencarbazone, topramezone, (3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydro-2H-pyrimidin-1-yl)-phenoxy]-pyridin-2-yloxy)-acetic acid ethyl ester, 6-amino-5-chloro-2-cyclopropyl-pyrimidine-4-carboxylic acid methyl ester, 6-chloro-3-(2-cyclopropyl-6-methyl-phenoxy)-pyridazin-4-ol, 4-amino-3-chloro-6-(4-chloro-phenyl)-5-fluoro-pyridine-2-carboxylic acid and 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxy-phenyl)-pyridine-2-carboxylic acid methyl ester, and 4-amino-3-chloro-6-(4-chloro-3-dimethylamino-2-fluoro-phenyl)-pyridine-2-carboxylic acid methyl ester. 15. A pesticide applicator as set forth in claim 11 wherein the pesticide composition comprises a propellant to pressurize the composition within the container. 16. A pesticide applicator as set forth in claim 15 wherein the total amount of propellants in the pesticide composition is at least about 1% by weight of the composition. 17. A pesticide applicator as set forth in claim 15 wherein the propellant is selected from the group consisting of propane, isobutane, carbon dioxide and mixtures thereof. 18. A pesticide applicator as set forth in claim 15 wherein the composition comprises propane and isobutane as propellants. 19. A pesticide applicator as set forth in claim 11 comprising a valve and an actuator connected to the valve for regulating the flow of the pesticide composition from the container. 20. A pesticide applicator as set forth in claim 11 wherein the applicator further comprises a delivery system and an adaptor clamp for connecting the delivery system. 21. A pesticide applicator as set forth in claim 20 wherein the delivery system comprises a wand and an exhaust port fluidly connected to a hose. 22. A pesticide applicator as set forth in claim 11 wherein the thickening agent is selected from the group consisting of bentonite clay, xantham gum, guar gum, gum arabic, alginin, gum tragacanth and sodium alginate. 23. A pesticide applicator as set forth in claim 11 comprising a foam stabilizer. 24. A pesticide applicator as set forth in claim 23 wherein the thickening agent is also the foam stabilizer. 25. A pesticide applicator as set forth in claim 11 wherein the composition comprises at least about 0.005% by weight particulate pesticide. | 1,600 |
819 | 14,921,898 | 1,618 | The present disclosure provides purified forms of iobenguane and preparations of a precursor to iobenguane, such as a polymer, the polymer comprising a monomer of formula (I)
or a pharmaceutically acceptable salt thereof, the preparation comprising leachable tin at a level of 0 ppm to 850 ppm. | 1. A preparation comprising a polymer, the polymer comprising a monomer of formula (I):
or a pharmaceutically acceptable salt thereof, wherein leachable tin is present in the preparation at a level within a range of about 0 ppm to about 150 ppm. 2. The preparation of claim 1, wherein the pharmaceutically acceptable salt is the HOAc salt. 3. The preparation of claim 1, which preparation is enclosed in a container under inert gas. 4. The preparation of claim 3, wherein the inert gas is nitrogen. 5. The preparation of claim 1, wherein the level of leachable tin is within a range of about 0 ppm to about 120 ppm. 6. The preparation of claim 1, wherein the level of leachable tin is within a range of about 0 ppm to about 50 ppm. 7. The preparation of claim 1, wherein the polymer comprising monomer of formula (I), or the pharmaceutically acceptable salt thereof, makes up at least 98% of the preparation. 8. The preparation of claim 1, the preparation comprising less than 1.5 wt % water relative to the wt % of the preparation. 9. The preparation of claim 1, the preparation comprising less than 1.0 wt % water relative to the wt % of the preparation. 10. The preparation of claim 1, the preparation comprising less than 0.5 wt % organic solvent relative to the wt % of the preparation. 11. The preparation of claim 1, the polymer comprising less than about 0.5 wt % of a monomer of formula (IV):
or a pharmaceutically acceptable salt thereof. 12. The preparation of claim 1, the polymer comprising less than about 0.5 wt % of a monomer of formula (V):
or a pharmaceutically acceptable salt thereof. 13. A kit comprising a preparation, the preparation comprising a polymer comprising a monomer of formula (I):
or a pharmaceutically acceptable salt thereof, wherein leachable tin is present in the preparation at a level within a range of about 0 ppm to about 150 ppm, and the kit further comprising a container that stores the polymer comprising monomer of formula (I) under inert gas. 14. The kit of claim 13, comprising any one of the preparations of claims 2-12. 15. The kit of claim 13, wherein the purified polymer comprising monomer of formula (I), or salt thereof, is least 98 wt % pure, for at least six months at −20° C. 16. The kit of claim 13, wherein the kit maintains leachable tin content at a level of less than 150 ppm for at least six months at −20° C. 17. The kit of claim 13, wherein the kit maintains leachable tin content at a level of less than 20 ppm for at least nine months at −20° C. 18. The kit of claim 13, comprising less than 1.5 wt % water relative to the wt % of the preparation. 19. The kit of claim 13, comprising less than 1.0 wt % water relative to the wt % of the preparation. 20. A pharmaceutical composition comprising:
(a) a compound of formula (VI):
or pharmaceutically acceptable salts thereof,
wherein R1 is a radioisotopic label, and
the compound of formula (VI) is formed by contacting a radioisotope of a halogen ion with a preparation of a polymer comprising monomer of formula (I):
or a pharmaceutically acceptable salt thereof, the preparation of the polymer comprising monomer of formula (I) comprising leachable tin at a level of 0 ppm to 150 ppm; and
(b) a pharmaceutically acceptable carrier, adjuvant, or vehicle. 21. The pharmaceutical composition of claim 20, comprising the preparation of claim 2. 22. The pharmaceutical composition of claim 20, wherein the radioisotope of a halogen ion is fluoride, bromide, iodide or astatine. 23. The pharmaceutical composition of claim 20, wherein the radioisotope of a halogen ion is 123I, 124I, 125I or 131I. 24. The pharmaceutical composition of claim 20, wherein the radioisotope of a halogen ion is 211At. 25. A pharmaceutical composition comprising:
(a) meta-iodobenzylguanidine (MIBG):
or a pharmaceutically acceptable salt thereof, wherein MIBG is formed by contacting an iodide salt with a preparation of a polymer comprising monomer of formula (I):
or a pharmaceutically acceptable salt thereof, the preparation of the polymer comprising monomer of formula (I) comprising leachable tin at a level of 0 ppm to 150 ppm; and
(b) a pharmaceutically acceptable carrier, adjuvant, or vehicle. 26. The pharmaceutical composition of claim 25, comprising the preparation of claim 2. 27. The pharmaceutical composition of claim 25, wherein not more than about 0.5 wt % meta-iodobenzylamine (MIBA):
or a pharmaceutically acceptable salt thereof, is present in the composition. 28. The pharmaceutical composition of claim 25, wherein not more than about 0.5 wt % meta-iodobenzylbiguanidine (MIBBG):
or a pharmaceutically acceptable salt thereof, is present in the composition. 29. The pharmaceutical composition of claim 25, wherein not more than about 0.5 wt % meta-hydroxybenzylguanidine (MHBG):
or a pharmaceutically acceptable salt thereof, is present in the composition. 30. The pharmaceutical composition of claim 25, wherein not more than about 0.5 wt % meta-iodobenzylamine (MIBA), meta-iodobenzylbiguanidine (MIBBG), and/or meta-hydroxybenzylguanidine (MHBG):
or pharmaceutically acceptable salts of any thereof, is present in the composition. 31. A pharmaceutical composition comprising:
a compound of formula (VI):
or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle;
wherein R1 is a radioisotopic label;
the pharmaceutical composition comprising leachable tin at a level of 0 ppm to 150 ppm. 32. A pharmaceutical composition comprising:
meta-iodobenzylguanidine (MIBG):
or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle;
the pharmaceutical composition comprising leachable tin at a level of 0 ppm to 150 ppm. 33. A method for preparing a purified composition of a polymer comprising monomer of formula (I):
or a pharmaceutically acceptable salt thereof, the method comprising the steps of:
solvent-treating a preparation comprising the polymer or pharmaceutically acceptable salt thereof, by contacting the preparation with a solvent, and then removing substantially all of the solvent so that a solvent-depleted material comprising the polymer, or pharmaceutically acceptable salt thereof, is generated; and
subjecting the solvent-depleted material to vacuum, and to a temperature within a range of about 30° C. to about 50° C.,
the subjecting being performed under conditions and for a time sufficient so that not more than about 150 ppm of leachable tin is present and, therefore, a purified composition of the polymer, or pharmaceutically acceptable salt thereof, has been produced. 34. The method of claim 33, wherein the solvent is or comprises an alcohol. 35. The method of claim 34, wherein the alcohol is or comprises ethanol. 36. The method of claim 33, wherein the step of solvent-treating the preparation comprises first and second solvent-treating steps, performed with first and second solvents, wherein the first solvent is an aqueous alcohol and the second solvent is an anhydrous alcohol. 37. The method of claim 36, wherein the first solvent is aqueous alcohol and the second solvent is anhydrous ethanol. 38. The method of claim 33, the purified composition comprising less than 1.5 wt % water relative to the wt % of the composition. 39. The method of claim 33, the purified composition comprising less than 1.0 wt % water relative to the wt % of the composition. 40. The method of claim 33, further comprising a step of: storing the purified composition under an inert gas. 41. A method for preparing meta-iodobenzylguanidine (MIBG):
or a pharmaceutically acceptable salt thereof, the method comprising steps of:
contacting an iodide salt with a preparation comprising a polymer comprising monomer of formula (I):
or a pharmaceutically acceptable salt thereof, the preparation being substantially free of leachable tin such that leachable tin is present in the preparation at a level below 150 ppm. 42. The method of claim 41, wherein the step of contacting comprises contacting with a preparation as set forth in claim 2. 43. The method of claim 41, wherein the iodide salt is sodium 1-131 iodide. 44. A method comprising administering to a subject a pharmaceutical composition comprising:
(a) meta-iodobenzylguanidine (MIBG):
or a pharmaceutically acceptable salt thereof, wherein MIBG is formed by contacting an iodide salt with a preparation of a polymer comprising monomer of formula (I):
or a pharmaceutically acceptable salt thereof, the preparation of the polymer comprising monomer of formula (I) comprising leachable tin at a level of 0 ppm to 150 ppm;
(b) a pharmaceutically acceptable carrier, adjuvant, or vehicle. 45. The method of claim 44, wherein the pharmaceutical composition comprises leachable tin at a level of 0 ppm to 150 ppm upon administration. | The present disclosure provides purified forms of iobenguane and preparations of a precursor to iobenguane, such as a polymer, the polymer comprising a monomer of formula (I)
or a pharmaceutically acceptable salt thereof, the preparation comprising leachable tin at a level of 0 ppm to 850 ppm.1. A preparation comprising a polymer, the polymer comprising a monomer of formula (I):
or a pharmaceutically acceptable salt thereof, wherein leachable tin is present in the preparation at a level within a range of about 0 ppm to about 150 ppm. 2. The preparation of claim 1, wherein the pharmaceutically acceptable salt is the HOAc salt. 3. The preparation of claim 1, which preparation is enclosed in a container under inert gas. 4. The preparation of claim 3, wherein the inert gas is nitrogen. 5. The preparation of claim 1, wherein the level of leachable tin is within a range of about 0 ppm to about 120 ppm. 6. The preparation of claim 1, wherein the level of leachable tin is within a range of about 0 ppm to about 50 ppm. 7. The preparation of claim 1, wherein the polymer comprising monomer of formula (I), or the pharmaceutically acceptable salt thereof, makes up at least 98% of the preparation. 8. The preparation of claim 1, the preparation comprising less than 1.5 wt % water relative to the wt % of the preparation. 9. The preparation of claim 1, the preparation comprising less than 1.0 wt % water relative to the wt % of the preparation. 10. The preparation of claim 1, the preparation comprising less than 0.5 wt % organic solvent relative to the wt % of the preparation. 11. The preparation of claim 1, the polymer comprising less than about 0.5 wt % of a monomer of formula (IV):
or a pharmaceutically acceptable salt thereof. 12. The preparation of claim 1, the polymer comprising less than about 0.5 wt % of a monomer of formula (V):
or a pharmaceutically acceptable salt thereof. 13. A kit comprising a preparation, the preparation comprising a polymer comprising a monomer of formula (I):
or a pharmaceutically acceptable salt thereof, wherein leachable tin is present in the preparation at a level within a range of about 0 ppm to about 150 ppm, and the kit further comprising a container that stores the polymer comprising monomer of formula (I) under inert gas. 14. The kit of claim 13, comprising any one of the preparations of claims 2-12. 15. The kit of claim 13, wherein the purified polymer comprising monomer of formula (I), or salt thereof, is least 98 wt % pure, for at least six months at −20° C. 16. The kit of claim 13, wherein the kit maintains leachable tin content at a level of less than 150 ppm for at least six months at −20° C. 17. The kit of claim 13, wherein the kit maintains leachable tin content at a level of less than 20 ppm for at least nine months at −20° C. 18. The kit of claim 13, comprising less than 1.5 wt % water relative to the wt % of the preparation. 19. The kit of claim 13, comprising less than 1.0 wt % water relative to the wt % of the preparation. 20. A pharmaceutical composition comprising:
(a) a compound of formula (VI):
or pharmaceutically acceptable salts thereof,
wherein R1 is a radioisotopic label, and
the compound of formula (VI) is formed by contacting a radioisotope of a halogen ion with a preparation of a polymer comprising monomer of formula (I):
or a pharmaceutically acceptable salt thereof, the preparation of the polymer comprising monomer of formula (I) comprising leachable tin at a level of 0 ppm to 150 ppm; and
(b) a pharmaceutically acceptable carrier, adjuvant, or vehicle. 21. The pharmaceutical composition of claim 20, comprising the preparation of claim 2. 22. The pharmaceutical composition of claim 20, wherein the radioisotope of a halogen ion is fluoride, bromide, iodide or astatine. 23. The pharmaceutical composition of claim 20, wherein the radioisotope of a halogen ion is 123I, 124I, 125I or 131I. 24. The pharmaceutical composition of claim 20, wherein the radioisotope of a halogen ion is 211At. 25. A pharmaceutical composition comprising:
(a) meta-iodobenzylguanidine (MIBG):
or a pharmaceutically acceptable salt thereof, wherein MIBG is formed by contacting an iodide salt with a preparation of a polymer comprising monomer of formula (I):
or a pharmaceutically acceptable salt thereof, the preparation of the polymer comprising monomer of formula (I) comprising leachable tin at a level of 0 ppm to 150 ppm; and
(b) a pharmaceutically acceptable carrier, adjuvant, or vehicle. 26. The pharmaceutical composition of claim 25, comprising the preparation of claim 2. 27. The pharmaceutical composition of claim 25, wherein not more than about 0.5 wt % meta-iodobenzylamine (MIBA):
or a pharmaceutically acceptable salt thereof, is present in the composition. 28. The pharmaceutical composition of claim 25, wherein not more than about 0.5 wt % meta-iodobenzylbiguanidine (MIBBG):
or a pharmaceutically acceptable salt thereof, is present in the composition. 29. The pharmaceutical composition of claim 25, wherein not more than about 0.5 wt % meta-hydroxybenzylguanidine (MHBG):
or a pharmaceutically acceptable salt thereof, is present in the composition. 30. The pharmaceutical composition of claim 25, wherein not more than about 0.5 wt % meta-iodobenzylamine (MIBA), meta-iodobenzylbiguanidine (MIBBG), and/or meta-hydroxybenzylguanidine (MHBG):
or pharmaceutically acceptable salts of any thereof, is present in the composition. 31. A pharmaceutical composition comprising:
a compound of formula (VI):
or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle;
wherein R1 is a radioisotopic label;
the pharmaceutical composition comprising leachable tin at a level of 0 ppm to 150 ppm. 32. A pharmaceutical composition comprising:
meta-iodobenzylguanidine (MIBG):
or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle;
the pharmaceutical composition comprising leachable tin at a level of 0 ppm to 150 ppm. 33. A method for preparing a purified composition of a polymer comprising monomer of formula (I):
or a pharmaceutically acceptable salt thereof, the method comprising the steps of:
solvent-treating a preparation comprising the polymer or pharmaceutically acceptable salt thereof, by contacting the preparation with a solvent, and then removing substantially all of the solvent so that a solvent-depleted material comprising the polymer, or pharmaceutically acceptable salt thereof, is generated; and
subjecting the solvent-depleted material to vacuum, and to a temperature within a range of about 30° C. to about 50° C.,
the subjecting being performed under conditions and for a time sufficient so that not more than about 150 ppm of leachable tin is present and, therefore, a purified composition of the polymer, or pharmaceutically acceptable salt thereof, has been produced. 34. The method of claim 33, wherein the solvent is or comprises an alcohol. 35. The method of claim 34, wherein the alcohol is or comprises ethanol. 36. The method of claim 33, wherein the step of solvent-treating the preparation comprises first and second solvent-treating steps, performed with first and second solvents, wherein the first solvent is an aqueous alcohol and the second solvent is an anhydrous alcohol. 37. The method of claim 36, wherein the first solvent is aqueous alcohol and the second solvent is anhydrous ethanol. 38. The method of claim 33, the purified composition comprising less than 1.5 wt % water relative to the wt % of the composition. 39. The method of claim 33, the purified composition comprising less than 1.0 wt % water relative to the wt % of the composition. 40. The method of claim 33, further comprising a step of: storing the purified composition under an inert gas. 41. A method for preparing meta-iodobenzylguanidine (MIBG):
or a pharmaceutically acceptable salt thereof, the method comprising steps of:
contacting an iodide salt with a preparation comprising a polymer comprising monomer of formula (I):
or a pharmaceutically acceptable salt thereof, the preparation being substantially free of leachable tin such that leachable tin is present in the preparation at a level below 150 ppm. 42. The method of claim 41, wherein the step of contacting comprises contacting with a preparation as set forth in claim 2. 43. The method of claim 41, wherein the iodide salt is sodium 1-131 iodide. 44. A method comprising administering to a subject a pharmaceutical composition comprising:
(a) meta-iodobenzylguanidine (MIBG):
or a pharmaceutically acceptable salt thereof, wherein MIBG is formed by contacting an iodide salt with a preparation of a polymer comprising monomer of formula (I):
or a pharmaceutically acceptable salt thereof, the preparation of the polymer comprising monomer of formula (I) comprising leachable tin at a level of 0 ppm to 150 ppm;
(b) a pharmaceutically acceptable carrier, adjuvant, or vehicle. 45. The method of claim 44, wherein the pharmaceutical composition comprises leachable tin at a level of 0 ppm to 150 ppm upon administration. | 1,600 |
820 | 14,846,290 | 1,631 | Systems and methods for genomic analysis are contemplated in which idiosyncratic markers or marker constellations are employed to characterize and compare genomic sequences. In especially preferred aspects, the idiosyncratic markers are predetermined SNPs and a marker profile is used in a sample record to so allow cross reference to other marker profiles of other sequences. | 1. A method of analyzing a genomic sequence of a target tissue of a mammal, comprising:
coupling an analysis engine to a sequence database that stores a genomic sequence for the target tissue of the mammal; characterizing, by the analysis engine, a plurality of predetermined idiosyncratic markers in the genomic sequence of the target tissue, and generating an idiosyncratic marker profile using the characterized idiosyncratic markers; generating or updating, by the analysis engine, a first sample record for the target tissue using the idiosyncratic marker profile; comparing, by the analysis engine, the idiosyncratic marker profile in the first sample record with a second idiosyncratic marker profile in a second sample record to thereby generate a match score; and annotating the first sample record using the match score. 2. The method of claim 1 wherein the predetermined idiosyncratic markers are selected from the group consisting of SNPs, epigenetic modifications, numbers of repeats of repeat sequences, and numbers of bases between pairs of predetermined restriction endonuclease sites. 3. The method of claim 1 wherein the plurality of predetermined idiosyncratic markers includes between 100 and 10,000 predetermined idiosyncratic markers. 4. The method of claim 1 wherein the predetermined idiosyncratic markers are SNPs. 5. The method of claim 1 wherein the predetermined idiosyncratic markers are predetermined on the basis of their known position within the genomic sequence. 6. The method of claim 1 wherein the predetermined idiosyncratic markers are predetermined on the basis of random selection and wherein the random selection is agnostic or ignorant of a disease or condition associated with the marker. 7. The method of claim 1 wherein at least some of the predetermined idiosyncratic markers are associated with respective diseases or conditions, and wherein the diseases or conditions are unrelated diseases or conditions. 8. The method of claim 1 wherein the idiosyncratic marker profile does not include identification of a disease or condition associated with at least some of the characterized idiosyncratic markers. 9. The method of claim 1 wherein the idiosyncratic marker profile comprises nucleotide base information for the characterized idiosyncratic markers. 10. The method of claim 1 wherein the sample record has a VCF format. 11. The method of claim 1 wherein the sample record comprises the genomic sequence. 12. The method of claim 1 wherein the match score comprises an identity percentage value. 13. The method of claim 1 wherein the match score comprises a matching value to at least one of a prior sample obtained from the same mammal, a matching value to an idiosyncratic marker profile that is characteristic for an ethnic group, a matching value to an idiosyncratic marker profile that is characteristic for an age group, and a matching value to an idiosyncratic marker profile that is characteristic for a disease. 14. The method of claim 1 wherein the genomic sequence for the target tissue of the mammal covers at least one chromosome of the mammal. 15. The method of claim 1 wherein the genomic sequence for the target tissue of the mammal covers at least 70% of the genome of the mammal. 16. The method of claim 1 wherein the target tissue of the mammal is a diseased tissue, and wherein the second sample record is obtained from a second sample of the mammal. 17. The method of claim 16 wherein the second sample of the mammal is from a non-diseased tissue of the mammal. 18. A method of selecting a genomic sequence in a sequence database, comprising:
coupling an analysis engine to a sequence database that stores for an individual a first genomic sequence and an associated first idiosyncratic marker profile; wherein the first idiosyncratic marker profile is based on characteristics for a plurality of predetermined idiosyncratic markers in the first genomic sequence of the individual; selecting, by the analysis engine, a second genomic sequence having an associated second idiosyncratic marker profile; and wherein the step of selecting uses the first and second idiosyncratic marker profiles and a desired match score between the first idiosyncratic marker profile and the second idiosyncratic marker profile. 19. The method of claim 18 wherein the predetermined idiosyncratic markers are selected from the group consisting of SNPs, epigenetic modifications, numbers of repeats of repeat sequences, and numbers of bases between pairs of predetermined restriction endonuclease sites. 20. The method of claim 18 wherein the plurality of predetermined idiosyncratic markers includes between 100 and 10,000 predetermined idiosyncratic markers. 21. The method of claim 18 wherein the idiosyncratic marker profile is in a bit string form. 22. The method of claim 18 wherein the desired match score is based on exclusive disjunction determination. 23. The method of claim 18 wherein the desired match score is a user-defined cut-off score for difference between the first and second genomic sequences. 24. The method of claim 18 wherein the second genomic sequence having the associated second idiosyncratic marker profile is derived from a second individual. 25. The method of claim 18 wherein the second genomic sequence having an associated second idiosyncratic marker profile is retrieved from the sequence data base. 26. A system for analysis of a genomic sequence of a target tissue of a mammal, comprising:
an analysis engine coupled to a sequence database that stores a genomic sequence for the target tissue of the mammal; wherein the analysis engine is configured to characterize a plurality of predetermined idiosyncratic markers in the genomic sequence of the target tissue, and to generate an idiosyncratic marker profile using the characterized idiosyncratic markers; generate or update a first sample record for the target tissue using the idiosyncratic marker profile; compare the idiosyncratic marker profile in the first sample record with a second idiosyncratic marker profile in a second sample record to thereby generate a match score; and annotate the first sample record using the match score. 27. The system of claim 26 wherein the predetermined idiosyncratic markers are selected from the group consisting of SNPs, epigenetic modifications, numbers of repeats of repeat sequences, and numbers of bases between pairs of predetermined restriction endonuclease sites. 28. The system of claim 26 wherein the plurality of predetermined idiosyncratic markers includes between 100 and 10,000 predetermined idiosyncratic markers. 29. The system of claim 26 wherein the predetermined idiosyncratic markers are SNPs. 30. The system of claim 26 wherein the predetermined idiosyncratic markers are predetermined on the basis of their known position within the genomic sequence. 31. The system of claim 26 wherein the predetermined idiosyncratic markers are predetermined on the basis of random selection and wherein the random selection is agnostic or ignorant of a disease or condition associated with the marker. 32. The system of claim 26 wherein at least some of the predetermined idiosyncratic markers are associated with respective diseases or conditions, and wherein the diseases or conditions are unrelated diseases or conditions. 33. The system of claim 26 wherein the idiosyncratic marker profile comprises nucleotide base information for the characterized idiosyncratic markers. 34. The system of claim 26 wherein the sample record has a VCF format. 35. The system of claim 26 wherein the sample record comprises the genomic sequence. 36. The system of claim 26 wherein the match score comprises an identity percentage value. 37. The system of claim 26 wherein the match score comprises a matching value to at least one of a prior sample obtained from the same mammal, a matching value to an idiosyncratic marker profile that is characteristic for an ethnic group, a matching value to an idiosyncratic marker profile that is characteristic for an age group, and a matching value to an idiosyncratic marker profile that is characteristic for a disease. 38. The system of claim 26 wherein the genomic sequence for the target tissue of the mammal covers at least one chromosome of the mammal. 39. A method of analyzing genomic information to determine sex of a individual, comprising:
coupling an analysis engine to a sequence database that stores a genomic sequence for the individual; determining, by the analysis engine, zygosity for at least one allele located on at least an X-chromosome to thereby produce a zygosity profile for the allele; deriving, by the analysis engine, a sex determination using the zygosity profile for the allele; and annotating the genomic information with the sex determination. 40. The method of claim 39 wherein the zygosity is additionally determined for at least one other allele on an Y-chromosome. 41. The method of claim 39 wherein the determination includes determination of aneuploidy for sex chromosomes. | Systems and methods for genomic analysis are contemplated in which idiosyncratic markers or marker constellations are employed to characterize and compare genomic sequences. In especially preferred aspects, the idiosyncratic markers are predetermined SNPs and a marker profile is used in a sample record to so allow cross reference to other marker profiles of other sequences.1. A method of analyzing a genomic sequence of a target tissue of a mammal, comprising:
coupling an analysis engine to a sequence database that stores a genomic sequence for the target tissue of the mammal; characterizing, by the analysis engine, a plurality of predetermined idiosyncratic markers in the genomic sequence of the target tissue, and generating an idiosyncratic marker profile using the characterized idiosyncratic markers; generating or updating, by the analysis engine, a first sample record for the target tissue using the idiosyncratic marker profile; comparing, by the analysis engine, the idiosyncratic marker profile in the first sample record with a second idiosyncratic marker profile in a second sample record to thereby generate a match score; and annotating the first sample record using the match score. 2. The method of claim 1 wherein the predetermined idiosyncratic markers are selected from the group consisting of SNPs, epigenetic modifications, numbers of repeats of repeat sequences, and numbers of bases between pairs of predetermined restriction endonuclease sites. 3. The method of claim 1 wherein the plurality of predetermined idiosyncratic markers includes between 100 and 10,000 predetermined idiosyncratic markers. 4. The method of claim 1 wherein the predetermined idiosyncratic markers are SNPs. 5. The method of claim 1 wherein the predetermined idiosyncratic markers are predetermined on the basis of their known position within the genomic sequence. 6. The method of claim 1 wherein the predetermined idiosyncratic markers are predetermined on the basis of random selection and wherein the random selection is agnostic or ignorant of a disease or condition associated with the marker. 7. The method of claim 1 wherein at least some of the predetermined idiosyncratic markers are associated with respective diseases or conditions, and wherein the diseases or conditions are unrelated diseases or conditions. 8. The method of claim 1 wherein the idiosyncratic marker profile does not include identification of a disease or condition associated with at least some of the characterized idiosyncratic markers. 9. The method of claim 1 wherein the idiosyncratic marker profile comprises nucleotide base information for the characterized idiosyncratic markers. 10. The method of claim 1 wherein the sample record has a VCF format. 11. The method of claim 1 wherein the sample record comprises the genomic sequence. 12. The method of claim 1 wherein the match score comprises an identity percentage value. 13. The method of claim 1 wherein the match score comprises a matching value to at least one of a prior sample obtained from the same mammal, a matching value to an idiosyncratic marker profile that is characteristic for an ethnic group, a matching value to an idiosyncratic marker profile that is characteristic for an age group, and a matching value to an idiosyncratic marker profile that is characteristic for a disease. 14. The method of claim 1 wherein the genomic sequence for the target tissue of the mammal covers at least one chromosome of the mammal. 15. The method of claim 1 wherein the genomic sequence for the target tissue of the mammal covers at least 70% of the genome of the mammal. 16. The method of claim 1 wherein the target tissue of the mammal is a diseased tissue, and wherein the second sample record is obtained from a second sample of the mammal. 17. The method of claim 16 wherein the second sample of the mammal is from a non-diseased tissue of the mammal. 18. A method of selecting a genomic sequence in a sequence database, comprising:
coupling an analysis engine to a sequence database that stores for an individual a first genomic sequence and an associated first idiosyncratic marker profile; wherein the first idiosyncratic marker profile is based on characteristics for a plurality of predetermined idiosyncratic markers in the first genomic sequence of the individual; selecting, by the analysis engine, a second genomic sequence having an associated second idiosyncratic marker profile; and wherein the step of selecting uses the first and second idiosyncratic marker profiles and a desired match score between the first idiosyncratic marker profile and the second idiosyncratic marker profile. 19. The method of claim 18 wherein the predetermined idiosyncratic markers are selected from the group consisting of SNPs, epigenetic modifications, numbers of repeats of repeat sequences, and numbers of bases between pairs of predetermined restriction endonuclease sites. 20. The method of claim 18 wherein the plurality of predetermined idiosyncratic markers includes between 100 and 10,000 predetermined idiosyncratic markers. 21. The method of claim 18 wherein the idiosyncratic marker profile is in a bit string form. 22. The method of claim 18 wherein the desired match score is based on exclusive disjunction determination. 23. The method of claim 18 wherein the desired match score is a user-defined cut-off score for difference between the first and second genomic sequences. 24. The method of claim 18 wherein the second genomic sequence having the associated second idiosyncratic marker profile is derived from a second individual. 25. The method of claim 18 wherein the second genomic sequence having an associated second idiosyncratic marker profile is retrieved from the sequence data base. 26. A system for analysis of a genomic sequence of a target tissue of a mammal, comprising:
an analysis engine coupled to a sequence database that stores a genomic sequence for the target tissue of the mammal; wherein the analysis engine is configured to characterize a plurality of predetermined idiosyncratic markers in the genomic sequence of the target tissue, and to generate an idiosyncratic marker profile using the characterized idiosyncratic markers; generate or update a first sample record for the target tissue using the idiosyncratic marker profile; compare the idiosyncratic marker profile in the first sample record with a second idiosyncratic marker profile in a second sample record to thereby generate a match score; and annotate the first sample record using the match score. 27. The system of claim 26 wherein the predetermined idiosyncratic markers are selected from the group consisting of SNPs, epigenetic modifications, numbers of repeats of repeat sequences, and numbers of bases between pairs of predetermined restriction endonuclease sites. 28. The system of claim 26 wherein the plurality of predetermined idiosyncratic markers includes between 100 and 10,000 predetermined idiosyncratic markers. 29. The system of claim 26 wherein the predetermined idiosyncratic markers are SNPs. 30. The system of claim 26 wherein the predetermined idiosyncratic markers are predetermined on the basis of their known position within the genomic sequence. 31. The system of claim 26 wherein the predetermined idiosyncratic markers are predetermined on the basis of random selection and wherein the random selection is agnostic or ignorant of a disease or condition associated with the marker. 32. The system of claim 26 wherein at least some of the predetermined idiosyncratic markers are associated with respective diseases or conditions, and wherein the diseases or conditions are unrelated diseases or conditions. 33. The system of claim 26 wherein the idiosyncratic marker profile comprises nucleotide base information for the characterized idiosyncratic markers. 34. The system of claim 26 wherein the sample record has a VCF format. 35. The system of claim 26 wherein the sample record comprises the genomic sequence. 36. The system of claim 26 wherein the match score comprises an identity percentage value. 37. The system of claim 26 wherein the match score comprises a matching value to at least one of a prior sample obtained from the same mammal, a matching value to an idiosyncratic marker profile that is characteristic for an ethnic group, a matching value to an idiosyncratic marker profile that is characteristic for an age group, and a matching value to an idiosyncratic marker profile that is characteristic for a disease. 38. The system of claim 26 wherein the genomic sequence for the target tissue of the mammal covers at least one chromosome of the mammal. 39. A method of analyzing genomic information to determine sex of a individual, comprising:
coupling an analysis engine to a sequence database that stores a genomic sequence for the individual; determining, by the analysis engine, zygosity for at least one allele located on at least an X-chromosome to thereby produce a zygosity profile for the allele; deriving, by the analysis engine, a sex determination using the zygosity profile for the allele; and annotating the genomic information with the sex determination. 40. The method of claim 39 wherein the zygosity is additionally determined for at least one other allele on an Y-chromosome. 41. The method of claim 39 wherein the determination includes determination of aneuploidy for sex chromosomes. | 1,600 |
821 | 14,905,990 | 1,619 | The present invention belongs to the field of pharmaceutical industry and relates to an amorphous solid dispersion comprising at least one polymer and dapagliflozin, to a pharmaceutical composition comprising said solid dispersion, to a process for the preparation thereof, and to the solid dispersion and pharmaceutical composition respectively obtainable by said process. Further, the present invention refers to an adsorbate comprising dapagliflozin and to a pharmaceutical composition comprising said adsorbate, as well as to a process for the preparation thereof. Finally, the present invention relates to the solid dispersion, the adsorbate or the pharmaceutical composition for use in the treatment of diseases related to hypoglycemia. | 1. Amorphous solid dispersion of at least one suitable polymer and dapagliflozin ((2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol) of formula 1
wherein the at least one polymer is selected from the group consisting of polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyacrylic acid (PAA), poly(ethylene glycol) (PEG), poly(ethylene oxide) (PEO), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), copovidone, hypromellose acetate succinate (AQOAT), polyacrylates, and mixtures thereof. 2. The solid dispersion according to claim 1, wherein the weight ratio of dapagliflozin and the at least one polymer is from 1:10 to 10:1. 3. The solid dispersion according to claim 1, wherein the dapagliflozin is stable in the amorphous state upon storage, optionally upon storage under stress conditions. 4. Pharmaceutical composition comprising the solid dispersion according to claim 1 and one or more pharmaceutically excipients selected from the group consisting of fillers, disintegrants, binders, lubricants, and surfactants, wherein the pharmaceutical composition comprises dapagliflozin as the sole pharmaceutically active ingredient. 5. Process for the preparation of the solid dispersion according to claim 1, comprising:
a) providing a solution of dapagliflozin and at least one suitable polymer in a suitable solvent or mixture of solvents; b) optionally spraying or dispersing the solution of step (a) onto a carrier to form granules; c) evaporating the solvent, thereby resulting in the formation of solid dispersion; and d) optionally blending the obtained solid dispersion of steps b) or c) with one or more pharmaceutically acceptable excipients. 6. Process for the preparation of a pharmaceutical composition, wherein dapagliflozin is present in the pharmaceutical composition only as amorphous dapagliflozin, comprising:
a) providing a solution of dapagliflozin of formula 1
and optionally at least one suitable polymer in a suitable solvent or mixture of solvents;
b) optionally spraying or dispersing the solution of step (a) onto carrier particles to form granules;
c) evaporating the solvent; and
d) blending the obtained composition of steps b) or c) with one or more pharmaceutically acceptable excipients. 7. Process according to claim 5, wherein the process is carried out in the absence of pharmaceutically active ingredients other than dapagliflozin. 8. Solid dispersion or pharmaceutical composition obtainable by the process according to claim 6. 9. Adsorbate comprising dapagliflozin ((2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol) of formula 1 adsorbed onto the surface of a substrate
wherein dapagliflozin is substantially amorphous and wherein the substrate is selected from the group consisting of
(a) an inorganic oxide;
(b) water insoluble inorganic salt;
(c) water insoluble polymer; and
(d) an activated carbon. 10. The adsorbate according to claim 9, wherein the substrate is selected from the group consisting of silicon dioxide and microcrystalline cellulose. 11. The adsorbate according to claim 9, wherein the dapagliflozin is stable in the amorphous state upon storage, optionally upon storage under stress conditions. 12. Process for the preparation of an adsorbate according to claim 9, comprising:
a) combining a solution of dapagliflozin of formula 1
in a solvent or mixture of solvents with a substrate;
b) removing the solvent or mixture of solvents under reduced pressure to form the adsorbate. 13. Process for the preparation of a pharmaceutical composition comprising an adsorbate as defined in claim 9, comprising:
a) providing a mixture of the adsorbate, and at least one pharmaceutically acceptable excipient; b) optionally fine-milling and/or sieving the mixture obtained in step a); c) formulation of the mixture of step a) or b) into a pharmaceutical composition by dry formulation. 14. Pharmaceutical composition comprising the adsorbate as defined claim 10, and one or more pharmaceutically excipients selected from the group consisting of fillers, disintegrants, binders, lubricants, and surfactants. 15. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition is a compressed dosage form. 16. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition is to be administered to patients in a country having an area with an Af or an Am climate, according to the Köppen-Geiger climate classification. 17. The pharmaceutical composition according to claim 4, wherein said pharmaceutical composition is packaged in a packaging material having a moisture vapour transmission rate of at least 0.4 g m−2 d−1 as measured according to standard DIN 53122-1. 18. The pharmaceutical composition according to claim 4, wherein the content uniformity, indicated in terms of acceptance value (AV) as defined by the legend of Table 2, of said pharmaceutical composition being packaged in a packaging material such as a blister containing N tablets is below 15. 19. The pharmaceutical composition according to claim 4, wherein, when carrying out dissolution testing, at a time point of 5 minutes more than 80%, of the dapagliflozin is dissolved, wherein the dissolution testing is carried out by applying the following parameters: 500 ml of dissolution medium 0.1 M HCl, Apparatus 2 at 50 rpm, peak vessel, 37° C. 20. Solid dispersion, adsorbate or pharmaceutical composition according to claim 1 for use in the treatment of diseases related to hypoglycemia. | The present invention belongs to the field of pharmaceutical industry and relates to an amorphous solid dispersion comprising at least one polymer and dapagliflozin, to a pharmaceutical composition comprising said solid dispersion, to a process for the preparation thereof, and to the solid dispersion and pharmaceutical composition respectively obtainable by said process. Further, the present invention refers to an adsorbate comprising dapagliflozin and to a pharmaceutical composition comprising said adsorbate, as well as to a process for the preparation thereof. Finally, the present invention relates to the solid dispersion, the adsorbate or the pharmaceutical composition for use in the treatment of diseases related to hypoglycemia.1. Amorphous solid dispersion of at least one suitable polymer and dapagliflozin ((2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol) of formula 1
wherein the at least one polymer is selected from the group consisting of polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyacrylic acid (PAA), poly(ethylene glycol) (PEG), poly(ethylene oxide) (PEO), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), copovidone, hypromellose acetate succinate (AQOAT), polyacrylates, and mixtures thereof. 2. The solid dispersion according to claim 1, wherein the weight ratio of dapagliflozin and the at least one polymer is from 1:10 to 10:1. 3. The solid dispersion according to claim 1, wherein the dapagliflozin is stable in the amorphous state upon storage, optionally upon storage under stress conditions. 4. Pharmaceutical composition comprising the solid dispersion according to claim 1 and one or more pharmaceutically excipients selected from the group consisting of fillers, disintegrants, binders, lubricants, and surfactants, wherein the pharmaceutical composition comprises dapagliflozin as the sole pharmaceutically active ingredient. 5. Process for the preparation of the solid dispersion according to claim 1, comprising:
a) providing a solution of dapagliflozin and at least one suitable polymer in a suitable solvent or mixture of solvents; b) optionally spraying or dispersing the solution of step (a) onto a carrier to form granules; c) evaporating the solvent, thereby resulting in the formation of solid dispersion; and d) optionally blending the obtained solid dispersion of steps b) or c) with one or more pharmaceutically acceptable excipients. 6. Process for the preparation of a pharmaceutical composition, wherein dapagliflozin is present in the pharmaceutical composition only as amorphous dapagliflozin, comprising:
a) providing a solution of dapagliflozin of formula 1
and optionally at least one suitable polymer in a suitable solvent or mixture of solvents;
b) optionally spraying or dispersing the solution of step (a) onto carrier particles to form granules;
c) evaporating the solvent; and
d) blending the obtained composition of steps b) or c) with one or more pharmaceutically acceptable excipients. 7. Process according to claim 5, wherein the process is carried out in the absence of pharmaceutically active ingredients other than dapagliflozin. 8. Solid dispersion or pharmaceutical composition obtainable by the process according to claim 6. 9. Adsorbate comprising dapagliflozin ((2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol) of formula 1 adsorbed onto the surface of a substrate
wherein dapagliflozin is substantially amorphous and wherein the substrate is selected from the group consisting of
(a) an inorganic oxide;
(b) water insoluble inorganic salt;
(c) water insoluble polymer; and
(d) an activated carbon. 10. The adsorbate according to claim 9, wherein the substrate is selected from the group consisting of silicon dioxide and microcrystalline cellulose. 11. The adsorbate according to claim 9, wherein the dapagliflozin is stable in the amorphous state upon storage, optionally upon storage under stress conditions. 12. Process for the preparation of an adsorbate according to claim 9, comprising:
a) combining a solution of dapagliflozin of formula 1
in a solvent or mixture of solvents with a substrate;
b) removing the solvent or mixture of solvents under reduced pressure to form the adsorbate. 13. Process for the preparation of a pharmaceutical composition comprising an adsorbate as defined in claim 9, comprising:
a) providing a mixture of the adsorbate, and at least one pharmaceutically acceptable excipient; b) optionally fine-milling and/or sieving the mixture obtained in step a); c) formulation of the mixture of step a) or b) into a pharmaceutical composition by dry formulation. 14. Pharmaceutical composition comprising the adsorbate as defined claim 10, and one or more pharmaceutically excipients selected from the group consisting of fillers, disintegrants, binders, lubricants, and surfactants. 15. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition is a compressed dosage form. 16. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition is to be administered to patients in a country having an area with an Af or an Am climate, according to the Köppen-Geiger climate classification. 17. The pharmaceutical composition according to claim 4, wherein said pharmaceutical composition is packaged in a packaging material having a moisture vapour transmission rate of at least 0.4 g m−2 d−1 as measured according to standard DIN 53122-1. 18. The pharmaceutical composition according to claim 4, wherein the content uniformity, indicated in terms of acceptance value (AV) as defined by the legend of Table 2, of said pharmaceutical composition being packaged in a packaging material such as a blister containing N tablets is below 15. 19. The pharmaceutical composition according to claim 4, wherein, when carrying out dissolution testing, at a time point of 5 minutes more than 80%, of the dapagliflozin is dissolved, wherein the dissolution testing is carried out by applying the following parameters: 500 ml of dissolution medium 0.1 M HCl, Apparatus 2 at 50 rpm, peak vessel, 37° C. 20. Solid dispersion, adsorbate or pharmaceutical composition according to claim 1 for use in the treatment of diseases related to hypoglycemia. | 1,600 |
822 | 15,283,751 | 1,615 | Provided herein are portable application devices and compositions for nasal and oral delivery of substances and compositions to treat overdose, addiction and/or behavioral disordered persons. | 1. A pharmaceutical formulation in the form of liquid solution for spray administration by the nasal and/or buccal route containing naltrexone and/or nalmefene as the active ingredient in amounts greater than 1% effective to block and/or reverse physiological effects of mixtures of opiates and opioids, including heroin and fentanyl and/or one or more fentanyl analogs. 2. Formulation according to claim 1, characterized in that the naltrexone and/or nalmefene is in an amount of about between 3-5 mg/injection. 3. Formulations according to claim 1, wherein said liquid solutions are aqueous or aqueous-alcoholic solutions. 4. Formulations according to claim 1, wherein said formulations also comprise a buffer selected from the group consisting of: citric acid/sodium citrate, citric acid/sodium hydroxide, dibasic sodium phosphate, citric acid, dibasic sodium phosphate/monobasic potassium phosphate, and acetic acid/sodium acetate buffer. 5. Formulations according to claim 4 additionally containing: antimicrobial preservatives, agents that increase the tonicity and agents that increase the viscosity of the solution. 6. Method for the administration of a formulation according to claim 1, characterized in that said formulations are administered in the form of spray. 7. A portable spray application device containing the formulation of claim 1 to treat substance addicted and/or behavioral disordered persons. 8. (canceled) 9. A portable spray application device containing the formulation of claim 1 for delivery of naltrexone and/or nalmefene in treatment of potential opioid overdose. 10. The device of claim 1 for treatment of potential respiratory failure. 11. The device of claim 2 for treatment of potential respiratory failure. 12. The device of claim 3 for treatment of potential respiratory failure, 13. The device of claim 4 for treatment of potential respiratory failure. 14. The device of claim 5 for treatment of potential respiratory failure. 15. The device of claim 6 for treatment of potential respiratory failure. 16. The device of claim 7 for treatment of potential respiratory failure. 17. The device of claim 8 for treatment of potential respiratory failure. 18. The device of claim 9 for treatment of potential respiratory failure. | Provided herein are portable application devices and compositions for nasal and oral delivery of substances and compositions to treat overdose, addiction and/or behavioral disordered persons.1. A pharmaceutical formulation in the form of liquid solution for spray administration by the nasal and/or buccal route containing naltrexone and/or nalmefene as the active ingredient in amounts greater than 1% effective to block and/or reverse physiological effects of mixtures of opiates and opioids, including heroin and fentanyl and/or one or more fentanyl analogs. 2. Formulation according to claim 1, characterized in that the naltrexone and/or nalmefene is in an amount of about between 3-5 mg/injection. 3. Formulations according to claim 1, wherein said liquid solutions are aqueous or aqueous-alcoholic solutions. 4. Formulations according to claim 1, wherein said formulations also comprise a buffer selected from the group consisting of: citric acid/sodium citrate, citric acid/sodium hydroxide, dibasic sodium phosphate, citric acid, dibasic sodium phosphate/monobasic potassium phosphate, and acetic acid/sodium acetate buffer. 5. Formulations according to claim 4 additionally containing: antimicrobial preservatives, agents that increase the tonicity and agents that increase the viscosity of the solution. 6. Method for the administration of a formulation according to claim 1, characterized in that said formulations are administered in the form of spray. 7. A portable spray application device containing the formulation of claim 1 to treat substance addicted and/or behavioral disordered persons. 8. (canceled) 9. A portable spray application device containing the formulation of claim 1 for delivery of naltrexone and/or nalmefene in treatment of potential opioid overdose. 10. The device of claim 1 for treatment of potential respiratory failure. 11. The device of claim 2 for treatment of potential respiratory failure. 12. The device of claim 3 for treatment of potential respiratory failure, 13. The device of claim 4 for treatment of potential respiratory failure. 14. The device of claim 5 for treatment of potential respiratory failure. 15. The device of claim 6 for treatment of potential respiratory failure. 16. The device of claim 7 for treatment of potential respiratory failure. 17. The device of claim 8 for treatment of potential respiratory failure. 18. The device of claim 9 for treatment of potential respiratory failure. | 1,600 |
823 | 14,766,913 | 1,644 | The present invention relates to particulate entity, such as a nanoparticle or conjugate, for use in particular as adjuvant in vaccine or immunotherapy. More specifically, the invention relates to a particulate entity comprising: iv. an iNKT cell agonist such as α Gal Car compound, and, v. one or more antigenic determinant(s) such as a tumour antigen(s) or pathogen-derived antigen(s), vi. a targeting agent that targets in vivo said iNKT cell agonist to dendritic cells, such as human BDCA3+ dendritic cells. | 1. A particulate entity comprising:
i. an invariant Natural Killer T (iNKT) cell agonist, ii. optionally, one or more antigenic determinant(s), and, iii. a targeting agent that targets in vivo said iNKT cell agonist, to dendritic cells. 2. The particulate entity of claim 1, wherein said targeting agent targets said iNKT cell agonist to human BDCA3+ cells. 3. The particulate entity of claim 1, wherein said particulate entity is a nanoparticle having a size between 10 to 2000 nm diameter. 4. The particulate entity of claim 3, which is a nanoparticle comprising a core containing polymers and a coating, wherein said targeting agent is covalently linked to the surface of the coating. 5. The particulate entity of claim 4, wherein said core comprises poly(lactic acid), poly(glycolic acid), or their co-polymers. 6. The particulate entity of claim 1, wherein said particulate entity is a conjugate consisting of said iNKT agonist covalently linked to the targeting agent, optionally via a linker. 7. The particulate entity of claim 1, wherein said iNKT agonist is α-galactosylceramide or its functional derivatives. 8. The particulate entity of claim 1, wherein said targeting agent comprises a binding molecule that specifically binds to a cell surface marker of human BDCA-3+ dendritic cells. 9. The particulate entity of claim 8, wherein said cell surface marker of BDCA-3+ dendritic cells is selected from the group consisting of XCR-1 and CLEC9A. 10. The particulate entity of claim 8, wherein said binding molecule is an antibody that binds specifically to at least one of the cell surface marker of human BDCA-3+ dendritic cells. 11. The particulate entity according to claim 1, further comprising one or more antigenic determinant(s). 12. The particulate entity of claim 11, wherein said one or more antigenic determinant(s) is specific for an infectious agent, a pathogen, a fungal cell, a bacterial cell, a viral particle or a tumor cell. 13. A pharmaceutical composition, comprising a particulate entity according to claim 1, and one or more physiologically acceptable excipients. 14. (canceled) 15. The particulate entity of claim 1, wherein said particulate entity does not comprise CD1d molecule. 16. A vaccine composition comprising a particulate entity according to claim 1 as an adjuvant and one or more antigenic determinants. 17. A method for treating a tumor in a subject in need thereof, comprising administering a therapeutically efficient amount of a particulate entity of claim 1 in said subject. 18. A method for treating autoimmune and inflammatory disorders in a subject in need thereof, comprising administering a therapeutically efficient amount of a particulate entity of claim 1 in said subject. | The present invention relates to particulate entity, such as a nanoparticle or conjugate, for use in particular as adjuvant in vaccine or immunotherapy. More specifically, the invention relates to a particulate entity comprising: iv. an iNKT cell agonist such as α Gal Car compound, and, v. one or more antigenic determinant(s) such as a tumour antigen(s) or pathogen-derived antigen(s), vi. a targeting agent that targets in vivo said iNKT cell agonist to dendritic cells, such as human BDCA3+ dendritic cells.1. A particulate entity comprising:
i. an invariant Natural Killer T (iNKT) cell agonist, ii. optionally, one or more antigenic determinant(s), and, iii. a targeting agent that targets in vivo said iNKT cell agonist, to dendritic cells. 2. The particulate entity of claim 1, wherein said targeting agent targets said iNKT cell agonist to human BDCA3+ cells. 3. The particulate entity of claim 1, wherein said particulate entity is a nanoparticle having a size between 10 to 2000 nm diameter. 4. The particulate entity of claim 3, which is a nanoparticle comprising a core containing polymers and a coating, wherein said targeting agent is covalently linked to the surface of the coating. 5. The particulate entity of claim 4, wherein said core comprises poly(lactic acid), poly(glycolic acid), or their co-polymers. 6. The particulate entity of claim 1, wherein said particulate entity is a conjugate consisting of said iNKT agonist covalently linked to the targeting agent, optionally via a linker. 7. The particulate entity of claim 1, wherein said iNKT agonist is α-galactosylceramide or its functional derivatives. 8. The particulate entity of claim 1, wherein said targeting agent comprises a binding molecule that specifically binds to a cell surface marker of human BDCA-3+ dendritic cells. 9. The particulate entity of claim 8, wherein said cell surface marker of BDCA-3+ dendritic cells is selected from the group consisting of XCR-1 and CLEC9A. 10. The particulate entity of claim 8, wherein said binding molecule is an antibody that binds specifically to at least one of the cell surface marker of human BDCA-3+ dendritic cells. 11. The particulate entity according to claim 1, further comprising one or more antigenic determinant(s). 12. The particulate entity of claim 11, wherein said one or more antigenic determinant(s) is specific for an infectious agent, a pathogen, a fungal cell, a bacterial cell, a viral particle or a tumor cell. 13. A pharmaceutical composition, comprising a particulate entity according to claim 1, and one or more physiologically acceptable excipients. 14. (canceled) 15. The particulate entity of claim 1, wherein said particulate entity does not comprise CD1d molecule. 16. A vaccine composition comprising a particulate entity according to claim 1 as an adjuvant and one or more antigenic determinants. 17. A method for treating a tumor in a subject in need thereof, comprising administering a therapeutically efficient amount of a particulate entity of claim 1 in said subject. 18. A method for treating autoimmune and inflammatory disorders in a subject in need thereof, comprising administering a therapeutically efficient amount of a particulate entity of claim 1 in said subject. | 1,600 |
824 | 15,487,263 | 1,628 | The present application provides methods for treating cardiovascular conditions. The methods can include administering a Transient Receptor Potential Vanilloid 1 (TRPV1) receptor agonist to an epidural space. The methods can be used to treat a variety of conditions such as hypertension, prehypertension, mild hypertension, severe hypertension, refractory hypertension, congestive heart failure and myocardial scarring. | 1. A method of treating a cardiovascular condition in a subject, said method comprising:
administering a Transient Receptor Potential Vanilloid 1 (TRPV1) receptor agonist to an epidural space located at one or more of the first through fourth thoracic vertebral level of the subject. 2. The method of claim 1, wherein the subject is a human. 3. The method of claim 1, wherein the cardiovascular condition is congestive heart failure. 4. The method of claim 1, wherein the cardiovascular condition is scarring of the subject's myocardium. 5. The method of claim 1, wherein the cardiovascular condition is selected from a group consisting of hypertension, prehypertension, or mild hypertension. 6. The method of claim 1, wherein the cardiovascular condition is selected from a group consisting of at least one of severe hypertension and refractory hypertension. 7. The method of claim 1, wherein the Transient Receptor Potential Vanilloid 1 (TRPV1) receptor agonist is administered to the epidural space proximate a first thoracic vertebra. 8. The method of claim 1, wherein the Transient Receptor Potential Vanilloid 1 (TRPV1) receptor agonist is administered to the epidural space proximate a second thoracic vertebra. 9. The method of claim 1, wherein the Transient Receptor Potential Vanilloid 1 (TRPV1) receptor agonist is administered to the epidural space proximate a third thoracic vertebra. 10. The method of claim 1, wherein the Transient Receptor Potential Vanilloid 1 (TRPV1) receptor agonist is administered to the epidural space proximate a fourth thoracic vertebra. 11. A method of decreasing blood pressure in a subject with high blood pressure, said method comprising:
administering a Transient Receptor Potential Vanilloid 1 (TRPV1) receptor agonist to an epidural space located at one or more of the first through fourth thoracic vertebral level of the subject. 12. A method of decreasing systolic blood pressure in a subject with high systolic blood pressure, said method comprising:
administering a Transient Receptor Potential Vanilloid 1 (TRPV1) receptor agonist to an epidural space located at one or more of the first through fourth thoracic vertebral level of the subject. 13. A method of decreasing diastolic blood pressure in a subject with high diastolic blood pressure, said method comprising:
administering a Transient Receptor Potential Vanilloid 1 (TRPV1) receptor agonist to an epidural space located at one or more of the first through fourth thoracic vertebral level of the subject. 14. A method of treating a cardiovascular condition in a subject, said method comprising administering resiniferatoxin to an epidural space at one or more of the first through fourth thoracic vertebral level of the subject. 15. The method of claim 14 wherein the subject is a human. 16. The method of claim 14, wherein the cardiovascular condition is congestive heart failure. 17. The method of claim 14, wherein the cardiovascular condition is scarring of the subject's myocardium. 18. The method of claim 14, wherein the cardiovascular condition is selected from a group consisting of hypertension, prehypertension, or mild hypertension. 19. The method of claim 14, wherein the cardiovascular condition is selected from a group consisting of at least one of severe hypertension and refractory hypertension. 20. The method of claim 14, wherein the resiniferatoxin is administered to the epidural space proximate a first thoracic vertebra. 21. The method of claim 14, wherein the resiniferatoxin is administered to the epidural space proximate a second thoracic vertebra. 22. The method of claim 14, wherein the resiniferatoxin is administered to the epidural space proximate a third thoracic vertebra. 23. The method of claim 14, wherein the resiniferatoxin is administered to the epidural space proximate a fourth thoracic vertebra. 24. A method of preventative treatment of a subject, the subject having pre-hypertension or mild hypertension, said method comprising administering a Transient Receptor Potential Vanilloid 1 (TRPV1) receptor agonist to an epidural space proximate a thoracic vertebra of the subject. 25. A method of preventative treatment of a subject, the subject having pre-hypertension or mild hypertension, said method comprising administering resiniferatoxin to an epidural space proximate a thoracicvertebra of the subject. 26. A method of treating a cardiovascular condition in a subject, said method comprising administering an amount of resiniferatoxin to an epidural space at one or more of the first through fourth thoracic vertebral levels of the subject, the amount being more than about 0.06 micrograms and less than about 30 micrograms. 27. A method of treating a cardiovascular condition in a subject, said method comprising administering a solution to an epidural space at one or more of the first through fourth thoracic vertebral levels of the subject, the solution comprising 0.6-10 micrograms of resiniferatoxin per milliliter of solution. 28. The method of claim 27, wherein the solution is administered at a volume of more than about 100 microliters and less than about 3 milliliters at each of said one or more vertebral levels. 29. A method of treating a cardiovascular condition in a subject, said method comprising:
administering an opioid receptor agonist to the subject; and administering a Transient Receptor Potential Vanilloid 1 (TRPV1) receptor agonist to an epidural space located at one or more of the first through fourth thoracic vertebral levels of the patient. 30. The method of claim 29 wherein the subject is a human. 31. The method of claim 29, wherein the opioid receptor is a μ-opioid receptor. 32. The method of claim 29, wherein the opioid receptor agonist is an opioid. 33. The method of claim 32, wherein the opioid is fentanyl. 34. The method of claim 33, wherein the fentanyl is administered in an amount corresponding to 50-100 μg fentanyl per kg of weight of the subject per 12 hours. 35. The method of claim 29 wherein the administration of the opioid receptor agonist is intravenous or intraperitoneal. | The present application provides methods for treating cardiovascular conditions. The methods can include administering a Transient Receptor Potential Vanilloid 1 (TRPV1) receptor agonist to an epidural space. The methods can be used to treat a variety of conditions such as hypertension, prehypertension, mild hypertension, severe hypertension, refractory hypertension, congestive heart failure and myocardial scarring.1. A method of treating a cardiovascular condition in a subject, said method comprising:
administering a Transient Receptor Potential Vanilloid 1 (TRPV1) receptor agonist to an epidural space located at one or more of the first through fourth thoracic vertebral level of the subject. 2. The method of claim 1, wherein the subject is a human. 3. The method of claim 1, wherein the cardiovascular condition is congestive heart failure. 4. The method of claim 1, wherein the cardiovascular condition is scarring of the subject's myocardium. 5. The method of claim 1, wherein the cardiovascular condition is selected from a group consisting of hypertension, prehypertension, or mild hypertension. 6. The method of claim 1, wherein the cardiovascular condition is selected from a group consisting of at least one of severe hypertension and refractory hypertension. 7. The method of claim 1, wherein the Transient Receptor Potential Vanilloid 1 (TRPV1) receptor agonist is administered to the epidural space proximate a first thoracic vertebra. 8. The method of claim 1, wherein the Transient Receptor Potential Vanilloid 1 (TRPV1) receptor agonist is administered to the epidural space proximate a second thoracic vertebra. 9. The method of claim 1, wherein the Transient Receptor Potential Vanilloid 1 (TRPV1) receptor agonist is administered to the epidural space proximate a third thoracic vertebra. 10. The method of claim 1, wherein the Transient Receptor Potential Vanilloid 1 (TRPV1) receptor agonist is administered to the epidural space proximate a fourth thoracic vertebra. 11. A method of decreasing blood pressure in a subject with high blood pressure, said method comprising:
administering a Transient Receptor Potential Vanilloid 1 (TRPV1) receptor agonist to an epidural space located at one or more of the first through fourth thoracic vertebral level of the subject. 12. A method of decreasing systolic blood pressure in a subject with high systolic blood pressure, said method comprising:
administering a Transient Receptor Potential Vanilloid 1 (TRPV1) receptor agonist to an epidural space located at one or more of the first through fourth thoracic vertebral level of the subject. 13. A method of decreasing diastolic blood pressure in a subject with high diastolic blood pressure, said method comprising:
administering a Transient Receptor Potential Vanilloid 1 (TRPV1) receptor agonist to an epidural space located at one or more of the first through fourth thoracic vertebral level of the subject. 14. A method of treating a cardiovascular condition in a subject, said method comprising administering resiniferatoxin to an epidural space at one or more of the first through fourth thoracic vertebral level of the subject. 15. The method of claim 14 wherein the subject is a human. 16. The method of claim 14, wherein the cardiovascular condition is congestive heart failure. 17. The method of claim 14, wherein the cardiovascular condition is scarring of the subject's myocardium. 18. The method of claim 14, wherein the cardiovascular condition is selected from a group consisting of hypertension, prehypertension, or mild hypertension. 19. The method of claim 14, wherein the cardiovascular condition is selected from a group consisting of at least one of severe hypertension and refractory hypertension. 20. The method of claim 14, wherein the resiniferatoxin is administered to the epidural space proximate a first thoracic vertebra. 21. The method of claim 14, wherein the resiniferatoxin is administered to the epidural space proximate a second thoracic vertebra. 22. The method of claim 14, wherein the resiniferatoxin is administered to the epidural space proximate a third thoracic vertebra. 23. The method of claim 14, wherein the resiniferatoxin is administered to the epidural space proximate a fourth thoracic vertebra. 24. A method of preventative treatment of a subject, the subject having pre-hypertension or mild hypertension, said method comprising administering a Transient Receptor Potential Vanilloid 1 (TRPV1) receptor agonist to an epidural space proximate a thoracic vertebra of the subject. 25. A method of preventative treatment of a subject, the subject having pre-hypertension or mild hypertension, said method comprising administering resiniferatoxin to an epidural space proximate a thoracicvertebra of the subject. 26. A method of treating a cardiovascular condition in a subject, said method comprising administering an amount of resiniferatoxin to an epidural space at one or more of the first through fourth thoracic vertebral levels of the subject, the amount being more than about 0.06 micrograms and less than about 30 micrograms. 27. A method of treating a cardiovascular condition in a subject, said method comprising administering a solution to an epidural space at one or more of the first through fourth thoracic vertebral levels of the subject, the solution comprising 0.6-10 micrograms of resiniferatoxin per milliliter of solution. 28. The method of claim 27, wherein the solution is administered at a volume of more than about 100 microliters and less than about 3 milliliters at each of said one or more vertebral levels. 29. A method of treating a cardiovascular condition in a subject, said method comprising:
administering an opioid receptor agonist to the subject; and administering a Transient Receptor Potential Vanilloid 1 (TRPV1) receptor agonist to an epidural space located at one or more of the first through fourth thoracic vertebral levels of the patient. 30. The method of claim 29 wherein the subject is a human. 31. The method of claim 29, wherein the opioid receptor is a μ-opioid receptor. 32. The method of claim 29, wherein the opioid receptor agonist is an opioid. 33. The method of claim 32, wherein the opioid is fentanyl. 34. The method of claim 33, wherein the fentanyl is administered in an amount corresponding to 50-100 μg fentanyl per kg of weight of the subject per 12 hours. 35. The method of claim 29 wherein the administration of the opioid receptor agonist is intravenous or intraperitoneal. | 1,600 |
825 | 15,960,886 | 1,619 | Methods and compositions for enhancing plant characteristics of leguminous and non-leguminous crops include combination treatments with at least one fungicide, insecticide, or combination thereof, and one or more plant inducers, such as nod factors. Optionally, an inoculant composition may be used with the invention to enhance nodulation and nitrogen fixation with legumes. | 1. A method of enhancing plant yield, said method comprising treating a seed and/or the plant that grows from said seed with a composition comprising:
a lipo-chitooligosaccharide; and an insecticide comprising imidacloprid, thiamethoxam and/or clothiandidin said lipo-chitooligosaccharide and said insecticide present in said composition in amounts sufficient to synergistically enhance the yield of said plant. 2. The method of claim 1, wherein the composition further comprises a fungicide. 3. The method of claim 1, wherein the composition further comprises mefenoxam, fludioxonil, azoxystrobin, captan, pentachloronitrobenzimidazole, thiabendazole and/or metalaxyl. 4. The method of claim 1, wherein the composition further comprises an inoculant. 5. The method of claim 1, wherein the composition further comprises a rhizobial species. 6. The method of claim 1, wherein the composition further comprises one or more strains of Bradyrhizobium, Rhizobium, and/or Sinorhizobium. 7. The method of claim 1, wherein the composition further comprises one or more strains of Bradyrhizobium japonicum. 8. The method of claim 1, wherein said seed is leguminous. 9. The method of claim 1, wherein said seed is soybean. 10. The method of claim 1, wherein said seed is non-leguminous. 11. The method of claim 1, wherein said seed is a cereal. 12. The method of claim 1, wherein said seed is corn. 13. The method of claim 1, wherein said seed is wheat. 14. A composition comprising a lipo-chitooligosaccharide and an insecticide comprising imidacloprid, thiamethoxam and/or clothiandidin.
said lipo-chitooligosaccharide and said insecticide present in amounts sufficient to synergistically enhance plant yield when said composition is applied to a seed and/or plant. 15. The composition of claim 14, further comprising a fungicide. 16. The composition of claim 14, further comprising mefenoxam, fludioxonil, azoxystrobin, captan, pentachloronitrobenzimidazole, thiabendazole and/or metalaxyl. 17. The composition of claim 14, further comprising an inoculant. 18. The composition of claim 14, further comprising a rhizobial species. 19. The composition of claim 14, further comprising one or more strains of Bradyrhizobium, Rhizobium, and/or Sinorhizobium. 20. The composition of claim 14, further comprising one or more strains of Bradyrhizobium japonicum. | Methods and compositions for enhancing plant characteristics of leguminous and non-leguminous crops include combination treatments with at least one fungicide, insecticide, or combination thereof, and one or more plant inducers, such as nod factors. Optionally, an inoculant composition may be used with the invention to enhance nodulation and nitrogen fixation with legumes.1. A method of enhancing plant yield, said method comprising treating a seed and/or the plant that grows from said seed with a composition comprising:
a lipo-chitooligosaccharide; and an insecticide comprising imidacloprid, thiamethoxam and/or clothiandidin said lipo-chitooligosaccharide and said insecticide present in said composition in amounts sufficient to synergistically enhance the yield of said plant. 2. The method of claim 1, wherein the composition further comprises a fungicide. 3. The method of claim 1, wherein the composition further comprises mefenoxam, fludioxonil, azoxystrobin, captan, pentachloronitrobenzimidazole, thiabendazole and/or metalaxyl. 4. The method of claim 1, wherein the composition further comprises an inoculant. 5. The method of claim 1, wherein the composition further comprises a rhizobial species. 6. The method of claim 1, wherein the composition further comprises one or more strains of Bradyrhizobium, Rhizobium, and/or Sinorhizobium. 7. The method of claim 1, wherein the composition further comprises one or more strains of Bradyrhizobium japonicum. 8. The method of claim 1, wherein said seed is leguminous. 9. The method of claim 1, wherein said seed is soybean. 10. The method of claim 1, wherein said seed is non-leguminous. 11. The method of claim 1, wherein said seed is a cereal. 12. The method of claim 1, wherein said seed is corn. 13. The method of claim 1, wherein said seed is wheat. 14. A composition comprising a lipo-chitooligosaccharide and an insecticide comprising imidacloprid, thiamethoxam and/or clothiandidin.
said lipo-chitooligosaccharide and said insecticide present in amounts sufficient to synergistically enhance plant yield when said composition is applied to a seed and/or plant. 15. The composition of claim 14, further comprising a fungicide. 16. The composition of claim 14, further comprising mefenoxam, fludioxonil, azoxystrobin, captan, pentachloronitrobenzimidazole, thiabendazole and/or metalaxyl. 17. The composition of claim 14, further comprising an inoculant. 18. The composition of claim 14, further comprising a rhizobial species. 19. The composition of claim 14, further comprising one or more strains of Bradyrhizobium, Rhizobium, and/or Sinorhizobium. 20. The composition of claim 14, further comprising one or more strains of Bradyrhizobium japonicum. | 1,600 |
826 | 12,274,765 | 1,653 | The present invention is directed to methods of cryopreserving cells and cryopreserved cells prepared according to the methods. In specific embodiments, the method comprises combining cells with a cross-linked hydrogel matrix in particulate form, the matrix comprising a polyglycan cross-linked to a polypeptide and subjecting the combination to cryopreservation conditions. In further embodiments, the invention provides cell-seeded compositions comprising cells and a cross-linked bioactive hydrogel matrix in particulate form, the matrix comprising a polyglycan cross-linked to a polypeptide, wherein the composition has been subjected to cryopreservation conditions. The cryopreserved cells can be thawed and used in methods of treatment without the need for intervening steps to make the cells viable for in vivo use. | 1. A method of cryopreserving cells comprising subjecting to cryopreservation conditions particles of a cross-linked bioactive hydrogel matrix, said hydrogel matrix particles retaining cells for cryopreservation. 2. The method of claim 1, wherein said step of subjecting to cryopreservation conditions comprises introducing the hydrogel matrix particles retaining the cells to an environment providing a cryopreservation temperature. 3. The method of claim 2, wherein said cryopreservation temperature is a temperature sufficiently below 0° C. to slow or stop biological activity within the cells. 4. The method of claim 2, wherein said cryopreservation temperature is a temperature of less than about −20° C. 5. The method of claim 1, wherein said step of subjecting to cryopreservation conditions includes contacting the hydrogel matrix particles retaining the cells with a cryoprotectant. 6. The method of claim 5, wherein the hydrogel matrix particles retaining the cells are in a suspension, and wherein the cryoprotectant comprises a material effective for lowering the freezing temperature of the suspension, increasing the viscosity of the suspension, or both. 7. The method of claim 1, wherein the cells are retained on an exposed surface on the hydrogel matrix particles. 8. The method of claim 1, wherein the cells are retained within one or more pores present in the hydrogel matrix particles. 9. The method of claim 8, wherein the hydrogel matrix particles have an average pore size of about 10 μm to about 1000 μm. 10. The method of claim 9, wherein the hydrogel matrix particles have an average pore size of about 100 μm to about 800 μm. 11. The method of claim 8, wherein the hydrogel matrix particles have an average interconnectivity pore size of less than about 200 μm. 12. The method of claim 8, wherein the hydrogel matrix particles have an average porosity of at least about 25%. 13. The method of claim 8, wherein the hydrogel matrix particles have an average porosity of about 30% to about 90%. 14. The method of claim 1, wherein the hydrogel matrix particles have an average particle size wherein greater than 90% of the particles pass through a 10 mesh screen, and greater than 90% of the particles are retained on a 100 mesh screen. 15. The method of claim 1, wherein the hydrogel matrix particles have an average particle size of about 0.01 mm to about 2 mm. 16. The method of claim 15, wherein the hydrogel matrix particles have an average particle size of about 0.1 mm to about 1 mm. 17. The method of claim 1, wherein the hydrogel matrix particles each retain an average of at least about 20 cells. 18. The method of claim 1, wherein the hydrogel matrix particles each retain an average of about 10 cells to about 200 cells. 19. The method of claim 1, wherein the cells for cryopreservation are selected from the group consisting of stem cells, progenitor cells, mesenchymal cells, pluripotent cells, multipotent cells, and combinations thereof. 20. The method of claim 1, wherein the cells for cryopreservation are selected from the group consisting of mesenchymal stem cells, neural stem cells, muscle stem cells, adipose-derived adult stem (ADAS) cells, liver cells, pancreatic cells, chondrocytes, osteoblasts, adipocytes, fibroblasts, and combinations thereof. 21. The method of claim 1, wherein the bioactive hydrogel matrix comprises a polyglycan cross-linked to a polypeptide. 22. The method of claim 21, wherein the polyglycan is a polysaccharide or a sulfated polysaccharide selected from the group consisting of dextran, heparan, heparin, hyaluronic acid, alginate, agarose, carageenan, amylopectin, amylose, glycogen, starch, cellulose, chitin, chitosan, heparan sulfate, chondroitin sulfate, dextran sulfate, dermatan sulfate, and keratan sulfate. 23. The method of claim 21, wherein the polypeptide is selected from the group consisting of collagens, gelatins, keratin, decorin, aggrecan, glycoproteins, laminin, nidogen, fibulin, and fibrillin. 24. The method of claim 21, wherein the polyglycan is dextran and the polypeptide is gelatin. 25. The method of claim 21, wherein the hydrogel matrix further comprises one or more enhancing agents selected from the group consisting of polar amino acids, intact collagen, divalent cation chelators, and combinations thereof. 26. The method of claim 1, wherein the hydrogel matrix comprises a synthetic polymer. 27. The method of claim 1 comprising, prior to said subjecting step, combining the cells with the hydrogel matrix particles for a time and under conditions sufficient to cause the cells to be retained by the particles. 28. The method of claim 27, wherein said combining step comprises providing the cells for cryopreservation in a cell suspension and contacting the hydrogel matrix particles with the cell suspension. 29. The method of claim 27, wherein the hydrogel matrix particles are prepared prior to said combining step by lyophilizing a cross-linked bioactive hydrogel matrix and milling the lyophilized cross-linked hydrogel matrix. 30. A cell-seeded composition comprising particles of a cross-linked bioactive hydrogel matrix and cells that are retained by the hydrogel matrix particles, the composition being in a cryopreserved form. 31. The composition of claim 30, wherein the cells are retained on an exposed surface on the hydrogel matrix particles. 32. The composition of claim 30, wherein the cells are retained within one or more pores present in the hydrogel matrix particles. 33. The composition of claim 32, wherein the hydrogel matrix particles have an average pore size of about 10 μm to about 1000 μm. 34. The composition of claim 32, wherein the hydrogel matrix particles have an average interconnectivity pore size of less than about 200 μm. 35. The composition of claim 32, wherein the hydrogel matrix particles have an average porosity of at least about 25%. 36. The composition of claim 30, wherein the hydrogel matrix particles have an average particle size of about 0.01 mm to about 2 mm. 37. The composition of claim 30, wherein the hydrogel matrix comprises a polyglycan cross-linked to a polypeptide. 38. The composition of claim 37, wherein the polyglycan is a polysaccharide or a sulfated polysaccharide selected from the group consisting of dextran, heparan, heparin, hyaluronic acid, alginate, agarose, carageenan, amylopectin, amylose, glycogen, starch, cellulose, chitin, chitosan, heparan sulfate, chondroitin sulfate, dextran sulfate, dermatan sulfate, and keratan sulfate. 39. The composition of claim 37, wherein the polypeptide is selected from the group consisting of collagens, gelatins, keratin, decorin, aggrecan, glycoproteins, laminin, nidogen, fibulin, and fibrillin. 40. The composition of claim 37, wherein the polyglycan is dextran and the polypeptide is gelatin. 41. The composition of claim 37, wherein the hydrogel matrix further comprises one or more enhancing agents selected from the group consisting of polar amino acids, intact collagen, divalent cation chelators, and combinations thereof. 42. The composition of claim 30, wherein the hydrogel matrix comprises a synthetic polymer. 43. The composition of claim 30, further comprising a cryoprotectant. 44. A cell-seeded composition comprising particles of a cross-linked bioactive hydrogel matrix, cells that are retained by the hydrogel matrix particles, and a cryoprotectant. 45. A method of administering viable cells to a site, the method comprising:
providing particles of a cross-linked bioactive hydrogel matrix and cells that are retained by the hydrogel matrix particles, the particles and the retained cells being in a cryopreserved form; thawing the cryopreserved particles and the retained cells; and administering the particles with the retained cells to the site. 46. The method of claim 45, further comprising, prior to said administering step, forming a suspension of the particles and the retained cells. 47. The method of claim 46, wherein the step of forming the suspension comprises combining the thawed particles and the retained cells with a thermoreversible hydrogel matrix comprising a polyglycan and a polypeptide. 48. The method of claim 45, wherein the cells are retained on an exposed surface on the hydrogel matrix particles. 49. The method of claim 45, wherein the cells are retained within one or more pores present in the hydrogel matrix particles. 50. The method of claim 49, wherein the hydrogel matrix particles have an average pore size of about 10 μm to about 1000 μm. 51. The method of claim 49, wherein the hydrogel matrix particles have an average interconnectivity pore size of less than about 200 μm. 52. The method of claim 49, wherein the hydrogel matrix particles have an average porosity of at least about 25%. 53. The method of claim 49, wherein the hydrogel matrix particles have an average porosity of about 30% to about 90%. 54. The method of claim 45, wherein the hydrogel matrix particles have an average particle size of about 0.01 mm to about 2 mm. 55. The method of claim 45, wherein the hydrogel matrix comprises a polyglycan cross-linked to a polypeptide. 56. The method of claim 55, wherein the polyglycan is dextran and the polypeptide is gelatin. 57. The method of claim 55, wherein the hydrogel matrix further comprises one or more enhancing agents selected from the group consisting of polar amino acids, intact collagen, divalent cation chelators, and combinations thereof. 58. The method of claim 45, wherein the hydrogel matrix comprises a synthetic polymer. | The present invention is directed to methods of cryopreserving cells and cryopreserved cells prepared according to the methods. In specific embodiments, the method comprises combining cells with a cross-linked hydrogel matrix in particulate form, the matrix comprising a polyglycan cross-linked to a polypeptide and subjecting the combination to cryopreservation conditions. In further embodiments, the invention provides cell-seeded compositions comprising cells and a cross-linked bioactive hydrogel matrix in particulate form, the matrix comprising a polyglycan cross-linked to a polypeptide, wherein the composition has been subjected to cryopreservation conditions. The cryopreserved cells can be thawed and used in methods of treatment without the need for intervening steps to make the cells viable for in vivo use.1. A method of cryopreserving cells comprising subjecting to cryopreservation conditions particles of a cross-linked bioactive hydrogel matrix, said hydrogel matrix particles retaining cells for cryopreservation. 2. The method of claim 1, wherein said step of subjecting to cryopreservation conditions comprises introducing the hydrogel matrix particles retaining the cells to an environment providing a cryopreservation temperature. 3. The method of claim 2, wherein said cryopreservation temperature is a temperature sufficiently below 0° C. to slow or stop biological activity within the cells. 4. The method of claim 2, wherein said cryopreservation temperature is a temperature of less than about −20° C. 5. The method of claim 1, wherein said step of subjecting to cryopreservation conditions includes contacting the hydrogel matrix particles retaining the cells with a cryoprotectant. 6. The method of claim 5, wherein the hydrogel matrix particles retaining the cells are in a suspension, and wherein the cryoprotectant comprises a material effective for lowering the freezing temperature of the suspension, increasing the viscosity of the suspension, or both. 7. The method of claim 1, wherein the cells are retained on an exposed surface on the hydrogel matrix particles. 8. The method of claim 1, wherein the cells are retained within one or more pores present in the hydrogel matrix particles. 9. The method of claim 8, wherein the hydrogel matrix particles have an average pore size of about 10 μm to about 1000 μm. 10. The method of claim 9, wherein the hydrogel matrix particles have an average pore size of about 100 μm to about 800 μm. 11. The method of claim 8, wherein the hydrogel matrix particles have an average interconnectivity pore size of less than about 200 μm. 12. The method of claim 8, wherein the hydrogel matrix particles have an average porosity of at least about 25%. 13. The method of claim 8, wherein the hydrogel matrix particles have an average porosity of about 30% to about 90%. 14. The method of claim 1, wherein the hydrogel matrix particles have an average particle size wherein greater than 90% of the particles pass through a 10 mesh screen, and greater than 90% of the particles are retained on a 100 mesh screen. 15. The method of claim 1, wherein the hydrogel matrix particles have an average particle size of about 0.01 mm to about 2 mm. 16. The method of claim 15, wherein the hydrogel matrix particles have an average particle size of about 0.1 mm to about 1 mm. 17. The method of claim 1, wherein the hydrogel matrix particles each retain an average of at least about 20 cells. 18. The method of claim 1, wherein the hydrogel matrix particles each retain an average of about 10 cells to about 200 cells. 19. The method of claim 1, wherein the cells for cryopreservation are selected from the group consisting of stem cells, progenitor cells, mesenchymal cells, pluripotent cells, multipotent cells, and combinations thereof. 20. The method of claim 1, wherein the cells for cryopreservation are selected from the group consisting of mesenchymal stem cells, neural stem cells, muscle stem cells, adipose-derived adult stem (ADAS) cells, liver cells, pancreatic cells, chondrocytes, osteoblasts, adipocytes, fibroblasts, and combinations thereof. 21. The method of claim 1, wherein the bioactive hydrogel matrix comprises a polyglycan cross-linked to a polypeptide. 22. The method of claim 21, wherein the polyglycan is a polysaccharide or a sulfated polysaccharide selected from the group consisting of dextran, heparan, heparin, hyaluronic acid, alginate, agarose, carageenan, amylopectin, amylose, glycogen, starch, cellulose, chitin, chitosan, heparan sulfate, chondroitin sulfate, dextran sulfate, dermatan sulfate, and keratan sulfate. 23. The method of claim 21, wherein the polypeptide is selected from the group consisting of collagens, gelatins, keratin, decorin, aggrecan, glycoproteins, laminin, nidogen, fibulin, and fibrillin. 24. The method of claim 21, wherein the polyglycan is dextran and the polypeptide is gelatin. 25. The method of claim 21, wherein the hydrogel matrix further comprises one or more enhancing agents selected from the group consisting of polar amino acids, intact collagen, divalent cation chelators, and combinations thereof. 26. The method of claim 1, wherein the hydrogel matrix comprises a synthetic polymer. 27. The method of claim 1 comprising, prior to said subjecting step, combining the cells with the hydrogel matrix particles for a time and under conditions sufficient to cause the cells to be retained by the particles. 28. The method of claim 27, wherein said combining step comprises providing the cells for cryopreservation in a cell suspension and contacting the hydrogel matrix particles with the cell suspension. 29. The method of claim 27, wherein the hydrogel matrix particles are prepared prior to said combining step by lyophilizing a cross-linked bioactive hydrogel matrix and milling the lyophilized cross-linked hydrogel matrix. 30. A cell-seeded composition comprising particles of a cross-linked bioactive hydrogel matrix and cells that are retained by the hydrogel matrix particles, the composition being in a cryopreserved form. 31. The composition of claim 30, wherein the cells are retained on an exposed surface on the hydrogel matrix particles. 32. The composition of claim 30, wherein the cells are retained within one or more pores present in the hydrogel matrix particles. 33. The composition of claim 32, wherein the hydrogel matrix particles have an average pore size of about 10 μm to about 1000 μm. 34. The composition of claim 32, wherein the hydrogel matrix particles have an average interconnectivity pore size of less than about 200 μm. 35. The composition of claim 32, wherein the hydrogel matrix particles have an average porosity of at least about 25%. 36. The composition of claim 30, wherein the hydrogel matrix particles have an average particle size of about 0.01 mm to about 2 mm. 37. The composition of claim 30, wherein the hydrogel matrix comprises a polyglycan cross-linked to a polypeptide. 38. The composition of claim 37, wherein the polyglycan is a polysaccharide or a sulfated polysaccharide selected from the group consisting of dextran, heparan, heparin, hyaluronic acid, alginate, agarose, carageenan, amylopectin, amylose, glycogen, starch, cellulose, chitin, chitosan, heparan sulfate, chondroitin sulfate, dextran sulfate, dermatan sulfate, and keratan sulfate. 39. The composition of claim 37, wherein the polypeptide is selected from the group consisting of collagens, gelatins, keratin, decorin, aggrecan, glycoproteins, laminin, nidogen, fibulin, and fibrillin. 40. The composition of claim 37, wherein the polyglycan is dextran and the polypeptide is gelatin. 41. The composition of claim 37, wherein the hydrogel matrix further comprises one or more enhancing agents selected from the group consisting of polar amino acids, intact collagen, divalent cation chelators, and combinations thereof. 42. The composition of claim 30, wherein the hydrogel matrix comprises a synthetic polymer. 43. The composition of claim 30, further comprising a cryoprotectant. 44. A cell-seeded composition comprising particles of a cross-linked bioactive hydrogel matrix, cells that are retained by the hydrogel matrix particles, and a cryoprotectant. 45. A method of administering viable cells to a site, the method comprising:
providing particles of a cross-linked bioactive hydrogel matrix and cells that are retained by the hydrogel matrix particles, the particles and the retained cells being in a cryopreserved form; thawing the cryopreserved particles and the retained cells; and administering the particles with the retained cells to the site. 46. The method of claim 45, further comprising, prior to said administering step, forming a suspension of the particles and the retained cells. 47. The method of claim 46, wherein the step of forming the suspension comprises combining the thawed particles and the retained cells with a thermoreversible hydrogel matrix comprising a polyglycan and a polypeptide. 48. The method of claim 45, wherein the cells are retained on an exposed surface on the hydrogel matrix particles. 49. The method of claim 45, wherein the cells are retained within one or more pores present in the hydrogel matrix particles. 50. The method of claim 49, wherein the hydrogel matrix particles have an average pore size of about 10 μm to about 1000 μm. 51. The method of claim 49, wherein the hydrogel matrix particles have an average interconnectivity pore size of less than about 200 μm. 52. The method of claim 49, wherein the hydrogel matrix particles have an average porosity of at least about 25%. 53. The method of claim 49, wherein the hydrogel matrix particles have an average porosity of about 30% to about 90%. 54. The method of claim 45, wherein the hydrogel matrix particles have an average particle size of about 0.01 mm to about 2 mm. 55. The method of claim 45, wherein the hydrogel matrix comprises a polyglycan cross-linked to a polypeptide. 56. The method of claim 55, wherein the polyglycan is dextran and the polypeptide is gelatin. 57. The method of claim 55, wherein the hydrogel matrix further comprises one or more enhancing agents selected from the group consisting of polar amino acids, intact collagen, divalent cation chelators, and combinations thereof. 58. The method of claim 45, wherein the hydrogel matrix comprises a synthetic polymer. | 1,600 |
827 | 15,411,211 | 1,612 | Disclosed are therapeutic oral compositions useful in the treatment of a variety of oral disorders, in which the composition can provide blockage of dentinal tubes, while at the same time provide antibacterial and anti-caries efficacy. The compositions include arginine in free or salt form, a mucoadhesive polymer, and at least one component selected from pyrophosphates, zinc salts, potassium salts, strontium salts, and mixtures thereof. | 1-20. (canceled) 21. An oral care composition comprising at least one arginine compound in free or salt form, at least one mucoadhesive polymer, and at least one component selected from the group consisting of pyrophosphate compounds, zinc salts, potassium salts, strontium salts, and mixtures thereof, wherein the arginine compound is present in D or L form, or as a salt with lauroyl sulfuric acid, and wherein the arginine compound is present in an amount within the range of from 0.6% to 1% by weight. 22. The composition as claimed in claim 21, wherein the arginine compound is present in an amount within the range of from 0.75% to 0.9% by weight. 23. The composition as claimed in claim 21, wherein the mucoadhesive polymer is selected from one or more the group consisting of polyvinylmethylether/maleic anhydride (PVME/MA) copolymer, acrylic acid/methylacrylate/styrene/2-acryloamido-2-methylpropane sulfonic acid copolymer, poly(vinylpyrrolidone) (PVP), carboxymethylcellulose (CMC), xanthan, and mixtures thereof. 24. The composition as claimed in claim 23, wherein the mucoadhesive polymer is a polyvinylmethylether/maleic anhydride (PVME/MA) copolymer. 25. The composition as claimed in claim 21, wherein the mucoadhesive polymer is present in an amount within the range of from 0.1% to 20% by weight. 26. The composition as claimed in claim 21, further comprising an antibacterial agent. 27. The composition as claimed in claim 21, wherein the pyrophosphate is selected from the group consisting of disodium dihydrogen pyrophosphate (Na2H2P2O7), tetrasodium pyrophosphate (Na4P2O7), tetrapotassium pyrophosphate (K4P2O7), and mixtures thereof. 28. The composition as claimed in claim 21, wherein the composition is in a form selected from the group consisting of a mouthwash, a dental gel, a periodontal gel and a liquid suitable for painting a dental surface. 29. The composition as claimed in claim 28, wherein the composition is a mouthwash. 30. The composition as claimed in claim 21, wherein the composition has a flow reduction above 50%, when measured using a hydraulic conductance test. 31. A method of one or more selected from the group consisting of: reducing hypersensitivity of the teeth; reducing or inhibiting formation of dental caries; reducing or inhibiting demineralization and promoting remineralization of the teeth; reducing or inhibiting gingivitis; inhibiting microbial biofilm formation in the oral cavity; reducing accumulation of plaque; treating dry mouth; reducing erosion of the teeth; protecting enamel after erosive challenges; and cleaning and/or whitening the teeth and cleaning the oral cavity, comprising:
a) preparing an oral composition of claim 1 comprising combining arginine in free or salt form, a mucoadhesive polymer, and at least one component selected from the group consisting of pyrophosphate compounds, zinc salts, potassium salts, strontium salts, and mixtures thereof; wherein the arginine compound is present in D or L form, or as a salt with lauryl sulfuric acid and wherein the arginine compound I spresent in an amount within the range of from 0.6% to 1% by weight; and b) applying the oral composition to the oral cavity. 32. The method as claimed in claim 31, wherein the composition is applied to the oral cavity at least once a day for at least two weeks. 33. The method as claimed in claim 31, wherein the arginine compound is present in an amount within the range of from 0.75% to 0.9% by weight. 34. The method as claimed in claim 31, wherein the mucoadhesive polymer is selected from one or more the group consisting of polyvinylmethylether/maleic anhydride (PVME/MA) copolymer, acrylic acid/methylacrylate/styrene/2-acryloamido-2-methylpropane sulfonic acid copolymer, poly(vinylpyrrolidone) (PVP), carboxymethylcellulose (CMC), xanthan, and mixtures thereof. 35. The method as claimed in claim 34, wherein the mucoadhesive polymer is a polyvinylmethylether/maleic anhydride (PVME/MA) copolymer. 36. The method as claimed in claim 31, wherein the mucoadhesive polymer is present in an amount within the range of from 0.1% to 20% by weight. 37. The method as claimed in claim 31, further comprising an antibacterial agent. 38. An article comprising packaging material and the composition as claimed in claim 21, wherein the packaging material comprises a label that indicates the oral composition is effective in retarding or preventing dentinal hypersensitivity. | Disclosed are therapeutic oral compositions useful in the treatment of a variety of oral disorders, in which the composition can provide blockage of dentinal tubes, while at the same time provide antibacterial and anti-caries efficacy. The compositions include arginine in free or salt form, a mucoadhesive polymer, and at least one component selected from pyrophosphates, zinc salts, potassium salts, strontium salts, and mixtures thereof.1-20. (canceled) 21. An oral care composition comprising at least one arginine compound in free or salt form, at least one mucoadhesive polymer, and at least one component selected from the group consisting of pyrophosphate compounds, zinc salts, potassium salts, strontium salts, and mixtures thereof, wherein the arginine compound is present in D or L form, or as a salt with lauroyl sulfuric acid, and wherein the arginine compound is present in an amount within the range of from 0.6% to 1% by weight. 22. The composition as claimed in claim 21, wherein the arginine compound is present in an amount within the range of from 0.75% to 0.9% by weight. 23. The composition as claimed in claim 21, wherein the mucoadhesive polymer is selected from one or more the group consisting of polyvinylmethylether/maleic anhydride (PVME/MA) copolymer, acrylic acid/methylacrylate/styrene/2-acryloamido-2-methylpropane sulfonic acid copolymer, poly(vinylpyrrolidone) (PVP), carboxymethylcellulose (CMC), xanthan, and mixtures thereof. 24. The composition as claimed in claim 23, wherein the mucoadhesive polymer is a polyvinylmethylether/maleic anhydride (PVME/MA) copolymer. 25. The composition as claimed in claim 21, wherein the mucoadhesive polymer is present in an amount within the range of from 0.1% to 20% by weight. 26. The composition as claimed in claim 21, further comprising an antibacterial agent. 27. The composition as claimed in claim 21, wherein the pyrophosphate is selected from the group consisting of disodium dihydrogen pyrophosphate (Na2H2P2O7), tetrasodium pyrophosphate (Na4P2O7), tetrapotassium pyrophosphate (K4P2O7), and mixtures thereof. 28. The composition as claimed in claim 21, wherein the composition is in a form selected from the group consisting of a mouthwash, a dental gel, a periodontal gel and a liquid suitable for painting a dental surface. 29. The composition as claimed in claim 28, wherein the composition is a mouthwash. 30. The composition as claimed in claim 21, wherein the composition has a flow reduction above 50%, when measured using a hydraulic conductance test. 31. A method of one or more selected from the group consisting of: reducing hypersensitivity of the teeth; reducing or inhibiting formation of dental caries; reducing or inhibiting demineralization and promoting remineralization of the teeth; reducing or inhibiting gingivitis; inhibiting microbial biofilm formation in the oral cavity; reducing accumulation of plaque; treating dry mouth; reducing erosion of the teeth; protecting enamel after erosive challenges; and cleaning and/or whitening the teeth and cleaning the oral cavity, comprising:
a) preparing an oral composition of claim 1 comprising combining arginine in free or salt form, a mucoadhesive polymer, and at least one component selected from the group consisting of pyrophosphate compounds, zinc salts, potassium salts, strontium salts, and mixtures thereof; wherein the arginine compound is present in D or L form, or as a salt with lauryl sulfuric acid and wherein the arginine compound I spresent in an amount within the range of from 0.6% to 1% by weight; and b) applying the oral composition to the oral cavity. 32. The method as claimed in claim 31, wherein the composition is applied to the oral cavity at least once a day for at least two weeks. 33. The method as claimed in claim 31, wherein the arginine compound is present in an amount within the range of from 0.75% to 0.9% by weight. 34. The method as claimed in claim 31, wherein the mucoadhesive polymer is selected from one or more the group consisting of polyvinylmethylether/maleic anhydride (PVME/MA) copolymer, acrylic acid/methylacrylate/styrene/2-acryloamido-2-methylpropane sulfonic acid copolymer, poly(vinylpyrrolidone) (PVP), carboxymethylcellulose (CMC), xanthan, and mixtures thereof. 35. The method as claimed in claim 34, wherein the mucoadhesive polymer is a polyvinylmethylether/maleic anhydride (PVME/MA) copolymer. 36. The method as claimed in claim 31, wherein the mucoadhesive polymer is present in an amount within the range of from 0.1% to 20% by weight. 37. The method as claimed in claim 31, further comprising an antibacterial agent. 38. An article comprising packaging material and the composition as claimed in claim 21, wherein the packaging material comprises a label that indicates the oral composition is effective in retarding or preventing dentinal hypersensitivity. | 1,600 |
828 | 14,595,695 | 1,612 | A phospholipid microbubble comprising a shell which comprises a plurality of polyunsaturated fatty acid (“PUFA”)-containing phospholipids, and a core of paramagnetic gas surrounded by the shell comprising the plurality of PUFA-containing phospholipids. The present invention also provides methods of delivering a prophylactically or therapeutically effective amount of PUFA to an area of disease or injury in a subject. The present invention also provides methods of preventing or treating a disease in a subject using a prophylactically or therapeutically effective amount of the aforementioned phospholipid microbubbles. | 1. A phospholipid microbubble comprising a shell which comprises a plurality of polyunsaturated fatty acid (“PUFA”)-containing phospholipids, and a core of paramagnetic gas surrounded by said shell comprising said plurality of PUFA-containing phospholipids. 2. The phospholipid microbubble of claim 1, wherein said plurality of PUFA-containing phospholipids comprising a plurality of polar head groups, said plurality of polar head groups comprising phosphatidylserine (“PS”), phosphadtidylcholine (“PC”), phosphatidyl-ethanolamine (“PE”), phosphatidylinositol (“PI”), or a combination thereof. 3. The phospholipid microbubble of claim 1, wherein said plurality of PUFA-containing phospholipids comprising a plurality of non-polar fatty acid tails, said plurality of non-polar fatty acid tails comprising an omega-3 PUFA, an omega-3 PUFA precursor, an omega-3 PUFA-derived metabolite, an omega-6 PUFA, an omega-9 PUFA, a conjugated linoleic acid, a conjugated linoleic acid isomer, or a combination thereof. 4. The phospholipid microbubble of claim 3, wherein said omega-3 PUFA is selected from eicosapentaenoic acid (“EPA”), docosahexaenoic acid (“DHA”), or a combination thereof. 5. The phospholipid microbubble of claim 3, wherein said omega-3 PUFA precursor is an □-linolenic acid. 6. The phospholipid microbubble of claim 3, wherein said omega-3 PUFA-derived metabolite is selected from a resolvin, a neuroprotectin, a lipoxin, a neuroprostane, or a combination thereof. 7. The phospholipid microbubble of claim 1, wherein said paramagnetic gas is selected from a perfluorocarbon compound, xenon, or hyperpolarized xenon. 8. The phospholipid microbubble of claim 1, wherein said phospholipid microbubble in a micellar form or a liposomal form. 9. The phospholipid microbubble of claim 1, wherein said plurality of PUFA-containing phospholipids comprises at least one PS-DHA phospholipid, PS-EPA phospholipid, PC-DHA phospholipid, or PC-EPA phospholipid. 10. The phospholipid microbubble of claim 1, wherein said phospholipid microbubble further comprises a drug, a fat-soluble compound, an antioxidant, an antibody or a fragment thereof, or a specific ligand is conjugated to said phospholipid microbubble. 11. A method of delivering a prophylactically or therapeutically effective amount of PUFA to an area of disease or injury in a subject, comprising the steps of:
administering to said subject a plurality of phospholipid microbubbles which comprises a shell comprising a plurality of PUFA-containing phospholipids, and a core of paramagnetic gas surrounded by said shell comprising said plurality of PUFA-containing phospholipids; allowing said phospholipid microbubbles to reach said area of disease or injury; and applying ultrasound to said area of disease or injury to explode said phospholipid microbubbles. 12. The method of claim 11, wherein said area of disease or injury is the heart. 13. The method of claim 11, wherein said plurality of phospholipid microbubbles comprises a micellar form of said phospholipid microbubbles, a liposomal form of phospholipid microbubbles, or a combination thereof. 14. A method of preventing or treating a disease in a subject, comprising the steps of:
administering to said subject a prophylatically or therapeutic effective amount of a plurality of phospholipid microbubbles which comprises a shell comprising a plurality of PUFA-containing phospholipids, and a core of paramagnetic gas surrounded by said shell comprising said plurality of PUFA-containing phospholipids; and applying ultrasound to said phospholipid microbubbles to explode said phospholipid microbubbles in said subject. 15. The method of claim 14, wherein said disease is lupus erythematosis, multiple sclerosis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, diabetes mellitus, prostate cancer, breast cancer, depression, Alzheimer's disease or myocardial infarction. 16. The method of claim 14, wherein said administration is a single intravenous administration of said plurality of phospholipid microbubbles. 17. The method of claim 14, wherein said plurality of PUFA-containing phospholipids comprising at least one PS-DHA phospholipid, PS-EPA phospholipid, PC-DHA phospholipid, or PC-EPA phospholipid. 18. The method of claim 14, wherein said plurality of phospholipid microbubbles comprises a micellar form of said phospholipid microbubbles, a liposomal form of said phospholipid microbubbles, or a combination thereof. 19. The method of claim 14, wherein said administration is a co-administration of a micellar form of said phospholipid microbubbles and a liposomal form of said phospholipid microbubbles. 20. The method of claim 19, wherein said co-administration is simultaneous, concurrent or sequential administration of said micellar form of said phospholipid microbubbles and said liposomal form of said phospholipid microbubbles. | A phospholipid microbubble comprising a shell which comprises a plurality of polyunsaturated fatty acid (“PUFA”)-containing phospholipids, and a core of paramagnetic gas surrounded by the shell comprising the plurality of PUFA-containing phospholipids. The present invention also provides methods of delivering a prophylactically or therapeutically effective amount of PUFA to an area of disease or injury in a subject. The present invention also provides methods of preventing or treating a disease in a subject using a prophylactically or therapeutically effective amount of the aforementioned phospholipid microbubbles.1. A phospholipid microbubble comprising a shell which comprises a plurality of polyunsaturated fatty acid (“PUFA”)-containing phospholipids, and a core of paramagnetic gas surrounded by said shell comprising said plurality of PUFA-containing phospholipids. 2. The phospholipid microbubble of claim 1, wherein said plurality of PUFA-containing phospholipids comprising a plurality of polar head groups, said plurality of polar head groups comprising phosphatidylserine (“PS”), phosphadtidylcholine (“PC”), phosphatidyl-ethanolamine (“PE”), phosphatidylinositol (“PI”), or a combination thereof. 3. The phospholipid microbubble of claim 1, wherein said plurality of PUFA-containing phospholipids comprising a plurality of non-polar fatty acid tails, said plurality of non-polar fatty acid tails comprising an omega-3 PUFA, an omega-3 PUFA precursor, an omega-3 PUFA-derived metabolite, an omega-6 PUFA, an omega-9 PUFA, a conjugated linoleic acid, a conjugated linoleic acid isomer, or a combination thereof. 4. The phospholipid microbubble of claim 3, wherein said omega-3 PUFA is selected from eicosapentaenoic acid (“EPA”), docosahexaenoic acid (“DHA”), or a combination thereof. 5. The phospholipid microbubble of claim 3, wherein said omega-3 PUFA precursor is an □-linolenic acid. 6. The phospholipid microbubble of claim 3, wherein said omega-3 PUFA-derived metabolite is selected from a resolvin, a neuroprotectin, a lipoxin, a neuroprostane, or a combination thereof. 7. The phospholipid microbubble of claim 1, wherein said paramagnetic gas is selected from a perfluorocarbon compound, xenon, or hyperpolarized xenon. 8. The phospholipid microbubble of claim 1, wherein said phospholipid microbubble in a micellar form or a liposomal form. 9. The phospholipid microbubble of claim 1, wherein said plurality of PUFA-containing phospholipids comprises at least one PS-DHA phospholipid, PS-EPA phospholipid, PC-DHA phospholipid, or PC-EPA phospholipid. 10. The phospholipid microbubble of claim 1, wherein said phospholipid microbubble further comprises a drug, a fat-soluble compound, an antioxidant, an antibody or a fragment thereof, or a specific ligand is conjugated to said phospholipid microbubble. 11. A method of delivering a prophylactically or therapeutically effective amount of PUFA to an area of disease or injury in a subject, comprising the steps of:
administering to said subject a plurality of phospholipid microbubbles which comprises a shell comprising a plurality of PUFA-containing phospholipids, and a core of paramagnetic gas surrounded by said shell comprising said plurality of PUFA-containing phospholipids; allowing said phospholipid microbubbles to reach said area of disease or injury; and applying ultrasound to said area of disease or injury to explode said phospholipid microbubbles. 12. The method of claim 11, wherein said area of disease or injury is the heart. 13. The method of claim 11, wherein said plurality of phospholipid microbubbles comprises a micellar form of said phospholipid microbubbles, a liposomal form of phospholipid microbubbles, or a combination thereof. 14. A method of preventing or treating a disease in a subject, comprising the steps of:
administering to said subject a prophylatically or therapeutic effective amount of a plurality of phospholipid microbubbles which comprises a shell comprising a plurality of PUFA-containing phospholipids, and a core of paramagnetic gas surrounded by said shell comprising said plurality of PUFA-containing phospholipids; and applying ultrasound to said phospholipid microbubbles to explode said phospholipid microbubbles in said subject. 15. The method of claim 14, wherein said disease is lupus erythematosis, multiple sclerosis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, diabetes mellitus, prostate cancer, breast cancer, depression, Alzheimer's disease or myocardial infarction. 16. The method of claim 14, wherein said administration is a single intravenous administration of said plurality of phospholipid microbubbles. 17. The method of claim 14, wherein said plurality of PUFA-containing phospholipids comprising at least one PS-DHA phospholipid, PS-EPA phospholipid, PC-DHA phospholipid, or PC-EPA phospholipid. 18. The method of claim 14, wherein said plurality of phospholipid microbubbles comprises a micellar form of said phospholipid microbubbles, a liposomal form of said phospholipid microbubbles, or a combination thereof. 19. The method of claim 14, wherein said administration is a co-administration of a micellar form of said phospholipid microbubbles and a liposomal form of said phospholipid microbubbles. 20. The method of claim 19, wherein said co-administration is simultaneous, concurrent or sequential administration of said micellar form of said phospholipid microbubbles and said liposomal form of said phospholipid microbubbles. | 1,600 |
829 | 13,380,839 | 1,631 | An electronic system is provided that simulates a glucose-insulin metabolic system of a T2DM or prediabetic subject, wherein the system includes a subsystem that models dynamic glucose concentration in a T2DM or prediabetic subject, including an electronic module that models endogenous glucose production (EGP(t)), or meal glucose rate of appearance (Ra(t>>, or glucose utilization (U(t)), or renal excretion of glucose (B(t)), a subsystem that models dynamic insulin concentration in said T2DM or prediabetic subject, including an electronic module that models insulin secretion (S(t)), an electronic database containing a population of virtual T2DM or prediabetic subjects, each virtual subject having a plurality of metabolic parameters, and a processing module that calculates an effect of variation of at least one metabolic parameter value on the glucose insulin metabolic system of a virtual subject by inputting the plurality of metabolic parameter values. | 1. An electronic system that simulates a glucose-insulin metabolic system of a T2DM or prediabetic subject, comprising:
a subsystem that models dynamic glucose concentration in a T2DM or prediabetic subject, including
an electronic module that models endogenous glucose production (EGP(t)),
an electronic module that models meal glucose rate of appearance (Ra(t)),
an electronic module that models glucose utilization (U(t)),
an electronic module that models renal excretion of glucose (E(t));
a subsystem that models dynamic insulin concentration in said T2DM or prediabetic subject, including
an electronic module that models insulin secretion (S(t));
an electronic database containing a population of virtual T2DM or prediabetic subjects, each virtual subject having a plurality of metabolic parameters with values within a range of values derived from in vivo T2DM or prediabetic subjects; and a processing module that calculates an effect of variation of at least one metabolic parameter value on the glucose-insulin metabolic system of a virtual subject by inputting said plurality of metabolic parameter values including said at least one varied metabolic parameter value into said glucose concentration and insulin concentration subsystems. 2. An electronic system as set forth in claim 1, wherein said glucose concentration subsystem models T2DM or prediabetic glucose concentration G(t) in accordance with the following equations:
{
G
.
p
(
t
)
=
EGP
(
t
)
+
Ra
(
t
)
-
U
ii
(
t
)
-
E
(
t
)
-
k
1
·
G
p
(
t
)
+
k
2
·
G
t
(
t
)
G
p
(
0
)
=
G
pb
G
.
t
(
t
)
=
-
U
id
(
t
)
+
k
1
·
G
p
(
t
)
-
k
2
·
G
t
(
t
)
G
t
(
0
)
=
G
tb
G
(
t
)
=
G
p
V
G
G
(
0
)
=
G
b 3. An electronic system as set forth in claim 2, wherein said EGP electronic module models EGP(t) according to the equation:
EGP(t)=k p1 −k p2 ·G p(t)−k p3 ·I d(t)−k p4 ·I po(t) EGP(0)=EGPb. 4. An electronic system as set forth in claim 3, wherein Id (pmol/l) is a delayed insulin signal realized with a chain of two compartments:
{
I
.
1
(
t
)
=
-
k
i
·
[
I
1
(
t
)
-
I
(
t
)
]
I
1
(
0
)
=
I
b
I
.
d
(
t
)
=
-
k
i
·
[
I
d
(
t
)
-
I
1
(
t
)
]
I
d
(
0
)
=
I
b 5. An electronic system as set forth in claim 3, wherein at basal steady state
k p1=EGPb +k p2 ·G pb +k p3 ·I b +k p4 ·I pob. 6. An electronic system as set forth in claim 2, wherein said glucose rate of appearance electronic module models Ra(t) according to the equations:
{
Q
sto
(
t
)
=
Q
sto
1
(
t
)
+
Q
sto
2
(
t
)
Q
sto
(
0
)
=
0
Q
.
sto
1
(
t
)
=
-
k
gri
·
Q
sto
1
(
t
)
+
D
·
δ
(
t
)
Q
sto
1
(
0
)
=
0
Q
.
sto
2
(
t
)
=
-
k
empt
(
Q
sto
)
·
Q
sto
2
(
t
)
+
k
gri
·
Q
sto
1
(
t
)
Q
sto
2
(
0
)
=
0
Q
.
gut
=
-
k
abs
·
Q
gut
(
t
)
+
k
empt
(
Q
sto
)
·
Q
sto
2
(
t
)
Q
gut
(
0
)
=
0
Ra
(
t
)
=
f
·
k
abs
·
Q
gut
(
t
)
BW
Ra
(
0
)
=
0 7. An electronic system as set forth in claim 2, wherein said glucose utilization electronic module models U(t) as the sum of insulin-independent utilization Uii(t)=Fcns, and insulin-dependent utilization
U
id
(
t
)
=
V
(
X
(
t
)
)
·
G
t
(
t
)
K
m
0
+
G
t
(
t
)
. 8. An electronic system as set forth in claim 7, wherein Vm(X(t)) is assumed to be linearly dependent from a remote insulin, X(t): Vm(X(t))=Vm0+Vmx·X(t). 9. An electronic system as set forth in claim 8, wherein X (pmol/L) is insulin in the interstitial fluid described by: {dot over (X)}(t)=−p2U·X(t)+p2U[I(t)−Ib] X(0)=0. 10. An electronic system as set forth in claim 2, wherein said renal excretion electronic module models renal excretion of glucose E(t) as
E
(
t
)
=
{
k
e
1
·
[
G
p
(
t
)
-
k
e
2
]
if
G
p
(
t
)
>
k
e
2
0
if
G
p
(
t
)
≤
k
e
2
. 11. An electronic system as set forth in claim 1, wherein said insulin concentration subsystem models T2DM or prediabetic insulin concentration I(t) in accordance with the following equations:
{
I
.
l
(
t
)
=
-
(
m
1
+
m
3
(
t
)
)
·
I
l
(
t
)
+
m
2
I
p
(
t
)
+
S
(
t
)
I
l
(
0
)
=
I
lb
I
.
p
(
t
)
=
-
(
m
2
+
m
4
)
·
I
p
(
t
)
+
m
1
·
I
l
(
t
)
I
p
(
0
)
=
I
pb
I
(
t
)
=
I
p
V
I
I
(
0
)
=
I
b 12. An electronic system as set forth in claim 11, wherein said insulin secretion electronic module models insulin secretion S(t) as S(t)=γ·Ipo(t), wherein
I
.
po
(
t
)
=
-
γ
·
I
po
(
t
)
+
S
po
(
t
)
I
po
(
0
)
=
I
pob
S
po
(
t
)
=
{
Y
(
t
)
+
K
·
G
.
(
t
)
+
S
b
for
G
.
>
0
Y
(
t
)
+
S
b
for
G
.
≤
0
and
Y
.
(
t
)
=
{
-
α
·
[
Y
(
t
)
-
β
·
(
G
(
t
)
-
h
)
]
if
β
·
(
G
(
t
)
-
h
)
≥
-
S
b
-
α
·
Y
(
t
)
-
α
·
S
b
if
β
·
(
G
(
t
)
-
h
)
<
-
S
b
;
Y
(
0
)
=
0. 13. An electronic system as set forth in claim 1, wherein a prediabetic subject is a subject with impaired fasting glucose (IFG). 14. An electronic system as set forth in claim 1, wherein a prediabetic subject is a subject with impaired glucose tolerance (IGT). 15. An electronic system as set forth in claim 1, wherein said plurality of metabolic parameters for each virtual subject includes at least one of the following parameters:
kabs=rate constant of glucose absorption by the intestine kmax=maximum rate constant of gastric emptying kmin=minimum rate constant of gastric emptying b=percentage of the dose for which kempt decreases at (kmax−kmin)/2 c=percentage of the dose for which kempt is back to (kmax−kmin)/2 ki=rate parameter accounting for delay between insulin signal and insulin action on the liver kp2=liver glucose effectiveness kp3=parameter governing amplitude of insulin action on the liver kp4=parameter governing amplitude of portal insulin action on the liver Vg=distribution volume of glucose Vmx=parameter governing amplitude of insulin action on glucose utilization km0=parameter governing glucose control on glucose utilization K2=rate parameter accounting for glucose transit from tissue to plasma K1=rate parameter accounting for glucose transit from plasma to tissue p2U=rate parameter accounting for delay between insulin signal and insulin action on glucose utilization Vi=distribution volume of insulin K=beta-cell responsivity to glucose rate of change β=beta-cell responsivity to glucose level α=rate parameter accounting for delay between glucose signal and insulin secretion m1=rate parameter of insulin kinetics m5=coefficient linking insulin hepatic extraction to insulin secretion rate Gb=basal plasma glucose concentration EGPb=basal endogenous glucose production BW=body weight Ib=basal plasma insulin concentration SRb=basal insulin secretion rate. 16. An electronic system as set forth in claim 1, wherein said subsystems and modules are implemented as computer executable software stored on a computer-readable storage medium and loaded into an electronic programmable computer. 17. An electronic system as set forth in claim 1, wherein said subsystems and modules are implemented as application specific integrated circuit modules. 18. A computer-executable program product embodied as computer executable code in a computer-readable storage medium, wherein said computer-executable program product simulates a glucose-insulin metabolic system of a T2DM or prediabetic subject, said computer-executable code comprising:
subsystem code that models dynamic glucose concentration in a T2DM or prediabetic subject, including
an electronic code module that models endogenous glucose production (EGP(t)),
an electronic code module that models meal glucose rate of appearance (Ra(t)),
an electronic code module that models glucose utilization (U(t)),
an electronic code module that models renal excretion of glucose (E(t));
subsystem code that models dynamic insulin concentration in said T2DM or prediabetic subject, including
an electronic code module that models insulin secretion (S(t));
an electronic database containing a population of virtual T2DM or prediabetic subjects, each virtual subject having a plurality of metabolic parameters with values within a range of values derived from in vivo T2DM or prediabetic subjects; and computer-executable code that calculates an effect of variation of at least one metabolic parameter value on the glucose-insulin metabolic system of a virtual subject by inputting said plurality of metabolic parameter values including said at least one varied metabolic parameter value into said glucose concentration and insulin concentration subsystems. 19. A computer-executable program product as set forth in claim 18, wherein said glucose concentration subsystem code models T2DM or prediabetic glucose concentration G(t) in accordance with the following equations:
{
G
.
p
(
t
)
=
EGP
(
t
)
+
Ra
(
t
)
-
U
ii
(
t
)
-
E
(
t
)
-
k
1
·
G
p
(
t
)
+
k
2
·
G
t
(
t
)
G
p
(
0
)
=
G
pb
G
.
t
(
t
)
=
-
U
id
(
t
)
+
k
1
·
G
p
(
t
)
-
k
2
·
G
t
(
t
)
G
t
(
0
)
=
G
tb
G
(
t
)
=
G
p
V
G
G
(
0
)
=
G
b 20. A computer-executable program product as set forth in claim 19, wherein said EGP code module models EGP(t) according to the equation:
EGP(t)=k p1 −k p2 ·G p(t)−k p3 ·I d(t)−k p4 ·I po(t) EGP(0)=EGPb. 21. A computer-executable program product as set forth in claim 20, wherein Id(pmol/l) is a delayed insulin signal realized with a chain of two compartments:
{
I
.
1
(
t
)
=
-
k
i
·
[
I
1
(
t
)
-
I
(
t
)
]
I
1
(
0
)
=
I
b
I
.
d
(
t
)
=
-
k
i
·
[
I
d
(
t
)
-
I
1
(
t
)
]
I
d
(
0
)
=
I
b 22. A computer-executable program product as set forth in claim 20, wherein at basal steady state kp1=EGPb+kp2·Gpb+kp3·I+kp4·Ipob. 23. A computer-executable program product as set forth in claim 19, wherein said glucose rate of appearance code module models Ra(t) according to the equations:
{
Q
sto
(
t
)
=
Q
sto
1
(
t
)
+
Q
sto
2
(
t
)
Q
sto
(
0
)
=
0
Q
.
sto
1
(
t
)
=
-
k
gri
·
Q
sto
1
(
t
)
+
D
·
δ
(
t
)
Q
sto
1
(
0
)
=
0
Q
.
sto
2
(
t
)
=
-
k
empt
(
Q
sto
)
·
Q
sto
2
(
t
)
+
k
gri
·
Q
sto
1
(
t
)
Q
sto
2
(
0
)
=
0
Q
.
gut
=
-
k
abs
·
Q
gut
(
t
)
+
k
empt
(
Q
sto
)
·
Q
sto
2
(
t
)
Q
gut
(
0
)
=
0
Ra
(
t
)
=
f
·
k
abs
·
Q
gut
(
t
)
BW
Ra
(
0
)
=
0 24. A computer-executable program product as set forth in claim 19, wherein said glucose utilization code module models U(t) as the sum of insulin-independent utilization Uii(t)=Fcns, and insulin-dependent utilization
U
id
(
t
)
=
V
(
X
(
t
)
)
·
G
t
(
t
)
K
m
0
+
G
t
(
t
)
. 25. A computer-executable program product as set forth in claim 24, wherein Vm(X(t)) is assumed to be linearly dependent from a remote insulin, X(t):
V m(X(t))=V m0 +V mx X(t). 26. A computer-executable program product as set forth in claim 25, wherein X (pmol/L) is insulin in the interstitial fluid described by:
{dot over (X)}(t)=−p 2U ·X(t)+p 2U [I(t)−I b ] X(0)=0. 27. A computer-executable program product as set forth in claim 18, wherein said renal excretion code module models renal excretion of glucose E(t) as
E
(
t
)
=
{
k
e
1
·
[
G
p
(
t
)
-
k
e
2
]
if
G
p
(
t
)
>
k
e
2
0
if
G
p
(
t
)
≤
k
e
2
. 28. A computer-executable program product as set forth in claim 18, wherein said insulin concentration subsystem code models T2DM or prediabetic insulin concentration I(t) in accordance with the following equations:
{
I
.
l
(
t
)
=
-
(
m
1
+
m
3
(
t
)
)
·
I
l
(
t
)
+
m
2
I
p
(
t
)
+
S
(
t
)
I
l
(
0
)
=
I
lb
I
.
p
(
t
)
=
-
(
m
2
+
m
4
)
·
I
p
(
t
)
+
m
1
·
I
l
(
t
)
I
p
(
0
)
=
I
pb
I
(
t
)
=
I
p
V
I
I
(
0
)
=
I
b 29. A computer-executable program product as set forth in claim 28, wherein said insulin secretion code module models insulin secretion S(t) as S(t)=γ·Ipo(t), wherein
I
.
po
(
t
)
=
-
γ
·
I
po
(
t
)
+
S
po
(
t
)
I
po
(
0
)
=
I
pob
S
po
(
t
)
=
{
Y
(
t
)
+
K
·
G
.
(
t
)
+
S
b
for
G
.
>
0
Y
(
t
)
+
S
b
for
G
.
≤
0
and
Y
.
(
t
)
=
{
-
α
·
[
Y
(
t
)
-
β
·
(
G
(
t
)
-
h
)
]
if
β
·
(
G
(
t
)
-
h
)
≥
-
S
b
-
α
·
Y
(
t
)
-
α
·
S
b
if
β
·
(
G
(
t
)
-
h
)
<
-
S
b
;
Y
(
0
)
=
0. 30. A computer-executable program product as set forth in claim 18, wherein a prediabetic subject is a subject with impaired fasting glucose (IFG). 31. A computer-executable program product as set forth in claim 18, wherein a prediabetic subject is a subject with impaired glucose tolerance (IGT). 32. A computer-executable program product as set forth in claim 18, wherein said plurality of metabolic parameters for each virtual subject includes at least one of the following parameters:
kabs=rate constant of glucose absorption by the intestine kmax=maximum rate constant of gastric emptying kmin=minimum rate constant of gastric emptying b=percentage of the dose for which kempt decreases at (kmax−kmin)/2 c=percentage of the dose for which kempt is back to (kmax−kmin)/2 ki=rate parameter accounting for delay between insulin signal and insulin action on the liver kp2=liver glucose effectiveness kp3=parameter governing amplitude of insulin action on the liver kp4=parameter governing amplitude of portal insulin action on the liver Vg=distribution volume of glucose Vmx=parameter governing amplitude of insulin action on glucose utilization km0=parameter governing glucose control on glucose utilization K2=rate parameter accounting for glucose transit from tissue to plasma K1=rate parameter accounting for glucose transit from plasma to tissue p2U=rate parameter accounting for delay between insulin signal and insulin action on glucose utilization Vi=distribution volume of insulin K=beta-cell responsivity to glucose rate of change β=beta-cell responsivity to glucose level α=rate parameter accounting for delay between glucose signal and insulin secretion m1=rate parameter of insulin kinetics m5=coefficient linking insulin hepatic extraction to insulin secretion rate Gb=basal plasma glucose concentration EGPb=basal endogenous glucose production BW=body weight Ib=basal plasma insulin concentration SRb=basal insulin secretion rate. | An electronic system is provided that simulates a glucose-insulin metabolic system of a T2DM or prediabetic subject, wherein the system includes a subsystem that models dynamic glucose concentration in a T2DM or prediabetic subject, including an electronic module that models endogenous glucose production (EGP(t)), or meal glucose rate of appearance (Ra(t>>, or glucose utilization (U(t)), or renal excretion of glucose (B(t)), a subsystem that models dynamic insulin concentration in said T2DM or prediabetic subject, including an electronic module that models insulin secretion (S(t)), an electronic database containing a population of virtual T2DM or prediabetic subjects, each virtual subject having a plurality of metabolic parameters, and a processing module that calculates an effect of variation of at least one metabolic parameter value on the glucose insulin metabolic system of a virtual subject by inputting the plurality of metabolic parameter values.1. An electronic system that simulates a glucose-insulin metabolic system of a T2DM or prediabetic subject, comprising:
a subsystem that models dynamic glucose concentration in a T2DM or prediabetic subject, including
an electronic module that models endogenous glucose production (EGP(t)),
an electronic module that models meal glucose rate of appearance (Ra(t)),
an electronic module that models glucose utilization (U(t)),
an electronic module that models renal excretion of glucose (E(t));
a subsystem that models dynamic insulin concentration in said T2DM or prediabetic subject, including
an electronic module that models insulin secretion (S(t));
an electronic database containing a population of virtual T2DM or prediabetic subjects, each virtual subject having a plurality of metabolic parameters with values within a range of values derived from in vivo T2DM or prediabetic subjects; and a processing module that calculates an effect of variation of at least one metabolic parameter value on the glucose-insulin metabolic system of a virtual subject by inputting said plurality of metabolic parameter values including said at least one varied metabolic parameter value into said glucose concentration and insulin concentration subsystems. 2. An electronic system as set forth in claim 1, wherein said glucose concentration subsystem models T2DM or prediabetic glucose concentration G(t) in accordance with the following equations:
{
G
.
p
(
t
)
=
EGP
(
t
)
+
Ra
(
t
)
-
U
ii
(
t
)
-
E
(
t
)
-
k
1
·
G
p
(
t
)
+
k
2
·
G
t
(
t
)
G
p
(
0
)
=
G
pb
G
.
t
(
t
)
=
-
U
id
(
t
)
+
k
1
·
G
p
(
t
)
-
k
2
·
G
t
(
t
)
G
t
(
0
)
=
G
tb
G
(
t
)
=
G
p
V
G
G
(
0
)
=
G
b 3. An electronic system as set forth in claim 2, wherein said EGP electronic module models EGP(t) according to the equation:
EGP(t)=k p1 −k p2 ·G p(t)−k p3 ·I d(t)−k p4 ·I po(t) EGP(0)=EGPb. 4. An electronic system as set forth in claim 3, wherein Id (pmol/l) is a delayed insulin signal realized with a chain of two compartments:
{
I
.
1
(
t
)
=
-
k
i
·
[
I
1
(
t
)
-
I
(
t
)
]
I
1
(
0
)
=
I
b
I
.
d
(
t
)
=
-
k
i
·
[
I
d
(
t
)
-
I
1
(
t
)
]
I
d
(
0
)
=
I
b 5. An electronic system as set forth in claim 3, wherein at basal steady state
k p1=EGPb +k p2 ·G pb +k p3 ·I b +k p4 ·I pob. 6. An electronic system as set forth in claim 2, wherein said glucose rate of appearance electronic module models Ra(t) according to the equations:
{
Q
sto
(
t
)
=
Q
sto
1
(
t
)
+
Q
sto
2
(
t
)
Q
sto
(
0
)
=
0
Q
.
sto
1
(
t
)
=
-
k
gri
·
Q
sto
1
(
t
)
+
D
·
δ
(
t
)
Q
sto
1
(
0
)
=
0
Q
.
sto
2
(
t
)
=
-
k
empt
(
Q
sto
)
·
Q
sto
2
(
t
)
+
k
gri
·
Q
sto
1
(
t
)
Q
sto
2
(
0
)
=
0
Q
.
gut
=
-
k
abs
·
Q
gut
(
t
)
+
k
empt
(
Q
sto
)
·
Q
sto
2
(
t
)
Q
gut
(
0
)
=
0
Ra
(
t
)
=
f
·
k
abs
·
Q
gut
(
t
)
BW
Ra
(
0
)
=
0 7. An electronic system as set forth in claim 2, wherein said glucose utilization electronic module models U(t) as the sum of insulin-independent utilization Uii(t)=Fcns, and insulin-dependent utilization
U
id
(
t
)
=
V
(
X
(
t
)
)
·
G
t
(
t
)
K
m
0
+
G
t
(
t
)
. 8. An electronic system as set forth in claim 7, wherein Vm(X(t)) is assumed to be linearly dependent from a remote insulin, X(t): Vm(X(t))=Vm0+Vmx·X(t). 9. An electronic system as set forth in claim 8, wherein X (pmol/L) is insulin in the interstitial fluid described by: {dot over (X)}(t)=−p2U·X(t)+p2U[I(t)−Ib] X(0)=0. 10. An electronic system as set forth in claim 2, wherein said renal excretion electronic module models renal excretion of glucose E(t) as
E
(
t
)
=
{
k
e
1
·
[
G
p
(
t
)
-
k
e
2
]
if
G
p
(
t
)
>
k
e
2
0
if
G
p
(
t
)
≤
k
e
2
. 11. An electronic system as set forth in claim 1, wherein said insulin concentration subsystem models T2DM or prediabetic insulin concentration I(t) in accordance with the following equations:
{
I
.
l
(
t
)
=
-
(
m
1
+
m
3
(
t
)
)
·
I
l
(
t
)
+
m
2
I
p
(
t
)
+
S
(
t
)
I
l
(
0
)
=
I
lb
I
.
p
(
t
)
=
-
(
m
2
+
m
4
)
·
I
p
(
t
)
+
m
1
·
I
l
(
t
)
I
p
(
0
)
=
I
pb
I
(
t
)
=
I
p
V
I
I
(
0
)
=
I
b 12. An electronic system as set forth in claim 11, wherein said insulin secretion electronic module models insulin secretion S(t) as S(t)=γ·Ipo(t), wherein
I
.
po
(
t
)
=
-
γ
·
I
po
(
t
)
+
S
po
(
t
)
I
po
(
0
)
=
I
pob
S
po
(
t
)
=
{
Y
(
t
)
+
K
·
G
.
(
t
)
+
S
b
for
G
.
>
0
Y
(
t
)
+
S
b
for
G
.
≤
0
and
Y
.
(
t
)
=
{
-
α
·
[
Y
(
t
)
-
β
·
(
G
(
t
)
-
h
)
]
if
β
·
(
G
(
t
)
-
h
)
≥
-
S
b
-
α
·
Y
(
t
)
-
α
·
S
b
if
β
·
(
G
(
t
)
-
h
)
<
-
S
b
;
Y
(
0
)
=
0. 13. An electronic system as set forth in claim 1, wherein a prediabetic subject is a subject with impaired fasting glucose (IFG). 14. An electronic system as set forth in claim 1, wherein a prediabetic subject is a subject with impaired glucose tolerance (IGT). 15. An electronic system as set forth in claim 1, wherein said plurality of metabolic parameters for each virtual subject includes at least one of the following parameters:
kabs=rate constant of glucose absorption by the intestine kmax=maximum rate constant of gastric emptying kmin=minimum rate constant of gastric emptying b=percentage of the dose for which kempt decreases at (kmax−kmin)/2 c=percentage of the dose for which kempt is back to (kmax−kmin)/2 ki=rate parameter accounting for delay between insulin signal and insulin action on the liver kp2=liver glucose effectiveness kp3=parameter governing amplitude of insulin action on the liver kp4=parameter governing amplitude of portal insulin action on the liver Vg=distribution volume of glucose Vmx=parameter governing amplitude of insulin action on glucose utilization km0=parameter governing glucose control on glucose utilization K2=rate parameter accounting for glucose transit from tissue to plasma K1=rate parameter accounting for glucose transit from plasma to tissue p2U=rate parameter accounting for delay between insulin signal and insulin action on glucose utilization Vi=distribution volume of insulin K=beta-cell responsivity to glucose rate of change β=beta-cell responsivity to glucose level α=rate parameter accounting for delay between glucose signal and insulin secretion m1=rate parameter of insulin kinetics m5=coefficient linking insulin hepatic extraction to insulin secretion rate Gb=basal plasma glucose concentration EGPb=basal endogenous glucose production BW=body weight Ib=basal plasma insulin concentration SRb=basal insulin secretion rate. 16. An electronic system as set forth in claim 1, wherein said subsystems and modules are implemented as computer executable software stored on a computer-readable storage medium and loaded into an electronic programmable computer. 17. An electronic system as set forth in claim 1, wherein said subsystems and modules are implemented as application specific integrated circuit modules. 18. A computer-executable program product embodied as computer executable code in a computer-readable storage medium, wherein said computer-executable program product simulates a glucose-insulin metabolic system of a T2DM or prediabetic subject, said computer-executable code comprising:
subsystem code that models dynamic glucose concentration in a T2DM or prediabetic subject, including
an electronic code module that models endogenous glucose production (EGP(t)),
an electronic code module that models meal glucose rate of appearance (Ra(t)),
an electronic code module that models glucose utilization (U(t)),
an electronic code module that models renal excretion of glucose (E(t));
subsystem code that models dynamic insulin concentration in said T2DM or prediabetic subject, including
an electronic code module that models insulin secretion (S(t));
an electronic database containing a population of virtual T2DM or prediabetic subjects, each virtual subject having a plurality of metabolic parameters with values within a range of values derived from in vivo T2DM or prediabetic subjects; and computer-executable code that calculates an effect of variation of at least one metabolic parameter value on the glucose-insulin metabolic system of a virtual subject by inputting said plurality of metabolic parameter values including said at least one varied metabolic parameter value into said glucose concentration and insulin concentration subsystems. 19. A computer-executable program product as set forth in claim 18, wherein said glucose concentration subsystem code models T2DM or prediabetic glucose concentration G(t) in accordance with the following equations:
{
G
.
p
(
t
)
=
EGP
(
t
)
+
Ra
(
t
)
-
U
ii
(
t
)
-
E
(
t
)
-
k
1
·
G
p
(
t
)
+
k
2
·
G
t
(
t
)
G
p
(
0
)
=
G
pb
G
.
t
(
t
)
=
-
U
id
(
t
)
+
k
1
·
G
p
(
t
)
-
k
2
·
G
t
(
t
)
G
t
(
0
)
=
G
tb
G
(
t
)
=
G
p
V
G
G
(
0
)
=
G
b 20. A computer-executable program product as set forth in claim 19, wherein said EGP code module models EGP(t) according to the equation:
EGP(t)=k p1 −k p2 ·G p(t)−k p3 ·I d(t)−k p4 ·I po(t) EGP(0)=EGPb. 21. A computer-executable program product as set forth in claim 20, wherein Id(pmol/l) is a delayed insulin signal realized with a chain of two compartments:
{
I
.
1
(
t
)
=
-
k
i
·
[
I
1
(
t
)
-
I
(
t
)
]
I
1
(
0
)
=
I
b
I
.
d
(
t
)
=
-
k
i
·
[
I
d
(
t
)
-
I
1
(
t
)
]
I
d
(
0
)
=
I
b 22. A computer-executable program product as set forth in claim 20, wherein at basal steady state kp1=EGPb+kp2·Gpb+kp3·I+kp4·Ipob. 23. A computer-executable program product as set forth in claim 19, wherein said glucose rate of appearance code module models Ra(t) according to the equations:
{
Q
sto
(
t
)
=
Q
sto
1
(
t
)
+
Q
sto
2
(
t
)
Q
sto
(
0
)
=
0
Q
.
sto
1
(
t
)
=
-
k
gri
·
Q
sto
1
(
t
)
+
D
·
δ
(
t
)
Q
sto
1
(
0
)
=
0
Q
.
sto
2
(
t
)
=
-
k
empt
(
Q
sto
)
·
Q
sto
2
(
t
)
+
k
gri
·
Q
sto
1
(
t
)
Q
sto
2
(
0
)
=
0
Q
.
gut
=
-
k
abs
·
Q
gut
(
t
)
+
k
empt
(
Q
sto
)
·
Q
sto
2
(
t
)
Q
gut
(
0
)
=
0
Ra
(
t
)
=
f
·
k
abs
·
Q
gut
(
t
)
BW
Ra
(
0
)
=
0 24. A computer-executable program product as set forth in claim 19, wherein said glucose utilization code module models U(t) as the sum of insulin-independent utilization Uii(t)=Fcns, and insulin-dependent utilization
U
id
(
t
)
=
V
(
X
(
t
)
)
·
G
t
(
t
)
K
m
0
+
G
t
(
t
)
. 25. A computer-executable program product as set forth in claim 24, wherein Vm(X(t)) is assumed to be linearly dependent from a remote insulin, X(t):
V m(X(t))=V m0 +V mx X(t). 26. A computer-executable program product as set forth in claim 25, wherein X (pmol/L) is insulin in the interstitial fluid described by:
{dot over (X)}(t)=−p 2U ·X(t)+p 2U [I(t)−I b ] X(0)=0. 27. A computer-executable program product as set forth in claim 18, wherein said renal excretion code module models renal excretion of glucose E(t) as
E
(
t
)
=
{
k
e
1
·
[
G
p
(
t
)
-
k
e
2
]
if
G
p
(
t
)
>
k
e
2
0
if
G
p
(
t
)
≤
k
e
2
. 28. A computer-executable program product as set forth in claim 18, wherein said insulin concentration subsystem code models T2DM or prediabetic insulin concentration I(t) in accordance with the following equations:
{
I
.
l
(
t
)
=
-
(
m
1
+
m
3
(
t
)
)
·
I
l
(
t
)
+
m
2
I
p
(
t
)
+
S
(
t
)
I
l
(
0
)
=
I
lb
I
.
p
(
t
)
=
-
(
m
2
+
m
4
)
·
I
p
(
t
)
+
m
1
·
I
l
(
t
)
I
p
(
0
)
=
I
pb
I
(
t
)
=
I
p
V
I
I
(
0
)
=
I
b 29. A computer-executable program product as set forth in claim 28, wherein said insulin secretion code module models insulin secretion S(t) as S(t)=γ·Ipo(t), wherein
I
.
po
(
t
)
=
-
γ
·
I
po
(
t
)
+
S
po
(
t
)
I
po
(
0
)
=
I
pob
S
po
(
t
)
=
{
Y
(
t
)
+
K
·
G
.
(
t
)
+
S
b
for
G
.
>
0
Y
(
t
)
+
S
b
for
G
.
≤
0
and
Y
.
(
t
)
=
{
-
α
·
[
Y
(
t
)
-
β
·
(
G
(
t
)
-
h
)
]
if
β
·
(
G
(
t
)
-
h
)
≥
-
S
b
-
α
·
Y
(
t
)
-
α
·
S
b
if
β
·
(
G
(
t
)
-
h
)
<
-
S
b
;
Y
(
0
)
=
0. 30. A computer-executable program product as set forth in claim 18, wherein a prediabetic subject is a subject with impaired fasting glucose (IFG). 31. A computer-executable program product as set forth in claim 18, wherein a prediabetic subject is a subject with impaired glucose tolerance (IGT). 32. A computer-executable program product as set forth in claim 18, wherein said plurality of metabolic parameters for each virtual subject includes at least one of the following parameters:
kabs=rate constant of glucose absorption by the intestine kmax=maximum rate constant of gastric emptying kmin=minimum rate constant of gastric emptying b=percentage of the dose for which kempt decreases at (kmax−kmin)/2 c=percentage of the dose for which kempt is back to (kmax−kmin)/2 ki=rate parameter accounting for delay between insulin signal and insulin action on the liver kp2=liver glucose effectiveness kp3=parameter governing amplitude of insulin action on the liver kp4=parameter governing amplitude of portal insulin action on the liver Vg=distribution volume of glucose Vmx=parameter governing amplitude of insulin action on glucose utilization km0=parameter governing glucose control on glucose utilization K2=rate parameter accounting for glucose transit from tissue to plasma K1=rate parameter accounting for glucose transit from plasma to tissue p2U=rate parameter accounting for delay between insulin signal and insulin action on glucose utilization Vi=distribution volume of insulin K=beta-cell responsivity to glucose rate of change β=beta-cell responsivity to glucose level α=rate parameter accounting for delay between glucose signal and insulin secretion m1=rate parameter of insulin kinetics m5=coefficient linking insulin hepatic extraction to insulin secretion rate Gb=basal plasma glucose concentration EGPb=basal endogenous glucose production BW=body weight Ib=basal plasma insulin concentration SRb=basal insulin secretion rate. | 1,600 |
830 | 14,163,948 | 1,613 | Disclosed herein are embodiments of a composition useful for treating and/or preventing dry eye disorders. The disclosed composition comprises components that maintain the composition's chemical and/or physical properties thereby providing a composition suitable for use. | 1. A composition for ophthalmic administration, comprising greater than 2% w/v to about 15% w/v polyvinylpyrrolidone. 2. The composition of claim 1, wherein the polyvinylpyrrolidone has an average molecular weight of from about 40,000 to about 60,000. 3. The composition of claim 1, wherein the polyvinylpyrrolidone contains less than about 400 ppm peroxide. 4. The composition of claim 1, wherein the polyvinylpyrrolidone is K30 grade. 5. The composition of claim 1, wherein the polyvinylpyrrolidone is present in an amount ranging from greater than 2% w/v to about 10% w/v. 6. The composition of claim 1, further comprising a buffer and a tonicity agent. 7. The composition of claim 6, wherein the buffer has a concentration ranging from about 20 mM to about 30 mM. 8. The composition of claim 6, wherein the buffer is a phosphate buffer comprising monobasic sodium phosphate monohydrate and dibasic sodium phosphate anhydrate. 9. The composition of claim 1, having a pH ranging from about 7.0 to about 8.0. 10. The composition of claim 6, wherein the tonicity agent is present in an amount sufficient to provide osmolality of from about 230 mOsm/kg to about 320 mOsm/kg. 11. The composition of claim 6, wherein the tonicity agent is present in an amount ranging from about 1% w/v to about 2% w/v. 12. The composition of claim 6, wherein the tonicity agent is propylene glycol. 13. The composition of claim 1, further comprising at least one additional pharmacologically active compound. 14. The composition of claim 13, wherein the at least one additional pharmacologically active compound is capable of treating, ameliorating, and/or preventing an eye disease or disorder. 15. The composition of claim 13, wherein the at least one additional pharmacologically active compound is
or a pharmaceutically acceptable salt, prodrug, N-oxide, or solvate thereof. 16. The composition of claim 13, wherein the at least one additional pharmacologically active compound is a corticosteroid, an antihistamine, an antibiotic, an anti-inflammatory, an antiviral, a glaucoma medication, or combinations thereof. 17. The composition of claim 13, wherein the at least one additional pharmacologically active compound is a corticosteroid, an antihistamine, an antibiotic, an anti-inflammatory, an antiviral, a glaucoma medication, a compound having a formula
or a pharmaceutically acceptable salt, prodrug, N-oxide, or solvate thereof, or a combination thereof. 18. The composition of claim 1, comprising greater than 2% w/v polyvinylpyrrolidone; and further comprising a buffer having a concentration of about 20 mM to about 30 mM, and 1% w/v to about 2% w/v of a tonicity agent. 19. The composition of claim 1, comprising about 7.5% w/v polyvinylpyrrolidone K30, and further comprising a monobasic sodium phosphate monohydrate/dibasic sodium phosphate anhydrate buffer having a concentration of 25 mM, and 1.6% w/v propylene glycol. 20. A composition formulated for administration to a subject suffering from an eye disease or disorder, the composition comprising an effective amount of a compound having a formula
or a pharmaceutically acceptable salt, prodrug, N-oxide, or solvate thereof. 21. The composition of claim 20, further comprising a solubilizer, a buffer, a tonicity agent, or combinations thereof. 22. The composition of claim 20, wherein the solubilizer is selected from propylene glycol monocaprylate, oleoyl macrogol-6 glycerides, oleoyl polyoxyl-6 glycerides, caprylocaproyl macrogol-8 glycerides, caprylocaproyl polyoxyl-8 glycerides, propylene glycol monolaurate, polyglyceryl-3 dioleate, polyvinylpyrrolidone, or combinations thereof. 23. The composition of claim 20, wherein physical and chemical properties of the compound, the solubilizer, the buffer, and the tonicity agent are optimized to prevent precipitation of the compound having a formula 24. The composition of claim 20, wherein the compound having the formula
is present in an amount less than about 300 μg/mL. 25. The composition of claim 20, wherein the pharmaceutically acceptable salt is a choline salt. 26. The composition of claim 20, wherein the effective amount of the compound ranges from about 1 mg/mL to about 25 mg/mL. 27. The composition of claim 20, wherein the effective amount of the compound ranges from about 2 mg/mL to about 20 mg/mL. 28. The composition of claim 20, wherein the eye disease or disorder is selected from keratitis sicca, diabetic retinopathy, macular degeneration uveitis, allergic conjunctivitis, glaucoma, rosacea, or combinations thereof. 29. The composition of claim 20, comprising about 1% w/v to about 10% w/v polyvinylpyrrolidone K30, and further comprising a monobasic sodium phosphate monohydrate/dibasic sodium phosphate anhydrate buffer having a concentration of about 20 mM to about 30 mM, about 1% w/v to about 2% w/v propylene glycol, and about 2 mg/mL to about 5 mg/mL of a compound having a formula 30. A method for treating an eye disease or disorder, comprising administering to a subject a composition comprising greater than 2% w/v to about 15% polyvinylpyrrolidone. 31. The method of claim 30, wherein the polyvinylpyrrolidone is added in combination with a buffer and a tonicity agent. 32. The method of claim 30, further comprising administering a compound having a formula
or a pharmaceutically acceptable salt, prodrug, N-oxide, or solvate thereof. 33. A method for treating an eye disease or disorder, comprising administering to a subject a composition comprising an effective amount of compound having a formula
or a pharmaceutically acceptable salt, prodrug, N-oxide, or solvate thereof. 34. The method of claim 33, wherein the composition further comprises a solubilizer, a buffer, a tonicity agent, and combinations thereof. 35. The method of claim 33, further comprising applying the composition to the subject's eye via topical placement or injection. 36. The method of claim 33 wherein topical placement comprises placing one or more drops of the composition onto the subject's eye. 37. The method of claim 33, further comprising performing punctal occlusion, fitting the subject with scleral or semi-scleral contact lenses that create a fluid-filled layer over the cornea, or combinations thereof. 38. The method of claim 33, further comprising administering one or more pharmacologically active agents selected from a corticosteroid, an antihistamine, an antibiotic, an anti-inflammatory, an antiviral, a glaucoma medication, or combinations thereof. 39. The method of claim 33, wherein the eye disease or disorder is selected from dry eye syndrome, diabetic retinopathy, macular degeneration uveitis, allergic conjunctivitis, glaucoma, rosacea, or combinations thereof. 40. The method of claim 33, wherein the subject is suffering from the eye disease or disorder or displays symptoms associated with the eye disease or disorder. | Disclosed herein are embodiments of a composition useful for treating and/or preventing dry eye disorders. The disclosed composition comprises components that maintain the composition's chemical and/or physical properties thereby providing a composition suitable for use.1. A composition for ophthalmic administration, comprising greater than 2% w/v to about 15% w/v polyvinylpyrrolidone. 2. The composition of claim 1, wherein the polyvinylpyrrolidone has an average molecular weight of from about 40,000 to about 60,000. 3. The composition of claim 1, wherein the polyvinylpyrrolidone contains less than about 400 ppm peroxide. 4. The composition of claim 1, wherein the polyvinylpyrrolidone is K30 grade. 5. The composition of claim 1, wherein the polyvinylpyrrolidone is present in an amount ranging from greater than 2% w/v to about 10% w/v. 6. The composition of claim 1, further comprising a buffer and a tonicity agent. 7. The composition of claim 6, wherein the buffer has a concentration ranging from about 20 mM to about 30 mM. 8. The composition of claim 6, wherein the buffer is a phosphate buffer comprising monobasic sodium phosphate monohydrate and dibasic sodium phosphate anhydrate. 9. The composition of claim 1, having a pH ranging from about 7.0 to about 8.0. 10. The composition of claim 6, wherein the tonicity agent is present in an amount sufficient to provide osmolality of from about 230 mOsm/kg to about 320 mOsm/kg. 11. The composition of claim 6, wherein the tonicity agent is present in an amount ranging from about 1% w/v to about 2% w/v. 12. The composition of claim 6, wherein the tonicity agent is propylene glycol. 13. The composition of claim 1, further comprising at least one additional pharmacologically active compound. 14. The composition of claim 13, wherein the at least one additional pharmacologically active compound is capable of treating, ameliorating, and/or preventing an eye disease or disorder. 15. The composition of claim 13, wherein the at least one additional pharmacologically active compound is
or a pharmaceutically acceptable salt, prodrug, N-oxide, or solvate thereof. 16. The composition of claim 13, wherein the at least one additional pharmacologically active compound is a corticosteroid, an antihistamine, an antibiotic, an anti-inflammatory, an antiviral, a glaucoma medication, or combinations thereof. 17. The composition of claim 13, wherein the at least one additional pharmacologically active compound is a corticosteroid, an antihistamine, an antibiotic, an anti-inflammatory, an antiviral, a glaucoma medication, a compound having a formula
or a pharmaceutically acceptable salt, prodrug, N-oxide, or solvate thereof, or a combination thereof. 18. The composition of claim 1, comprising greater than 2% w/v polyvinylpyrrolidone; and further comprising a buffer having a concentration of about 20 mM to about 30 mM, and 1% w/v to about 2% w/v of a tonicity agent. 19. The composition of claim 1, comprising about 7.5% w/v polyvinylpyrrolidone K30, and further comprising a monobasic sodium phosphate monohydrate/dibasic sodium phosphate anhydrate buffer having a concentration of 25 mM, and 1.6% w/v propylene glycol. 20. A composition formulated for administration to a subject suffering from an eye disease or disorder, the composition comprising an effective amount of a compound having a formula
or a pharmaceutically acceptable salt, prodrug, N-oxide, or solvate thereof. 21. The composition of claim 20, further comprising a solubilizer, a buffer, a tonicity agent, or combinations thereof. 22. The composition of claim 20, wherein the solubilizer is selected from propylene glycol monocaprylate, oleoyl macrogol-6 glycerides, oleoyl polyoxyl-6 glycerides, caprylocaproyl macrogol-8 glycerides, caprylocaproyl polyoxyl-8 glycerides, propylene glycol monolaurate, polyglyceryl-3 dioleate, polyvinylpyrrolidone, or combinations thereof. 23. The composition of claim 20, wherein physical and chemical properties of the compound, the solubilizer, the buffer, and the tonicity agent are optimized to prevent precipitation of the compound having a formula 24. The composition of claim 20, wherein the compound having the formula
is present in an amount less than about 300 μg/mL. 25. The composition of claim 20, wherein the pharmaceutically acceptable salt is a choline salt. 26. The composition of claim 20, wherein the effective amount of the compound ranges from about 1 mg/mL to about 25 mg/mL. 27. The composition of claim 20, wherein the effective amount of the compound ranges from about 2 mg/mL to about 20 mg/mL. 28. The composition of claim 20, wherein the eye disease or disorder is selected from keratitis sicca, diabetic retinopathy, macular degeneration uveitis, allergic conjunctivitis, glaucoma, rosacea, or combinations thereof. 29. The composition of claim 20, comprising about 1% w/v to about 10% w/v polyvinylpyrrolidone K30, and further comprising a monobasic sodium phosphate monohydrate/dibasic sodium phosphate anhydrate buffer having a concentration of about 20 mM to about 30 mM, about 1% w/v to about 2% w/v propylene glycol, and about 2 mg/mL to about 5 mg/mL of a compound having a formula 30. A method for treating an eye disease or disorder, comprising administering to a subject a composition comprising greater than 2% w/v to about 15% polyvinylpyrrolidone. 31. The method of claim 30, wherein the polyvinylpyrrolidone is added in combination with a buffer and a tonicity agent. 32. The method of claim 30, further comprising administering a compound having a formula
or a pharmaceutically acceptable salt, prodrug, N-oxide, or solvate thereof. 33. A method for treating an eye disease or disorder, comprising administering to a subject a composition comprising an effective amount of compound having a formula
or a pharmaceutically acceptable salt, prodrug, N-oxide, or solvate thereof. 34. The method of claim 33, wherein the composition further comprises a solubilizer, a buffer, a tonicity agent, and combinations thereof. 35. The method of claim 33, further comprising applying the composition to the subject's eye via topical placement or injection. 36. The method of claim 33 wherein topical placement comprises placing one or more drops of the composition onto the subject's eye. 37. The method of claim 33, further comprising performing punctal occlusion, fitting the subject with scleral or semi-scleral contact lenses that create a fluid-filled layer over the cornea, or combinations thereof. 38. The method of claim 33, further comprising administering one or more pharmacologically active agents selected from a corticosteroid, an antihistamine, an antibiotic, an anti-inflammatory, an antiviral, a glaucoma medication, or combinations thereof. 39. The method of claim 33, wherein the eye disease or disorder is selected from dry eye syndrome, diabetic retinopathy, macular degeneration uveitis, allergic conjunctivitis, glaucoma, rosacea, or combinations thereof. 40. The method of claim 33, wherein the subject is suffering from the eye disease or disorder or displays symptoms associated with the eye disease or disorder. | 1,600 |
831 | 12,479,576 | 1,612 | The present invention is directed to methods of treating nasal and/or ophthalmic diseases, symptoms, or disorders that are therapeutically responsive to corticosteroid therapy by delivering aqueous solution formulations comprising a corticosteroid to nasal and ophthalmic tissues. The invention is also directed to methods, systems, devices, and compositions for delivering aqueous solution formulations comprising a corticosteroid and an antihistamine to nasal and ophthalmic tissues. | 1. A method for treating an allergic symptom or disorder in a subject in need thereof, comprising: nasally administering to the subject a corticosteroid solution comprising a therapeutically effective amount of a corticosteroid, SAE-CD, and a pharmaceutically acceptable aqueous liquid carrier,
wherein the allergic symptom or disorder includes a non-nasal symptom selected from the group consisting of itchy/gritty eyes, tearing/watery eyes, red/burning eyes, itchy ears/palate and combinations thereof. 2. The method of claim 1, wherein the allergic symptom or disorder further comprises symptoms selected from the group consisting of runny nose, itchy nose, nasal congestion, sneezing and combinations thereof. 3. The method of claim 1, wherein said corticosteroid solution further comprises a therapeutically effective amount of an antihistamine. 4. The method of claim 3, wherein the antihistamine is azelastine, olopatadine pharmaceutically acceptable salts thereof, pharmaceutically active metabolites thereof, optically active isomers or racemates, and mixtures thereof; the corticosteroid is budesonide; and the SAE-CD is CAPTISOL cyclodextrin (sulfobutylether β-cyclodextrin). 5. The method of claim 4, wherein the azelastine is present in an amount of about 30 μg to about 275 μg per unit dose, or the olopatadine is present in an amount of about 150 μg to about 1400 μg per unit dose, the budesonide is present in an amount of about 5 μg to about 500 μg per unit dose, and the CAPTISOL is present in an amount of 100 μg to 100 mg per unit dose. 6. The method of claim 1, wherein the corticosteroid solution is administered 1-2 times per day. 7. A method for treating an ocular symptom or disorder in a subject in need thereof, comprising: nasally administering to the subject a corticosteroid solution comprising a therapeutically effective amount of a corticosteroid, SAE-CD, and a pharmaceutically acceptable aqueous liquid carrier,
wherein the allergic symptom or disorder includes a non-nasal symptom selected from the group consisting of itchy/gritty eyes, tearing/watery eyes, red/burning eyes, itchy ears/palate and combinations thereof. 8. The method of claim 7, wherein said corticosteroid solution further comprises a therapeutically effective amount of an antihistamine. 9. The method of claim 8, wherein the antihistamine is azelastine, olopatadine, pharmaceutically acceptable salts thereof, pharmaceutically active metabolites thereof, optically active isomers or racemates, and mixtures thereof; the corticosteroid is budesonide; and the SAE-CD is CAPTISOL cyclodextrin (sulfobutylether β-cyclodextrin). 10. The method of claim 9, wherein the azelastine is present in an amount of about 30 μg to about 275 μg per unit dose or the olopatadine is present in an amount of about 150 μg to about 1400 μg per unit dose, the budesonide is present in an amount of about 5 μg to about 500 μg per unit dose, and the CAPTISOL is present in an amount of 100 μg to 100 mg per unit dose. 11. The method of claim 7, wherein the corticosteroid solution is administered 1-2 times per day. 12. A method for treating ocular inflammation in a subject in need thereof, comprising: ophthalmically administering to the subject a corticosteroid solution comprising a therapeutically effective amount of a corticosteroid, SAE-CD, and a pharmaceutically acceptable aqueous liquid carrier,
wherein the corticosteroid solution provides more rapid reduction in ocular inflammation compared with a corticosteroid suspension at the same unit dose. 13. The method of claim 12, wherein said corticosteroid solution further comprises a therapeutically effective amount of an antihistamine. 14. The method of claim 13, wherein the antihistamine is azelastine, olopatadine, pharmaceutically acceptable salts thereof, pharmaceutically active metabolites thereof, optically active isomers or racemates, and mixtures thereof; the corticosteroid is budesonide; and the SAE-CD is CAPTISOL cyclodextrin (sulfobutylether β-cyclodextrin). 15. The method of claim 14, wherein the azelastine is present in an amount of about 30 μg to about 275 μg per unit dose or the olopatadine is present in an amount of about 150 μg to about 1400 μg per unit dose, the budesonide is present in an amount of about 5 μg to about 500 μg per unit dose, and the CAPTISOL is present in an amount of 100 μg to 100 mg per unit dose. 16. The method of claim 12, wherein the corticosteroid solution is administered 1-2 times per day. 17. A metered dose device for nasal or ophthalmic administration comprising: corticosteroid solution comprising a therapeutically effective amount of corticosteroid, a therapeutically effective amount of an antihistamine, SAE-CD, and a pharmaceutically acceptable aqueous liquid carrier. 18. The device of claim 17, wherein the antihistamine is azelastine, olopatadine, pharmaceutically acceptable salts thereof, pharmaceutically active metabolites thereof, optically active isomers or racemates, and mixtures thereof; the corticosteroid is budesonide; and the SAE-CD is CAPTISOL cyclodextrin (sulfobutylether β-cyclodextrin). 19. The device of claim 18, wherein the azelastine is present in an amount of about 30 μg to about 275 μg per unit dose or the olopatadine is present in an amount of about 150 μg to about 1400 μg per unit dose, the budesonide is present in an amount of about 5 μg to about 500 μg per unit dose, and the CAPTISOL is present in an amount of 100 μg to 100 mg per unit dose. 20. A system for treating an allergic symptom comprising: corticosteroid solution comprising a therapeutically effective amount of a corticosteroid, a therapeutically effective amount of an antihistamine, SAE-CD and a pharmaceutically acceptable aqueous liquid carrier, and a metered dose device for nasal or ophthalmic administration of the corticosteroid solution to the subject. 21. The system of claim 20, wherein the allergic symptom is selected from the group consisting of runny nose, itchy nose, nasal congestion, sneezing, itchy/gritty eyes, red/burning eyes, tearing/watery eyes and itchy ears/palate and combinations thereof. 22. The system of claim 21, wherein the allergic symptom is selected from the group consisting of itchy/gritty eyes, tearing/watery eyes, red/burning eyes, itchy ears and palate and combinations thereof. 23. The system of claim 20, wherein the antihistamine is azelastine, olopatadine, pharmaceutically acceptable salts thereof, pharmaceutically active metabolites thereof, optically active isomers or racemates, and mixtures thereof; the corticosteroid is budesonide; and the SAE-CD is CAPTISOL cyclodextrin (sulfobutylether β-cyclodextrin). 24. The system of claim 23 wherein the azelastine is present in an amount of about 30 μg to about 275 μg per unit dose or the olopatadine is present in an amount of about 150 μg to about 1400 μg per unit dose, the budesonide is present in an amount of about 5 μg to about 500 μg per unit dose, and the CAPTISOL is present in an amount of 100 μg to 100 mg per unit dose. | The present invention is directed to methods of treating nasal and/or ophthalmic diseases, symptoms, or disorders that are therapeutically responsive to corticosteroid therapy by delivering aqueous solution formulations comprising a corticosteroid to nasal and ophthalmic tissues. The invention is also directed to methods, systems, devices, and compositions for delivering aqueous solution formulations comprising a corticosteroid and an antihistamine to nasal and ophthalmic tissues.1. A method for treating an allergic symptom or disorder in a subject in need thereof, comprising: nasally administering to the subject a corticosteroid solution comprising a therapeutically effective amount of a corticosteroid, SAE-CD, and a pharmaceutically acceptable aqueous liquid carrier,
wherein the allergic symptom or disorder includes a non-nasal symptom selected from the group consisting of itchy/gritty eyes, tearing/watery eyes, red/burning eyes, itchy ears/palate and combinations thereof. 2. The method of claim 1, wherein the allergic symptom or disorder further comprises symptoms selected from the group consisting of runny nose, itchy nose, nasal congestion, sneezing and combinations thereof. 3. The method of claim 1, wherein said corticosteroid solution further comprises a therapeutically effective amount of an antihistamine. 4. The method of claim 3, wherein the antihistamine is azelastine, olopatadine pharmaceutically acceptable salts thereof, pharmaceutically active metabolites thereof, optically active isomers or racemates, and mixtures thereof; the corticosteroid is budesonide; and the SAE-CD is CAPTISOL cyclodextrin (sulfobutylether β-cyclodextrin). 5. The method of claim 4, wherein the azelastine is present in an amount of about 30 μg to about 275 μg per unit dose, or the olopatadine is present in an amount of about 150 μg to about 1400 μg per unit dose, the budesonide is present in an amount of about 5 μg to about 500 μg per unit dose, and the CAPTISOL is present in an amount of 100 μg to 100 mg per unit dose. 6. The method of claim 1, wherein the corticosteroid solution is administered 1-2 times per day. 7. A method for treating an ocular symptom or disorder in a subject in need thereof, comprising: nasally administering to the subject a corticosteroid solution comprising a therapeutically effective amount of a corticosteroid, SAE-CD, and a pharmaceutically acceptable aqueous liquid carrier,
wherein the allergic symptom or disorder includes a non-nasal symptom selected from the group consisting of itchy/gritty eyes, tearing/watery eyes, red/burning eyes, itchy ears/palate and combinations thereof. 8. The method of claim 7, wherein said corticosteroid solution further comprises a therapeutically effective amount of an antihistamine. 9. The method of claim 8, wherein the antihistamine is azelastine, olopatadine, pharmaceutically acceptable salts thereof, pharmaceutically active metabolites thereof, optically active isomers or racemates, and mixtures thereof; the corticosteroid is budesonide; and the SAE-CD is CAPTISOL cyclodextrin (sulfobutylether β-cyclodextrin). 10. The method of claim 9, wherein the azelastine is present in an amount of about 30 μg to about 275 μg per unit dose or the olopatadine is present in an amount of about 150 μg to about 1400 μg per unit dose, the budesonide is present in an amount of about 5 μg to about 500 μg per unit dose, and the CAPTISOL is present in an amount of 100 μg to 100 mg per unit dose. 11. The method of claim 7, wherein the corticosteroid solution is administered 1-2 times per day. 12. A method for treating ocular inflammation in a subject in need thereof, comprising: ophthalmically administering to the subject a corticosteroid solution comprising a therapeutically effective amount of a corticosteroid, SAE-CD, and a pharmaceutically acceptable aqueous liquid carrier,
wherein the corticosteroid solution provides more rapid reduction in ocular inflammation compared with a corticosteroid suspension at the same unit dose. 13. The method of claim 12, wherein said corticosteroid solution further comprises a therapeutically effective amount of an antihistamine. 14. The method of claim 13, wherein the antihistamine is azelastine, olopatadine, pharmaceutically acceptable salts thereof, pharmaceutically active metabolites thereof, optically active isomers or racemates, and mixtures thereof; the corticosteroid is budesonide; and the SAE-CD is CAPTISOL cyclodextrin (sulfobutylether β-cyclodextrin). 15. The method of claim 14, wherein the azelastine is present in an amount of about 30 μg to about 275 μg per unit dose or the olopatadine is present in an amount of about 150 μg to about 1400 μg per unit dose, the budesonide is present in an amount of about 5 μg to about 500 μg per unit dose, and the CAPTISOL is present in an amount of 100 μg to 100 mg per unit dose. 16. The method of claim 12, wherein the corticosteroid solution is administered 1-2 times per day. 17. A metered dose device for nasal or ophthalmic administration comprising: corticosteroid solution comprising a therapeutically effective amount of corticosteroid, a therapeutically effective amount of an antihistamine, SAE-CD, and a pharmaceutically acceptable aqueous liquid carrier. 18. The device of claim 17, wherein the antihistamine is azelastine, olopatadine, pharmaceutically acceptable salts thereof, pharmaceutically active metabolites thereof, optically active isomers or racemates, and mixtures thereof; the corticosteroid is budesonide; and the SAE-CD is CAPTISOL cyclodextrin (sulfobutylether β-cyclodextrin). 19. The device of claim 18, wherein the azelastine is present in an amount of about 30 μg to about 275 μg per unit dose or the olopatadine is present in an amount of about 150 μg to about 1400 μg per unit dose, the budesonide is present in an amount of about 5 μg to about 500 μg per unit dose, and the CAPTISOL is present in an amount of 100 μg to 100 mg per unit dose. 20. A system for treating an allergic symptom comprising: corticosteroid solution comprising a therapeutically effective amount of a corticosteroid, a therapeutically effective amount of an antihistamine, SAE-CD and a pharmaceutically acceptable aqueous liquid carrier, and a metered dose device for nasal or ophthalmic administration of the corticosteroid solution to the subject. 21. The system of claim 20, wherein the allergic symptom is selected from the group consisting of runny nose, itchy nose, nasal congestion, sneezing, itchy/gritty eyes, red/burning eyes, tearing/watery eyes and itchy ears/palate and combinations thereof. 22. The system of claim 21, wherein the allergic symptom is selected from the group consisting of itchy/gritty eyes, tearing/watery eyes, red/burning eyes, itchy ears and palate and combinations thereof. 23. The system of claim 20, wherein the antihistamine is azelastine, olopatadine, pharmaceutically acceptable salts thereof, pharmaceutically active metabolites thereof, optically active isomers or racemates, and mixtures thereof; the corticosteroid is budesonide; and the SAE-CD is CAPTISOL cyclodextrin (sulfobutylether β-cyclodextrin). 24. The system of claim 23 wherein the azelastine is present in an amount of about 30 μg to about 275 μg per unit dose or the olopatadine is present in an amount of about 150 μg to about 1400 μg per unit dose, the budesonide is present in an amount of about 5 μg to about 500 μg per unit dose, and the CAPTISOL is present in an amount of 100 μg to 100 mg per unit dose. | 1,600 |
832 | 15,515,193 | 1,617 | This invention provides for a solid, particulate insecticidal formulation in the form of a granule, a bait or a tablet for mechanical incorporation into or onto soil comprising a volatile insecticidal active ingredient that is microencapsulated and combined with a bulking agent and a disintegrating agent. The solid particulate formulation is characterized in that the volatile insecticide is selected from insecticidal active ingredients having: (a) a vapour pressure at 25° C. in the range from about 1 mPa to about 1,000 mPa; and (b) a water solubility at 25° C. less than about 100 mg/Litre. | 1. A solid particulate insecticidal formulation which is formulated to be mechanically incorporated into or onto soil, the formulation comprising:
i. a microencapsulated volatile insecticide selected from insecticidal active ingredients having:
(a) a vapour pressure at 25° C. in the range from about 1 mPa to about 1,000 mPa; and
(b) a water solubility at 25° C. less than about 100 mg/Litre;
ii a bulking agent; and iii. a disintegrating agent. 2. The formulation according to claim 1, further comprising:
iv. a binding agent, and/or v. a dispersing agent. 3. The formulation according to claim 2, further comprising:
vi. a rheology modifier. 4. The formulation according to claim 1, wherein the formulation is formulated as a granule, a bait, or a tablet. 5. The formulation according to claim 4, wherein the formulation is formulated as a granule. 6. The formulation according to claim 2, wherein the volatile insecticidal active ingredient is selected from chlorethoxyfos, chlorpyrifos, chlorpyrifos-methyl, diazinon, dichlorvos, disulfoton, fenitrothion, fenthion, phorate, pirimiphos-methyl, tebupirimfos, tefluthrin, terbufos, thiodicarb, and a mixture thereof. 7. The formulation according to claim 1, wherein the microencapsulated volatile insecticide has a mean microcapsule diameter from about 100 nm to about 1,000 μm. 8. The formulation according to claim 7, wherein the mean microcapsule diameter is from about 200 nm to about 50 μm. 9. The formulation according to claim 8, wherein the mean microcapsule diameter is from about 500 nm to about 20 μm. 10. The formulation according to claim 1, wherein the microencapsulated volatile insecticide is a blend of two microcapsules, each containing a different active ingredient. 11. The formulation according to claim 1, wherein the formulation contains from 0.1% to 50% by weight of the insecticidal active ingredient based on the total weight of the formulation. 12. The formulation according to claim 2, wherein the:
ii. bulking agent is selected from clays, starches, lactose, calcium carbonate, calcium sulphate, calcium phosphate, and a mixture thereof; and iii. disintegrating agent is selected from microcrystalline cellulose, sodium starch glycolate, crosslinked PVP, sodium sulphate, sodium citrate, polycarboxylates, sodium phenylsulphonates, and a mixture thereof. 13. The formulation according to claim 3, wherein the
ii. bulking agent is selected from clays, starches, lactose, calcium carbonate, calcium sulphate, calcium phosphate, and a mixture thereof; iii. disintegrating agent is selected from microcrystalline cellulose, sodium starch glycolate, crosslinked PVP, sodium sulphate, sodium citrate, polycarboxylates, sodium phenylsulphonates, and a mixture thereof; iv. binding agent is selected from polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetate copolymers, polyacrylate, gelatine, polyacrylamide, oligosaccharides, sugar alcohols, lecithin, and a mixture thereof; and v. dispersing agent is selected from calcium, aluminium or sodium lignosulfonate, sodium naphthalene sulfonate, polymeric dispersants, and a mixture thereof. 14. The formulation according to claim 13, further comprising
vi. a rheology modifier selected from magnesium aluminium silicates, xanthan gum, methyl cellulose, ethyl cellulose, and a mixture thereof. 15. The formulation according to claim 14, wherein the solid formulation comprises 10-80% by weight of the bulking agent, 2-20% by weight of the disintegrating agent, 2-20% by weight of the binding agent, 2-20% by weight of the dispersing agent, and 0.1-15% by weight of the rheology modifier. 16. The formulation according to claim 1, wherein the microencapsulated volatile insecticidal active ingredient is supplemented with a different insecticidal active ingredient having a mode of action other than vapour phase activity. 17. The formulation according to claim 16, wherein the supplementary active ingredient is root absorbed and systemically active, and is soluble in a water-immiscible solvent appropriate for microencapsulation. 18. A method for producing a solid particulate insecticidal formulation according to claim 1, said method comprising:
(A) preparing a suspension by combining components comprising a microencapsulated volatile insecticide selected from insecticidal active ingredients having:
(a) a vapour pressure at 25° C. in the range from about 1 mPa to about 1,000 mPa, and
(b) a water solubility at 25° C. less than about 100 mg/Litre; and
iv. a binding agent;
v. a dispersing agent; and
vi. optionally a rheology modifier;
(B) preparing a dry mixture by combining and thoroughly mixing dry ingredients comprising:
ii. a bulking agent; and
iii. a disintegrating agent;
(C) combining the microcapsule suspension (A) and the dry mixture (B) and mixing to produce a homogeneous moist mass; (D) extruding the homogeneous moist mass (C) to a diameter ranging from about 0.2 mm about 5 mm to form an extruded mass; and (E) reducing the moisture content of the extruded mass by drying. 19. The method according to claim 18, wherein the dry mixture (B) optionally further comprises a dry binding agent and/or a dry dispersing agent. 20. The method according to claim 18, further comprising spheronizing the extruded mass prior to drying. 21. A method of treating soil to minimise insect attack from soil dwelling insects on planted seeds, growing plants and/or mature plants by incorporating into the soil or applying onto the soil a solid particulate insecticidal formulation according to claim 1 in the form of a granule, a bait, or a tablet. 22. The method according to claim 21 wherein the formulation is applied at a rate of from about 200 grams gai/ha to about 3,000 gai/ha. 23. The method according to claim 21, wherein the formulation is applied at the time of drilling or planting, or at any subsequent stage of the crop or pasture growth cycle. | This invention provides for a solid, particulate insecticidal formulation in the form of a granule, a bait or a tablet for mechanical incorporation into or onto soil comprising a volatile insecticidal active ingredient that is microencapsulated and combined with a bulking agent and a disintegrating agent. The solid particulate formulation is characterized in that the volatile insecticide is selected from insecticidal active ingredients having: (a) a vapour pressure at 25° C. in the range from about 1 mPa to about 1,000 mPa; and (b) a water solubility at 25° C. less than about 100 mg/Litre.1. A solid particulate insecticidal formulation which is formulated to be mechanically incorporated into or onto soil, the formulation comprising:
i. a microencapsulated volatile insecticide selected from insecticidal active ingredients having:
(a) a vapour pressure at 25° C. in the range from about 1 mPa to about 1,000 mPa; and
(b) a water solubility at 25° C. less than about 100 mg/Litre;
ii a bulking agent; and iii. a disintegrating agent. 2. The formulation according to claim 1, further comprising:
iv. a binding agent, and/or v. a dispersing agent. 3. The formulation according to claim 2, further comprising:
vi. a rheology modifier. 4. The formulation according to claim 1, wherein the formulation is formulated as a granule, a bait, or a tablet. 5. The formulation according to claim 4, wherein the formulation is formulated as a granule. 6. The formulation according to claim 2, wherein the volatile insecticidal active ingredient is selected from chlorethoxyfos, chlorpyrifos, chlorpyrifos-methyl, diazinon, dichlorvos, disulfoton, fenitrothion, fenthion, phorate, pirimiphos-methyl, tebupirimfos, tefluthrin, terbufos, thiodicarb, and a mixture thereof. 7. The formulation according to claim 1, wherein the microencapsulated volatile insecticide has a mean microcapsule diameter from about 100 nm to about 1,000 μm. 8. The formulation according to claim 7, wherein the mean microcapsule diameter is from about 200 nm to about 50 μm. 9. The formulation according to claim 8, wherein the mean microcapsule diameter is from about 500 nm to about 20 μm. 10. The formulation according to claim 1, wherein the microencapsulated volatile insecticide is a blend of two microcapsules, each containing a different active ingredient. 11. The formulation according to claim 1, wherein the formulation contains from 0.1% to 50% by weight of the insecticidal active ingredient based on the total weight of the formulation. 12. The formulation according to claim 2, wherein the:
ii. bulking agent is selected from clays, starches, lactose, calcium carbonate, calcium sulphate, calcium phosphate, and a mixture thereof; and iii. disintegrating agent is selected from microcrystalline cellulose, sodium starch glycolate, crosslinked PVP, sodium sulphate, sodium citrate, polycarboxylates, sodium phenylsulphonates, and a mixture thereof. 13. The formulation according to claim 3, wherein the
ii. bulking agent is selected from clays, starches, lactose, calcium carbonate, calcium sulphate, calcium phosphate, and a mixture thereof; iii. disintegrating agent is selected from microcrystalline cellulose, sodium starch glycolate, crosslinked PVP, sodium sulphate, sodium citrate, polycarboxylates, sodium phenylsulphonates, and a mixture thereof; iv. binding agent is selected from polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetate copolymers, polyacrylate, gelatine, polyacrylamide, oligosaccharides, sugar alcohols, lecithin, and a mixture thereof; and v. dispersing agent is selected from calcium, aluminium or sodium lignosulfonate, sodium naphthalene sulfonate, polymeric dispersants, and a mixture thereof. 14. The formulation according to claim 13, further comprising
vi. a rheology modifier selected from magnesium aluminium silicates, xanthan gum, methyl cellulose, ethyl cellulose, and a mixture thereof. 15. The formulation according to claim 14, wherein the solid formulation comprises 10-80% by weight of the bulking agent, 2-20% by weight of the disintegrating agent, 2-20% by weight of the binding agent, 2-20% by weight of the dispersing agent, and 0.1-15% by weight of the rheology modifier. 16. The formulation according to claim 1, wherein the microencapsulated volatile insecticidal active ingredient is supplemented with a different insecticidal active ingredient having a mode of action other than vapour phase activity. 17. The formulation according to claim 16, wherein the supplementary active ingredient is root absorbed and systemically active, and is soluble in a water-immiscible solvent appropriate for microencapsulation. 18. A method for producing a solid particulate insecticidal formulation according to claim 1, said method comprising:
(A) preparing a suspension by combining components comprising a microencapsulated volatile insecticide selected from insecticidal active ingredients having:
(a) a vapour pressure at 25° C. in the range from about 1 mPa to about 1,000 mPa, and
(b) a water solubility at 25° C. less than about 100 mg/Litre; and
iv. a binding agent;
v. a dispersing agent; and
vi. optionally a rheology modifier;
(B) preparing a dry mixture by combining and thoroughly mixing dry ingredients comprising:
ii. a bulking agent; and
iii. a disintegrating agent;
(C) combining the microcapsule suspension (A) and the dry mixture (B) and mixing to produce a homogeneous moist mass; (D) extruding the homogeneous moist mass (C) to a diameter ranging from about 0.2 mm about 5 mm to form an extruded mass; and (E) reducing the moisture content of the extruded mass by drying. 19. The method according to claim 18, wherein the dry mixture (B) optionally further comprises a dry binding agent and/or a dry dispersing agent. 20. The method according to claim 18, further comprising spheronizing the extruded mass prior to drying. 21. A method of treating soil to minimise insect attack from soil dwelling insects on planted seeds, growing plants and/or mature plants by incorporating into the soil or applying onto the soil a solid particulate insecticidal formulation according to claim 1 in the form of a granule, a bait, or a tablet. 22. The method according to claim 21 wherein the formulation is applied at a rate of from about 200 grams gai/ha to about 3,000 gai/ha. 23. The method according to claim 21, wherein the formulation is applied at the time of drilling or planting, or at any subsequent stage of the crop or pasture growth cycle. | 1,600 |
833 | 14,243,466 | 1,616 | Disclosed herein is a powder composition containing an alkaline material comprising hydroxide-containing compounds, a starch, a silica material, a liquid fatty substance, an acrylic polymer, wax, and a chelant compound. When the powder composition is mixed with an aqueous composition, a ready to use composition for relaxing or straightening hair is formed. | 1. A powder composition comprising:
(a) from about 1% to about 30% by weight of active material of at least one alkaline material comprising at least one hydroxide-containing compound selected from alkali metal hydroxides, alkaline-earth metal hydroxides, transition metal hydroxides, and mixtures thereof; (b) from about 1% to about 25% by weight of at least one starch; (c) from about 0.1% to about 20% by weight of at least one silica material; (d) from about 5% to about 50% by weight of at least one liquid fatty substance; (e) from about 0.5% to about 15% by weight of at least one acrylic polymer; and (f) from about 0.5% to about 20% by weight of at least one wax; (g) from about 0.5% to about 5% by weight of at least one chelant compound;
all weights above being based on the total weight of the powder composition. 2. The powder composition of claim 1, wherein the alkaline material is present in an amount of from about 1% to about 20% by weight of active material, based on the total weight of the powder composition. 3. The powder composition of claim 2, wherein the hydroxide-containing compound is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, strontium hydroxide, manganese hydroxide, zinc hydroxide, and mixtures thereof and is present in an amount of from about 1% to about 30% by weight of active material of the least one alkaline material. 4. The powder composition of claim 3, wherein the hydroxide-containing compound is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, and mixtures thereof. 5. The powder composition of claim 3, wherein the starch is selected from: (i) starches derived from a plant source selected from corn, potato, sweet potato, pea, barley, wheat, rice, oat, sago, tapioca and sorghum; (ii) hydrolyzed starches selected from dextrin and maltodextrin; (iii) modified starches; and mixtures thereof. 6. The powder composition of claim 5, wherein the starch is selected from corn starch, potato starch, dextrin, maltodextrin, and mixtures thereof. 7. The powder composition of claim 5, wherein the starch is present in an amount of from about 3% to about 22.5% by weight, based on the total weight of the powder composition. 8. The powder composition of claim 7, wherein the silica material comprises silica particles selected from hydrated silica, hydrophobic silica aerogel particle, and mixtures thereof. 9. The powder composition of claim 8, wherein the silica material is present in an amount of from about 2% to about 16% by weight, based on the total weight of the powder composition. 10. The powder composition of claim 7, wherein the liquid fatty substance is selected from C6-C16 alkanes, non-silicone oils of plant, mineral or synthetic origin, liquid fatty alcohols, liquid fatty acids and liquid esters of a fatty acid and/or of a fatty alcohol, or mixtures thereof. 11. The powder composition of claim 10, wherein the liquid fatty substance is present in an amount of from about 7% to about 30% by weight, based on the total weight of the powder composition. 12. The powder composition of claim 11, wherein the acrylic polymer is a crosslinked acrylic polymer and is present in an amount of from about 3% to about 12.8% by weight, based on the total weight of the powder composition. 13. The powder composition of claim 12, wherein the crosslinked acrylic polymer is selected from sodium polyacrylate, carbomer, acrylates C10-30 alkyl acrylate crosspolymer, and mixtures thereof. 14. The powder composition of claim 1, wherein the chelant compound is selected from ethylenediaminetetraacetic acid (EDTA), and its salts; N-(hydroxyethyl)ethylene diamine triacetic acid and its salts; aminotrimethylene phosphonic acid and its salts; diethylenetriamine-pentaacetatic acid and its salts; lauroyl ethylene diamine triacetic acid and its salts; nitrilotriacetic acid and its salts; iminodisuccinic acid and its salts; tartaric acid and its salts; citric acid and its salts; N-2-hydroxyethyliminodiacetic acid and its salts; ethyleneglycol-bis(beta-amino ethyl ether)-N,N-tetraacetic acid; and pentasodium aminotrimethylene phosphonate, and mixtures thereof. 15. The powder composition of claim 12, further comprising at least one non-starch, non-acrylic polymer selected from thickening agents, viscosity agents and gelling agents. 16. The powder composition of claim 15, wherein the non-starch, non-acrylic polymer is selected from xanthan gum, cellulose gum, guar gum, algin, chitosan, hydroxyethylcellulose, hydroxypropylcellulose, cetyl hydroxyethylcellulose, polyvinylpyrrolidone and mixtures thereof. 17. The powder composition of claim 15, wherein the non-starch polymer, non-acrylic polymer is present in an amount of from about 0.1% to about 10% by weight, based on the total weight of the powder composition. 18. The powder composition of claim 1, wherein the powder composition is essentially free of water. 19. The powder composition of claim 12, wherein the composition further comprises at least one clay selected from kaolin, bentonites, montmorillonites, hectorites, beidellites, saponites, laponite, dickite, nacrite, optionally modified clays of the family of halloysite, vermiculite, talc, stevensite, chlorite, sepiolite, and mixtures thereof. 20. The powder composition of claim 19, wherein the clay is present in an amount of from about 1% to about 30% by weight, based on the total weight of the powder composition. 21. The powder composition of claim 1, wherein the powder composition is capable of being mixed with an aqueous composition comprising a cosmetically acceptable solvent selected from water and a water/organic solvent mixture in order to form a ready to use composition. 22. The powder composition of claim 1, wherein the powder composition is capable of being mixed with an aqueous composition comprising a cosmetically acceptable solvent selected from water and a water/organic solvent mixture in order to form a ready to use composition in a weight ratio of from about 1:3 to about 1:10. 23. The powder composition of claim 22, wherein the ready to use composition has a viscosity of from about 50 uD to about 90 uD. 24. The powder composition of claim 23, wherein the ready to use composition has a pH of from about 9 to about 14. 25. A process of relaxing or straightening hair, comprising contacting hair with the ready to use composition of claim 24. 26. The powder composition and/or the aqueous composition of claim 22, further comprising at least one surfactant selected from anionic surfactants, nonionic surfactants, amphoteric surfactants and mixtures thereof. 27. The powder composition and/or the aqueous composition of claim 22, further comprising at least one auxiliary ingredient selected from organic amines, carbonate compounds, emulsifying agents, fillers, pigments, conditioning agents, moisturizing agents, additional viscosity or thickening agents, shine agents, sequestering agents, fragrances, preservatives, pH modifiers/neutralizing agents, stabilizers, and mixtures thereof. 28. A ready to use composition for relaxing or straightening hair comprising:
A. a powder composition containing:
(a) from about 1% to about 20% by weight of active material of at least one alkaline material comprising at least one hydroxide-containing compound selected from alkali metal hydroxides, alkaline-earth metal hydroxides, transition metal hydroxides, and mixtures thereof;
(b) from about 2% to about 25% by weight of at least one starch;
(c) from about 0.1% to about 20% by weight of at least one silica material;
(d) from about 5% to about 50% by weight of at least one liquid fatty substance;
(e) from about 0.5% to about 15% by weight of at least one acrylic polymer; and
(f) from about 0.5% to about 20% by weight of at least one wax;
all weights above being based on the total weight of the powder composition;
B. an aqueous composition containing a cosmetically acceptable solvent selected from water and a water/organic solvent mixture;
wherein the powder composition and/or the aqueous composition additionally contains at least one chelant compound;
wherein the weight ratio of the powder composition to the aqueous composition of from about 1:3 to about 1:10;
wherein the pH of the ready to use composition ranges from about 9 to about 14; and
wherein the viscosity of the ready to use composition is from about 50 uD to about 90 uD. 29. A powder composition comprising:
(a) from about 6% to about 12.5% by weight of active material of at least one alkaline material comprising at least one hydroxide-containing compound selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, and mixtures thereof; (b) from about 3% to about 22.5% by weight of at least one starch selected from: (i) starches derived from a plant source selected from corn, potato, sweet potato, pea, barley, wheat, rice, oat, sago, tapioca and sorghum; (ii) hydrolyzed starches selected from dextrin and maltodextrin; (iii) modified starches; and mixtures thereof; (c) from about 2% to about 16% by weight of at least one silica material comprising silica particles selected from hydrated silica, hydrophobic silica aerogel particle, and mixtures thereof; (d) from about 7% to about 25% by weight of at least one liquid fatty substance comprising mineral oil; (e) from about 1% to about 12% by weight of at least one acrylic polymer selected from sodium polyacrylate, carbomer, acrylates C10-30 alkyl acrylate cross polymer, and mixtures thereof; and (f) from about 4% to about 16% by weight of at least one wax; (g) from about 0.5% to about 5% by weight of at least one chelant compound selected from ethylenediaminetetraacetic acid (EDTA), its salts, and mixtures thereof; (h) from about 1% to about 10% by weight of non-starch, non-acrylic polymer selected from a polyvinylpyrrolidone, a polysaccharide, and mixtures thereof; (i) from about 1% to about 30% by weight of at least one clay; and
all weights above being based on the total weight of the powder composition. 30. A method of relaxing or straightening hair, the method comprising the steps of:
1) mixing a powder composition with an aqueous composition in a weight ratio of from about 1:3 to about 1:10 in order to form a ready to use composition for relaxing or straightening the hair,
wherein the powder composition contains:
(a) from about 1% to about 30% by weight of active material of at least one alkaline material comprising at least one hydroxide-containing compound selected from alkali metal hydroxides, alkaline-earth metal hydroxides, transition metal hydroxides, and mixtures thereof;
(b) from about 1% to about 25% by weight of at least one starch;
(c) from about 0.1% to about 20% by weight of at least one silica material;
(d) from about 5% to about 50% by weight of at least one liquid fatty substance;
(e) from about 0.5% to about 15% by weight of at least one acrylic polymer; and
(f) from about 0.5% to about 20% by weight of at least one wax;
all weights above being based on the total weight of the powder composition;
wherein the aqueous composition contains a cosmetically acceptable solvent selected from selected from water and a water/organic solvent mixture;
wherein the powder composition and/or the aqueous composition additionally contains from about 0.5% to about 5% by weight of at least one chelant compound;
wherein the pH of the ready to use composition ranges from about 9 to about 14; and
wherein the viscosity of the ready to use composition is from about 50 uD to about 90 uD; and
2) contacting the hair with the ready to use composition for a sufficient period of time to achieve a desired relaxation or straightening. 31. A multi-compartment kit for relaxing or straightening hair comprising at least two compartments,
wherein a first compartment contains a powder composition comprising:
(a) from about 1% to about 30% by weight of active material of at least one alkaline material comprising at least one hydroxide-containing compound selected from alkali metal hydroxides, alkaline-earth metal hydroxides, transition metal hydroxides, and mixtures thereof;
(b) from about 2% to about 25% by weight of at least one starch;
(c) from about 0.1% to about 20% by weight of at least one silica material;
(d) from about 5% to about 50% by weight of at least one liquid fatty substance;
(e) from about 0.5% to about 15% by weight of at least one acrylic polymer;
(f) from about 0.5% to about 20% by weight of at least one wax; and
(g) from about 0.5% to about 5% by weight of at least one chelant compound;
all weights above being based on the total weight of the powder composition; and
wherein a second compartment contains an aqueous composition comprising a cosmetically acceptable solvent selected from selected from water and a water/organic solvent mixture. | Disclosed herein is a powder composition containing an alkaline material comprising hydroxide-containing compounds, a starch, a silica material, a liquid fatty substance, an acrylic polymer, wax, and a chelant compound. When the powder composition is mixed with an aqueous composition, a ready to use composition for relaxing or straightening hair is formed.1. A powder composition comprising:
(a) from about 1% to about 30% by weight of active material of at least one alkaline material comprising at least one hydroxide-containing compound selected from alkali metal hydroxides, alkaline-earth metal hydroxides, transition metal hydroxides, and mixtures thereof; (b) from about 1% to about 25% by weight of at least one starch; (c) from about 0.1% to about 20% by weight of at least one silica material; (d) from about 5% to about 50% by weight of at least one liquid fatty substance; (e) from about 0.5% to about 15% by weight of at least one acrylic polymer; and (f) from about 0.5% to about 20% by weight of at least one wax; (g) from about 0.5% to about 5% by weight of at least one chelant compound;
all weights above being based on the total weight of the powder composition. 2. The powder composition of claim 1, wherein the alkaline material is present in an amount of from about 1% to about 20% by weight of active material, based on the total weight of the powder composition. 3. The powder composition of claim 2, wherein the hydroxide-containing compound is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, strontium hydroxide, manganese hydroxide, zinc hydroxide, and mixtures thereof and is present in an amount of from about 1% to about 30% by weight of active material of the least one alkaline material. 4. The powder composition of claim 3, wherein the hydroxide-containing compound is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, and mixtures thereof. 5. The powder composition of claim 3, wherein the starch is selected from: (i) starches derived from a plant source selected from corn, potato, sweet potato, pea, barley, wheat, rice, oat, sago, tapioca and sorghum; (ii) hydrolyzed starches selected from dextrin and maltodextrin; (iii) modified starches; and mixtures thereof. 6. The powder composition of claim 5, wherein the starch is selected from corn starch, potato starch, dextrin, maltodextrin, and mixtures thereof. 7. The powder composition of claim 5, wherein the starch is present in an amount of from about 3% to about 22.5% by weight, based on the total weight of the powder composition. 8. The powder composition of claim 7, wherein the silica material comprises silica particles selected from hydrated silica, hydrophobic silica aerogel particle, and mixtures thereof. 9. The powder composition of claim 8, wherein the silica material is present in an amount of from about 2% to about 16% by weight, based on the total weight of the powder composition. 10. The powder composition of claim 7, wherein the liquid fatty substance is selected from C6-C16 alkanes, non-silicone oils of plant, mineral or synthetic origin, liquid fatty alcohols, liquid fatty acids and liquid esters of a fatty acid and/or of a fatty alcohol, or mixtures thereof. 11. The powder composition of claim 10, wherein the liquid fatty substance is present in an amount of from about 7% to about 30% by weight, based on the total weight of the powder composition. 12. The powder composition of claim 11, wherein the acrylic polymer is a crosslinked acrylic polymer and is present in an amount of from about 3% to about 12.8% by weight, based on the total weight of the powder composition. 13. The powder composition of claim 12, wherein the crosslinked acrylic polymer is selected from sodium polyacrylate, carbomer, acrylates C10-30 alkyl acrylate crosspolymer, and mixtures thereof. 14. The powder composition of claim 1, wherein the chelant compound is selected from ethylenediaminetetraacetic acid (EDTA), and its salts; N-(hydroxyethyl)ethylene diamine triacetic acid and its salts; aminotrimethylene phosphonic acid and its salts; diethylenetriamine-pentaacetatic acid and its salts; lauroyl ethylene diamine triacetic acid and its salts; nitrilotriacetic acid and its salts; iminodisuccinic acid and its salts; tartaric acid and its salts; citric acid and its salts; N-2-hydroxyethyliminodiacetic acid and its salts; ethyleneglycol-bis(beta-amino ethyl ether)-N,N-tetraacetic acid; and pentasodium aminotrimethylene phosphonate, and mixtures thereof. 15. The powder composition of claim 12, further comprising at least one non-starch, non-acrylic polymer selected from thickening agents, viscosity agents and gelling agents. 16. The powder composition of claim 15, wherein the non-starch, non-acrylic polymer is selected from xanthan gum, cellulose gum, guar gum, algin, chitosan, hydroxyethylcellulose, hydroxypropylcellulose, cetyl hydroxyethylcellulose, polyvinylpyrrolidone and mixtures thereof. 17. The powder composition of claim 15, wherein the non-starch polymer, non-acrylic polymer is present in an amount of from about 0.1% to about 10% by weight, based on the total weight of the powder composition. 18. The powder composition of claim 1, wherein the powder composition is essentially free of water. 19. The powder composition of claim 12, wherein the composition further comprises at least one clay selected from kaolin, bentonites, montmorillonites, hectorites, beidellites, saponites, laponite, dickite, nacrite, optionally modified clays of the family of halloysite, vermiculite, talc, stevensite, chlorite, sepiolite, and mixtures thereof. 20. The powder composition of claim 19, wherein the clay is present in an amount of from about 1% to about 30% by weight, based on the total weight of the powder composition. 21. The powder composition of claim 1, wherein the powder composition is capable of being mixed with an aqueous composition comprising a cosmetically acceptable solvent selected from water and a water/organic solvent mixture in order to form a ready to use composition. 22. The powder composition of claim 1, wherein the powder composition is capable of being mixed with an aqueous composition comprising a cosmetically acceptable solvent selected from water and a water/organic solvent mixture in order to form a ready to use composition in a weight ratio of from about 1:3 to about 1:10. 23. The powder composition of claim 22, wherein the ready to use composition has a viscosity of from about 50 uD to about 90 uD. 24. The powder composition of claim 23, wherein the ready to use composition has a pH of from about 9 to about 14. 25. A process of relaxing or straightening hair, comprising contacting hair with the ready to use composition of claim 24. 26. The powder composition and/or the aqueous composition of claim 22, further comprising at least one surfactant selected from anionic surfactants, nonionic surfactants, amphoteric surfactants and mixtures thereof. 27. The powder composition and/or the aqueous composition of claim 22, further comprising at least one auxiliary ingredient selected from organic amines, carbonate compounds, emulsifying agents, fillers, pigments, conditioning agents, moisturizing agents, additional viscosity or thickening agents, shine agents, sequestering agents, fragrances, preservatives, pH modifiers/neutralizing agents, stabilizers, and mixtures thereof. 28. A ready to use composition for relaxing or straightening hair comprising:
A. a powder composition containing:
(a) from about 1% to about 20% by weight of active material of at least one alkaline material comprising at least one hydroxide-containing compound selected from alkali metal hydroxides, alkaline-earth metal hydroxides, transition metal hydroxides, and mixtures thereof;
(b) from about 2% to about 25% by weight of at least one starch;
(c) from about 0.1% to about 20% by weight of at least one silica material;
(d) from about 5% to about 50% by weight of at least one liquid fatty substance;
(e) from about 0.5% to about 15% by weight of at least one acrylic polymer; and
(f) from about 0.5% to about 20% by weight of at least one wax;
all weights above being based on the total weight of the powder composition;
B. an aqueous composition containing a cosmetically acceptable solvent selected from water and a water/organic solvent mixture;
wherein the powder composition and/or the aqueous composition additionally contains at least one chelant compound;
wherein the weight ratio of the powder composition to the aqueous composition of from about 1:3 to about 1:10;
wherein the pH of the ready to use composition ranges from about 9 to about 14; and
wherein the viscosity of the ready to use composition is from about 50 uD to about 90 uD. 29. A powder composition comprising:
(a) from about 6% to about 12.5% by weight of active material of at least one alkaline material comprising at least one hydroxide-containing compound selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, and mixtures thereof; (b) from about 3% to about 22.5% by weight of at least one starch selected from: (i) starches derived from a plant source selected from corn, potato, sweet potato, pea, barley, wheat, rice, oat, sago, tapioca and sorghum; (ii) hydrolyzed starches selected from dextrin and maltodextrin; (iii) modified starches; and mixtures thereof; (c) from about 2% to about 16% by weight of at least one silica material comprising silica particles selected from hydrated silica, hydrophobic silica aerogel particle, and mixtures thereof; (d) from about 7% to about 25% by weight of at least one liquid fatty substance comprising mineral oil; (e) from about 1% to about 12% by weight of at least one acrylic polymer selected from sodium polyacrylate, carbomer, acrylates C10-30 alkyl acrylate cross polymer, and mixtures thereof; and (f) from about 4% to about 16% by weight of at least one wax; (g) from about 0.5% to about 5% by weight of at least one chelant compound selected from ethylenediaminetetraacetic acid (EDTA), its salts, and mixtures thereof; (h) from about 1% to about 10% by weight of non-starch, non-acrylic polymer selected from a polyvinylpyrrolidone, a polysaccharide, and mixtures thereof; (i) from about 1% to about 30% by weight of at least one clay; and
all weights above being based on the total weight of the powder composition. 30. A method of relaxing or straightening hair, the method comprising the steps of:
1) mixing a powder composition with an aqueous composition in a weight ratio of from about 1:3 to about 1:10 in order to form a ready to use composition for relaxing or straightening the hair,
wherein the powder composition contains:
(a) from about 1% to about 30% by weight of active material of at least one alkaline material comprising at least one hydroxide-containing compound selected from alkali metal hydroxides, alkaline-earth metal hydroxides, transition metal hydroxides, and mixtures thereof;
(b) from about 1% to about 25% by weight of at least one starch;
(c) from about 0.1% to about 20% by weight of at least one silica material;
(d) from about 5% to about 50% by weight of at least one liquid fatty substance;
(e) from about 0.5% to about 15% by weight of at least one acrylic polymer; and
(f) from about 0.5% to about 20% by weight of at least one wax;
all weights above being based on the total weight of the powder composition;
wherein the aqueous composition contains a cosmetically acceptable solvent selected from selected from water and a water/organic solvent mixture;
wherein the powder composition and/or the aqueous composition additionally contains from about 0.5% to about 5% by weight of at least one chelant compound;
wherein the pH of the ready to use composition ranges from about 9 to about 14; and
wherein the viscosity of the ready to use composition is from about 50 uD to about 90 uD; and
2) contacting the hair with the ready to use composition for a sufficient period of time to achieve a desired relaxation or straightening. 31. A multi-compartment kit for relaxing or straightening hair comprising at least two compartments,
wherein a first compartment contains a powder composition comprising:
(a) from about 1% to about 30% by weight of active material of at least one alkaline material comprising at least one hydroxide-containing compound selected from alkali metal hydroxides, alkaline-earth metal hydroxides, transition metal hydroxides, and mixtures thereof;
(b) from about 2% to about 25% by weight of at least one starch;
(c) from about 0.1% to about 20% by weight of at least one silica material;
(d) from about 5% to about 50% by weight of at least one liquid fatty substance;
(e) from about 0.5% to about 15% by weight of at least one acrylic polymer;
(f) from about 0.5% to about 20% by weight of at least one wax; and
(g) from about 0.5% to about 5% by weight of at least one chelant compound;
all weights above being based on the total weight of the powder composition; and
wherein a second compartment contains an aqueous composition comprising a cosmetically acceptable solvent selected from selected from water and a water/organic solvent mixture. | 1,600 |
834 | 14,504,893 | 1,653 | A method for monitoring a reaction and a reaction system are provided. The reaction system includes at least one vessel for the reaction medium, which is in fluid communication with an injection tube; at least one vessel for a carrier fluid that is immiscible with the reaction medium, which is in fluid communication with a reaction tube; the injection tube being mounted so as to lead into the reaction tube such that individual drops of the reaction medium can be injected into the reaction tube and into the immiscible carrier fluid, so as to form a train of reaction chambers; at least one detector for monitoring a reaction; a means for classifying the reaction chambers; and at least one means for recirculating reaction chambers in front of at least one detector for monitoring a reaction. | 1. A reaction system, notably of cultures of microorganisms, comprising:
at least one reservoir of reaction mixture fluidically connected to a capillary injection tube; at least one reservoir of a carrier fluid that is immiscible with the reaction mixture, fluidically connected to a capillary reaction tube, the capillary injection tube being mounted opening into the capillary reaction tube so that individual drops of reaction mixture are injectable into the capillary reaction tube, into the immiscible carrier fluid, so as to form a succession of reactors, at least one reaction monitoring detector, wherein the system comprises a means of referencing the reactors for identifying them uniquely in the succession of reactors, and at least one means for recirculating the reactors in front of at least one reaction monitoring detector. 2. The reaction system as claimed in claim 1, in which the recirculating means comprises a loop for recirculating the reactors in front of the detector or detectors, said recirculating loop comprising a capillary discharging upstream and downstream of the detector or detectors. 3. The reaction system as claimed in claim 1, in which the recirculating means comprises a recirculating means able to reverse the direction of circulation of the reactors. 4. The reaction system as claimed in claim 1, further comprising at least one reservoir of a separating fluid that is immiscible with the carrier fluid and immiscible with the reaction mixture, fluidically connected to the capillary reaction tube so that drops of separating fluid can be injected into the carrier fluid between two reactors. 5. The reaction system as claimed in claim 1, further comprising at least one reservoir of reagent fluidically connected to the capillary injection tube and/or to the capillary reaction tube, so that reagent can be mixed with the reaction mixture. 6. The reaction system as claimed in claim 4, in which the carrier fluid and the separating fluid are mutually immiscible oils, the reaction mixture being an aqueous medium that is immiscible with the aforementioned oils. 7. The reaction system as claimed in claim 1, further comprising at least one detector, the capillary reaction tube comprising at least one portion that is transparent to a signal emitted and/or detected by the detector. 8. The reaction system as claimed in claim 1, further comprising a central control unit connected to the circulating means and configured for:
controlling the injection of individual drops of reaction mixture into the capillary reaction tube, into the carrier fluid, imposing a velocity and a duration of circulation of the reaction medium, so as to form a plurality of reactors; controlling the circulation of the carrier fluid by imposing a velocity, duration and direction of circulation of the carrier fluid in the capillary reaction tube; counting the reactors in the carrier medium and storing the position of each reactor relative to a reference reactor; recirculating the reservoirs in the capillary reaction tube. 9. The reaction system as claimed in claim 4, further comprising a central control unit connected to the circulating means and configured for:
controlling the injection of individual drops of reaction mixture into the capillary reaction tube, into the carrier fluid, imposing a velocity and a duration of circulation of the reaction medium, so as to form a plurality of reactors; controlling the circulation of the carrier fluid by imposing a velocity, duration and direction of circulation of the carrier fluid in the capillary reaction tube; counting the reactors in the carrier medium and storing the position of each reactor relative to a reference reactor; recirculating the reservoirs in the capillary reaction tube, and wherein the central control unit is capable of controlling the injection of drops of separating fluid between two reactors. 10. A method of monitoring a reaction in a reaction mixture, wherein in the method comprises the following steps:
a) filling a capillary reaction tube with a carrier medium that is immiscible with the reaction mixture; b) injecting, by means of a capillary injection tube, an individual drop of reaction mixture in the capillary reaction tube, into the immiscible carrier fluid; c) circulating the carrier fluid so that the drop of reaction mixture is moved relative to the capillary injection tube; e) repeating steps b) and c) to create an ordered succession of drops of reaction mixture in the carrier fluid to form a plurality of reactors; f) measuring at least one representative parameter of each reactor; g) recirculating at least one reactor to measure said at least one representative parameter over time. 11. The method of monitoring a reaction in a reaction mixture as claimed in claim 10, for the culture of microorganisms in a culture medium, comprising the following steps:
a) filling a capillary culture tube with a carrier medium that is immiscible with the culture medium; b) injecting, by means of a capillary injection tube, an individual drop of culture medium in the capillary culture tube, into the immiscible carrier fluid; c) circulating the carrier fluid so that the drop of culture medium is moved relative to the capillary injection tube; e) repeating steps b) and c) to create an ordered succession of drops of culture medium in the carrier fluid to form a plurality of reactors for culture of microorganisms; f) measuring at least one representative parameter of each culture reactor, wherein said parameter can be representative of the quantity of microorganisms present in each reactor; g) recirculating at least one reactor to measure said at least one representative parameter over time. 12. The method of monitoring a reaction in a reaction mixture as claimed in claim 10, further comprising, after step c) and before step e), a step d) comprising injection, into the carrier fluid, of a drop of a separating fluid, immiscible with the carrier fluid and immiscible with the reaction mixture, so that at least one drop of separating fluid is interposed between two reactors and prevents their coalescence. 13. The method of monitoring a reaction in a reaction mixture as claimed in claim 10, in which measurement is carried out by an optical method selected from the group consisting of measurements of absorbance, of diffusion, and of fluorescence, or by an electrical measurement comprising measuring impedance. 14. The method of monitoring a reaction in a reaction mixture as claimed in claim 10, further comprising, after step e), a step f) of recovery of at least one reactor of interest by aspiration of said reactor of interest into a sampling capillary tube mounted opening into the capillary reaction tube. 15. A method for monitoring reaction kinetics in a reaction medium between at least one component of the reaction medium and each of a plurality of different reagents, comprising:
generating an ordered stream of drops in a carrier fluid to form a plurality of reactors, said stream of drops comprising a series of elementary streams of drops, each elementary stream of drops being associated with at least one reagent of the plurality of reagents, whereby each drop of an elementary stream comprises the or each reagent associated with the elementary stream, circulating at least one part of the ordered stream of drops, measuring at least one parameter representative of each reagent over time. 16. The method according to claim 15, wherein each elementary stream of drops comprises at least one reagent not included in an adjacent elementary stream of drops. 17. The method according to claim 15, wherein generating the ordered stream of drops comprises:
generating a plurality of consecutive elementary streams of drops, each of which is associated with at least one reagent of the plurality of reagents, between which intermediate streams of drops are arranged, and suppressing the intermediate streams of drops; 18. The method according to claim 15, wherein the concentration of at least one reagent varies within at least one elementary stream of drops, in particular according to a gradient. 19. The method according to claim 15, wherein generating the ordered stream of drops includes the following steps:
(a′) generating a flow of reaction medium, (b′) filling a capillary reaction tube with a carrier fluid that is immiscible with the reaction medium, (c′) injecting an individual drop of reaction medium in the capillary reaction tube by means of a capillary injection tube, (d′) circulating the carrier fluid (so that the drop of reaction medium will be displaced relative to the capillary injection tube, (f′) the repetition of steps c′) and d′) to create an ordered stream of drops of reaction medium in the carrier fluid. 20. The method according to claim 19, wherein generating the flow of reaction medium comprises:
forming a flow of reagents comprising a series of elementary reagent flows, each of which comprises at least one reagent of the plurality of reagents; mixing the reagent flow with a culture medium comprising the component to form the reaction medium flow; 21. The method according to claim 20, wherein forming the flow of reagents comprises the following steps:
(α) generating a continuous flow of a solvent in a mixing channel; (β) simultaneously with step α), injecting, by means of a capillary tube, a reagent chosen from the plurality of reagents in the mixing channel to form an elementary reagent flow; (γ) repeating step β13) for each of the successive reagents of the plurality of reagents; 22. The method according to claim 21, wherein forming the reagent flow comprises, after the formation of each elementary reagent flow and before step γ), a step δ) of injecting a cleaning liquid into each mixing channel by means of a capillary tube. 23. The method according to claim 19, wherein generating the ordered series of drops further includes, after step d′) and before step f′), a step e′) comprising injecting into the carrier fluid of a drop of a separating fluid immiscible with the carrier fluid or the reaction medium, such that at least one drop of separating fluid is intercalated between two reactors and prevents them coalescing. | A method for monitoring a reaction and a reaction system are provided. The reaction system includes at least one vessel for the reaction medium, which is in fluid communication with an injection tube; at least one vessel for a carrier fluid that is immiscible with the reaction medium, which is in fluid communication with a reaction tube; the injection tube being mounted so as to lead into the reaction tube such that individual drops of the reaction medium can be injected into the reaction tube and into the immiscible carrier fluid, so as to form a train of reaction chambers; at least one detector for monitoring a reaction; a means for classifying the reaction chambers; and at least one means for recirculating reaction chambers in front of at least one detector for monitoring a reaction.1. A reaction system, notably of cultures of microorganisms, comprising:
at least one reservoir of reaction mixture fluidically connected to a capillary injection tube; at least one reservoir of a carrier fluid that is immiscible with the reaction mixture, fluidically connected to a capillary reaction tube, the capillary injection tube being mounted opening into the capillary reaction tube so that individual drops of reaction mixture are injectable into the capillary reaction tube, into the immiscible carrier fluid, so as to form a succession of reactors, at least one reaction monitoring detector, wherein the system comprises a means of referencing the reactors for identifying them uniquely in the succession of reactors, and at least one means for recirculating the reactors in front of at least one reaction monitoring detector. 2. The reaction system as claimed in claim 1, in which the recirculating means comprises a loop for recirculating the reactors in front of the detector or detectors, said recirculating loop comprising a capillary discharging upstream and downstream of the detector or detectors. 3. The reaction system as claimed in claim 1, in which the recirculating means comprises a recirculating means able to reverse the direction of circulation of the reactors. 4. The reaction system as claimed in claim 1, further comprising at least one reservoir of a separating fluid that is immiscible with the carrier fluid and immiscible with the reaction mixture, fluidically connected to the capillary reaction tube so that drops of separating fluid can be injected into the carrier fluid between two reactors. 5. The reaction system as claimed in claim 1, further comprising at least one reservoir of reagent fluidically connected to the capillary injection tube and/or to the capillary reaction tube, so that reagent can be mixed with the reaction mixture. 6. The reaction system as claimed in claim 4, in which the carrier fluid and the separating fluid are mutually immiscible oils, the reaction mixture being an aqueous medium that is immiscible with the aforementioned oils. 7. The reaction system as claimed in claim 1, further comprising at least one detector, the capillary reaction tube comprising at least one portion that is transparent to a signal emitted and/or detected by the detector. 8. The reaction system as claimed in claim 1, further comprising a central control unit connected to the circulating means and configured for:
controlling the injection of individual drops of reaction mixture into the capillary reaction tube, into the carrier fluid, imposing a velocity and a duration of circulation of the reaction medium, so as to form a plurality of reactors; controlling the circulation of the carrier fluid by imposing a velocity, duration and direction of circulation of the carrier fluid in the capillary reaction tube; counting the reactors in the carrier medium and storing the position of each reactor relative to a reference reactor; recirculating the reservoirs in the capillary reaction tube. 9. The reaction system as claimed in claim 4, further comprising a central control unit connected to the circulating means and configured for:
controlling the injection of individual drops of reaction mixture into the capillary reaction tube, into the carrier fluid, imposing a velocity and a duration of circulation of the reaction medium, so as to form a plurality of reactors; controlling the circulation of the carrier fluid by imposing a velocity, duration and direction of circulation of the carrier fluid in the capillary reaction tube; counting the reactors in the carrier medium and storing the position of each reactor relative to a reference reactor; recirculating the reservoirs in the capillary reaction tube, and wherein the central control unit is capable of controlling the injection of drops of separating fluid between two reactors. 10. A method of monitoring a reaction in a reaction mixture, wherein in the method comprises the following steps:
a) filling a capillary reaction tube with a carrier medium that is immiscible with the reaction mixture; b) injecting, by means of a capillary injection tube, an individual drop of reaction mixture in the capillary reaction tube, into the immiscible carrier fluid; c) circulating the carrier fluid so that the drop of reaction mixture is moved relative to the capillary injection tube; e) repeating steps b) and c) to create an ordered succession of drops of reaction mixture in the carrier fluid to form a plurality of reactors; f) measuring at least one representative parameter of each reactor; g) recirculating at least one reactor to measure said at least one representative parameter over time. 11. The method of monitoring a reaction in a reaction mixture as claimed in claim 10, for the culture of microorganisms in a culture medium, comprising the following steps:
a) filling a capillary culture tube with a carrier medium that is immiscible with the culture medium; b) injecting, by means of a capillary injection tube, an individual drop of culture medium in the capillary culture tube, into the immiscible carrier fluid; c) circulating the carrier fluid so that the drop of culture medium is moved relative to the capillary injection tube; e) repeating steps b) and c) to create an ordered succession of drops of culture medium in the carrier fluid to form a plurality of reactors for culture of microorganisms; f) measuring at least one representative parameter of each culture reactor, wherein said parameter can be representative of the quantity of microorganisms present in each reactor; g) recirculating at least one reactor to measure said at least one representative parameter over time. 12. The method of monitoring a reaction in a reaction mixture as claimed in claim 10, further comprising, after step c) and before step e), a step d) comprising injection, into the carrier fluid, of a drop of a separating fluid, immiscible with the carrier fluid and immiscible with the reaction mixture, so that at least one drop of separating fluid is interposed between two reactors and prevents their coalescence. 13. The method of monitoring a reaction in a reaction mixture as claimed in claim 10, in which measurement is carried out by an optical method selected from the group consisting of measurements of absorbance, of diffusion, and of fluorescence, or by an electrical measurement comprising measuring impedance. 14. The method of monitoring a reaction in a reaction mixture as claimed in claim 10, further comprising, after step e), a step f) of recovery of at least one reactor of interest by aspiration of said reactor of interest into a sampling capillary tube mounted opening into the capillary reaction tube. 15. A method for monitoring reaction kinetics in a reaction medium between at least one component of the reaction medium and each of a plurality of different reagents, comprising:
generating an ordered stream of drops in a carrier fluid to form a plurality of reactors, said stream of drops comprising a series of elementary streams of drops, each elementary stream of drops being associated with at least one reagent of the plurality of reagents, whereby each drop of an elementary stream comprises the or each reagent associated with the elementary stream, circulating at least one part of the ordered stream of drops, measuring at least one parameter representative of each reagent over time. 16. The method according to claim 15, wherein each elementary stream of drops comprises at least one reagent not included in an adjacent elementary stream of drops. 17. The method according to claim 15, wherein generating the ordered stream of drops comprises:
generating a plurality of consecutive elementary streams of drops, each of which is associated with at least one reagent of the plurality of reagents, between which intermediate streams of drops are arranged, and suppressing the intermediate streams of drops; 18. The method according to claim 15, wherein the concentration of at least one reagent varies within at least one elementary stream of drops, in particular according to a gradient. 19. The method according to claim 15, wherein generating the ordered stream of drops includes the following steps:
(a′) generating a flow of reaction medium, (b′) filling a capillary reaction tube with a carrier fluid that is immiscible with the reaction medium, (c′) injecting an individual drop of reaction medium in the capillary reaction tube by means of a capillary injection tube, (d′) circulating the carrier fluid (so that the drop of reaction medium will be displaced relative to the capillary injection tube, (f′) the repetition of steps c′) and d′) to create an ordered stream of drops of reaction medium in the carrier fluid. 20. The method according to claim 19, wherein generating the flow of reaction medium comprises:
forming a flow of reagents comprising a series of elementary reagent flows, each of which comprises at least one reagent of the plurality of reagents; mixing the reagent flow with a culture medium comprising the component to form the reaction medium flow; 21. The method according to claim 20, wherein forming the flow of reagents comprises the following steps:
(α) generating a continuous flow of a solvent in a mixing channel; (β) simultaneously with step α), injecting, by means of a capillary tube, a reagent chosen from the plurality of reagents in the mixing channel to form an elementary reagent flow; (γ) repeating step β13) for each of the successive reagents of the plurality of reagents; 22. The method according to claim 21, wherein forming the reagent flow comprises, after the formation of each elementary reagent flow and before step γ), a step δ) of injecting a cleaning liquid into each mixing channel by means of a capillary tube. 23. The method according to claim 19, wherein generating the ordered series of drops further includes, after step d′) and before step f′), a step e′) comprising injecting into the carrier fluid of a drop of a separating fluid immiscible with the carrier fluid or the reaction medium, such that at least one drop of separating fluid is intercalated between two reactors and prevents them coalescing. | 1,600 |
835 | 14,134,342 | 1,644 | A method can include administering a donor-specific human leukocyte antigen antibody to a tissue transplant recipient where the antibody is an immunoglobulin G subclass 4 antibody (G4). Various other examples of devices, assemblies, systems, methods, etc., are also disclosed. | 1. A method comprising:
administering a donor-specific human leukocyte antigen antibody to a tissue transplant recipient wherein the antibody comprises an immunoglobulin G subclass 4 antibody (G4). 2. The method of claim 1 comprising monitoring level of G4 in the recipient. 3. The method of claim 2 comprising repeating the administering based at least in part on the monitoring. 4. The method of claim 3 comprising determining a ratio for a level of G4 with respect to a level of another immunoglobulin G subclass antibody. 5. The method of claim 4 comprising, prior to repeating the administering, adjusting at least a G4 dose amount or a G4 dose frequency based on the ratio. 6. The method of claim 2 comprising comparing a monitored level of G4 to a target level of G4. 7. A method comprising:
administering a donor-specific human leukocyte antigen to a prospective tissue transplant recipient to increase level of an immunoglobulin G subclass 4 antibody (G4); and monitoring level of G4 in the prospective tissue transplant recipient. 8. The method of claim 7 comprising deciding to transplant the prospective tissue transplant recipient with tissue based at least in part on the monitoring. 9. The method of claim 8 comprising performing the transplant such that the prospective tissue transplant recipient is a tissue transplant recipient. 10. The method of claim 9 comprising administering the G4 antibody to the tissue transplant recipient. | A method can include administering a donor-specific human leukocyte antigen antibody to a tissue transplant recipient where the antibody is an immunoglobulin G subclass 4 antibody (G4). Various other examples of devices, assemblies, systems, methods, etc., are also disclosed.1. A method comprising:
administering a donor-specific human leukocyte antigen antibody to a tissue transplant recipient wherein the antibody comprises an immunoglobulin G subclass 4 antibody (G4). 2. The method of claim 1 comprising monitoring level of G4 in the recipient. 3. The method of claim 2 comprising repeating the administering based at least in part on the monitoring. 4. The method of claim 3 comprising determining a ratio for a level of G4 with respect to a level of another immunoglobulin G subclass antibody. 5. The method of claim 4 comprising, prior to repeating the administering, adjusting at least a G4 dose amount or a G4 dose frequency based on the ratio. 6. The method of claim 2 comprising comparing a monitored level of G4 to a target level of G4. 7. A method comprising:
administering a donor-specific human leukocyte antigen to a prospective tissue transplant recipient to increase level of an immunoglobulin G subclass 4 antibody (G4); and monitoring level of G4 in the prospective tissue transplant recipient. 8. The method of claim 7 comprising deciding to transplant the prospective tissue transplant recipient with tissue based at least in part on the monitoring. 9. The method of claim 8 comprising performing the transplant such that the prospective tissue transplant recipient is a tissue transplant recipient. 10. The method of claim 9 comprising administering the G4 antibody to the tissue transplant recipient. | 1,600 |
836 | 15,548,964 | 1,616 | The invention relates to microcapsules comprising at least one active substance selected from lutein and lutein esters embedded in a matrix comprising gum acacia and optionally one or more other matrix components, wherein the content of said at least one active substance calculated as free lutein is from 0.5 to 25% of total weight of the microcapsule, and which microcapsule does not comprise any added emulsifier.
The invention further relates to a process of preparing the microcapsule as well as uses and products comprising the microcapsule. | 1.-18. (canceled) 19. A microcapsule comprising at least one active substance selected from lutein and lutein esters embedded in a matrix comprising native gum acacia and optionally one or more other matrix components, wherein the content of said at least one active substance calculated as free lutein is from 0.5 to 25% of total weight of the microcapsule, and which microcapsule does not comprise any added emulsifier. 20. The microcapsule according to claim 19, wherein the content of said at least one active substance calculated as free lutein is from 1 to 20% of total weight of the microcapsule. 21. The microcapsule according to claim 19, wherein the content of said at least one active substance calculated as free lutein is from 3 to 15% of total weight of the microcapsule. 22. The microcapsule according to claim 19, wherein the content of said at least one active substance calculated as free lutein is from 4 to 13% of total weight of the microcapsule. 23. The microcapsule according to claim 19, wherein the content of said at least one active substance calculated as free lutein is from 5 to 10% of total weight of the microcapsule. 24. The microcapsule according to claim 19 further comprising at least one antioxidant and/or plasticizer. 25. The microcapsule according to claim 19, wherein said gum acacia is a quality gained from Acacia Senegal. 26. The microcapsule according to claim 19 prepared from an emulsion of melted or dissolved lutein or lutein ester concentrate(s) in an aqueous solution of said native gum acacia in the absence of an emulsifier, wherein said lutein or lutein ester concentrate(s) is optionally melted or dissolved in an edible oil. 27. The microcapsule according to claim 19 prepared from non-crystalline lutein ester. 28. A process of preparing the microcapsule according to claim 19, which process comprises the steps of
melting or dissolving lutein or lutein ester concentrate(s), providing an aqueous solution of native gum acacia and said optionally other matrix components, mixing said aqueous solution and said melted or dissolved lutein or lutein ester concentrate(s), homogenizing the resulting preparation without addition of an emulsifier, finely dividing and drying the mixture thus obtained to prepare a mass of particles each containing lutein or lutein ester(s) embedded in native gum acacia. 29. The process according to claim 28 wherein the lutein ester concentrate(s) is melted or dissolved in edible oil. 30. The process according to claim 28 wherein the lutein ester concentrate(s) is melted or dissolved in sunflower oil, olive oil, cotton seed oil, safflower oil, MCT oil, palm oil or hydrogenated palm oil. 31. The process according to claim 28 wherein said aqueous solution of native gum acacia is added to said melted or dissolved lutein or lutein ester concentrate(s) before homogenization. 32. The process according to claim 28 wherein said melted or dissolved lutein or lutein ester concentrate(s) is added to said aqueous solution of native gum acacia before homogenization. 33. The process according to claim 28 comprising a further step of homogenization. 34. The process according to claim 28 comprising a further step of high pressure homogenization. 35. A microcapsule comprising at least one active substance selected from lutein and lutein esters embedded in a matrix comprising native gum acacia and optionally one or more other matrix components, wherein the content of said at least one active substance calculated as free lutein is from 0.5 to 25% of total weight of the microcapsule, and which microcapsule does not comprise any added emulsifier obtainable by a process comprising the steps of
melting or dissolving lutein or lutein ester concentrate(s), providing an aqueous solution of said native gum acacia and said optionally other matrix components, mixing said aqueous solution and said melted or dissolved lutein or lutein ester concentrate(s), homogenizing the resulting preparation without addition of an emulsifier, finely dividing and drying the mixture thus obtained to prepare a mass of particles each containing lutein or lutein ester(s) embedded in native gum acacia. 36. A product comprising microcapsules according to claim 19. 37. The product according to claim 36, wherein the product is a tablet, a dietary supplement, a food, a food supplement, a dairy, a pharmaceutical or veterinary product, a feed or feed supplement, a beverage, a personal care products or a household product. 38. A tablet, dietary supplement or food comprising the microcapsules according to claim 19 wherein said native gum acacia is a quality gained from Acacia Senegal. | The invention relates to microcapsules comprising at least one active substance selected from lutein and lutein esters embedded in a matrix comprising gum acacia and optionally one or more other matrix components, wherein the content of said at least one active substance calculated as free lutein is from 0.5 to 25% of total weight of the microcapsule, and which microcapsule does not comprise any added emulsifier.
The invention further relates to a process of preparing the microcapsule as well as uses and products comprising the microcapsule.1.-18. (canceled) 19. A microcapsule comprising at least one active substance selected from lutein and lutein esters embedded in a matrix comprising native gum acacia and optionally one or more other matrix components, wherein the content of said at least one active substance calculated as free lutein is from 0.5 to 25% of total weight of the microcapsule, and which microcapsule does not comprise any added emulsifier. 20. The microcapsule according to claim 19, wherein the content of said at least one active substance calculated as free lutein is from 1 to 20% of total weight of the microcapsule. 21. The microcapsule according to claim 19, wherein the content of said at least one active substance calculated as free lutein is from 3 to 15% of total weight of the microcapsule. 22. The microcapsule according to claim 19, wherein the content of said at least one active substance calculated as free lutein is from 4 to 13% of total weight of the microcapsule. 23. The microcapsule according to claim 19, wherein the content of said at least one active substance calculated as free lutein is from 5 to 10% of total weight of the microcapsule. 24. The microcapsule according to claim 19 further comprising at least one antioxidant and/or plasticizer. 25. The microcapsule according to claim 19, wherein said gum acacia is a quality gained from Acacia Senegal. 26. The microcapsule according to claim 19 prepared from an emulsion of melted or dissolved lutein or lutein ester concentrate(s) in an aqueous solution of said native gum acacia in the absence of an emulsifier, wherein said lutein or lutein ester concentrate(s) is optionally melted or dissolved in an edible oil. 27. The microcapsule according to claim 19 prepared from non-crystalline lutein ester. 28. A process of preparing the microcapsule according to claim 19, which process comprises the steps of
melting or dissolving lutein or lutein ester concentrate(s), providing an aqueous solution of native gum acacia and said optionally other matrix components, mixing said aqueous solution and said melted or dissolved lutein or lutein ester concentrate(s), homogenizing the resulting preparation without addition of an emulsifier, finely dividing and drying the mixture thus obtained to prepare a mass of particles each containing lutein or lutein ester(s) embedded in native gum acacia. 29. The process according to claim 28 wherein the lutein ester concentrate(s) is melted or dissolved in edible oil. 30. The process according to claim 28 wherein the lutein ester concentrate(s) is melted or dissolved in sunflower oil, olive oil, cotton seed oil, safflower oil, MCT oil, palm oil or hydrogenated palm oil. 31. The process according to claim 28 wherein said aqueous solution of native gum acacia is added to said melted or dissolved lutein or lutein ester concentrate(s) before homogenization. 32. The process according to claim 28 wherein said melted or dissolved lutein or lutein ester concentrate(s) is added to said aqueous solution of native gum acacia before homogenization. 33. The process according to claim 28 comprising a further step of homogenization. 34. The process according to claim 28 comprising a further step of high pressure homogenization. 35. A microcapsule comprising at least one active substance selected from lutein and lutein esters embedded in a matrix comprising native gum acacia and optionally one or more other matrix components, wherein the content of said at least one active substance calculated as free lutein is from 0.5 to 25% of total weight of the microcapsule, and which microcapsule does not comprise any added emulsifier obtainable by a process comprising the steps of
melting or dissolving lutein or lutein ester concentrate(s), providing an aqueous solution of said native gum acacia and said optionally other matrix components, mixing said aqueous solution and said melted or dissolved lutein or lutein ester concentrate(s), homogenizing the resulting preparation without addition of an emulsifier, finely dividing and drying the mixture thus obtained to prepare a mass of particles each containing lutein or lutein ester(s) embedded in native gum acacia. 36. A product comprising microcapsules according to claim 19. 37. The product according to claim 36, wherein the product is a tablet, a dietary supplement, a food, a food supplement, a dairy, a pharmaceutical or veterinary product, a feed or feed supplement, a beverage, a personal care products or a household product. 38. A tablet, dietary supplement or food comprising the microcapsules according to claim 19 wherein said native gum acacia is a quality gained from Acacia Senegal. | 1,600 |
837 | 15,561,763 | 1,612 | Provided is a dental membrane which includes: a first support made by accumulating first nanofibers of a biodegradable polymer obtained by electrospinning and having a plurality of pores formed therein; a second support made by accumulating second nanofibers of a biodegradable polymer obtained by electrospinning on the first support, and having a plurality of pores formed therein, in which the second nanofibers have diameters larger than the diameters of the first nanofibers; and a third support made by accumulating third nanofibers of a biodegradable polymer obtained by electrospinning on the second support, and having a plurality of pores formed therein, in which the third nanofibers have diameters smaller than the diameters of the second nanofibers. | 1. A dental membrane comprising:
a first support made by accumulating first nanofibers of a biodegradable polymer obtained by electrospinning and having a plurality of pores formed therein; a second support made by accumulating second nanofibers of a biodegradable polymer obtained by electrospinning on the first support, and having a plurality of pores formed therein, in which the second nanofibers have diameters larger than the diameters of the first nanofibers; and a third support made by accumulating third nanofibers of a biodegradable polymer obtained by electrospinning on the second support, and having a plurality of pores formed therein, in which the third nanofibers have diameters smaller than the diameters of the second nanofibers. 2. The dental membrane of claim 1, wherein the diameters in size of the third nanofiber of the third support are smaller than the diameters in size of the first nanofiber of the first support. 3. The dental membrane of claim 1, wherein the diameters of the first nanofibers are less than 100 nm. 4. The dental membrane of claim 1, wherein the diameters of the third nanofibers are in the range of 200 nm to 1 μm. 5. The dental membrane of claim 1, wherein the biodegradable polymer is one or a mixture of at least two of PLA (Poly Lactic Acid), PLLA (Poly(L-lactic acid)), PGA (Poly(glycolic acid)), PLGA (Poly(lactide-co-glycolide)), PCL (Polycaprolactone) and PDO (1,3-Propanediol). 6. The dental membrane of claim 1, wherein at least one of the first to third nanofibers includes a hydrophilic agent. 7. The dental membrane of claim 6, wherein the hydrophilic agent is one of Tween 80, Pluronic and PVP. 8. The dental membrane of claim 1, wherein the first support is in contact with a living tissue to be grown, the thickness of the second support is thicker than the thickness of the first support, and the thickness of the third support is thicker than the thicknesses of the first and second supports. 9. The dental membrane of claim 8, wherein the first support has a thickness capable of being decomposed in 1 to 2 months, the second support has a thickness capable of being decomposed in 3 to 4 months, and the third support has a thickness capable of being decomposed in 5 to 6 months. 10. A dental membrane comprising:
a first support made by accumulating nanofibers containing biodegradable polymers obtained by electrospinning and bone growth factors and having a plurality of pores formed therein; a second support made by accumulating nanofibers containing biodegradable polymers obtained by electrospinning and regrowth factors on the first support and having a plurality of pores formed therein; and a third support made by accumulating nanofibers of the biodegradable polymers obtained by electrospinning on the second support and having a plurality of pores formed therein. 11. The dental membrane of claim 10, wherein the diameters in size of the nanofibers of the third support are smaller than the diameters in size of the nanofibers of the first support. 12. The dental membrane of claim 10, wherein the thickness of the first support, the second support, and the third support are gradually increased in sequence of the first to third supports. | Provided is a dental membrane which includes: a first support made by accumulating first nanofibers of a biodegradable polymer obtained by electrospinning and having a plurality of pores formed therein; a second support made by accumulating second nanofibers of a biodegradable polymer obtained by electrospinning on the first support, and having a plurality of pores formed therein, in which the second nanofibers have diameters larger than the diameters of the first nanofibers; and a third support made by accumulating third nanofibers of a biodegradable polymer obtained by electrospinning on the second support, and having a plurality of pores formed therein, in which the third nanofibers have diameters smaller than the diameters of the second nanofibers.1. A dental membrane comprising:
a first support made by accumulating first nanofibers of a biodegradable polymer obtained by electrospinning and having a plurality of pores formed therein; a second support made by accumulating second nanofibers of a biodegradable polymer obtained by electrospinning on the first support, and having a plurality of pores formed therein, in which the second nanofibers have diameters larger than the diameters of the first nanofibers; and a third support made by accumulating third nanofibers of a biodegradable polymer obtained by electrospinning on the second support, and having a plurality of pores formed therein, in which the third nanofibers have diameters smaller than the diameters of the second nanofibers. 2. The dental membrane of claim 1, wherein the diameters in size of the third nanofiber of the third support are smaller than the diameters in size of the first nanofiber of the first support. 3. The dental membrane of claim 1, wherein the diameters of the first nanofibers are less than 100 nm. 4. The dental membrane of claim 1, wherein the diameters of the third nanofibers are in the range of 200 nm to 1 μm. 5. The dental membrane of claim 1, wherein the biodegradable polymer is one or a mixture of at least two of PLA (Poly Lactic Acid), PLLA (Poly(L-lactic acid)), PGA (Poly(glycolic acid)), PLGA (Poly(lactide-co-glycolide)), PCL (Polycaprolactone) and PDO (1,3-Propanediol). 6. The dental membrane of claim 1, wherein at least one of the first to third nanofibers includes a hydrophilic agent. 7. The dental membrane of claim 6, wherein the hydrophilic agent is one of Tween 80, Pluronic and PVP. 8. The dental membrane of claim 1, wherein the first support is in contact with a living tissue to be grown, the thickness of the second support is thicker than the thickness of the first support, and the thickness of the third support is thicker than the thicknesses of the first and second supports. 9. The dental membrane of claim 8, wherein the first support has a thickness capable of being decomposed in 1 to 2 months, the second support has a thickness capable of being decomposed in 3 to 4 months, and the third support has a thickness capable of being decomposed in 5 to 6 months. 10. A dental membrane comprising:
a first support made by accumulating nanofibers containing biodegradable polymers obtained by electrospinning and bone growth factors and having a plurality of pores formed therein; a second support made by accumulating nanofibers containing biodegradable polymers obtained by electrospinning and regrowth factors on the first support and having a plurality of pores formed therein; and a third support made by accumulating nanofibers of the biodegradable polymers obtained by electrospinning on the second support and having a plurality of pores formed therein. 11. The dental membrane of claim 10, wherein the diameters in size of the nanofibers of the third support are smaller than the diameters in size of the nanofibers of the first support. 12. The dental membrane of claim 10, wherein the thickness of the first support, the second support, and the third support are gradually increased in sequence of the first to third supports. | 1,600 |
838 | 15,037,978 | 1,649 | The invention provides methods of monitoring immunotherapy directed against alpha-synuclein by comparing a subject's constipation symptoms before treatment and at one or more times during and/or after treatment. The immunotherapeutic regime can be monitored depending on the results of treatment. | 1. A method of assessing the efficacy of immunotherapy against alpha-synuclein in subjects diagnosed with a Lewy Body disease and having one or more constipation symptoms, comprising:
(a) evaluating the subjects' constipation symptoms before administration of an immunotherapeutic agent in a first regime; (b) administering the immunotherapeutic agent to the subjects in the first regime; (c) evaluating the subjects' constipation symptoms after administering the iummunotherapeutic agent in the first regime, (d) comparing the subjects' constipation symptoms before and after administering the immunotherapeutic agent in the first regime; (e) administering a second regime to subjects whose symptoms improve and a third regime to subjects whose symptoms deteriorate, the second and third regimes being different. 2. The method of claim 1, wherein the second regime is the same as the first regime. 3. The method of claim any preceding claim, wherein the second regime administers the same immunotherapy agent as the first regime at a reduced dosage or frequency. 4. The method of claim any preceding claim, wherein the third regime administers the same immunotherapy agent as the first regime at an increased dosage or frequency. 5. The method of any of claims 1-3, wherein the third regime administers a different immunotherapy agent than the first regime, or a non-immunotherapy agent. 6. The method of any preceding claim, wherein the Lewy body disease is Parkinson's disease. 7. The method of any of claims 1-5, wherein the Lewy body disease is dementia with Lewy bodies. 8. The method of any preceding claim, wherein the immunotherapy agent is an antibody that specifically binds to alpha-synuclein. 9. The method of any of claims 1-7, wherein the immunotherapy agent induces an antibody that specifically binds to alpha-synuclein. 10. The method of claim 8 or 9, wherein the antibody binds to an epitope within residues 1-10, 91-99, 118-126 or 130-140 of alpha-synuclein. 11. The method of any of claims 1-9, wherein the antibody binds to an epitope within residues 118-126 of alpha-synuclein. 12. The method of any of claims 1-9 or 11, wherein the immunotherapeutic agent is an antibody comprising the six Kabat CDRs of 9E4, 5C1, 1H7, 6H7, or 8A5. 13. The method of claim 12, wherein the antibody is humanized 9E4 comprising a heavy chain variable region of SEQ ID NO:37 and a light chain variable region of SEQ ID NO:32. 14. The method of any preceding claims, wherein the subject's constipation symptoms are evaluated from subject answers to a questionnaire. 15. The method of claim 14, wherein the questionnaire is the PAC-SYM questionnaire. 16. The method of any preceding claims, wherein the subjects' constipation symptoms are evaluated on at least first and second occasions respectively after first and second administrations of the immunotherapy agent in the first regime. 17. The method of any preceding claims, wherein the dose or frequency is reduced by at least half in the second regime relative to the first regime. 18. The method of any preceding claims, wherein the dose or frequency is increased by at least a factor of two in the third regime relative to the second regime. 19. The method of any preceding claims, further comprising monitoring the subjects for changes in one or more signs or symptoms of the Lewy body disease other than constipation in response to the first regime. 20. The method of claim 19, wherein the signs or symptoms include motor functioning, cognitive function, and level of alpha-synuclein in the brain or body fluid. 21. A method of any preceding claim, wherein the immunotherapeutic agent is a humanized 9E4 antibody and the dose is 0.3-1.0 mg/kg, 1.0-3.0 mg/kg, 3.0-10 mg/kg or 10-30 mg/kg administered with a frequency of once every 28-31 days, optionally monthly. 22. A method of treating constipation in a subject with a Lewy body disease and having one or more symptoms of constipation, comprising
administering immunotherapy against alpha-synuclein to the subject in a regime effective to reduce the constipation symptoms. 23. The method of claim 22, further comprising monitoring the constipation symptoms. 24. The method of any of claims 21-23, wherein the immunotherapeutic agent is a humanized 9E4 antibody and the dose is 0.3-1.0 mg/kg, 1.0-3.0 mg/kg, 3.0-10 mg/kg or 10-30 mg/kg administered with a frequency of once every 28-31 days, optionally monthly. 25. A method of evaluating an immunotherapy regime comprising
administering an immunotherapy regime against alpha-synuclein to a transgenic animal model expressing an alpha-synuclein transgene and disposed to develop signs and symptoms of a Lewy body disease; and determining one or more symptoms of constipation before and after administering the immunotherapy regime, and improvement of the symptoms providing an indication that the immunotherapy regime is useful for treating Lewy body disease. 26. The method of claim 25, wherein the immunotherapeutic agent is a humanized 9E4 antibody and the dose is 0.3-1.0 mg/kg, 1.0-3.0 mg/kg, 3.0-10 mg/kg or 10-30 mg/kg administered with a frequency of once every 28-31 days, optionally monthly. 27. A method of assessing the efficacy of immunotherapy against alpha-synuclein in a subject diagnosed with a Lewy Body disease and having one or more constipation symptoms, comprising:
(a) evaluating the subject's constipation symptoms before administration of an immunotherapeutic agent in a first regime; (b) administering the immunotherapeutic agent to the subject in the first regime; (c) evaluating the subject's constipation symptoms after administering the immunotherapeutic agent in the first regime, (d) comparing the subject's constipation symptoms before and after administering the immunotherapeutic agent in the first regime; wherein the subject's symptoms improve; (e) administering a second regime, which is the same as the first regime, or which administers the same immunotherapeutic agent as the first regime at a reduced dose or frequency. 28. The method of claim 27, wherein the immunotherapeutic agent is a humanized 9E4 antibody and the dose is 0.3-1.0 mg/kg, 1.0-3.0 mg/kg, 3.0-10 mg/kg or 10-30 mg/kg administered with a frequency of once every 28-31 days, optionally monthly. 29. A method of assessing the efficacy of immunotherapy against alpha-synuclein in a subject diagnosed with a Lewy Body disease and having one or more constipation symptoms, comprising:
(a) evaluating the subject's constipation symptoms before administration of an immunotherapeutic agent in a first regime; (b) administering the immunotherapeutic agent to the subject in the first regime; (c) evaluating the subject's constipation symptoms after administering the immunotherapeutic agent in the first regime, (d) comparing the subject's constipation symptoms before and after administering the immunotherapeutic agent in the first regime; wherein the subject's symptoms remain the same or deteriorate; (e) administering a second regime, which administers the same immunotherapeutic agent as the first regime at an increased dose or frequency or which administers a different immunotherapeutic agent or which administers a non-immunotherapeutic agent effective for treatment of Lewy body disease. 30. The method of claim 29, wherein the immunotherapeutic agent is a humanized 9E4 antibody and the dose is 0.3-1.0 mg/kg, 1.0-3.0 mg/kg, 3.0-10 mg/kg or 10-30 mg/kg administered with a frequency of once 28-31 days, optionally monthly. 31. A method of treating a subject with a Lewy body disease, comprising
administering a humanized 9E4 antibody to the subject at a dose of 0.3 mg/kg to 30 mg/kg at a frequency of once every 28-31 days, optionally monthly. 32. The method of claim 31, wherein the dose is 0.3-1.0 mg/kg. 33. The method of claim 31, wherein the dose is 1.0-3.0 mg/kg. 34. The method of claim 31, wherein the dose is 3.0-10 mg/kg. 35. The method of claim 31, wherein the dose is 10-30 mg/kg. 36. The method of claim 31, wherein the dose is 0.3 mg/kg. 37. The method of claim 31, wherein the dose is 1.0 mg/kg. 38. The method of claim 31, wherein the dose is 3 mg/kg. 39. The method of claim 31, wherein the dose is 10 mg/kg. 40. The method of claim 31, wherein the dose is 30 mg/kg. 41. The method of any of claims 31 to 40, wherein the humanized 9E4 antibody has a light chain variable region of SEQ ID NO:32 and a heavy chain variable region of SEQ ID NO:37. | The invention provides methods of monitoring immunotherapy directed against alpha-synuclein by comparing a subject's constipation symptoms before treatment and at one or more times during and/or after treatment. The immunotherapeutic regime can be monitored depending on the results of treatment.1. A method of assessing the efficacy of immunotherapy against alpha-synuclein in subjects diagnosed with a Lewy Body disease and having one or more constipation symptoms, comprising:
(a) evaluating the subjects' constipation symptoms before administration of an immunotherapeutic agent in a first regime; (b) administering the immunotherapeutic agent to the subjects in the first regime; (c) evaluating the subjects' constipation symptoms after administering the iummunotherapeutic agent in the first regime, (d) comparing the subjects' constipation symptoms before and after administering the immunotherapeutic agent in the first regime; (e) administering a second regime to subjects whose symptoms improve and a third regime to subjects whose symptoms deteriorate, the second and third regimes being different. 2. The method of claim 1, wherein the second regime is the same as the first regime. 3. The method of claim any preceding claim, wherein the second regime administers the same immunotherapy agent as the first regime at a reduced dosage or frequency. 4. The method of claim any preceding claim, wherein the third regime administers the same immunotherapy agent as the first regime at an increased dosage or frequency. 5. The method of any of claims 1-3, wherein the third regime administers a different immunotherapy agent than the first regime, or a non-immunotherapy agent. 6. The method of any preceding claim, wherein the Lewy body disease is Parkinson's disease. 7. The method of any of claims 1-5, wherein the Lewy body disease is dementia with Lewy bodies. 8. The method of any preceding claim, wherein the immunotherapy agent is an antibody that specifically binds to alpha-synuclein. 9. The method of any of claims 1-7, wherein the immunotherapy agent induces an antibody that specifically binds to alpha-synuclein. 10. The method of claim 8 or 9, wherein the antibody binds to an epitope within residues 1-10, 91-99, 118-126 or 130-140 of alpha-synuclein. 11. The method of any of claims 1-9, wherein the antibody binds to an epitope within residues 118-126 of alpha-synuclein. 12. The method of any of claims 1-9 or 11, wherein the immunotherapeutic agent is an antibody comprising the six Kabat CDRs of 9E4, 5C1, 1H7, 6H7, or 8A5. 13. The method of claim 12, wherein the antibody is humanized 9E4 comprising a heavy chain variable region of SEQ ID NO:37 and a light chain variable region of SEQ ID NO:32. 14. The method of any preceding claims, wherein the subject's constipation symptoms are evaluated from subject answers to a questionnaire. 15. The method of claim 14, wherein the questionnaire is the PAC-SYM questionnaire. 16. The method of any preceding claims, wherein the subjects' constipation symptoms are evaluated on at least first and second occasions respectively after first and second administrations of the immunotherapy agent in the first regime. 17. The method of any preceding claims, wherein the dose or frequency is reduced by at least half in the second regime relative to the first regime. 18. The method of any preceding claims, wherein the dose or frequency is increased by at least a factor of two in the third regime relative to the second regime. 19. The method of any preceding claims, further comprising monitoring the subjects for changes in one or more signs or symptoms of the Lewy body disease other than constipation in response to the first regime. 20. The method of claim 19, wherein the signs or symptoms include motor functioning, cognitive function, and level of alpha-synuclein in the brain or body fluid. 21. A method of any preceding claim, wherein the immunotherapeutic agent is a humanized 9E4 antibody and the dose is 0.3-1.0 mg/kg, 1.0-3.0 mg/kg, 3.0-10 mg/kg or 10-30 mg/kg administered with a frequency of once every 28-31 days, optionally monthly. 22. A method of treating constipation in a subject with a Lewy body disease and having one or more symptoms of constipation, comprising
administering immunotherapy against alpha-synuclein to the subject in a regime effective to reduce the constipation symptoms. 23. The method of claim 22, further comprising monitoring the constipation symptoms. 24. The method of any of claims 21-23, wherein the immunotherapeutic agent is a humanized 9E4 antibody and the dose is 0.3-1.0 mg/kg, 1.0-3.0 mg/kg, 3.0-10 mg/kg or 10-30 mg/kg administered with a frequency of once every 28-31 days, optionally monthly. 25. A method of evaluating an immunotherapy regime comprising
administering an immunotherapy regime against alpha-synuclein to a transgenic animal model expressing an alpha-synuclein transgene and disposed to develop signs and symptoms of a Lewy body disease; and determining one or more symptoms of constipation before and after administering the immunotherapy regime, and improvement of the symptoms providing an indication that the immunotherapy regime is useful for treating Lewy body disease. 26. The method of claim 25, wherein the immunotherapeutic agent is a humanized 9E4 antibody and the dose is 0.3-1.0 mg/kg, 1.0-3.0 mg/kg, 3.0-10 mg/kg or 10-30 mg/kg administered with a frequency of once every 28-31 days, optionally monthly. 27. A method of assessing the efficacy of immunotherapy against alpha-synuclein in a subject diagnosed with a Lewy Body disease and having one or more constipation symptoms, comprising:
(a) evaluating the subject's constipation symptoms before administration of an immunotherapeutic agent in a first regime; (b) administering the immunotherapeutic agent to the subject in the first regime; (c) evaluating the subject's constipation symptoms after administering the immunotherapeutic agent in the first regime, (d) comparing the subject's constipation symptoms before and after administering the immunotherapeutic agent in the first regime; wherein the subject's symptoms improve; (e) administering a second regime, which is the same as the first regime, or which administers the same immunotherapeutic agent as the first regime at a reduced dose or frequency. 28. The method of claim 27, wherein the immunotherapeutic agent is a humanized 9E4 antibody and the dose is 0.3-1.0 mg/kg, 1.0-3.0 mg/kg, 3.0-10 mg/kg or 10-30 mg/kg administered with a frequency of once every 28-31 days, optionally monthly. 29. A method of assessing the efficacy of immunotherapy against alpha-synuclein in a subject diagnosed with a Lewy Body disease and having one or more constipation symptoms, comprising:
(a) evaluating the subject's constipation symptoms before administration of an immunotherapeutic agent in a first regime; (b) administering the immunotherapeutic agent to the subject in the first regime; (c) evaluating the subject's constipation symptoms after administering the immunotherapeutic agent in the first regime, (d) comparing the subject's constipation symptoms before and after administering the immunotherapeutic agent in the first regime; wherein the subject's symptoms remain the same or deteriorate; (e) administering a second regime, which administers the same immunotherapeutic agent as the first regime at an increased dose or frequency or which administers a different immunotherapeutic agent or which administers a non-immunotherapeutic agent effective for treatment of Lewy body disease. 30. The method of claim 29, wherein the immunotherapeutic agent is a humanized 9E4 antibody and the dose is 0.3-1.0 mg/kg, 1.0-3.0 mg/kg, 3.0-10 mg/kg or 10-30 mg/kg administered with a frequency of once 28-31 days, optionally monthly. 31. A method of treating a subject with a Lewy body disease, comprising
administering a humanized 9E4 antibody to the subject at a dose of 0.3 mg/kg to 30 mg/kg at a frequency of once every 28-31 days, optionally monthly. 32. The method of claim 31, wherein the dose is 0.3-1.0 mg/kg. 33. The method of claim 31, wherein the dose is 1.0-3.0 mg/kg. 34. The method of claim 31, wherein the dose is 3.0-10 mg/kg. 35. The method of claim 31, wherein the dose is 10-30 mg/kg. 36. The method of claim 31, wherein the dose is 0.3 mg/kg. 37. The method of claim 31, wherein the dose is 1.0 mg/kg. 38. The method of claim 31, wherein the dose is 3 mg/kg. 39. The method of claim 31, wherein the dose is 10 mg/kg. 40. The method of claim 31, wherein the dose is 30 mg/kg. 41. The method of any of claims 31 to 40, wherein the humanized 9E4 antibody has a light chain variable region of SEQ ID NO:32 and a heavy chain variable region of SEQ ID NO:37. | 1,600 |
839 | 15,397,193 | 1,633 | A biodegradable cationic polymer is disclosed, comprising first repeat units derived from a first cyclic carbonyl monomer by ring-opening polymerization, wherein more than 0% of the first repeat units comprise a side chain moiety comprising a quaternary amine group; a subunit derived from a monomeric diol initiator for the ring-opening polymerization; and an optional endcap group. The biodegradable cationic polymers have low cytotoxicity and form complexes with biologically active materials useful in gene therapeutics and drug delivery. | 1. A polymer complex, comprising:
a negatively charged biologically active material selected from the group consisting of genes, nucleotides, proteins, peptides, drugs, and combinations thereof; and a biodegradable cationic polymer comprising two polymer chains joined by a divalent linking group, wherein each of the polymer chains comprises
i) a first repeat unit selected from the group consisting of
and
ii) an optional second repeat unit;
wherein
the biologically active material and the cationic polymer are bound together by non-covalent interactions, and
the polymer complex is capable of entering a cell by endocytosis and releasing the biologically active material within the cell. 2. The polymer complex of claim 1, wherein the first repeat unit is 3. The polymer complex of claim 1, wherein the first repeat unit is 4. The polymer complex of claim 1, wherein the first repeat unit is 5. The polymer complex of claim 1, wherein each of the polymer chains is a polycarbonate homopolymer of the first repeat unit. 6. The polymer complex of claim 1, wherein each of the polymer chains is a polycarbonate random copolymer of the first repeat unit and the second repeat unit, wherein the second repeat unit is selected from the group consisting of 7. The polymer complex of claim 6, wherein the second repeat unit is 8. The polymer complex of claim 1, wherein each of the polymer chains is a diblock copolymer chain comprising i) a hydrophobic core block linked to the divalent linking group of the cationic polymer and ii) a hydrophilic outer block linked to the hydrophobic core block, the hydrophilic outer block comprising the first repeat unit. 9. The polymer complex of claim 8, wherein the hydrophobic core block is a polycarbonate. 10. The polymer complex of claim 9, wherein the hydrophobic core block is a poly(trimethylene carbonate). 11. The polymer complex of claim 8, wherein the hydrophobic core block is a polyester. 12. The polymer complex of claim 11, wherein the hydrophobic core block is poly(L-lactide). 13. The polymer complex of claim 11, wherein the hydrophobic core block is poly(D-lactide). 14. The polymer complex of claim 1, wherein the cationic polymer self-assembles in water to form nanoparticles having an average particle size of 10 nm to 500 nm at a pH of from 5.0 to 8.0. 15. The polymer complex of claim 14, wherein in water the nanoparticles of the cationic polymer have a positively charged surface and a hydrophobic core. 16. The polymer complex of claim 1, wherein the polymer complex in water has an average particle size of 50 nm to 500 nm at a pH of from 5.0 to 8.0. 17. The polymer complex of claim 1, wherein the biologically active material is a gene. 18. The polymer complex of claim 1, wherein the biologically active material is a drug. 19. The polymer complex of claim 1, wherein the cationic polymer is biodegradable in accordance with ASTM D6400. 20. A method of treating a cell, comprising:
contacting the cell with nanoparticles of the polymer complex of claim 1 in water, wherein the polymer complex enters the cell, the polymer complex releases the biologically active material within the cell, and the released biologically active material alters a chemical structure and/or activity of the cell. 21. The method of claim 20, wherein the nanoparticles have an average particle size of 50 nm to 500 nm at a pH of from 5.0 to 8.0. 22. The method of claim 20, wherein the cell is a eukaryotic cell. 23. The method of claim 22, wherein the biologically active material is a gene, the polymer complex releases the gene within the cell, and the gene is incorporated into deoxyribonucleic acid (DNA) of the cell. 24. The method of claim 23, wherein the cell expresses the gene. 25. The method of claim 20, wherein the biologically active material is a drug. | A biodegradable cationic polymer is disclosed, comprising first repeat units derived from a first cyclic carbonyl monomer by ring-opening polymerization, wherein more than 0% of the first repeat units comprise a side chain moiety comprising a quaternary amine group; a subunit derived from a monomeric diol initiator for the ring-opening polymerization; and an optional endcap group. The biodegradable cationic polymers have low cytotoxicity and form complexes with biologically active materials useful in gene therapeutics and drug delivery.1. A polymer complex, comprising:
a negatively charged biologically active material selected from the group consisting of genes, nucleotides, proteins, peptides, drugs, and combinations thereof; and a biodegradable cationic polymer comprising two polymer chains joined by a divalent linking group, wherein each of the polymer chains comprises
i) a first repeat unit selected from the group consisting of
and
ii) an optional second repeat unit;
wherein
the biologically active material and the cationic polymer are bound together by non-covalent interactions, and
the polymer complex is capable of entering a cell by endocytosis and releasing the biologically active material within the cell. 2. The polymer complex of claim 1, wherein the first repeat unit is 3. The polymer complex of claim 1, wherein the first repeat unit is 4. The polymer complex of claim 1, wherein the first repeat unit is 5. The polymer complex of claim 1, wherein each of the polymer chains is a polycarbonate homopolymer of the first repeat unit. 6. The polymer complex of claim 1, wherein each of the polymer chains is a polycarbonate random copolymer of the first repeat unit and the second repeat unit, wherein the second repeat unit is selected from the group consisting of 7. The polymer complex of claim 6, wherein the second repeat unit is 8. The polymer complex of claim 1, wherein each of the polymer chains is a diblock copolymer chain comprising i) a hydrophobic core block linked to the divalent linking group of the cationic polymer and ii) a hydrophilic outer block linked to the hydrophobic core block, the hydrophilic outer block comprising the first repeat unit. 9. The polymer complex of claim 8, wherein the hydrophobic core block is a polycarbonate. 10. The polymer complex of claim 9, wherein the hydrophobic core block is a poly(trimethylene carbonate). 11. The polymer complex of claim 8, wherein the hydrophobic core block is a polyester. 12. The polymer complex of claim 11, wherein the hydrophobic core block is poly(L-lactide). 13. The polymer complex of claim 11, wherein the hydrophobic core block is poly(D-lactide). 14. The polymer complex of claim 1, wherein the cationic polymer self-assembles in water to form nanoparticles having an average particle size of 10 nm to 500 nm at a pH of from 5.0 to 8.0. 15. The polymer complex of claim 14, wherein in water the nanoparticles of the cationic polymer have a positively charged surface and a hydrophobic core. 16. The polymer complex of claim 1, wherein the polymer complex in water has an average particle size of 50 nm to 500 nm at a pH of from 5.0 to 8.0. 17. The polymer complex of claim 1, wherein the biologically active material is a gene. 18. The polymer complex of claim 1, wherein the biologically active material is a drug. 19. The polymer complex of claim 1, wherein the cationic polymer is biodegradable in accordance with ASTM D6400. 20. A method of treating a cell, comprising:
contacting the cell with nanoparticles of the polymer complex of claim 1 in water, wherein the polymer complex enters the cell, the polymer complex releases the biologically active material within the cell, and the released biologically active material alters a chemical structure and/or activity of the cell. 21. The method of claim 20, wherein the nanoparticles have an average particle size of 50 nm to 500 nm at a pH of from 5.0 to 8.0. 22. The method of claim 20, wherein the cell is a eukaryotic cell. 23. The method of claim 22, wherein the biologically active material is a gene, the polymer complex releases the gene within the cell, and the gene is incorporated into deoxyribonucleic acid (DNA) of the cell. 24. The method of claim 23, wherein the cell expresses the gene. 25. The method of claim 20, wherein the biologically active material is a drug. | 1,600 |
840 | 15,921,596 | 1,658 | Pyrrolidine carboxamido derivatives, optical isomers thereof, and salts thereof that are able to prevent, improve, and/or treat inflammatory conditions, including inflammatory bowel disease, and methods for preparing and using the same are provided. | 1. A method for preventing, improving, or treating inflammatory bowel disease, which comprises administering to a subject in need a composition containing, as an active component, a compound represented by the following Formula 1, an optical isomer thereof, or a salt thereof:
wherein:
n is 0, 1, or 2;
A is -al-, which is an amino acid independently selected from the group consisting of alanine, (Ala, A), arginine (Arg, R), asparagine (Asn, N), aspartic acid (Asp, D), cysteine (Cys, C), glutamic acid (Glu, E), glutamine (Gln, Q), glycine (Gly, G), histidine (His, H), isoleucine (Ile, I), leucine (Leu, L), lysine (Lys, K), methionine (Met, M), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), tryptophan (Trp, W), tyrosine (Tyr, Y), and valine (Val, V), both terminal ends of the amino acid being coupled to a carbonyl group or an amine group by an amide bond; and
R1 is a straight chain or branched chain C1-36 alkyl, a straight chain or branched chain C2-36 alkenyl including at least one double bond, or a straight chain or branched chain C2-36 alkynyl including at least one triple bond (SEQ ID NO: 1). 2. The method of claim 1, wherein the composition is administered via oral, nasal, pulmonary, rectal, buccal, vaginal, ocular and transdermal routes. 3. The method of claim 1, wherein the inflammatory bowel disease includes ulcerative colitis, Behcet's disease, and Crohn's disease. 4. The method of claim 1, wherein the composition, wherein the composition inhibits formation of an inflammatory signal transduction complex mediated by MyD88, inhibits formation of an inflammatory signal transduction complex mediated by Pellino-1, inhibits formation of an inflammatory signal transduction complex mediated by Rip1, suppresses expression of at least one protein selected from the group consisting of G-CSF, IL-2, SCF, VEGF, CX3CL1, IGFBP5, IGFBP6, IL-1α, IL-1β, IL-6, IL-9, MCP-1, MIP-3α, IL12p40/70, MIG, TNF-α, and VCAM-1, or suppresses activity of N F-κB. 5. A method for preventing, improving, or treating disease or syndrome, which comprises administering to a subject in need a composition containing, as an active component, a compound represented by the following Formula 1, an optical isomer thereof, or a salt thereof, wherein the disease or syndrome involves formation of a Pellino-1 induced inflammatory signal transduction complex containing MyD88, RIP1, or both:
wherein:
n is 0, 1, or 2;
A is -a1-, which is an amino acid independently selected from the group consisting of alanine, (Ala, A), arginine (Arg, R), asparagine (Asn, N), aspartic acid (Asp, D), cysteine (Cys, C), glutamic acid (Glu, E), glutamine (Gln, Q), glycine (Gly, G), histidine (His, H), isoleucine (Ile, I), leucine (Leu, L), lysine (Lys, K), methionine (Met, M), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), tryptophan (Trp, W), tyrosine (Tyr, Y), and valine (Val, V), both terminal ends of the amino acid being coupled to a carbonyl group or an amine group by an amide bond; and
R1 is a straight chain or branched chain C1-36 alkyl, a straight chain or branched chain C2-36 alkenyl including at least one double bond, or a straight chain or branched chain C2-36 alkynyl including at least one triple bond (SEQ ID NO: 1). 6. The method of claim 5, wherein the disease or syndrome is inflammatory bowel disease. 7. The method of claim 6, wherein the inflammatory bowel disease includes ulcerative colitis, Behcet's disease, and Crohn's disease. 8. The method of claim 5, wherein the disease or syndrome includes multiple sclerosis, psoriasis, sepsis, geographic atrophy, wet age-related macular disease, dry age-related macular disease, diabetic retinopathy, infectious lung diseases, bacterial pneumonia, viral pneumonia, diffuse large B-cell lymphoma, viral infection, autoimmune disease, blood cancer including lymphoma, and tumors in internal organs. 9. A method for suppressing expression of cytokines and/or chemokines, which comprises administering to a subject in need a composition containing, as an active component, a compound represented by the following Formula 1, an optical isomer thereof, or a salt thereof:
wherein:
n is 0, 1, or 2;
A is -a1-, which is an amino acid independently selected from the group consisting of alanine, (Ala, A), arginine (Arg, R), asparagine (Asn, N), aspartic acid (Asp, D), cysteine (Cys, C), glutamic acid (Glu, E), glutamine (Gln, Q), glycine (Gly, G), histidine (His, H), isoleucine (Ile, I), leucine (Leu, L), lysine (Lys, K), methionine (Met, M), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), tryptophan (Trp, W), tyrosine (Tyr, Y), and valine (Val, V), both terminal ends of the amino acid being coupled to a carbonyl group or an amine group by an amide bond; and
R1 is a straight chain or branched chain C1-36 alkyl, a straight chain or branched chain C2-36 alkenyl including at least one double bond, or a straight chain or branched chain C2-36 alkynyl including at least one triple bond (SEQ ID NO: 1). | Pyrrolidine carboxamido derivatives, optical isomers thereof, and salts thereof that are able to prevent, improve, and/or treat inflammatory conditions, including inflammatory bowel disease, and methods for preparing and using the same are provided.1. A method for preventing, improving, or treating inflammatory bowel disease, which comprises administering to a subject in need a composition containing, as an active component, a compound represented by the following Formula 1, an optical isomer thereof, or a salt thereof:
wherein:
n is 0, 1, or 2;
A is -al-, which is an amino acid independently selected from the group consisting of alanine, (Ala, A), arginine (Arg, R), asparagine (Asn, N), aspartic acid (Asp, D), cysteine (Cys, C), glutamic acid (Glu, E), glutamine (Gln, Q), glycine (Gly, G), histidine (His, H), isoleucine (Ile, I), leucine (Leu, L), lysine (Lys, K), methionine (Met, M), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), tryptophan (Trp, W), tyrosine (Tyr, Y), and valine (Val, V), both terminal ends of the amino acid being coupled to a carbonyl group or an amine group by an amide bond; and
R1 is a straight chain or branched chain C1-36 alkyl, a straight chain or branched chain C2-36 alkenyl including at least one double bond, or a straight chain or branched chain C2-36 alkynyl including at least one triple bond (SEQ ID NO: 1). 2. The method of claim 1, wherein the composition is administered via oral, nasal, pulmonary, rectal, buccal, vaginal, ocular and transdermal routes. 3. The method of claim 1, wherein the inflammatory bowel disease includes ulcerative colitis, Behcet's disease, and Crohn's disease. 4. The method of claim 1, wherein the composition, wherein the composition inhibits formation of an inflammatory signal transduction complex mediated by MyD88, inhibits formation of an inflammatory signal transduction complex mediated by Pellino-1, inhibits formation of an inflammatory signal transduction complex mediated by Rip1, suppresses expression of at least one protein selected from the group consisting of G-CSF, IL-2, SCF, VEGF, CX3CL1, IGFBP5, IGFBP6, IL-1α, IL-1β, IL-6, IL-9, MCP-1, MIP-3α, IL12p40/70, MIG, TNF-α, and VCAM-1, or suppresses activity of N F-κB. 5. A method for preventing, improving, or treating disease or syndrome, which comprises administering to a subject in need a composition containing, as an active component, a compound represented by the following Formula 1, an optical isomer thereof, or a salt thereof, wherein the disease or syndrome involves formation of a Pellino-1 induced inflammatory signal transduction complex containing MyD88, RIP1, or both:
wherein:
n is 0, 1, or 2;
A is -a1-, which is an amino acid independently selected from the group consisting of alanine, (Ala, A), arginine (Arg, R), asparagine (Asn, N), aspartic acid (Asp, D), cysteine (Cys, C), glutamic acid (Glu, E), glutamine (Gln, Q), glycine (Gly, G), histidine (His, H), isoleucine (Ile, I), leucine (Leu, L), lysine (Lys, K), methionine (Met, M), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), tryptophan (Trp, W), tyrosine (Tyr, Y), and valine (Val, V), both terminal ends of the amino acid being coupled to a carbonyl group or an amine group by an amide bond; and
R1 is a straight chain or branched chain C1-36 alkyl, a straight chain or branched chain C2-36 alkenyl including at least one double bond, or a straight chain or branched chain C2-36 alkynyl including at least one triple bond (SEQ ID NO: 1). 6. The method of claim 5, wherein the disease or syndrome is inflammatory bowel disease. 7. The method of claim 6, wherein the inflammatory bowel disease includes ulcerative colitis, Behcet's disease, and Crohn's disease. 8. The method of claim 5, wherein the disease or syndrome includes multiple sclerosis, psoriasis, sepsis, geographic atrophy, wet age-related macular disease, dry age-related macular disease, diabetic retinopathy, infectious lung diseases, bacterial pneumonia, viral pneumonia, diffuse large B-cell lymphoma, viral infection, autoimmune disease, blood cancer including lymphoma, and tumors in internal organs. 9. A method for suppressing expression of cytokines and/or chemokines, which comprises administering to a subject in need a composition containing, as an active component, a compound represented by the following Formula 1, an optical isomer thereof, or a salt thereof:
wherein:
n is 0, 1, or 2;
A is -a1-, which is an amino acid independently selected from the group consisting of alanine, (Ala, A), arginine (Arg, R), asparagine (Asn, N), aspartic acid (Asp, D), cysteine (Cys, C), glutamic acid (Glu, E), glutamine (Gln, Q), glycine (Gly, G), histidine (His, H), isoleucine (Ile, I), leucine (Leu, L), lysine (Lys, K), methionine (Met, M), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), tryptophan (Trp, W), tyrosine (Tyr, Y), and valine (Val, V), both terminal ends of the amino acid being coupled to a carbonyl group or an amine group by an amide bond; and
R1 is a straight chain or branched chain C1-36 alkyl, a straight chain or branched chain C2-36 alkenyl including at least one double bond, or a straight chain or branched chain C2-36 alkynyl including at least one triple bond (SEQ ID NO: 1). | 1,600 |
841 | 15,205,853 | 1,658 | Pyrrolidine carboxamido derivatives, optical isomers thereof, and salts thereof that are able to prevent, improve, and/or treat inflammatory conditions, including inflammatory bowel disease, and methods for preparing and using the same are provided. | 1. A compound represented by the following Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
wherein:
n is 0, 1, or 2;
A is -a1-, which is an amino acid independently selected from the group consisting of alanine, (Ala, A), arginine (Arg, R), asparagine (Asn, N), aspartic acid (Asp, D), cysteine (Cys, C), glutamic acid (Glu, E), glutamine (Gln, Q), glycine (Gly, G), histidine (His, H), isoleucine (Ile, I), leucine (Leu, L), lysine (Lys, K), methionine (Met, M), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), tryptophan (Trp, W), tyrosine (Tyr, Y), and valine (Val, V), both terminal ends of the amino acid being coupled to a carbonyl group or an amine group by an amide bond; and
R1 is a straight chain or branched chain C1-36 alkyl, a straight chain or branched chain C2-36 alkenyl including at least one double bond, or a straight chain or branched chain C2-36 alkynyl including at least one triple bond. 2. The compound of claim 1, wherein:
n is 0, 1, or 2; a 1 is
both terminal ends of which is coupled to a carbonyl group or amide group thereof by an amide bond; and
R1 is a straight chain or branched chain C1-36 alkyl. 3. The compound of claim 1 selected from the group consisting of the following compounds. 4. A method for preparing the compound of claim 1 represented by Formula 1, which comprises, as represented by the following Reaction Scheme 1:
reacting a compound 2 with a compound 3 to prepare a compound 4;
hydrolyzing the compound 4 in the presence of a base to prepare a compound 5;
reacting the compound 5 with a compound 6 to prepare a compound 7;
hydrolyzing the compound 7 in the presence of a base to prepare a compound 8;
reacting the compound 8 with a compound 9 to prepare a compound 10;
hydrolyzing the compound 10 in the presence of a base to prepare the compound of claim 1.
wherein A, R1 and n are the same as defined in claim 1 and R2 is a straight chain or branched chain C1-5 alkyl. 5. A composition for preventing, improving, or treating inflammatory bowel disease, which comprises, as an active component, the compound, the optical isomer, or the salt of claim 1. 6. The composition of claim 5, which inhibits formation of an inflammatory signal transduction complex mediated by MyD88, inhibits formation of an inflammatory signal transduction complex mediated by Pellino-1, inhibits formation of an inflammatory signal transduction complex mediated by Rip1, suppresses expression of at least one protein selected from the group consisting of G-CSF, IL-2, SCF, VEGF, CX3CL1, IGFBP5, IGFBP6, IL-1α, IL-1β, IL-6, IL-9, MCP-1, MIP-3α, IL12p40/70, MIG, TNF-α, and VCAM-1, or suppresses activity of NF-κB. 7. The composition of claim 5, wherein the inflammatory bowel disease includes ulcerative colitis, Behcet's disease, and Crohn's disease. 8. A method for preventing, improving, or treating inflammatory bowel disease, which comprises administering to a subject in need a composition containing, as an active component, the compound, the optical isomer, or the salt of claim 1. 9. The method of claim 8, wherein the composition is administered via oral, nasal, pulmonary, rectal, buccal, vaginal, ocular and transdermal routes. 10. The method of claim 8, wherein the inflammatory bowel disease includes ulcerative colitis, Behcet's disease, and Crohn's disease. 11. The method of claim 8, wherein the composition, wherein the composition inhibits formation of an inflammatory signal transduction complex mediated by MyD88, inhibits formation of an inflammatory signal transduction complex mediated by Pellino-1, inhibits formation of an inflammatory signal transduction complex mediated by Rip1, suppresses expression of at least one protein selected from the group consisting of G-CSF, IL-2, SCF, VEGF, CX3CL1, IGFBP5, IGFBP6, IL-1α, IL-1β, IL-6, IL-9, MCP-1, MIP-3α, ID 2p40/70, MIG, TNF-α, and VCAM-1, or suppresses activity of NF-κB. 12. A method for preventing, improving, or treating disease or syndrome, which comprises administering to a subject in need a composition containing, as an active component, the compound, the optical isomer, or the salt of claim 1, wherein the disease or syndrome involves formation of a Pellino-1 induced inflammatory signal transduction complex containing MyD88, RIP1, or both. 13. The method of claim 12, wherein the disease or syndrome is inflammatory bowel disease. 14. The method of claim 13, wherein the inflammatory bowel disease includes ulcerative colitis, Behcet's disease, and Crohn's disease. 15. The method of claim 12, wherein the disease or syndrome includes multiple sclerosis, psoriasis, sepsis, geographic atrophy, wet age-related macular disease, dry age-related macular disease, diabetic retinopathy, infectious lung diseases, bacterial pneumonia, viral pneumonia, diffuse large B-cell lymphoma, viral infection, autoimmune disease, blood cancer including lymphoma, and tumors in internal organs. 16. A composition for preventing, improving, or treating disease or syndrome, which comprises, as an active component, the compound, the optical isomer, or the salt of claim 1, wherein the disease or syndrome includes geographic atrophy, wet age-related macular disease, dry age-related macular disease, and diabetic retinopathy. 17. The composition of claim 16, wherein the compound, the optimal isomer, or the salt of claim 1 has a pharmaceutical effect on retinal pigment epithelium cells. 18. The composition of claim 16, wherein the compound, the optimal isomer, or the salt of claim 1 inhibits expression, in retinal pigment epithelium cells, of at least one protein selected from the group consisting of Nox-4, VEGF, VEGFR1, VEGFR2, Ang2, EPO and EPOR. 19. The composition of claim 16, wherein the compound, the optimal isomer, or the salt of claim 1 increases expression, in retinal pigment epithelium cells, of Ang 1, Tie2, or both. 20. A composition for preventing, improving, or treating disease or syndrome, which comprises, as an active component, the compound, the optical isomer, or the salt of claim 1, wherein the disease or syndrome includes sepsis and multiple sclerosis. 21. A composition for preventing, improving, or treating alopecia, which comprises, as an active component, the compound, the optical isomer, or the salt of claim 1, wherein the active component inhibits expression of IL-6 in scalp and hair follicles. 22. A composition for preventing, improving, or treating disease or syndrome, which comprises, as an active component, the compound, the optical isomer, or the salt of claim 1, wherein the disease or syndrome involves formation of a Pellino-1 induced inflammatory signal transduction complex containing MyD88, RIP1, or both. 23. The composition of claim 22, wherein the disease or syndrome is inflammatory bowel disease. 24. The composition of claim 23, wherein the inflammatory bowel disease includes ulcerative colitis, Behcet's disease, and Crohn's disease. 25. The composition of claim 22, wherein the disease or syndrome includes multiple sclerosis, psoriasis, sepsis, geographic atrophy, wet age-related macular disease, dry age-related macular disease, diabetic retinopathy, infectious lung diseases, bacterial pneumonia, viral pneumonia, diffuse large B-cell lymphoma, viral infection, autoimmune disease, blood cancer including lymphoma, and tumors in internal organs. 26. A method for suppressing expression of cytokines and/or chemokines, which comprises administering to a subject in need a composition containing, as an active component, the compound, the optical isomer, or the salt of claim 1. | Pyrrolidine carboxamido derivatives, optical isomers thereof, and salts thereof that are able to prevent, improve, and/or treat inflammatory conditions, including inflammatory bowel disease, and methods for preparing and using the same are provided.1. A compound represented by the following Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
wherein:
n is 0, 1, or 2;
A is -a1-, which is an amino acid independently selected from the group consisting of alanine, (Ala, A), arginine (Arg, R), asparagine (Asn, N), aspartic acid (Asp, D), cysteine (Cys, C), glutamic acid (Glu, E), glutamine (Gln, Q), glycine (Gly, G), histidine (His, H), isoleucine (Ile, I), leucine (Leu, L), lysine (Lys, K), methionine (Met, M), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), tryptophan (Trp, W), tyrosine (Tyr, Y), and valine (Val, V), both terminal ends of the amino acid being coupled to a carbonyl group or an amine group by an amide bond; and
R1 is a straight chain or branched chain C1-36 alkyl, a straight chain or branched chain C2-36 alkenyl including at least one double bond, or a straight chain or branched chain C2-36 alkynyl including at least one triple bond. 2. The compound of claim 1, wherein:
n is 0, 1, or 2; a 1 is
both terminal ends of which is coupled to a carbonyl group or amide group thereof by an amide bond; and
R1 is a straight chain or branched chain C1-36 alkyl. 3. The compound of claim 1 selected from the group consisting of the following compounds. 4. A method for preparing the compound of claim 1 represented by Formula 1, which comprises, as represented by the following Reaction Scheme 1:
reacting a compound 2 with a compound 3 to prepare a compound 4;
hydrolyzing the compound 4 in the presence of a base to prepare a compound 5;
reacting the compound 5 with a compound 6 to prepare a compound 7;
hydrolyzing the compound 7 in the presence of a base to prepare a compound 8;
reacting the compound 8 with a compound 9 to prepare a compound 10;
hydrolyzing the compound 10 in the presence of a base to prepare the compound of claim 1.
wherein A, R1 and n are the same as defined in claim 1 and R2 is a straight chain or branched chain C1-5 alkyl. 5. A composition for preventing, improving, or treating inflammatory bowel disease, which comprises, as an active component, the compound, the optical isomer, or the salt of claim 1. 6. The composition of claim 5, which inhibits formation of an inflammatory signal transduction complex mediated by MyD88, inhibits formation of an inflammatory signal transduction complex mediated by Pellino-1, inhibits formation of an inflammatory signal transduction complex mediated by Rip1, suppresses expression of at least one protein selected from the group consisting of G-CSF, IL-2, SCF, VEGF, CX3CL1, IGFBP5, IGFBP6, IL-1α, IL-1β, IL-6, IL-9, MCP-1, MIP-3α, IL12p40/70, MIG, TNF-α, and VCAM-1, or suppresses activity of NF-κB. 7. The composition of claim 5, wherein the inflammatory bowel disease includes ulcerative colitis, Behcet's disease, and Crohn's disease. 8. A method for preventing, improving, or treating inflammatory bowel disease, which comprises administering to a subject in need a composition containing, as an active component, the compound, the optical isomer, or the salt of claim 1. 9. The method of claim 8, wherein the composition is administered via oral, nasal, pulmonary, rectal, buccal, vaginal, ocular and transdermal routes. 10. The method of claim 8, wherein the inflammatory bowel disease includes ulcerative colitis, Behcet's disease, and Crohn's disease. 11. The method of claim 8, wherein the composition, wherein the composition inhibits formation of an inflammatory signal transduction complex mediated by MyD88, inhibits formation of an inflammatory signal transduction complex mediated by Pellino-1, inhibits formation of an inflammatory signal transduction complex mediated by Rip1, suppresses expression of at least one protein selected from the group consisting of G-CSF, IL-2, SCF, VEGF, CX3CL1, IGFBP5, IGFBP6, IL-1α, IL-1β, IL-6, IL-9, MCP-1, MIP-3α, ID 2p40/70, MIG, TNF-α, and VCAM-1, or suppresses activity of NF-κB. 12. A method for preventing, improving, or treating disease or syndrome, which comprises administering to a subject in need a composition containing, as an active component, the compound, the optical isomer, or the salt of claim 1, wherein the disease or syndrome involves formation of a Pellino-1 induced inflammatory signal transduction complex containing MyD88, RIP1, or both. 13. The method of claim 12, wherein the disease or syndrome is inflammatory bowel disease. 14. The method of claim 13, wherein the inflammatory bowel disease includes ulcerative colitis, Behcet's disease, and Crohn's disease. 15. The method of claim 12, wherein the disease or syndrome includes multiple sclerosis, psoriasis, sepsis, geographic atrophy, wet age-related macular disease, dry age-related macular disease, diabetic retinopathy, infectious lung diseases, bacterial pneumonia, viral pneumonia, diffuse large B-cell lymphoma, viral infection, autoimmune disease, blood cancer including lymphoma, and tumors in internal organs. 16. A composition for preventing, improving, or treating disease or syndrome, which comprises, as an active component, the compound, the optical isomer, or the salt of claim 1, wherein the disease or syndrome includes geographic atrophy, wet age-related macular disease, dry age-related macular disease, and diabetic retinopathy. 17. The composition of claim 16, wherein the compound, the optimal isomer, or the salt of claim 1 has a pharmaceutical effect on retinal pigment epithelium cells. 18. The composition of claim 16, wherein the compound, the optimal isomer, or the salt of claim 1 inhibits expression, in retinal pigment epithelium cells, of at least one protein selected from the group consisting of Nox-4, VEGF, VEGFR1, VEGFR2, Ang2, EPO and EPOR. 19. The composition of claim 16, wherein the compound, the optimal isomer, or the salt of claim 1 increases expression, in retinal pigment epithelium cells, of Ang 1, Tie2, or both. 20. A composition for preventing, improving, or treating disease or syndrome, which comprises, as an active component, the compound, the optical isomer, or the salt of claim 1, wherein the disease or syndrome includes sepsis and multiple sclerosis. 21. A composition for preventing, improving, or treating alopecia, which comprises, as an active component, the compound, the optical isomer, or the salt of claim 1, wherein the active component inhibits expression of IL-6 in scalp and hair follicles. 22. A composition for preventing, improving, or treating disease or syndrome, which comprises, as an active component, the compound, the optical isomer, or the salt of claim 1, wherein the disease or syndrome involves formation of a Pellino-1 induced inflammatory signal transduction complex containing MyD88, RIP1, or both. 23. The composition of claim 22, wherein the disease or syndrome is inflammatory bowel disease. 24. The composition of claim 23, wherein the inflammatory bowel disease includes ulcerative colitis, Behcet's disease, and Crohn's disease. 25. The composition of claim 22, wherein the disease or syndrome includes multiple sclerosis, psoriasis, sepsis, geographic atrophy, wet age-related macular disease, dry age-related macular disease, diabetic retinopathy, infectious lung diseases, bacterial pneumonia, viral pneumonia, diffuse large B-cell lymphoma, viral infection, autoimmune disease, blood cancer including lymphoma, and tumors in internal organs. 26. A method for suppressing expression of cytokines and/or chemokines, which comprises administering to a subject in need a composition containing, as an active component, the compound, the optical isomer, or the salt of claim 1. | 1,600 |
842 | 13,377,514 | 1,643 | The present invention provides a method for treating a subject having chronic lymphocytic leukemia (CLL) comprising administering to the subject one or more agents that target cell surface membrane antigens expressed preferentially on cells of the proliferative compartment of a CLL clone of the subject to treat chronic lymphocytic leukemia in the subject. The present invention also provides a method for treating a subject having chronic lymphocytic leukemia comprising administering to the subject one or more agents that target cell surface membrane antigens expressed preferentially on cells of the “resting re-entry compartment” to treat chronic lymphocytic leukemia in the subject. | 1. A method for treating a subject having chronic lymphocytic leukemia (CLL) comprising administering to the subject one or more agents that target cell surface membrane antigens expressed preferentially on cells of the proliferative compartment of a CLL clone of the subject to treat chronic lymphocytic leukemia in the subject. 2. The method of claim 1, wherein the cell surface membrane antigens expressed preferentially on cells of the proliferative CLL compartment of a CLL clone of the subject are identified by associating members of a set of surface membrane antigens with the cells in the subject's CLL leukemic clone that divide most vigorously. 3. The method of claim 1, wherein the cell surface membrane antigens are selected from the set comprising CD5, CD11a, CD19, CD20, CD23, CD27, CD38, CD48, CD49d, CD52, CD62L, and CD100. 4. The method of claim 1, wherein the differential expression by cells of the proliferative compartment comprises (i) down regulated expression of CXCR4 and CCR7 and (ii) up-regulated expression of one or more of CD5, CD11a, CD20, CD23, CD27, CD38, CD48, CD49d, CD52, CD62L, and CD100. 5. The method of claim 1, wherein the proliferating cells are identified by enrichment in 2H-labeled DNA. 6. The method of claim 1, wherein the proliferating cells are identified by Ki-67 expression. 7. The method of claim 1, wherein the one or more agents bind to at least two of CD11a, CD19, CD20, CD23, CD27, CD38, CD48, CD49d, CD52, CD62L, and CD100. 8-33. (canceled) 34. The method of claim 1, wherein the agent or agents is one or more antibodies, aptamers, peptides or T lymphocytes or natural killer cells with a chimeric bispecific receptors. 35. The method of claim 1, wherein the agent is a bi-specific antibody that binds to (i) CD19 and CD11a, (ii) CD19 and CD23, (iii) CD19 and CD27, (iv) CD19 and CD38, (v) CD19 and CD48, (vi) CD19 and CD49d, (vii) CD19 and CD52, (viii) CD19 and CD62L, and (ix) CD19 and CD100; (x) CD20 and CD11a, (xi) CD20 and CD23, (xii) CD20 and CD27, (xiii) CD20 and CD38, (xiv) CD20 and CD48, (xv) CD20 and CD49d, (xvi) CD20 and CD52, (xvii) CD20 and CD62L, and (xviii) CD20 and CD100; (xix) CD23 and CD11a, (xx) CD23 and CD27, (xxi) CD23 and CD38, (xxii) CD23 and CD48, (xxiii) CD23 and CD49d, (xxiv) CD23 and CD52, (xxv) CD23 and CD62L, and (xxvi) CD23 and CD100. 36. The method of claim 1, wherein the agents are antibodies that bind to (i) CD19 and CD11a, respectively, (ii) CD19 and CD23, respectively, (iii) CD19 and CD27, respectively, (iv) CD19 and CD38, respectively, (v) CD19 and CD48, respectively, (vi) CD19 and CD49d, respectively, (vii) CD19 and CD52, respectively, (viii) CD19 and CD62L, respectively, and (ix) CD19 and CD100, respectively; (x) CD20 and CD11a, respectively, (xi) CD20 and CD23, respectively, (xii) CD20 and CD27, respectively, (xiii) CD20 and CD38, respectively, (xiv) CD20 and CD48, respectively, (xv) CD20 and CD49d, respectively, (xvi) CD20 and CD52, respectively, (xvii) CD20 and CD62L, respectively, and (xviii) CD20 and CD100, respectively; (xix) CD23 and CD11a, respectively, (xx) CD23 and CD27, respectively, (xxi) CD23 and CD38, respectively, (xxii) CD23 and CD48, respectively, (xxiii) CD23 and CD49d, respectively, (xxiv) CD23 and CD52, respectively, (xxv) CD23 and CD62L, respectively, and (xxvi) CD23 and CD100, respectively. 37. The method of claim 34, wherein the antibody or antibodies are monoclonal antibodies. 38. The method of claim 34, wherein the agents are administered simultaneously or in tandem. 39. The method of claim 1, wherein the agent or agents are conjugated with a toxin or radioligand. 40. The method of claim 1, wherein the agent or agents are administered to the bone marrow and/or to the blood of the subject. 41. The method of claim 1, wherein the agent or agents are administered prior to, following or in combination with other therapeutic treatments for chronic lymphocytic leukemia. 42. An agent or combination of agents that binds to (i) CD19 and CD11a, (ii) CD19 and CD23, (iii) CD19 and CD27, (iv) CD19 and CD38, (v) CD19 and CD48, (vi) CD19 and CD49d, (vii) CD19 and CD52, (viii) CD19 and CD62L, and (ix) CD19 and CD100; (x) CD20 and CD11a, (xi) CD20 and CD23, (xii) CD20 and CD27, (xiii) CD20 and CD38, (xiv) CD20 and CD48, (xv) CD20 and CD49d, (xvi) CD20 and CD52, (xvii) CD20 and CD62L, and (xviii) CD20 and CD100; (xix) CD23 and CD11a, (xx) CD23 and CD27, (xxi) CD23 and CD38, (xxii) CD23 and CD48, (xxiii) CD23 and CD49d, (xxiv) CD23 and CD52, (xxv) CD23 and CD62L, and/or (xxvi) CD23 and CD100. 43. (canceled) 44. The agent or combination of agents of claim 42, wherein the agent or agents are antibodies, aptamers, peptides or T lymphocytes or natural killer cells with a chimeric bispecific receptors. 45. A pharmaceutical composition comprising the agent or combination of agents of claim 42. 46. A method for treating a subject having chronic lymphocytic leukemia comprising administering to the subject one or more agents that target cell surface membrane antigens expressed preferentially on cells of the “resting re-entry compartment” to treat chronic lymphocytic leukemia in the subject. 47. The method of claim 46, wherein the cell surface membrane antigens expressed preferentially on cells are identified by co-expression of a series of surface membrane molecules. 48. The method of claim 46, wherein the cell surface membrane antigens are selected from CD19, CD20, CCR7, and CXCR4. 49. The method of claim 46, wherein the cells of the resting “re-entry compartment” down regulate expression of one or more of CD5, CD11a, CD23, CD27, CD38, CD48, CD49d, CD52, CD62L, and CD100 and up-regulate expression of one or more of CXCR4 and CCR7. 50. A method for diagnosing chronic lymphocytic leukemia or monitoring the progression of chronic lympocytic leukemia comprising (i) identifying and quantifying the number of proliferative cells associated with chronic lympocytic leukemia, and (ii) correlating the type and quantity of the cells to a control to diagnose chronic lymphocytic leukemia or monitor the progression of chronic lympocytic leukemia. 51. The method of claim 50, where the cells are cells of the proliferative compartment and/or cells of the “resting, re-entry compartment”. 52. The method of claim 50, wherein the cell surface membrane antigens expressed preferentially on cells are identified by associating members of a set of surface membrane antigens to identify cells in a CLL leukemic clone that divide most vigorously. 53. The method of claim 50, wherein the cell surface membrane antigens are selected from CD5, CD11a, CD19, CD20, CD23, CD27, CD38, CD48, CD49d, CD52, CD62L, and CD100. 54. The method of claim 50, wherein the cells of the proliferative compartment down regulate expression of CXCR4 and up-regulate expression of one or more of CD5, CD11a, CD19, CD20, CD23, CD27, CD38, CD48, CD49d, CD52, CD62L, and CD100. 55. The method of claim 50, wherein the proliferating cells are identified by enrichment in 2H-labeled DNA. 56. The method of claim 50, wherein the proliferating cells are identified by Ki-67 expression. 57. The method of claim 50, wherein the cells of the “resting, re-entry compartment” down regulate expression of one or more of CD5, CD11a, CD19, CD20, CD23, CD27, CD38, CD48, CD49d, CD52, CD62L, and CD100 and up-regulate expression of one or more of CXCR4 and CCR7. | The present invention provides a method for treating a subject having chronic lymphocytic leukemia (CLL) comprising administering to the subject one or more agents that target cell surface membrane antigens expressed preferentially on cells of the proliferative compartment of a CLL clone of the subject to treat chronic lymphocytic leukemia in the subject. The present invention also provides a method for treating a subject having chronic lymphocytic leukemia comprising administering to the subject one or more agents that target cell surface membrane antigens expressed preferentially on cells of the “resting re-entry compartment” to treat chronic lymphocytic leukemia in the subject.1. A method for treating a subject having chronic lymphocytic leukemia (CLL) comprising administering to the subject one or more agents that target cell surface membrane antigens expressed preferentially on cells of the proliferative compartment of a CLL clone of the subject to treat chronic lymphocytic leukemia in the subject. 2. The method of claim 1, wherein the cell surface membrane antigens expressed preferentially on cells of the proliferative CLL compartment of a CLL clone of the subject are identified by associating members of a set of surface membrane antigens with the cells in the subject's CLL leukemic clone that divide most vigorously. 3. The method of claim 1, wherein the cell surface membrane antigens are selected from the set comprising CD5, CD11a, CD19, CD20, CD23, CD27, CD38, CD48, CD49d, CD52, CD62L, and CD100. 4. The method of claim 1, wherein the differential expression by cells of the proliferative compartment comprises (i) down regulated expression of CXCR4 and CCR7 and (ii) up-regulated expression of one or more of CD5, CD11a, CD20, CD23, CD27, CD38, CD48, CD49d, CD52, CD62L, and CD100. 5. The method of claim 1, wherein the proliferating cells are identified by enrichment in 2H-labeled DNA. 6. The method of claim 1, wherein the proliferating cells are identified by Ki-67 expression. 7. The method of claim 1, wherein the one or more agents bind to at least two of CD11a, CD19, CD20, CD23, CD27, CD38, CD48, CD49d, CD52, CD62L, and CD100. 8-33. (canceled) 34. The method of claim 1, wherein the agent or agents is one or more antibodies, aptamers, peptides or T lymphocytes or natural killer cells with a chimeric bispecific receptors. 35. The method of claim 1, wherein the agent is a bi-specific antibody that binds to (i) CD19 and CD11a, (ii) CD19 and CD23, (iii) CD19 and CD27, (iv) CD19 and CD38, (v) CD19 and CD48, (vi) CD19 and CD49d, (vii) CD19 and CD52, (viii) CD19 and CD62L, and (ix) CD19 and CD100; (x) CD20 and CD11a, (xi) CD20 and CD23, (xii) CD20 and CD27, (xiii) CD20 and CD38, (xiv) CD20 and CD48, (xv) CD20 and CD49d, (xvi) CD20 and CD52, (xvii) CD20 and CD62L, and (xviii) CD20 and CD100; (xix) CD23 and CD11a, (xx) CD23 and CD27, (xxi) CD23 and CD38, (xxii) CD23 and CD48, (xxiii) CD23 and CD49d, (xxiv) CD23 and CD52, (xxv) CD23 and CD62L, and (xxvi) CD23 and CD100. 36. The method of claim 1, wherein the agents are antibodies that bind to (i) CD19 and CD11a, respectively, (ii) CD19 and CD23, respectively, (iii) CD19 and CD27, respectively, (iv) CD19 and CD38, respectively, (v) CD19 and CD48, respectively, (vi) CD19 and CD49d, respectively, (vii) CD19 and CD52, respectively, (viii) CD19 and CD62L, respectively, and (ix) CD19 and CD100, respectively; (x) CD20 and CD11a, respectively, (xi) CD20 and CD23, respectively, (xii) CD20 and CD27, respectively, (xiii) CD20 and CD38, respectively, (xiv) CD20 and CD48, respectively, (xv) CD20 and CD49d, respectively, (xvi) CD20 and CD52, respectively, (xvii) CD20 and CD62L, respectively, and (xviii) CD20 and CD100, respectively; (xix) CD23 and CD11a, respectively, (xx) CD23 and CD27, respectively, (xxi) CD23 and CD38, respectively, (xxii) CD23 and CD48, respectively, (xxiii) CD23 and CD49d, respectively, (xxiv) CD23 and CD52, respectively, (xxv) CD23 and CD62L, respectively, and (xxvi) CD23 and CD100, respectively. 37. The method of claim 34, wherein the antibody or antibodies are monoclonal antibodies. 38. The method of claim 34, wherein the agents are administered simultaneously or in tandem. 39. The method of claim 1, wherein the agent or agents are conjugated with a toxin or radioligand. 40. The method of claim 1, wherein the agent or agents are administered to the bone marrow and/or to the blood of the subject. 41. The method of claim 1, wherein the agent or agents are administered prior to, following or in combination with other therapeutic treatments for chronic lymphocytic leukemia. 42. An agent or combination of agents that binds to (i) CD19 and CD11a, (ii) CD19 and CD23, (iii) CD19 and CD27, (iv) CD19 and CD38, (v) CD19 and CD48, (vi) CD19 and CD49d, (vii) CD19 and CD52, (viii) CD19 and CD62L, and (ix) CD19 and CD100; (x) CD20 and CD11a, (xi) CD20 and CD23, (xii) CD20 and CD27, (xiii) CD20 and CD38, (xiv) CD20 and CD48, (xv) CD20 and CD49d, (xvi) CD20 and CD52, (xvii) CD20 and CD62L, and (xviii) CD20 and CD100; (xix) CD23 and CD11a, (xx) CD23 and CD27, (xxi) CD23 and CD38, (xxii) CD23 and CD48, (xxiii) CD23 and CD49d, (xxiv) CD23 and CD52, (xxv) CD23 and CD62L, and/or (xxvi) CD23 and CD100. 43. (canceled) 44. The agent or combination of agents of claim 42, wherein the agent or agents are antibodies, aptamers, peptides or T lymphocytes or natural killer cells with a chimeric bispecific receptors. 45. A pharmaceutical composition comprising the agent or combination of agents of claim 42. 46. A method for treating a subject having chronic lymphocytic leukemia comprising administering to the subject one or more agents that target cell surface membrane antigens expressed preferentially on cells of the “resting re-entry compartment” to treat chronic lymphocytic leukemia in the subject. 47. The method of claim 46, wherein the cell surface membrane antigens expressed preferentially on cells are identified by co-expression of a series of surface membrane molecules. 48. The method of claim 46, wherein the cell surface membrane antigens are selected from CD19, CD20, CCR7, and CXCR4. 49. The method of claim 46, wherein the cells of the resting “re-entry compartment” down regulate expression of one or more of CD5, CD11a, CD23, CD27, CD38, CD48, CD49d, CD52, CD62L, and CD100 and up-regulate expression of one or more of CXCR4 and CCR7. 50. A method for diagnosing chronic lymphocytic leukemia or monitoring the progression of chronic lympocytic leukemia comprising (i) identifying and quantifying the number of proliferative cells associated with chronic lympocytic leukemia, and (ii) correlating the type and quantity of the cells to a control to diagnose chronic lymphocytic leukemia or monitor the progression of chronic lympocytic leukemia. 51. The method of claim 50, where the cells are cells of the proliferative compartment and/or cells of the “resting, re-entry compartment”. 52. The method of claim 50, wherein the cell surface membrane antigens expressed preferentially on cells are identified by associating members of a set of surface membrane antigens to identify cells in a CLL leukemic clone that divide most vigorously. 53. The method of claim 50, wherein the cell surface membrane antigens are selected from CD5, CD11a, CD19, CD20, CD23, CD27, CD38, CD48, CD49d, CD52, CD62L, and CD100. 54. The method of claim 50, wherein the cells of the proliferative compartment down regulate expression of CXCR4 and up-regulate expression of one or more of CD5, CD11a, CD19, CD20, CD23, CD27, CD38, CD48, CD49d, CD52, CD62L, and CD100. 55. The method of claim 50, wherein the proliferating cells are identified by enrichment in 2H-labeled DNA. 56. The method of claim 50, wherein the proliferating cells are identified by Ki-67 expression. 57. The method of claim 50, wherein the cells of the “resting, re-entry compartment” down regulate expression of one or more of CD5, CD11a, CD19, CD20, CD23, CD27, CD38, CD48, CD49d, CD52, CD62L, and CD100 and up-regulate expression of one or more of CXCR4 and CCR7. | 1,600 |
843 | 15,950,246 | 1,628 | Combinations of betaine and vitamin C are used to suppress or prevent malignant tumors or to treat viruses, e.g., by combining the two ingredients in a product consumed by a human, dog, or cat, such as an aqueous liquid such as grape juice, the ingredients being provided in containers with instructions for use, or in finished products, especially with support of tests demonstrating the effectiveness of the treatment for, e.g., preventing tumors in populations known to be at risk of developing tumors, or, treating existing cancers in combination with other cancer drugs such as anastrozole and/or fulvestrant and/or artemisinin either concurrently or sequentially to prevent the cancer from growing when the cancer drug is not being used, or in the treatment of viruses. | 1-20. (canceled) 21. A product to help ensure compliance and optimize effectiveness in a treatment for minimizing the harmful effects of at least one of a malignant cancer tumor or virus, said product comprising the ingredients betaine, or its functional equivalent homolog, and vitamin C, or its functional equivalent, in a form which can be used in the treatment of humans, canines, or felines, said product providing protection for each of said ingredients from moisture air and contamination and prevention of interaction during storage and where said product either includes or is in association with instructions as to an appropriate dosage for treating at least one of a malignant cancer tumor or virus and instructions to promptly take said ingredients when they are no longer protected and are together in a dosage so as to ensure maximum effect when the said dosage is taken. 22. The product of claim 21 wherein said product is suitable for and includes, or is in association, with instructions for using said product in the treatment of said malignant cancer tumor. 23. The product of claim 22 in single dosage form to ensure proper dosage and to make compliance easier. 24. The product of claim 23 for use by a human wherein each dosage contains at least about one gram of betaine and one gram of vitamin C. 25. The product of claim 24 wherein said product also includes, or is in association with, instructions to take from one to three dosages per day. 26. The product of claim 22 suitable for use by a human wherein each of the ingredients is in a separate package in bulk, wherein said product includes or is in association with instructions to measure out at least about one gram of each of the ingredients betaine and vitamin C, to add the said ingredients to an aqueous medium to create a single dosage, and to promptly take the said single dosage, said product also either including, or being in association with, instructions on the importance of continuing treatment to control said malignant cancer tumor. 27. The product of claim 26 wherein at said product includes, or is in association with, instructions to take said dosage for from one to three times a day. 28. The product of claim 21 wherein said product includes or is in association, with instructions for treatment of a virus. 29. The product of claim 28 wherein said virus is either a common cold virus or a flu virus. 30. The product of claim 28 packaged in a single dosage form that provides separate packaging for each ingredient to ensure proper dosage and to make compliance with dosing instructions easier. 31. The product of claim 30 suitable for use by a human wherein each dosage contains at least about one gram of betaine and one gram of vitamin C. 32. The product of claim 31 which includes, or is in association with, instructions to take from one to three dosages per day. 33. The product of claim 31 wherein said package includes, or is in association with, instructions to take more than three dosages per day if the condition is serious. 34. The product of claim 28 wherein each of the ingredients betaine and vitamin C is in a bulk package with instructions on at least one of said packages to measure out at least about one gram of each of sail ingredients into an aqueous medium to create a single dosage, and to promptly take said dosage. 35. The product of claim 34 wherein at least one of said bulk packages includes, or is in association with, instructions to take said dosages for from one to three times a day for a normal treatment or for more times a day for a serious condition. 36. A product to help ensure compliance and effectiveness in a treatment for minimizing the harmful effects of a malignant cancer tumor or virus condition, said product comprising the ingredients betaine and vitamin C each of which is in a form which can be used in the treatment of humans, said product being in single dosage form to ensure proper dosage and promote compliance with dosing instructions and having separate protection for each ingredient from moisture, air, and contamination and said product either including on said packaging, or being in association with, instructions to promptly take said ingredients, after they are removed from said packaging and mixed together to ensure maximum effect. 37. The product of claim 36 wherein the ingredients are powders, the instructions include the instruction to add the ingredients together into an aqueous liquid, and the condition is a virus. 38. The product of claim 37 where said packaging is foil with a separate pocket for each ingredient, the amount of each ingredient is at least one gram, and the instructions include the advice to use up to three or more dosages per day depending on the severity of the condition. 39. The product of claim 36 wherein the condition is a malignant cancer tumor. 40. The product of claim 21 which is a food product suitable for treating canines, said food product containing vitamin C and betaine, the food product being in single dosage form containing and protecting the Vitamin C and betaine from moisture and air and which prevents the Vitamin C and betaine from interacting until after ingestion. | Combinations of betaine and vitamin C are used to suppress or prevent malignant tumors or to treat viruses, e.g., by combining the two ingredients in a product consumed by a human, dog, or cat, such as an aqueous liquid such as grape juice, the ingredients being provided in containers with instructions for use, or in finished products, especially with support of tests demonstrating the effectiveness of the treatment for, e.g., preventing tumors in populations known to be at risk of developing tumors, or, treating existing cancers in combination with other cancer drugs such as anastrozole and/or fulvestrant and/or artemisinin either concurrently or sequentially to prevent the cancer from growing when the cancer drug is not being used, or in the treatment of viruses.1-20. (canceled) 21. A product to help ensure compliance and optimize effectiveness in a treatment for minimizing the harmful effects of at least one of a malignant cancer tumor or virus, said product comprising the ingredients betaine, or its functional equivalent homolog, and vitamin C, or its functional equivalent, in a form which can be used in the treatment of humans, canines, or felines, said product providing protection for each of said ingredients from moisture air and contamination and prevention of interaction during storage and where said product either includes or is in association with instructions as to an appropriate dosage for treating at least one of a malignant cancer tumor or virus and instructions to promptly take said ingredients when they are no longer protected and are together in a dosage so as to ensure maximum effect when the said dosage is taken. 22. The product of claim 21 wherein said product is suitable for and includes, or is in association, with instructions for using said product in the treatment of said malignant cancer tumor. 23. The product of claim 22 in single dosage form to ensure proper dosage and to make compliance easier. 24. The product of claim 23 for use by a human wherein each dosage contains at least about one gram of betaine and one gram of vitamin C. 25. The product of claim 24 wherein said product also includes, or is in association with, instructions to take from one to three dosages per day. 26. The product of claim 22 suitable for use by a human wherein each of the ingredients is in a separate package in bulk, wherein said product includes or is in association with instructions to measure out at least about one gram of each of the ingredients betaine and vitamin C, to add the said ingredients to an aqueous medium to create a single dosage, and to promptly take the said single dosage, said product also either including, or being in association with, instructions on the importance of continuing treatment to control said malignant cancer tumor. 27. The product of claim 26 wherein at said product includes, or is in association with, instructions to take said dosage for from one to three times a day. 28. The product of claim 21 wherein said product includes or is in association, with instructions for treatment of a virus. 29. The product of claim 28 wherein said virus is either a common cold virus or a flu virus. 30. The product of claim 28 packaged in a single dosage form that provides separate packaging for each ingredient to ensure proper dosage and to make compliance with dosing instructions easier. 31. The product of claim 30 suitable for use by a human wherein each dosage contains at least about one gram of betaine and one gram of vitamin C. 32. The product of claim 31 which includes, or is in association with, instructions to take from one to three dosages per day. 33. The product of claim 31 wherein said package includes, or is in association with, instructions to take more than three dosages per day if the condition is serious. 34. The product of claim 28 wherein each of the ingredients betaine and vitamin C is in a bulk package with instructions on at least one of said packages to measure out at least about one gram of each of sail ingredients into an aqueous medium to create a single dosage, and to promptly take said dosage. 35. The product of claim 34 wherein at least one of said bulk packages includes, or is in association with, instructions to take said dosages for from one to three times a day for a normal treatment or for more times a day for a serious condition. 36. A product to help ensure compliance and effectiveness in a treatment for minimizing the harmful effects of a malignant cancer tumor or virus condition, said product comprising the ingredients betaine and vitamin C each of which is in a form which can be used in the treatment of humans, said product being in single dosage form to ensure proper dosage and promote compliance with dosing instructions and having separate protection for each ingredient from moisture, air, and contamination and said product either including on said packaging, or being in association with, instructions to promptly take said ingredients, after they are removed from said packaging and mixed together to ensure maximum effect. 37. The product of claim 36 wherein the ingredients are powders, the instructions include the instruction to add the ingredients together into an aqueous liquid, and the condition is a virus. 38. The product of claim 37 where said packaging is foil with a separate pocket for each ingredient, the amount of each ingredient is at least one gram, and the instructions include the advice to use up to three or more dosages per day depending on the severity of the condition. 39. The product of claim 36 wherein the condition is a malignant cancer tumor. 40. The product of claim 21 which is a food product suitable for treating canines, said food product containing vitamin C and betaine, the food product being in single dosage form containing and protecting the Vitamin C and betaine from moisture and air and which prevents the Vitamin C and betaine from interacting until after ingestion. | 1,600 |
844 | 12,093,912 | 1,634 | The invention provides a method of karyotyping (for example for the detection of trisomy) a target cell to detect chromosomal imbalance therein, the method comprising: (a) interrogating closely adjacent biallelic SNPs across the chromosome of the target cell (b) comparing the result at (a) with the SNP haplotype of paternal and maternal chromosomes to assemble a notional haplotype of target cell chromosomes of paternal origin and of maternal origin (c) assessing the notional SNP haplotype of target cell chromosomes of paternal origin and of maternal origin to detect aneuploidy of the chromosome in the target cell. Also provided are related computer-implemented embodiments and systems. | 1. A method of karyotyping a human target cell to detect chromosomal imbalance therein, the method comprising:
(a) interrogating closely adjacent biallelic SNPs across the chromosome of the target cell (b) comparing the result at (a) with the SNP haplotype of paternal and maternal chromosomes to assemble a notional haplotype of target cell chromosomes of paternal origin and of maternal origin (c) assessing the notional SNP haplotype of target cell chromosomes of paternal origin and of maternal origin to detect aneuploidy of the chromosome in the target cell, wherein the notional SNP haplotype of the target cell chromosomes of paternal origin and of maternal origin is assembled in step (b) using:
(i) informative SNP alleles that positively identify from which one of the four paternal and maternal chromosomes a chromosome in the target cell has originated, or positively identify from which paternal chromosome and which maternal chromosome a pair of chromosomes in the target cell has originated, and optionally
(ii) semi-informative SNP alleles that Positively identify from which of two possible combinations of the four possible pair-wise combinations of paternal and maternal chromosomes a pair of chromosomes in the target cell has originated. 2. (canceled) 3. A method as claimed in claim 1 wherein:
(i) at least 2, 3, 4, 5, 6, or 7 of the chromosomes selected from the group consisting of: X, Y, 22, 21, 18, 16 and 13 are interrogated, or (ii) all 24 chromosomes are interrogated. 4.-6. (canceled) 7. A method as claimed in claim 1 wherein aneuploidy of the chromosome in the target cell is detected in step (c) by:
(c1) assessing the notional SNP haplotype of target cell chromosomes of paternal origin and of maternal origin and thereby assigning each chromosome as recombinant or non-recombinant and\or present in 0, 1, or more copies, (c2) deducing aneuploidy of the chromosome in the target cell wherein step (c1) indicates an imbalance of chromosomes of paternal origin and of maternal origin. 8. A method as claimed in claim 1 wherein a chromosome in the target cell is identified as non-recombinant wherein the results of its notional SNP haplotype are consistent with:
(i) its SNP alleles being identical to the SNP alleles of one of the two paternal chromosomes or one of the two maternal chromosomes along the length of the chromosome, and (ii) an absence of the SNP alleles of the alternative of the two paternal or maternal chromosomes, and wherein a chromosome in the target cell is identified as recombinant wherein the results of its notional SNP haplotype correspond to SNP alleles of both of the two paternal chromosomes or two maternal chromosomes in one or more alternating segments consistent with normal recombination between the two chromosomes. 9. (canceled) 10. A method as claimed in claim 1 wherein the notional SNP haplotype of target cell chromosomes indicates the presence of both of the two paternal chromosomes or two maternal chromosomes in a pattern and\or frequency inconsistent with normal recombination between the two chromosomes, the cell is deduced to be trisomic for all or part of the relevant chromosome or chromosome segment. 11. A method as claimed in claim 10 wherein consistency with normal recombination is assessed based on the statistical likelihood of normal recombination between particular adjacent, informative SNP alleles of the two paternal chromosomes or two maternal chromosomes during the first meiotic division, and wherein the statistical likelihood is assessed based on one or more of the following criteria:
(i) the average number of recombination events for the specific paternal or maternal chromosome, (ii) distance between apparent recombination events on each chromosome arm, and their position relative to each other, the centromere and the telomere. 12.-13. (canceled) 14. A method as claimed in claim 1 wherein the notional SNP haplotype of target cell chromosomes indicates
(i) the presence of one chromosome of paternal origin and one chromosome of maternal origin and the cell is deduced to be normal diploid in respect of the relevant chromosome, or indicates (ii) an absence of any chromosome or chromosome segment of paternal origin and maternal origin, the cell is deduced to be nullsomic for the relevant chromosome or chromosome segment, or indicates (iii) an absence of a chromosome or chromosome segment of either paternal origin or maternal origin but not both, the cell is deduced to be monosomic for the relevant chromosome or chromosome segment. 15.-16. (canceled) 17. A method as claimed in claim 1 wherein the average distance between the interrogated SNPs is less than 0.1, 0.2, 0.3, 0.4 or 0.5 kb or less than 0.1, 0.2, 0.3, 0.4 or 0.5 cM. 18. (canceled) 19. A method as claimed in claim 1 further comprising the step of quantitation of interrogated SNP alleles. 20. A method as claimed in claim 1 further comprising:
(i) diagnosing the presence of an inherited genetic disease in the target cell by comparing the notional SNP haplotype of the target cell with the SNP alleles of the paternal chromosomes and the maternal chromosomes and one or more affected siblings to diagnose the disease in the target cell by linkage and\or (ii) diagnosing susceptibility to a common disease or cancer in the target cell by comparing the notional SNP haplotype with a haplotype known to be associated with said disease. 21. (canceled) 22. A method as claimed in claim 1 wherein the SNP haplotype of paternal and maternal chromosomes is derived from analysis of the SNP haplotype of cells removed from sibling fertilized embryos following in vitro fertilisation (IVF) following whole genome amplification or from analysis of multiple single parental haploid gametes following whole genome amplification. 23. (canceled) 24. A method as claimed in claim 1 wherein the target cell has been provided from a mammalian embryo which has optionally resulted from IVF and is optionally a Pre-implantation embryo. 25.-26. (canceled) 27. A method as claimed in claim 1 wherein a number equal to 1, 2, 3, 4, or 5 target cells are provided and tested. 28. A method as claimed in claim 1 wherein SNP interrogation is preceded by whole genome amplification. 29. (canceled) 30. A method as claimed in claim 1 wherein the SNP interrogation is performed by means of an oligonucleotide chip. 31. A computer-usable medium having computer-readable program code stored thereon for causing a computer to execute a method to determine aneuploidy or chromosomal recombination in a target cell, which method is the method of claim 1. 32. A computer-usable medium having computer-readable program code stored thereon for causing a computer to execute a method to determine aneuploidy or chromosomal recombination in a target cell, which method comprises:
(a) accessing a database comprising genotype data obtained from a plurality of closely adjacent biallelic SNP loci present in a chromosome of the target cell, (b) accessing a database comprising SNP haplotype data of the corresponding paternal and maternal chromosomes, (c) comparing target cell SNP data from the database of step (a) with SNP haplotype data from the database of step (b) to assemble a notional haplotype of regions of the target cell chromosomes of paternal origin and of maternal origin, (d) assessing the notional SNP haplotype of target cell chromosomes of paternal origin and of maternal origin to determine aneuploidy or chromosomal recombination of the chromosome in the target cell. 33. A computer-usable medium as claimed in claim 32 wherein each SNP locus of the ‘x’ SNPs of the database in step (b) is assigned a value ‘n’ in accordance with which of the 16 combinations of four parental SNP alleles is present at that locus, and wherein step (c) comprises assembling a notional haplotype at that locus by comparing:
(i) the genotype data for the biallelic SNP at that locus from the database of step (a) and, (ii) the value ‘n’ at that locus from the database of step (b) with, (iii) a chromosomal origin table,
and thereby assigning the locus of the target cell chromosomes as originating from a paternal or maternal chromosome. 34. A computer-usable medium as claimed in claim 32 wherein the notional SNP haplotype of regions of the target cell chromosomes of paternal origin and of maternal origin is assembled using a subset of the ‘x’ SNP loci from the database in step (b), which subset consists of:
(i) informative SNP alleles that positively identify which one of the four paternal and maternal chromosomes, a chromosome in the target cell has originated from, or positively identify which paternal chromosome and which maternal chromosome a pair of chromosomes in the target cell have originated from, and optionally (ii) semi-informative SNP alleles that positively identify which of two possible combinations of the four possible pair-wise combinations of paternal and maternal chromosomes, a pair of chromosomes in the target cell has originated from, wherein a threshold number of positive and negative informative and optionally semi-informative SNPs is set, and a karyotype is determined only when this number is exceeded. 35.-37. (canceled) 38. A computer-usable medium as claimed in claim 32 wherein the chromosome in the target cell is identified as non-recombinant wherein the results of its notional SNP haplotype are consistent with:
(i) its SNP alleles being identical to the SNP alleles of one of the two paternal chromosomes or one of the two maternal chromosomes along the length of the chromosome, and (ii) an absence of the SNP alleles of the alternative of the two paternal or maternal chromosomes, and wherein the chromosome in the target cell is identified as recombinant wherein the results of its notional SNP haplotype correspond to SNP alleles of both of the two paternal chromosomes or two maternal chromosomes in one or more alternating segments consistent with normal recombination between the two chromosomes. 39. (canceled) 40. A computer-usable medium as claimed in claim 32 wherein:
(i) the chromosome in the target cell is identified as trisomic for the chromosome where the notional SNP haplotype of the target cell chromosome indicates the presence of both of the two paternal chromosomes or two maternal chromosomes in a pattern and\or frequency inconsistent with normal recombination between the two chromosomes; (ii) the chromosome in the target cell is identified as nullsomic for the chromosome where the notional SNP haplotype of target cell chromosome indicates an absence of the chromosome or a segment thereof of both paternal origin and maternal origin; or (iii) the chromosome in the target cell is identified as monosomic for the chromosome where the notional SNP haplotype of the target cell chromosome indicates an absence of the chromosome or a segment thereof of paternal origin and maternal origin but not both. 41.-45. (canceled) 46. A system for karyotyping a target cell to detect chromosomal imbalance therein, the system comprising:
(i) means for interrogating closely adjacent biallelic SNPs across the chromosome of the target cell, which is an oligonucleotide chip, and (ii) a computer programmed to execute a method as claimed in claim 1. 47.-49. (canceled) 50. A system for karyotyping a target cell to detect chromosomal imbalance therein, the system comprising:
(i) means for interrogating closely adjacent biallelic SNPs across the chromosome of the target cell, which is an oligonucleotide chip, and (ii) a computer programmed with the computer-usable medium as claimed in claim 31. | The invention provides a method of karyotyping (for example for the detection of trisomy) a target cell to detect chromosomal imbalance therein, the method comprising: (a) interrogating closely adjacent biallelic SNPs across the chromosome of the target cell (b) comparing the result at (a) with the SNP haplotype of paternal and maternal chromosomes to assemble a notional haplotype of target cell chromosomes of paternal origin and of maternal origin (c) assessing the notional SNP haplotype of target cell chromosomes of paternal origin and of maternal origin to detect aneuploidy of the chromosome in the target cell. Also provided are related computer-implemented embodiments and systems.1. A method of karyotyping a human target cell to detect chromosomal imbalance therein, the method comprising:
(a) interrogating closely adjacent biallelic SNPs across the chromosome of the target cell (b) comparing the result at (a) with the SNP haplotype of paternal and maternal chromosomes to assemble a notional haplotype of target cell chromosomes of paternal origin and of maternal origin (c) assessing the notional SNP haplotype of target cell chromosomes of paternal origin and of maternal origin to detect aneuploidy of the chromosome in the target cell, wherein the notional SNP haplotype of the target cell chromosomes of paternal origin and of maternal origin is assembled in step (b) using:
(i) informative SNP alleles that positively identify from which one of the four paternal and maternal chromosomes a chromosome in the target cell has originated, or positively identify from which paternal chromosome and which maternal chromosome a pair of chromosomes in the target cell has originated, and optionally
(ii) semi-informative SNP alleles that Positively identify from which of two possible combinations of the four possible pair-wise combinations of paternal and maternal chromosomes a pair of chromosomes in the target cell has originated. 2. (canceled) 3. A method as claimed in claim 1 wherein:
(i) at least 2, 3, 4, 5, 6, or 7 of the chromosomes selected from the group consisting of: X, Y, 22, 21, 18, 16 and 13 are interrogated, or (ii) all 24 chromosomes are interrogated. 4.-6. (canceled) 7. A method as claimed in claim 1 wherein aneuploidy of the chromosome in the target cell is detected in step (c) by:
(c1) assessing the notional SNP haplotype of target cell chromosomes of paternal origin and of maternal origin and thereby assigning each chromosome as recombinant or non-recombinant and\or present in 0, 1, or more copies, (c2) deducing aneuploidy of the chromosome in the target cell wherein step (c1) indicates an imbalance of chromosomes of paternal origin and of maternal origin. 8. A method as claimed in claim 1 wherein a chromosome in the target cell is identified as non-recombinant wherein the results of its notional SNP haplotype are consistent with:
(i) its SNP alleles being identical to the SNP alleles of one of the two paternal chromosomes or one of the two maternal chromosomes along the length of the chromosome, and (ii) an absence of the SNP alleles of the alternative of the two paternal or maternal chromosomes, and wherein a chromosome in the target cell is identified as recombinant wherein the results of its notional SNP haplotype correspond to SNP alleles of both of the two paternal chromosomes or two maternal chromosomes in one or more alternating segments consistent with normal recombination between the two chromosomes. 9. (canceled) 10. A method as claimed in claim 1 wherein the notional SNP haplotype of target cell chromosomes indicates the presence of both of the two paternal chromosomes or two maternal chromosomes in a pattern and\or frequency inconsistent with normal recombination between the two chromosomes, the cell is deduced to be trisomic for all or part of the relevant chromosome or chromosome segment. 11. A method as claimed in claim 10 wherein consistency with normal recombination is assessed based on the statistical likelihood of normal recombination between particular adjacent, informative SNP alleles of the two paternal chromosomes or two maternal chromosomes during the first meiotic division, and wherein the statistical likelihood is assessed based on one or more of the following criteria:
(i) the average number of recombination events for the specific paternal or maternal chromosome, (ii) distance between apparent recombination events on each chromosome arm, and their position relative to each other, the centromere and the telomere. 12.-13. (canceled) 14. A method as claimed in claim 1 wherein the notional SNP haplotype of target cell chromosomes indicates
(i) the presence of one chromosome of paternal origin and one chromosome of maternal origin and the cell is deduced to be normal diploid in respect of the relevant chromosome, or indicates (ii) an absence of any chromosome or chromosome segment of paternal origin and maternal origin, the cell is deduced to be nullsomic for the relevant chromosome or chromosome segment, or indicates (iii) an absence of a chromosome or chromosome segment of either paternal origin or maternal origin but not both, the cell is deduced to be monosomic for the relevant chromosome or chromosome segment. 15.-16. (canceled) 17. A method as claimed in claim 1 wherein the average distance between the interrogated SNPs is less than 0.1, 0.2, 0.3, 0.4 or 0.5 kb or less than 0.1, 0.2, 0.3, 0.4 or 0.5 cM. 18. (canceled) 19. A method as claimed in claim 1 further comprising the step of quantitation of interrogated SNP alleles. 20. A method as claimed in claim 1 further comprising:
(i) diagnosing the presence of an inherited genetic disease in the target cell by comparing the notional SNP haplotype of the target cell with the SNP alleles of the paternal chromosomes and the maternal chromosomes and one or more affected siblings to diagnose the disease in the target cell by linkage and\or (ii) diagnosing susceptibility to a common disease or cancer in the target cell by comparing the notional SNP haplotype with a haplotype known to be associated with said disease. 21. (canceled) 22. A method as claimed in claim 1 wherein the SNP haplotype of paternal and maternal chromosomes is derived from analysis of the SNP haplotype of cells removed from sibling fertilized embryos following in vitro fertilisation (IVF) following whole genome amplification or from analysis of multiple single parental haploid gametes following whole genome amplification. 23. (canceled) 24. A method as claimed in claim 1 wherein the target cell has been provided from a mammalian embryo which has optionally resulted from IVF and is optionally a Pre-implantation embryo. 25.-26. (canceled) 27. A method as claimed in claim 1 wherein a number equal to 1, 2, 3, 4, or 5 target cells are provided and tested. 28. A method as claimed in claim 1 wherein SNP interrogation is preceded by whole genome amplification. 29. (canceled) 30. A method as claimed in claim 1 wherein the SNP interrogation is performed by means of an oligonucleotide chip. 31. A computer-usable medium having computer-readable program code stored thereon for causing a computer to execute a method to determine aneuploidy or chromosomal recombination in a target cell, which method is the method of claim 1. 32. A computer-usable medium having computer-readable program code stored thereon for causing a computer to execute a method to determine aneuploidy or chromosomal recombination in a target cell, which method comprises:
(a) accessing a database comprising genotype data obtained from a plurality of closely adjacent biallelic SNP loci present in a chromosome of the target cell, (b) accessing a database comprising SNP haplotype data of the corresponding paternal and maternal chromosomes, (c) comparing target cell SNP data from the database of step (a) with SNP haplotype data from the database of step (b) to assemble a notional haplotype of regions of the target cell chromosomes of paternal origin and of maternal origin, (d) assessing the notional SNP haplotype of target cell chromosomes of paternal origin and of maternal origin to determine aneuploidy or chromosomal recombination of the chromosome in the target cell. 33. A computer-usable medium as claimed in claim 32 wherein each SNP locus of the ‘x’ SNPs of the database in step (b) is assigned a value ‘n’ in accordance with which of the 16 combinations of four parental SNP alleles is present at that locus, and wherein step (c) comprises assembling a notional haplotype at that locus by comparing:
(i) the genotype data for the biallelic SNP at that locus from the database of step (a) and, (ii) the value ‘n’ at that locus from the database of step (b) with, (iii) a chromosomal origin table,
and thereby assigning the locus of the target cell chromosomes as originating from a paternal or maternal chromosome. 34. A computer-usable medium as claimed in claim 32 wherein the notional SNP haplotype of regions of the target cell chromosomes of paternal origin and of maternal origin is assembled using a subset of the ‘x’ SNP loci from the database in step (b), which subset consists of:
(i) informative SNP alleles that positively identify which one of the four paternal and maternal chromosomes, a chromosome in the target cell has originated from, or positively identify which paternal chromosome and which maternal chromosome a pair of chromosomes in the target cell have originated from, and optionally (ii) semi-informative SNP alleles that positively identify which of two possible combinations of the four possible pair-wise combinations of paternal and maternal chromosomes, a pair of chromosomes in the target cell has originated from, wherein a threshold number of positive and negative informative and optionally semi-informative SNPs is set, and a karyotype is determined only when this number is exceeded. 35.-37. (canceled) 38. A computer-usable medium as claimed in claim 32 wherein the chromosome in the target cell is identified as non-recombinant wherein the results of its notional SNP haplotype are consistent with:
(i) its SNP alleles being identical to the SNP alleles of one of the two paternal chromosomes or one of the two maternal chromosomes along the length of the chromosome, and (ii) an absence of the SNP alleles of the alternative of the two paternal or maternal chromosomes, and wherein the chromosome in the target cell is identified as recombinant wherein the results of its notional SNP haplotype correspond to SNP alleles of both of the two paternal chromosomes or two maternal chromosomes in one or more alternating segments consistent with normal recombination between the two chromosomes. 39. (canceled) 40. A computer-usable medium as claimed in claim 32 wherein:
(i) the chromosome in the target cell is identified as trisomic for the chromosome where the notional SNP haplotype of the target cell chromosome indicates the presence of both of the two paternal chromosomes or two maternal chromosomes in a pattern and\or frequency inconsistent with normal recombination between the two chromosomes; (ii) the chromosome in the target cell is identified as nullsomic for the chromosome where the notional SNP haplotype of target cell chromosome indicates an absence of the chromosome or a segment thereof of both paternal origin and maternal origin; or (iii) the chromosome in the target cell is identified as monosomic for the chromosome where the notional SNP haplotype of the target cell chromosome indicates an absence of the chromosome or a segment thereof of paternal origin and maternal origin but not both. 41.-45. (canceled) 46. A system for karyotyping a target cell to detect chromosomal imbalance therein, the system comprising:
(i) means for interrogating closely adjacent biallelic SNPs across the chromosome of the target cell, which is an oligonucleotide chip, and (ii) a computer programmed to execute a method as claimed in claim 1. 47.-49. (canceled) 50. A system for karyotyping a target cell to detect chromosomal imbalance therein, the system comprising:
(i) means for interrogating closely adjacent biallelic SNPs across the chromosome of the target cell, which is an oligonucleotide chip, and (ii) a computer programmed with the computer-usable medium as claimed in claim 31. | 1,600 |
845 | 15,063,446 | 1,642 | The invention features methods of treating melanoma by modulating an activity of GDF6 in melanoma cells. In one aspect, the methods involve downregulating an activity of GDF6, for example, by using an anti-GDF6 binding molecule, such as an inactivating antibody. Another aspect features treating a subject by first screening for the presence of GDF6 and then treating the subject with an inhibitor of a GDF6 activity. Screening assays for identification of modulators of an activity of GDF6 are also featured. | 1. A method of treating a melanoma in a subject, the method comprising administering to a subject in need thereof an effective amount of an inhibitor of at least one GDF6 activity. 2. The method of claim 1, wherein the subject is a non-human mammal. 3. The method of claim 1, wherein the subject is a human. 4. The method of claim 1, wherein inhibiting the at least one GDF6 activity comprises apoptosis of at least one melanoma cell. 5. The method of claim 1, wherein inhibiting the at least one GDF6 activity comprises reducing downstream signaling from a BMP receptor with which the GDF6 interacts when compared to a suitable control. 6. The method of claim 5, wherein the reducing downstream signaling comprises reducing SMAD1/5/8 phosphorylation. 7. The method of claim 1, wherein the inhibitor is selected from the group consisting of an antibody, an antibody fragment, an anti-sense nucleic acid, a soluble receptor polypeptide, and a small molecule. 8. The method of claim 7, wherein the anti-sense nucleic acid is selected from the group consisting of a RNAi, a ribozyme, an α-anomeric nucleic acid molecule, and a peptide nucleic acid. 9. The method of claim 8, wherein the anti-sense molecule is an RNAi molecule and is a siRNA or a shRNA. 10. The method of claim 7, wherein the soluble receptor polypeptide comprises an ALK3 polypeptide. 11. The method of claim 10, wherein the soluble receptor polypeptide comprises an ALK3(24-152)-Fc fusion polypeptide comprising an amino acid sequence of SEQ ID NO:9. 12. A screening assay method for identifying a compound that decreases GDF6 activity, comprising
(a) providing an in vitro composition that comprises at least one melanoma cell; (b) contacting the composition with a test compound; and (c) determining an effect of the test compound on an activity of GDF6 in the composition, wherein a decrease in the activity of GDF6 in the presence of the compound, relative to a suitable control, identifies the compound as one that decreases GDF6 activity. 13. The method of claim 12, wherein decreasing an activity of GDF6 comprises apoptosis of at least one melanoma cell in the composition. 14. The method of claim 12, wherein decreasing an activity of GDF6 comprises reducing downstream signaling from a BMP receptor with which the GDF6 interacts. 15. The method of claim 14, wherein the reduced downstream signaling comprises reducing SMAD1/5/8 phosphorylation. 16. The method of claim 12, wherein the test compound is selected from the group consisting of an antibody, an antibody fragment, anti-sense nucleic acid, a soluble receptor polypeptide and a small molecule. 17. The method of claim 16, wherein the anti-sense nucleic acid is selected from the group consisting of a RNAi, a ribozyme, an α-anomeric nucleic acid molecule, and a peptide nucleic acid. 18. The method of claim 17, wherein the anti-sense molecule is an RNAi molecule and is a siRNA or a shRNA. 19. The method of claim 12, wherein the soluble receptor polypeptide comprises an ALK3 polypeptide. 20. The method of claim 19, wherein the soluble receptor polypeptide comprises an ALK3(24-152)-Fc fusion polypeptide comprising an amino acid sequence of SEQ ID NO:9. 21. A screening assay method for identifying a compound that decreases a GDF6 activity, comprising
(a) providing a subject that comprises at least one melanoma cell; (b) administering to the subject a test compound; and (c) determining an effect of the test compound on an activity of GDF6 in the subject, wherein a decrease in the activity of GDF6 in the presence of the compound, relative to a suitable control, identifies the compound as one that decreases GDF6 activity. 22. The method of claim 21, wherein decreasing an activity of GDF6 comprises apoptosis of at least one melanoma cell. 23. The method of claim 21, wherein decreasing an activity of GDF6 comprises reducing downstream signaling from a BMP receptor with which the GDF6 interacts. 24. The method of claim 23, wherein the reduced downstream signaling comprises reducing SMAD1/5/8 phosphorylation. 25. The method of claim 21, wherein the test compound is selected from the group consisting of an antibody, an antibody fragment, anti-sense nucleic acid, and a small molecule. 26. The method of claim 25, wherein the anti-sense nucleic acid is selected from the group consisting of a RNAi, a ribozyme, an α-anomeric nucleic acid molecule, and a peptide nucleic acid. 27. The method of claim 26, wherein the anti-sense molecule is an RNAi molecule and is a siRNA or a shRNA. 28. The method of claim 21, wherein the soluble receptor polypeptide comprises an ALK3 polypeptide. 29. The method of claim 28, wherein the soluble receptor polypeptide comprises an ALK3(24-152)-Fc fusion polypeptide comprising an amino acid sequence of SEQ ID NO:9. 30. Use of a compound that decreases GDF6 activity identified according to claim 12 to treat a melanoma in a subject. 31. The use of the compound of claim 30, wherein the subject is a non-human mammal. 32. The use of the compound of claim 30, wherein the subject is a human. 33. A method of inhibiting melanoma formation in a subject at risk for melanoma formation, comprising administering to the subject an effective amount of an inhibitor of a GDF6 activity. 34. The method of claim 33, wherein the subject is a non-human mammal. 35. The method of claim 33, wherein the subject is a human. 36. The method of claim 33, wherein inhibiting the at least one GDF6 activity comprises apoptosis of at least one melanoma cell. 37. The method of claim 33, wherein inhibiting the at least one GDF6 activity comprises reducing downstream signaling from a BMP receptor with which the GDF6 interacts when compared to a suitable control. 38. The method of claim 37, wherein the reducing downstream signaling comprises reducing SMAD1/5/8 phosphorylation. 39. The method of claim 33, wherein the inhibitor is selected from the group consisting of an antibody, an antibody fragment, anti-sense nucleic acid, a soluble receptor polypeptide, and a small molecule. 40. The method of claim 33, wherein the anti-sense nucleic acid is selected from the group consisting of a RNAi, a ribozyme, an α-anomeric nucleic acid molecule, and a peptide nucleic acid. 41. The method of claim 40, wherein the anti-sense molecule is an RNAi molecule and is a siRNA or a shRNA. 42. The method of claim 33, wherein the soluble receptor polypeptide comprises an ALK3 polypeptide. 43. The method of claim 42, wherein the soluble receptor polypeptide comprises an ALK3(24-152)-Fc fusion polypeptide comprising an amino acid sequence of SEQ ID NO:9. 44. A method of treating a melanoma in a subject, comprising
(a) obtaining a sample from a suspected area of the subject's skin; (b) determining the presence of GDF6; (c) obtaining a suitable control; (d) comparing the presence of GDF6 in the sample of step (b) with the suitable control of step (c); (e) determining if the subject displays a melanoma, wherein the presence of GDF6 in the sample but not in the suitable control indicates melanoma; (f) treating the subject with a GDF6 inhibitor to inhibit an activity of the GDF6 if the subject has melanoma. 45. The method of claim 44, wherein the subject is a non-human mammal. 46. The method of claim 44, wherein the subject is a human. 47. The method of claim 44, wherein inhibiting the at least one GDF6 activity comprises apoptosis of at least one melanoma cell. 48. The method of claim 44, wherein inhibiting the at least one GDF6 activity comprises reducing downstream signaling from a BMP receptor with which the GDF6 interacts when compared to a suitable control. 49. The method of claim 48, wherein the reducing downstream signaling comprises reducing SMAD1/5/8 phosphorylation. 50. The method of claim 44, wherein the inhibitor is selected from the group consisting of an antibody, an antibody fragment, anti-sense nucleic acid, a soluble receptor polypeptide, and a small molecule. 51. The method of claim 50, wherein the anti-sense nucleic acid is selected from the group consisting of a RNAi, a ribozyme, an α-anomeric nucleic acid molecule, and a peptide nucleic acid. 52. The method of claim 51, wherein the anti-sense molecule is an RNAi molecule and is a siRNA or a shRNA. 53. The method of claim 44, wherein the soluble receptor polypeptide comprises an ALK3 polypeptide. 54. The method of claim 53, wherein the soluble receptor polypeptide comprises an ALK3(24-152)-Fc fusion polypeptide comprising an amino acid sequence of SEQ ID NO:9. | The invention features methods of treating melanoma by modulating an activity of GDF6 in melanoma cells. In one aspect, the methods involve downregulating an activity of GDF6, for example, by using an anti-GDF6 binding molecule, such as an inactivating antibody. Another aspect features treating a subject by first screening for the presence of GDF6 and then treating the subject with an inhibitor of a GDF6 activity. Screening assays for identification of modulators of an activity of GDF6 are also featured.1. A method of treating a melanoma in a subject, the method comprising administering to a subject in need thereof an effective amount of an inhibitor of at least one GDF6 activity. 2. The method of claim 1, wherein the subject is a non-human mammal. 3. The method of claim 1, wherein the subject is a human. 4. The method of claim 1, wherein inhibiting the at least one GDF6 activity comprises apoptosis of at least one melanoma cell. 5. The method of claim 1, wherein inhibiting the at least one GDF6 activity comprises reducing downstream signaling from a BMP receptor with which the GDF6 interacts when compared to a suitable control. 6. The method of claim 5, wherein the reducing downstream signaling comprises reducing SMAD1/5/8 phosphorylation. 7. The method of claim 1, wherein the inhibitor is selected from the group consisting of an antibody, an antibody fragment, an anti-sense nucleic acid, a soluble receptor polypeptide, and a small molecule. 8. The method of claim 7, wherein the anti-sense nucleic acid is selected from the group consisting of a RNAi, a ribozyme, an α-anomeric nucleic acid molecule, and a peptide nucleic acid. 9. The method of claim 8, wherein the anti-sense molecule is an RNAi molecule and is a siRNA or a shRNA. 10. The method of claim 7, wherein the soluble receptor polypeptide comprises an ALK3 polypeptide. 11. The method of claim 10, wherein the soluble receptor polypeptide comprises an ALK3(24-152)-Fc fusion polypeptide comprising an amino acid sequence of SEQ ID NO:9. 12. A screening assay method for identifying a compound that decreases GDF6 activity, comprising
(a) providing an in vitro composition that comprises at least one melanoma cell; (b) contacting the composition with a test compound; and (c) determining an effect of the test compound on an activity of GDF6 in the composition, wherein a decrease in the activity of GDF6 in the presence of the compound, relative to a suitable control, identifies the compound as one that decreases GDF6 activity. 13. The method of claim 12, wherein decreasing an activity of GDF6 comprises apoptosis of at least one melanoma cell in the composition. 14. The method of claim 12, wherein decreasing an activity of GDF6 comprises reducing downstream signaling from a BMP receptor with which the GDF6 interacts. 15. The method of claim 14, wherein the reduced downstream signaling comprises reducing SMAD1/5/8 phosphorylation. 16. The method of claim 12, wherein the test compound is selected from the group consisting of an antibody, an antibody fragment, anti-sense nucleic acid, a soluble receptor polypeptide and a small molecule. 17. The method of claim 16, wherein the anti-sense nucleic acid is selected from the group consisting of a RNAi, a ribozyme, an α-anomeric nucleic acid molecule, and a peptide nucleic acid. 18. The method of claim 17, wherein the anti-sense molecule is an RNAi molecule and is a siRNA or a shRNA. 19. The method of claim 12, wherein the soluble receptor polypeptide comprises an ALK3 polypeptide. 20. The method of claim 19, wherein the soluble receptor polypeptide comprises an ALK3(24-152)-Fc fusion polypeptide comprising an amino acid sequence of SEQ ID NO:9. 21. A screening assay method for identifying a compound that decreases a GDF6 activity, comprising
(a) providing a subject that comprises at least one melanoma cell; (b) administering to the subject a test compound; and (c) determining an effect of the test compound on an activity of GDF6 in the subject, wherein a decrease in the activity of GDF6 in the presence of the compound, relative to a suitable control, identifies the compound as one that decreases GDF6 activity. 22. The method of claim 21, wherein decreasing an activity of GDF6 comprises apoptosis of at least one melanoma cell. 23. The method of claim 21, wherein decreasing an activity of GDF6 comprises reducing downstream signaling from a BMP receptor with which the GDF6 interacts. 24. The method of claim 23, wherein the reduced downstream signaling comprises reducing SMAD1/5/8 phosphorylation. 25. The method of claim 21, wherein the test compound is selected from the group consisting of an antibody, an antibody fragment, anti-sense nucleic acid, and a small molecule. 26. The method of claim 25, wherein the anti-sense nucleic acid is selected from the group consisting of a RNAi, a ribozyme, an α-anomeric nucleic acid molecule, and a peptide nucleic acid. 27. The method of claim 26, wherein the anti-sense molecule is an RNAi molecule and is a siRNA or a shRNA. 28. The method of claim 21, wherein the soluble receptor polypeptide comprises an ALK3 polypeptide. 29. The method of claim 28, wherein the soluble receptor polypeptide comprises an ALK3(24-152)-Fc fusion polypeptide comprising an amino acid sequence of SEQ ID NO:9. 30. Use of a compound that decreases GDF6 activity identified according to claim 12 to treat a melanoma in a subject. 31. The use of the compound of claim 30, wherein the subject is a non-human mammal. 32. The use of the compound of claim 30, wherein the subject is a human. 33. A method of inhibiting melanoma formation in a subject at risk for melanoma formation, comprising administering to the subject an effective amount of an inhibitor of a GDF6 activity. 34. The method of claim 33, wherein the subject is a non-human mammal. 35. The method of claim 33, wherein the subject is a human. 36. The method of claim 33, wherein inhibiting the at least one GDF6 activity comprises apoptosis of at least one melanoma cell. 37. The method of claim 33, wherein inhibiting the at least one GDF6 activity comprises reducing downstream signaling from a BMP receptor with which the GDF6 interacts when compared to a suitable control. 38. The method of claim 37, wherein the reducing downstream signaling comprises reducing SMAD1/5/8 phosphorylation. 39. The method of claim 33, wherein the inhibitor is selected from the group consisting of an antibody, an antibody fragment, anti-sense nucleic acid, a soluble receptor polypeptide, and a small molecule. 40. The method of claim 33, wherein the anti-sense nucleic acid is selected from the group consisting of a RNAi, a ribozyme, an α-anomeric nucleic acid molecule, and a peptide nucleic acid. 41. The method of claim 40, wherein the anti-sense molecule is an RNAi molecule and is a siRNA or a shRNA. 42. The method of claim 33, wherein the soluble receptor polypeptide comprises an ALK3 polypeptide. 43. The method of claim 42, wherein the soluble receptor polypeptide comprises an ALK3(24-152)-Fc fusion polypeptide comprising an amino acid sequence of SEQ ID NO:9. 44. A method of treating a melanoma in a subject, comprising
(a) obtaining a sample from a suspected area of the subject's skin; (b) determining the presence of GDF6; (c) obtaining a suitable control; (d) comparing the presence of GDF6 in the sample of step (b) with the suitable control of step (c); (e) determining if the subject displays a melanoma, wherein the presence of GDF6 in the sample but not in the suitable control indicates melanoma; (f) treating the subject with a GDF6 inhibitor to inhibit an activity of the GDF6 if the subject has melanoma. 45. The method of claim 44, wherein the subject is a non-human mammal. 46. The method of claim 44, wherein the subject is a human. 47. The method of claim 44, wherein inhibiting the at least one GDF6 activity comprises apoptosis of at least one melanoma cell. 48. The method of claim 44, wherein inhibiting the at least one GDF6 activity comprises reducing downstream signaling from a BMP receptor with which the GDF6 interacts when compared to a suitable control. 49. The method of claim 48, wherein the reducing downstream signaling comprises reducing SMAD1/5/8 phosphorylation. 50. The method of claim 44, wherein the inhibitor is selected from the group consisting of an antibody, an antibody fragment, anti-sense nucleic acid, a soluble receptor polypeptide, and a small molecule. 51. The method of claim 50, wherein the anti-sense nucleic acid is selected from the group consisting of a RNAi, a ribozyme, an α-anomeric nucleic acid molecule, and a peptide nucleic acid. 52. The method of claim 51, wherein the anti-sense molecule is an RNAi molecule and is a siRNA or a shRNA. 53. The method of claim 44, wherein the soluble receptor polypeptide comprises an ALK3 polypeptide. 54. The method of claim 53, wherein the soluble receptor polypeptide comprises an ALK3(24-152)-Fc fusion polypeptide comprising an amino acid sequence of SEQ ID NO:9. | 1,600 |
846 | 14,521,351 | 1,633 | The present invention provides, among other things, methods of treating Argininosuccinate Synthetase Deficiency (ASD), including administering to a subject in need of treatment a composition comprising an mRNA encoding argininosuccinate synthetase (ASS1) at an effective dose and an administration interval such that at least one symptom or feature of ASD is reduced in intensity, severity, or frequency or has delayed in onset. In some embodiments, the mRNA is encapsulated in a liposome comprising one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids and one or more PEG-modified lipids | 1. A method of treating Argininosuccinate Synthetase Deficiency (ASD), comprising administering to a subject in need of treatment a composition comprising an mRNA encoding argininosuccinate synthetase (ASS1) at an effective dose and an administration interval such that at least one symptom or feature of ASD is reduced in intensity, severity, or frequency or has delayed in onset. 2. The method of claim 1, wherein the mRNA is encapsulated within a liposome. 3. The method of claim 2, wherein the liposome comprises one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids and one or more PEG-modified lipids. 4. The method of claim 3, wherein the one or more cationic lipids comprise a cationic lipid selected from the group consisting of C12-200, MC3, DLinDMA, DLinkC2DMA, cKK-E12, ICE (Imidazol-based), HGT5000, HGT5001, DODAC, DDAB, DMRIE, DOSPA, DOGS, DODAP, DODMA and DMDMA, DODAC, DLenDMA, DMRIE, CLinDMA, CpLinDMA, DMOBA, DOcarbDAP, DLinDAP, DLincarbDAP, DLinCDAP, KLin-K-DMA, DLin-K-XTC2-DMA, HGT4003, and combination thereof. 5. The method of claim 4, wherein the one or more cationic lipids comprise cKK-E12: 6. The method of claim 3, wherein the one or more cholesterol-based lipids are cholesterol and/or PEGylated cholesterol. 7. The method of claim 3, wherein the cationic lipid constitutes about 30-50% of the liposome by weight. 8. The method of claim 3, wherein the ratio of cationic lipid:non-cationic lipid:cholesterol:PEGylated lipid is approximately 40:30:20:10 by molar ratio. 9. The method of claim 2, wherein the liposome comprises a combination selected from:
cKK-E12, DOPE, cholesterol and DMG-PEG2K; C12-200, DOPE, cholesterol and DMG-PEG2K; HGT4003, DOPE, cholesterol and DMG-PEG2K; or ICE, DOPE, cholesterol and DMG-PEG2K. 10. The method of claim 2, wherein the liposome has a size less than about 100 nm. 11. The method of claim 1, wherein the mRNA is administered at the effective dose ranging from about 0.1-5.0 mg/kg body weight. 12. The method of claim 1, wherein the composition is administered intravenously. 13. The method of claim 1, wherein the composition is administered once a week. 14. The method of claim 1, wherein the administering of the composition results in increased serum ASS1 protein level. 15. The method of claim 1, wherein the administering of the composition results in reduced citrulline level in the subject as compared to the baseline citrulline level before the treatment. 16. The method of claim 1, wherein the administering of the composition results in reduced ammonia level in the subject as compared to the baseline ammonia level before the treatment. 17. The method of claim 1, wherein the mRNA is codon optimized. 18. The method of claim 17, wherein the codon-optimized mRNA comprises SEQ ID NO:3. 19. The method of claim 1, wherein the mRNA comprises one or more modified nucleotides. 20. The method of claim 1, wherein the mRNA is unmodified. 21. A composition for treating Argininosuccinate Synthetase Deficiency (ASD), comprising an mRNA encoding argininosuccinate synthetase (ASS1) at an effective dose amount encapsulated within a liposome, wherein the liposome comprises a cationic lipid cKK-E12: 22. The composition of claim 21, wherein the liposome further comprises one or more non-cationic lipids, one or more cholesterol-based lipids, and one or more PEG-modified lipids. 23. The composition of claim 22, wherein the one or more non-cationic lipids are selected from DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine), DOPE (1,2-dioleyl-sn-glycero-3-phosphoethanolamine), DOPC (1,2-dioleyl-sn-glycero-3-phosphotidylcholine) DPPE (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine), DMPE (1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine), DOPG (,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol)). 24. The composition of claim 22, wherein the one or more cholesterol-based lipids are selected from cholesterol and/or PEGylated cholesterol. 25. The composition of claim 21, wherein the liposome comprises cKK-E12, DOPE, cholesterol and DMG-PEG2K. 26. The composition of claim 21, wherein the cationic lipid constitutes about 30-50% of the liposome by molar ratio. 27. The composition of claim 25, wherein the ratio of cKK-E12:DOPE:cholesterol:DMG-PEG2K is approximately 40:30:20:10 by molar ratio. 28. The composition of claim 21, wherein the liposome has a size less than about 100 nm. 29. The composition of claim 21, wherein the mRNA comprises SEQ ID NO:3. 30. A composition for treating Argininosuccinate Synthetase Deficiency (ASD), comprising an mRNA encoding argininosuccinate synthetase (ASS1) at an effective dose amount encapsulated within a liposome, wherein the mRNA comprises SEQ ID NO:3 and
further wherein the liposome comprises cationic or non-cationic lipid, cholesterol-based lipid and PEG-modified lipid. | The present invention provides, among other things, methods of treating Argininosuccinate Synthetase Deficiency (ASD), including administering to a subject in need of treatment a composition comprising an mRNA encoding argininosuccinate synthetase (ASS1) at an effective dose and an administration interval such that at least one symptom or feature of ASD is reduced in intensity, severity, or frequency or has delayed in onset. In some embodiments, the mRNA is encapsulated in a liposome comprising one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids and one or more PEG-modified lipids1. A method of treating Argininosuccinate Synthetase Deficiency (ASD), comprising administering to a subject in need of treatment a composition comprising an mRNA encoding argininosuccinate synthetase (ASS1) at an effective dose and an administration interval such that at least one symptom or feature of ASD is reduced in intensity, severity, or frequency or has delayed in onset. 2. The method of claim 1, wherein the mRNA is encapsulated within a liposome. 3. The method of claim 2, wherein the liposome comprises one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids and one or more PEG-modified lipids. 4. The method of claim 3, wherein the one or more cationic lipids comprise a cationic lipid selected from the group consisting of C12-200, MC3, DLinDMA, DLinkC2DMA, cKK-E12, ICE (Imidazol-based), HGT5000, HGT5001, DODAC, DDAB, DMRIE, DOSPA, DOGS, DODAP, DODMA and DMDMA, DODAC, DLenDMA, DMRIE, CLinDMA, CpLinDMA, DMOBA, DOcarbDAP, DLinDAP, DLincarbDAP, DLinCDAP, KLin-K-DMA, DLin-K-XTC2-DMA, HGT4003, and combination thereof. 5. The method of claim 4, wherein the one or more cationic lipids comprise cKK-E12: 6. The method of claim 3, wherein the one or more cholesterol-based lipids are cholesterol and/or PEGylated cholesterol. 7. The method of claim 3, wherein the cationic lipid constitutes about 30-50% of the liposome by weight. 8. The method of claim 3, wherein the ratio of cationic lipid:non-cationic lipid:cholesterol:PEGylated lipid is approximately 40:30:20:10 by molar ratio. 9. The method of claim 2, wherein the liposome comprises a combination selected from:
cKK-E12, DOPE, cholesterol and DMG-PEG2K; C12-200, DOPE, cholesterol and DMG-PEG2K; HGT4003, DOPE, cholesterol and DMG-PEG2K; or ICE, DOPE, cholesterol and DMG-PEG2K. 10. The method of claim 2, wherein the liposome has a size less than about 100 nm. 11. The method of claim 1, wherein the mRNA is administered at the effective dose ranging from about 0.1-5.0 mg/kg body weight. 12. The method of claim 1, wherein the composition is administered intravenously. 13. The method of claim 1, wherein the composition is administered once a week. 14. The method of claim 1, wherein the administering of the composition results in increased serum ASS1 protein level. 15. The method of claim 1, wherein the administering of the composition results in reduced citrulline level in the subject as compared to the baseline citrulline level before the treatment. 16. The method of claim 1, wherein the administering of the composition results in reduced ammonia level in the subject as compared to the baseline ammonia level before the treatment. 17. The method of claim 1, wherein the mRNA is codon optimized. 18. The method of claim 17, wherein the codon-optimized mRNA comprises SEQ ID NO:3. 19. The method of claim 1, wherein the mRNA comprises one or more modified nucleotides. 20. The method of claim 1, wherein the mRNA is unmodified. 21. A composition for treating Argininosuccinate Synthetase Deficiency (ASD), comprising an mRNA encoding argininosuccinate synthetase (ASS1) at an effective dose amount encapsulated within a liposome, wherein the liposome comprises a cationic lipid cKK-E12: 22. The composition of claim 21, wherein the liposome further comprises one or more non-cationic lipids, one or more cholesterol-based lipids, and one or more PEG-modified lipids. 23. The composition of claim 22, wherein the one or more non-cationic lipids are selected from DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine), DOPE (1,2-dioleyl-sn-glycero-3-phosphoethanolamine), DOPC (1,2-dioleyl-sn-glycero-3-phosphotidylcholine) DPPE (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine), DMPE (1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine), DOPG (,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol)). 24. The composition of claim 22, wherein the one or more cholesterol-based lipids are selected from cholesterol and/or PEGylated cholesterol. 25. The composition of claim 21, wherein the liposome comprises cKK-E12, DOPE, cholesterol and DMG-PEG2K. 26. The composition of claim 21, wherein the cationic lipid constitutes about 30-50% of the liposome by molar ratio. 27. The composition of claim 25, wherein the ratio of cKK-E12:DOPE:cholesterol:DMG-PEG2K is approximately 40:30:20:10 by molar ratio. 28. The composition of claim 21, wherein the liposome has a size less than about 100 nm. 29. The composition of claim 21, wherein the mRNA comprises SEQ ID NO:3. 30. A composition for treating Argininosuccinate Synthetase Deficiency (ASD), comprising an mRNA encoding argininosuccinate synthetase (ASS1) at an effective dose amount encapsulated within a liposome, wherein the mRNA comprises SEQ ID NO:3 and
further wherein the liposome comprises cationic or non-cationic lipid, cholesterol-based lipid and PEG-modified lipid. | 1,600 |
847 | 15,008,937 | 1,617 | A preservative composition is described that may be used in personal care products and other products for protecting the products against bacteria and fungus during production and during use. The composition can about 3 to about 15% by weight of an organic acid; about 3 to about 15% by weight of a C 8 -C 18 fatty alcohol; about 30 to about 60% by weight of an aromatic alcohol; and about 30 to about 60% by weight of an organic solvent. | 1. A fluid preservative composition comprising
(i) about 3 to about 15% by weight of an organic acid; (ii) about 3 to about 15% by weight of a C8-C18 fatty alcohol; (iii) about 30 to about 60% by weight of an aromatic alcohol; and (iv) about 30 to about 60% by weight of an organic solvent. 2. The preservative composition according to claim 1, wherein the organic acid is sorbic acid. 3. The preservative composition according to claim 1, wherein the solvent is a diol compound. 4. The preservative composition according to claim 2, wherein the diol compound is selected from the group consisting of a propanediol, butanediol, pentanediol, hexanediol, heptanediol, and a mixture of two or more of the diols. 5. The preservative composition according to claim 3, wherein the solvent comprises 1,3-butanediol. 6. The preservative composition according to claim 1, wherein the aromatic alcohol comprises benzyl alcohol. 7. The preservative composition according to claim 1, wherein the C8-C18 fatty alcohol comprises lauryl alcohol. 8. The preservative composition according to claim 1, wherein the C8-C18 fatty alcohol comprises myristyl alcohol. 9. The preservative composition according to claim 1, wherein the C8-C18 fatty alcohol comprises a mixture of lauryl alcohol and myristyl alcohol. 10. The preservative composition according to claim 1, further comprising a stabilizer in an amount up to 5% by weight. 11. The preservative composition according to claim 10, wherein the stabilizer comprises tocopherol or gluconolactone. 12. The preservative composition according to claim 11, wherein the stabilizer is tocopherol and is present in an amount of about 0.1 to about 1.0% by weight. 13. The preservative composition according to claim 1, further comprising a dispersant or solubilizer in an amount from about 1% up to about 20%. 14. The preservative composition according to claim 13, wherein the solubilizer comprises caprylic/capric triglycerides. 15. The preservative composition according to claim 1, wherein the composition comprises
(i) about 4 to about 10% by weight of the organic acid; (ii) about 4 to about 10% by weight of the C8-C18 fatty alcohol; (iii) about 35 to about 45% by weight of the aromatic alcohol; and (iv) about 35 to about 50% by weight of the organic solvent. 16. The preservative composition according to claim 15, wherein the composition comprises
(i) about 4 to about 9% by weight of the organic acid; (ii) about 4 to about 9% by weight of the C8-C18 fatty alcohol; (iii) about 37.5 to about 42.5% by weight of the aromatic alcohol; and (iv) about 40 to about 45% by weight of the organic solvent. 17. The preservative composition according to claim 1, wherein the organic acid is sorbic acid, C8-C18 fatty alcohol comprises mixture of lauryl alcohol and myristyl alcohol; the aromatic alcohol comprises benzyl alcohol and the organic solvent comprises 1,3 -butanediol. 18. A personal care product comprising
(i) a base formulation and (ii) an effective amount of the preservative composition according to claim 1 to aid in preventing a bacterial and/or fungal infection or contamination of the base formulation. 19. The personal care product according to claim 18, wherein the preservative composition comprises between about 0.1% to about 5% by weight of the personal care product. 20. The personal care product according to claim 18, wherein the organic solvent comprises a diol and wherein the organic acid comprises sorbic acid. 21. The personal care product according to claim 18, wherein the base formulation is a formulation for a shampoo, a hair conditioner, a hair dye, an aftershave, a shave preparation, a bath soap, a perfume, a sun care product, an indoor tanning product, a body or hand lotion, a personal cleaner, a skin care product, makeup remover, makeup, or a wet wipe formulation. 22. A preserved composition for use in a hygiene product, a health care product, an industrial product, or household cleaning products containing the preservative composition according to claim 1. 23. A method of preserving a personal care formulation in need of preservation against bacteria and fungus infection or contamination, said method comprising adding the preservative composition according to claim 1 to a base formulation, and mixing the preservative composition with the base formulation. 24. The method according to claim 23, wherein the organic solvent comprises a diol and wherein the organic acid comprises sorbic acid. | A preservative composition is described that may be used in personal care products and other products for protecting the products against bacteria and fungus during production and during use. The composition can about 3 to about 15% by weight of an organic acid; about 3 to about 15% by weight of a C 8 -C 18 fatty alcohol; about 30 to about 60% by weight of an aromatic alcohol; and about 30 to about 60% by weight of an organic solvent.1. A fluid preservative composition comprising
(i) about 3 to about 15% by weight of an organic acid; (ii) about 3 to about 15% by weight of a C8-C18 fatty alcohol; (iii) about 30 to about 60% by weight of an aromatic alcohol; and (iv) about 30 to about 60% by weight of an organic solvent. 2. The preservative composition according to claim 1, wherein the organic acid is sorbic acid. 3. The preservative composition according to claim 1, wherein the solvent is a diol compound. 4. The preservative composition according to claim 2, wherein the diol compound is selected from the group consisting of a propanediol, butanediol, pentanediol, hexanediol, heptanediol, and a mixture of two or more of the diols. 5. The preservative composition according to claim 3, wherein the solvent comprises 1,3-butanediol. 6. The preservative composition according to claim 1, wherein the aromatic alcohol comprises benzyl alcohol. 7. The preservative composition according to claim 1, wherein the C8-C18 fatty alcohol comprises lauryl alcohol. 8. The preservative composition according to claim 1, wherein the C8-C18 fatty alcohol comprises myristyl alcohol. 9. The preservative composition according to claim 1, wherein the C8-C18 fatty alcohol comprises a mixture of lauryl alcohol and myristyl alcohol. 10. The preservative composition according to claim 1, further comprising a stabilizer in an amount up to 5% by weight. 11. The preservative composition according to claim 10, wherein the stabilizer comprises tocopherol or gluconolactone. 12. The preservative composition according to claim 11, wherein the stabilizer is tocopherol and is present in an amount of about 0.1 to about 1.0% by weight. 13. The preservative composition according to claim 1, further comprising a dispersant or solubilizer in an amount from about 1% up to about 20%. 14. The preservative composition according to claim 13, wherein the solubilizer comprises caprylic/capric triglycerides. 15. The preservative composition according to claim 1, wherein the composition comprises
(i) about 4 to about 10% by weight of the organic acid; (ii) about 4 to about 10% by weight of the C8-C18 fatty alcohol; (iii) about 35 to about 45% by weight of the aromatic alcohol; and (iv) about 35 to about 50% by weight of the organic solvent. 16. The preservative composition according to claim 15, wherein the composition comprises
(i) about 4 to about 9% by weight of the organic acid; (ii) about 4 to about 9% by weight of the C8-C18 fatty alcohol; (iii) about 37.5 to about 42.5% by weight of the aromatic alcohol; and (iv) about 40 to about 45% by weight of the organic solvent. 17. The preservative composition according to claim 1, wherein the organic acid is sorbic acid, C8-C18 fatty alcohol comprises mixture of lauryl alcohol and myristyl alcohol; the aromatic alcohol comprises benzyl alcohol and the organic solvent comprises 1,3 -butanediol. 18. A personal care product comprising
(i) a base formulation and (ii) an effective amount of the preservative composition according to claim 1 to aid in preventing a bacterial and/or fungal infection or contamination of the base formulation. 19. The personal care product according to claim 18, wherein the preservative composition comprises between about 0.1% to about 5% by weight of the personal care product. 20. The personal care product according to claim 18, wherein the organic solvent comprises a diol and wherein the organic acid comprises sorbic acid. 21. The personal care product according to claim 18, wherein the base formulation is a formulation for a shampoo, a hair conditioner, a hair dye, an aftershave, a shave preparation, a bath soap, a perfume, a sun care product, an indoor tanning product, a body or hand lotion, a personal cleaner, a skin care product, makeup remover, makeup, or a wet wipe formulation. 22. A preserved composition for use in a hygiene product, a health care product, an industrial product, or household cleaning products containing the preservative composition according to claim 1. 23. A method of preserving a personal care formulation in need of preservation against bacteria and fungus infection or contamination, said method comprising adding the preservative composition according to claim 1 to a base formulation, and mixing the preservative composition with the base formulation. 24. The method according to claim 23, wherein the organic solvent comprises a diol and wherein the organic acid comprises sorbic acid. | 1,600 |
848 | 15,764,089 | 1,619 | A sunscreen cosmetic eliminates instability of a dibenzoylmethane derivative that is a UVA absorbing-agent, which exhibits excellent ultraviolet radiation protection performance across a wide wavelength region from UVA to UVB, and which exhibits excellent light resistance, is stable over time, and does not suffer from discoloration or crystal precipitation, and with which unnatural whiteness does not occur. A sunscreen cosmetic contains (a) a dibenzoylmethane derivative and (b) a powder that is surface-hydrophobized by means of treatment with a metal soap comprising a higher fatty acid and an alkaline earth metal or a combined treatment involving the use of a higher fatty acid and an alkaline earth metal hydroxide. The alkaline earth metal is preferably calcium or magnesium, and the higher fatty acid is preferably isostearic acid. | 1.-12. (canceled) 13. A sunscreen cosmetic, comprising:
(a) a dibenzoylmethane derivative; and (b) a powder that is surface-hydrophobized by treatment with a metal soap consisting of a higher fatty acid and an alkaline earth metal, or by a combination treatment with a higher fatty acid and an alkaline earth metal hydroxide. 14. The sunscreen cosmetic, according to claim 13, wherein:
said alkaline earth metal is calcium or magnesium. 15. The sunscreen cosmetic, according to claim 13, wherein:
said higher fatty acid is a fatty acid having 12 to 18 carbon atoms. 16. The sunscreen cosmetic, according to claim 13, wherein:
a blended amount of the (a) dibenzoylmethane derivative is 0.5 to 4.0 mass %, and a blended amount of the (b) powder that is surface hydrophobidized is 1.0 to 15.0 mass %. 17. The sunscreen cosmetic, according to claim 16, wherein:
a blended amount ratio between the blended amount of the (a) dibenzoylmethane derivative and the blended amount of the (b) hydrophobized powder that is surface-hydrophobidized is within a range of (a):(b)=1:24 to 3:1 18. A method, for stabilizing a composition comprising a dibenzoylmethane derivative composition for use in a sunscreen cosmetic, comprising step of:
blending in a powder that is surface-hydrophobidized by treatment with a metal soap consisting of a higher fatty acid and an alkaline earth metal, or by a combination treatment with a higher fatty acid and an alkaline earth metal hydroxide. | A sunscreen cosmetic eliminates instability of a dibenzoylmethane derivative that is a UVA absorbing-agent, which exhibits excellent ultraviolet radiation protection performance across a wide wavelength region from UVA to UVB, and which exhibits excellent light resistance, is stable over time, and does not suffer from discoloration or crystal precipitation, and with which unnatural whiteness does not occur. A sunscreen cosmetic contains (a) a dibenzoylmethane derivative and (b) a powder that is surface-hydrophobized by means of treatment with a metal soap comprising a higher fatty acid and an alkaline earth metal or a combined treatment involving the use of a higher fatty acid and an alkaline earth metal hydroxide. The alkaline earth metal is preferably calcium or magnesium, and the higher fatty acid is preferably isostearic acid.1.-12. (canceled) 13. A sunscreen cosmetic, comprising:
(a) a dibenzoylmethane derivative; and (b) a powder that is surface-hydrophobized by treatment with a metal soap consisting of a higher fatty acid and an alkaline earth metal, or by a combination treatment with a higher fatty acid and an alkaline earth metal hydroxide. 14. The sunscreen cosmetic, according to claim 13, wherein:
said alkaline earth metal is calcium or magnesium. 15. The sunscreen cosmetic, according to claim 13, wherein:
said higher fatty acid is a fatty acid having 12 to 18 carbon atoms. 16. The sunscreen cosmetic, according to claim 13, wherein:
a blended amount of the (a) dibenzoylmethane derivative is 0.5 to 4.0 mass %, and a blended amount of the (b) powder that is surface hydrophobidized is 1.0 to 15.0 mass %. 17. The sunscreen cosmetic, according to claim 16, wherein:
a blended amount ratio between the blended amount of the (a) dibenzoylmethane derivative and the blended amount of the (b) hydrophobized powder that is surface-hydrophobidized is within a range of (a):(b)=1:24 to 3:1 18. A method, for stabilizing a composition comprising a dibenzoylmethane derivative composition for use in a sunscreen cosmetic, comprising step of:
blending in a powder that is surface-hydrophobidized by treatment with a metal soap consisting of a higher fatty acid and an alkaline earth metal, or by a combination treatment with a higher fatty acid and an alkaline earth metal hydroxide. | 1,600 |
849 | 15,603,267 | 1,628 | Neuro-enhancing agents, compositions and methods are disclosed herein. Preferred neuro-enhancing agents of the present invention include progesterone and metabolites of progesterone, such as 3α-hydroxy-5α-pregnan-20-one (THP). These agents yield neuro-enhancing effects on neural cells that include neural progenitor and/or stem cells, whereby the agents stimulate mitosis of neural progenitor cells, stimulate neurite growth and organization, protect against neural loss, or one or more of these neural processes. Thus, the neuro-enhancing agents, compositions and methods disclosed herein are useful to reverse or prevent neurological disease or defects associated with neural loss or degeneration, such as Alzheimer's disease, neurological injuries, including injuries resulting from radiation therapy, and age-related neurological decline, including impairments in memory and learning. | 1. The method of claim 15, wherein the 3α-hydroxy-5α-pregnan-20-one, a derivative or analog thereof, or a pharmaceutically acceptable salt thereof is formulated as a pharmaceutical composition for systemic administration via a route selected from the group consisting of transdermal administration, subcutaneous injection, intravenous injection and pulmonary administration. 2. The method of claim 1, wherein the formulation includes a dextrin. 3. The method of claim 1, wherein the composition is in the form of a transdermal gel. 4. The method of claim 3, wherein the gel comprises a thickening agent. 5. The method of claim 4, wherein the thickening agent is a cross linked acrylic acid polymer. 6. The method of claim 5, wherein the crosslinked acrylic acid polymer is carbomer 940. 7. The method of claim 3, wherein the gel further comprises a solvent selected from the group consisting of diglycol monoethyl ether, ethylene glycol, propylene glycol, dimethyl isosorbide, isopropyl alcohol, and ethanol. 8-9. (canceled) 10. The method of claim 3, wherein the gel further comprises one or more penetration enhancers. 11. The method of claim 15, wherein the 3α-hydroxy-5α-pregnan-20-one, a derivative or analog thereof, or a pharmaceutically acceptable salt thereof is present in an amount effective to reduce learning and/or memory deficits in an individual suffering from a neurodegenerative disease, defect, or injury. 12. The method of claim 1, wherein the 3α-hydroxy-5α-pregnan-20-one, a derivative or analog thereof, or a pharmaceutically acceptable salt thereof is present in an amount effective to reverse learning and/or memory deficits in the individual. 13. The method of claim 1, wherein the hydroxy-5α-pregnan-20-one, a derivative or analog thereof, or a pharmaceutically acceptable salt thereof is present in an amount effective to prevent learning and/or memory deficits in the individual. 14. (canceled) 15. A method for treating or preventing neurological deficits in an individual suffering from a neurodegenerative disease, defect, or injury or age-related neurological decline, or at risk of a neurodegenerative disease, defect, or injury,
the method comprising administering systemically to the individual an effective amount of 3α-hydroxy-5α-pregnan-20-one, a derivative or analog thereof, or a pharmaceutically acceptable salt thereof, to treat neurological deficits in the individual, wherein the 3α-hydroxy-5α-pregnan-20-one, a derivative or analog thereof, or a pharmaceutically acceptable salt thereof is administered once a week or less frequently. 16. The method of claim 15, wherein the composition is administered for a period of at least one month. 17. The method of claim 15, wherein the composition is administered for a period of at least three months. 18. The method of claim 15, wherein the composition is administered for a period of at least six months. 19. The method of claim 18, wherein the composition is administered once a week for a period of six months. 20. The method of claim 15, wherein the amount of 3α-hydroxy-5α-pregnan-20-one or a derivative or analog thereof in the composition is from about 0.1 to about 1000 mg, preferably from about 0.1 to about 500 mg, more preferably from about 0.1 to about 100 mg. 21. The method of claim 15, wherein the amount of 3α-hydroxy-5α-pregnan-20-one or a derivative or analog thereof is 10 mg. 22. The method of claim 15, wherein the neurodegenerative disease or disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease and traumatic brain injury. 23-35. (canceled) | Neuro-enhancing agents, compositions and methods are disclosed herein. Preferred neuro-enhancing agents of the present invention include progesterone and metabolites of progesterone, such as 3α-hydroxy-5α-pregnan-20-one (THP). These agents yield neuro-enhancing effects on neural cells that include neural progenitor and/or stem cells, whereby the agents stimulate mitosis of neural progenitor cells, stimulate neurite growth and organization, protect against neural loss, or one or more of these neural processes. Thus, the neuro-enhancing agents, compositions and methods disclosed herein are useful to reverse or prevent neurological disease or defects associated with neural loss or degeneration, such as Alzheimer's disease, neurological injuries, including injuries resulting from radiation therapy, and age-related neurological decline, including impairments in memory and learning.1. The method of claim 15, wherein the 3α-hydroxy-5α-pregnan-20-one, a derivative or analog thereof, or a pharmaceutically acceptable salt thereof is formulated as a pharmaceutical composition for systemic administration via a route selected from the group consisting of transdermal administration, subcutaneous injection, intravenous injection and pulmonary administration. 2. The method of claim 1, wherein the formulation includes a dextrin. 3. The method of claim 1, wherein the composition is in the form of a transdermal gel. 4. The method of claim 3, wherein the gel comprises a thickening agent. 5. The method of claim 4, wherein the thickening agent is a cross linked acrylic acid polymer. 6. The method of claim 5, wherein the crosslinked acrylic acid polymer is carbomer 940. 7. The method of claim 3, wherein the gel further comprises a solvent selected from the group consisting of diglycol monoethyl ether, ethylene glycol, propylene glycol, dimethyl isosorbide, isopropyl alcohol, and ethanol. 8-9. (canceled) 10. The method of claim 3, wherein the gel further comprises one or more penetration enhancers. 11. The method of claim 15, wherein the 3α-hydroxy-5α-pregnan-20-one, a derivative or analog thereof, or a pharmaceutically acceptable salt thereof is present in an amount effective to reduce learning and/or memory deficits in an individual suffering from a neurodegenerative disease, defect, or injury. 12. The method of claim 1, wherein the 3α-hydroxy-5α-pregnan-20-one, a derivative or analog thereof, or a pharmaceutically acceptable salt thereof is present in an amount effective to reverse learning and/or memory deficits in the individual. 13. The method of claim 1, wherein the hydroxy-5α-pregnan-20-one, a derivative or analog thereof, or a pharmaceutically acceptable salt thereof is present in an amount effective to prevent learning and/or memory deficits in the individual. 14. (canceled) 15. A method for treating or preventing neurological deficits in an individual suffering from a neurodegenerative disease, defect, or injury or age-related neurological decline, or at risk of a neurodegenerative disease, defect, or injury,
the method comprising administering systemically to the individual an effective amount of 3α-hydroxy-5α-pregnan-20-one, a derivative or analog thereof, or a pharmaceutically acceptable salt thereof, to treat neurological deficits in the individual, wherein the 3α-hydroxy-5α-pregnan-20-one, a derivative or analog thereof, or a pharmaceutically acceptable salt thereof is administered once a week or less frequently. 16. The method of claim 15, wherein the composition is administered for a period of at least one month. 17. The method of claim 15, wherein the composition is administered for a period of at least three months. 18. The method of claim 15, wherein the composition is administered for a period of at least six months. 19. The method of claim 18, wherein the composition is administered once a week for a period of six months. 20. The method of claim 15, wherein the amount of 3α-hydroxy-5α-pregnan-20-one or a derivative or analog thereof in the composition is from about 0.1 to about 1000 mg, preferably from about 0.1 to about 500 mg, more preferably from about 0.1 to about 100 mg. 21. The method of claim 15, wherein the amount of 3α-hydroxy-5α-pregnan-20-one or a derivative or analog thereof is 10 mg. 22. The method of claim 15, wherein the neurodegenerative disease or disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease and traumatic brain injury. 23-35. (canceled) | 1,600 |
850 | 14,896,294 | 1,633 | The present disclosure provides a method of treating a human patient comprising the steps of: systemically administering multiple doses of a parenteral formulation of a replication capable oncolytic adenovirus of subgroup B in a single treatment cycle, wherein the total dose given in each dose is in the range of 1×10 10 to 1×10 14 viral particles, and wherein each dose of virus is administered over a period of 1 to 90 minutes, for example at a rate of viral particle delivery in the range of 2×10 10 particles per minute to 2×10 12 particles per minute. The disclosure further extends to formulations of the said oncolytic adenoviruses and combination therapies of the viruses and formulations with other therapeutic agents. | 1. A method of treating a human patient, said method comprising the steps of:
systemically administering multiple doses of a parenteral formulation of a replication capable oncolytic adenovirus of subgroup B in a single treatment cycle, wherein the total dose given in each administration is in the range of 1×1010 to 1×1014 viral particles per dose, and wherein each dose of virus is administered such that the rate of viral particle delivery is in the range of 2×1010 particles per minute to 2×1012 particles per minute. 2. A method according to claim 1, wherein the total dose given in each administration is in the range of 1×1012 to 1×1013 viral particles per dose, for example the total dose given in each administration is in the range of 3×1012 to 9×1012 viral particles per dose, in particular wherein the total dose given in each administration is 6×1012 viral particles per dose. 3. A method according to claim 1 or 2, wherein the period between each dose administration is in the range of 6 hours to 72 hours, such as 48 hours. 4. A method according to any one of claims 1 to 3, wherein the multiple doses are 2, 3, 4, 5, 6 or 7 doses in a single treatment cycle. 5. A method according to any one of claims 1 to 4, wherein the treatment cycle is a period of 14 days or less, such as 7 days or 5 days. 6. A method according to any one of claims 1 to 5, wherein each dose of virus is administered such that the rate of viral particle delivery is in the range of 1×1011 viral particles per minute to 3×1011 viral particles per minute, such as 2×1011 viral particles per minute or 1.67×1011 viral particles per minute, per dose, in particular each dose of virus is administered such that the rate of viral particle delivery is 1.5×1011 viral particles per minute, per dose. 7. A method according to any one of claims 1 to 6, wherein 1×1013 viral particles are administered over a 60 minute period per dose or wherein 6×1012 viral particles are administered over a 40 minute period per dose. 8. A method according to any one of claims 1 to 7, wherein the plasma level of virus after administration of the second and optionally subsequent doses reaches a level of at least 2×106 viral particles per mL. 9. A method according to claim 8, wherein the plasma level of viral particles is maintained for 15 minutes or greater, for example 20, 30, 40, 50 or 60 minutes. 10. A method according to any one of claims 1 to 9, wherein the volume of the formulation administered is 100 mL or less, for example 30 mLs or less, such as about 3 mLs or 5 mLs. 11. A method according to any one of claims 1 to 10, wherein a first dose is administered on day 1 and the further therapeutic doses are administered every second day thereafter, for example wherein the first dose is administered on day 1 and the further therapeutic doses are administered on days 3 and 5. 12. A method according to any one of claims 1 to 11, wherein the adenovirus is a chimeric adenovirus, for example wherein the chimeric adenovirus is ColoAd1. 13. A method according to any one of claims 1 to 12, wherein the virus is administered in combination with the administration of any other anti-cancer therapy including a chemotherapeutic agent, an immunotherapeutic agent such as an antibody or fragment thereof, a small molecule inhibitor such as a kinase inhibitor or an mTOR inhibitor, radiotherapy, radio-isotope therapy or any combination thereof. 14. A method according to any one of claims 1 to 13, wherein the virus is administered in combination with the administration of one or more prophylactic agents, for example selected from an antipyretic, an antiemetic, a steroid and an analgesic. 15. A method according to any one of claims 1 to 14 for the treatment of a tumour, for example a solid tumour, such as a colorectal malignancy. 16. A method according to any one of claims 1 to 23 wherein the first and therapeutic dose is in the range 109 to 1014 viral particles. 17. A method according to any one of claims 1 to 16, wherein the adenovirus is formulated to at least partially avoid the patient's immune system. 18. A method according to any one of claims 1 to 17, wherein the adenovirus contains a transgene. 19. A method according to any one of claims 1 to 17, wherein the treatment results in the necrosis of the cancer cells accompanied by an increase in plasma cytokine levels. 20. A method of treating a patient with a pharmaceutical formulation comprising ColoAd1 comprising the steps of intravenously administering to said patient
a first therapeutic dose on day 1 followed by a second therapeutic dose on day 3 and a third therapeutic dose on day 5. 21. A method of treating a human patient, said method comprising systemically administering multiple doses of a parenteral formulation comprising a replication capable oncolytic adenovirus of subgroup B in a single treatment cycle, wherein the total dose given in each administration is in the range 1×1010 to 1×1013 viral particles, and is administered over a period of 1 minute to 90 minutes, for example wherein the total dose given in each administration is 6×1012 viral particles, and is administered over a period of 40 minutes. 22. A replication capable oncolytic adenovirus of subgroup B for use in treatment of a human patient by systemically administering multiple doses of a parenteral formulation comprising the adenovirus in a single treatment cycle, wherein the total dose given in each administration is in the range 1×1010 to 1×1014 or 1×1010 to 1×1013 viral particles, and is administered over a period of 1 minute to 90 minutes. 23. A parenteral formulation of a replication capable oncolytic adenovirus of subgroup B, for use according to claim 22, wherein the total dose administered is in the range 1×1010 to 1×1014 viral particles per dose and each dose of virus is administered such that the rate of particle delivery is in the range of 2×1010 particles per minute to 2×1012 per minute. 24. Use of a replication capable oncolytic adenovirus of subgroup B for the manufacture of a medicament use in treatment of a human patient by systemically administering multiple doses of a parenteral formulation comprising the adenovirus in a single treatment cycle, wherein the total dose given in each administration is in the range 1×1010 to 6×1012 viral particles, and is administered over a period of 1 minute to 90 minutes. 25. Use of a glass or plastic syringe with an internal volume in the range of 3 to 50 ml, said syringe containing a parenteral formulation comprising 1×1010 to 6×1012 viral particles of a replication capable oncolytic adenovirus of subgroup B, wherein the formulation is sterile and was filled into the syringe under aseptic conditions, for use in treatment, in particular for use in the manufacture of a medicament which is capable of injection or intravenous infusion to a human subject, for example according to any one of claims 1 to 21. 26. ColoAd1 for use in treating ovarian cancer, for example administering a therapeutically effective amount of ColoAd1 to a patient with ovarian cancer, for example employing a dosing regimen described herein. 27. A combination therapy comprising oncolytic type B adenovirus, such as ColoAd1, and a chemotherapeutic agent which does not interfere with the adenovirus activity, such as viral replication in vivo. | The present disclosure provides a method of treating a human patient comprising the steps of: systemically administering multiple doses of a parenteral formulation of a replication capable oncolytic adenovirus of subgroup B in a single treatment cycle, wherein the total dose given in each dose is in the range of 1×10 10 to 1×10 14 viral particles, and wherein each dose of virus is administered over a period of 1 to 90 minutes, for example at a rate of viral particle delivery in the range of 2×10 10 particles per minute to 2×10 12 particles per minute. The disclosure further extends to formulations of the said oncolytic adenoviruses and combination therapies of the viruses and formulations with other therapeutic agents.1. A method of treating a human patient, said method comprising the steps of:
systemically administering multiple doses of a parenteral formulation of a replication capable oncolytic adenovirus of subgroup B in a single treatment cycle, wherein the total dose given in each administration is in the range of 1×1010 to 1×1014 viral particles per dose, and wherein each dose of virus is administered such that the rate of viral particle delivery is in the range of 2×1010 particles per minute to 2×1012 particles per minute. 2. A method according to claim 1, wherein the total dose given in each administration is in the range of 1×1012 to 1×1013 viral particles per dose, for example the total dose given in each administration is in the range of 3×1012 to 9×1012 viral particles per dose, in particular wherein the total dose given in each administration is 6×1012 viral particles per dose. 3. A method according to claim 1 or 2, wherein the period between each dose administration is in the range of 6 hours to 72 hours, such as 48 hours. 4. A method according to any one of claims 1 to 3, wherein the multiple doses are 2, 3, 4, 5, 6 or 7 doses in a single treatment cycle. 5. A method according to any one of claims 1 to 4, wherein the treatment cycle is a period of 14 days or less, such as 7 days or 5 days. 6. A method according to any one of claims 1 to 5, wherein each dose of virus is administered such that the rate of viral particle delivery is in the range of 1×1011 viral particles per minute to 3×1011 viral particles per minute, such as 2×1011 viral particles per minute or 1.67×1011 viral particles per minute, per dose, in particular each dose of virus is administered such that the rate of viral particle delivery is 1.5×1011 viral particles per minute, per dose. 7. A method according to any one of claims 1 to 6, wherein 1×1013 viral particles are administered over a 60 minute period per dose or wherein 6×1012 viral particles are administered over a 40 minute period per dose. 8. A method according to any one of claims 1 to 7, wherein the plasma level of virus after administration of the second and optionally subsequent doses reaches a level of at least 2×106 viral particles per mL. 9. A method according to claim 8, wherein the plasma level of viral particles is maintained for 15 minutes or greater, for example 20, 30, 40, 50 or 60 minutes. 10. A method according to any one of claims 1 to 9, wherein the volume of the formulation administered is 100 mL or less, for example 30 mLs or less, such as about 3 mLs or 5 mLs. 11. A method according to any one of claims 1 to 10, wherein a first dose is administered on day 1 and the further therapeutic doses are administered every second day thereafter, for example wherein the first dose is administered on day 1 and the further therapeutic doses are administered on days 3 and 5. 12. A method according to any one of claims 1 to 11, wherein the adenovirus is a chimeric adenovirus, for example wherein the chimeric adenovirus is ColoAd1. 13. A method according to any one of claims 1 to 12, wherein the virus is administered in combination with the administration of any other anti-cancer therapy including a chemotherapeutic agent, an immunotherapeutic agent such as an antibody or fragment thereof, a small molecule inhibitor such as a kinase inhibitor or an mTOR inhibitor, radiotherapy, radio-isotope therapy or any combination thereof. 14. A method according to any one of claims 1 to 13, wherein the virus is administered in combination with the administration of one or more prophylactic agents, for example selected from an antipyretic, an antiemetic, a steroid and an analgesic. 15. A method according to any one of claims 1 to 14 for the treatment of a tumour, for example a solid tumour, such as a colorectal malignancy. 16. A method according to any one of claims 1 to 23 wherein the first and therapeutic dose is in the range 109 to 1014 viral particles. 17. A method according to any one of claims 1 to 16, wherein the adenovirus is formulated to at least partially avoid the patient's immune system. 18. A method according to any one of claims 1 to 17, wherein the adenovirus contains a transgene. 19. A method according to any one of claims 1 to 17, wherein the treatment results in the necrosis of the cancer cells accompanied by an increase in plasma cytokine levels. 20. A method of treating a patient with a pharmaceutical formulation comprising ColoAd1 comprising the steps of intravenously administering to said patient
a first therapeutic dose on day 1 followed by a second therapeutic dose on day 3 and a third therapeutic dose on day 5. 21. A method of treating a human patient, said method comprising systemically administering multiple doses of a parenteral formulation comprising a replication capable oncolytic adenovirus of subgroup B in a single treatment cycle, wherein the total dose given in each administration is in the range 1×1010 to 1×1013 viral particles, and is administered over a period of 1 minute to 90 minutes, for example wherein the total dose given in each administration is 6×1012 viral particles, and is administered over a period of 40 minutes. 22. A replication capable oncolytic adenovirus of subgroup B for use in treatment of a human patient by systemically administering multiple doses of a parenteral formulation comprising the adenovirus in a single treatment cycle, wherein the total dose given in each administration is in the range 1×1010 to 1×1014 or 1×1010 to 1×1013 viral particles, and is administered over a period of 1 minute to 90 minutes. 23. A parenteral formulation of a replication capable oncolytic adenovirus of subgroup B, for use according to claim 22, wherein the total dose administered is in the range 1×1010 to 1×1014 viral particles per dose and each dose of virus is administered such that the rate of particle delivery is in the range of 2×1010 particles per minute to 2×1012 per minute. 24. Use of a replication capable oncolytic adenovirus of subgroup B for the manufacture of a medicament use in treatment of a human patient by systemically administering multiple doses of a parenteral formulation comprising the adenovirus in a single treatment cycle, wherein the total dose given in each administration is in the range 1×1010 to 6×1012 viral particles, and is administered over a period of 1 minute to 90 minutes. 25. Use of a glass or plastic syringe with an internal volume in the range of 3 to 50 ml, said syringe containing a parenteral formulation comprising 1×1010 to 6×1012 viral particles of a replication capable oncolytic adenovirus of subgroup B, wherein the formulation is sterile and was filled into the syringe under aseptic conditions, for use in treatment, in particular for use in the manufacture of a medicament which is capable of injection or intravenous infusion to a human subject, for example according to any one of claims 1 to 21. 26. ColoAd1 for use in treating ovarian cancer, for example administering a therapeutically effective amount of ColoAd1 to a patient with ovarian cancer, for example employing a dosing regimen described herein. 27. A combination therapy comprising oncolytic type B adenovirus, such as ColoAd1, and a chemotherapeutic agent which does not interfere with the adenovirus activity, such as viral replication in vivo. | 1,600 |
851 | 14,906,507 | 1,618 | The disclosure relates generally to ionic salts, particularly low-melting ionic salts such as ionic liquids, of poorly-water soluble drugs. The disclosure further relates to methods of preparing the ionic salts of poorly-water soluble drugs, lipid formulations comprising them and their use in drug delivery. | 1.-31. (canceled) 32. A lipid formulation of a poorly water soluble drug comprising a low melting ionic salt of the poorly water soluble drug, together with a substantially non-aqueous lipid vehicle. 33. The lipid formulation according to claim 32 wherein the low melting ionic salt is a ionic liquid salt of the poorly water soluble drug. 34. The lipid formulation according to claim 33 wherein the ionic liquid salt has a melting point of about 90° C. or less. 35. The lipid formulation according to claim 33 wherein the ionic liquid salt has a melting point of about 70° C. or less. 36. The lipid formulation according to claim 33 wherein the ionic liquid salt has a melting point of about 50° C. or less. 37. The lipid formulation according to claim 33 wherein the ionic liquid salt has a melting point of about 40° C. or less. 38. The lipid formulation according to claim 33 wherein the ionic liquid salt has a melting point of about 30° C. or less. 39. The lipid formulation according to claim 33 wherein the ionic liquid salt has a melting point of about 25° C. or less. 40. The lipid formulation according to claim 33 wherein the ionic liquid salt is an oil at room temperature. 41. The lipid formulation according to claim 32 wherein the low melting ionic salt of the poorly water soluble drug is at least twice as soluble in the non-aqueous lipid vehicle as the non-ionised drug. 42. The lipid formulation according to claim 41 wherein the low melting ionic salt of the poorly water soluble drug is at least 4-5 times as soluble in the non-aqueous lipid vehicle as the non-ionised drug. 43. The lipid formulation according to claim 32 wherein the poorly water soluble drug forms the cation of the low melting ionic salt and contains at least one basic ionisable nitrogen atom. 44. The lipid formulation according to claim 43 wherein the poorly water soluble drug forms a low melting ionic salt with an anion formed from carboxylic acids (RC(O)O−), phosphates (ROP(O)O2 −), phosphonates (RP(O)O2 −), sulfonates (RSO(O)2O−), sulfates (ROS(O)2O−), tetrazolys (R-tetrazolate) or bis(sulfonyl)imides (RSO2—N−—SO2R), where R is an optionally substituted hydrocarbon group having at least 2 carbon atoms. 45. The lipid formulation according to claim 44 wherein the poorly water soluble drug forms low melting ionic salt with an anion formed from phosphates (ROP(O)O2 −), or sulfates (ROS(O)2O−). 46. The lipid formulation according to claim 43 wherein R is optionally substituted and is selected from the group consisting of an alkyl, alkenyl or alkynl group, each having from 4-40 carbon atoms, and a cycloalkyl or unsaturated cyclic hydrocarbon group, each having from 3-10 carbon atoms. 47. The lipid formulation according to claim 46 wherein R is an optionally substituted alkyl group having 4-24 carbon atoms. 48. The lipid formulation according to claim 32 wherein the poorly water soluble drug forms the anion of the low melting ionic salt and contains at least one acidic group. 49. The lipid formulation according to claim 48 wherein the poorly water soluble drug forms a low melting ionic salt with a cation selected from +NR′4 and +PR′4, wherein each R′ is independently selected from hydrogen and R″ where R″ is selected from the group of an alkyl, alkenyl or alkynl group each having from 4-40 carbon atoms and a cycloalkyl or unsaturated cyclic hydrocarbon group each having from 3-10 carbon atoms. 50. The lipid formulation of claim 32, wherein the substantially non-aqueous lipid vehicle comprises at least one oil or lipid. 51. The lipid formulation of claim 32, wherein the substantially non-aqueous lipid vehicle consists essentially of at least one oil or lipid. 52. The lipid formulation of claim 50, wherein the substantially non-aqueous lipid vehicle comprises at least one oil or lipid and at least one surfactant. 53. The lipid formulation of claim 51, wherein the substantially non-aqueous lipid vehicle comprises at least one oil or lipid, at least one surfactant and at least one co-solvent. 54. The lipid formulation of claim 32, wherein the substantially non-aqueous lipid vehicle comprises at least one surfactant and, optionally, at least one co-solvent. 55. The lipid formulation of claim 32, wherein the substantially non-aqueous lipid vehicle consists essentially of at least one surfactant and/or solvent, optionally with one or more co-surfactants or co-emulsifiers. 56. The lipid formulation of claim 32 consisting essentially of an ionic liquid salt of the poorly water soluble drug, together with one or more oils and/or liquids. 57. The lipid formulation of claim 32 consisting essentially of an ionic liquid salt of the poorly water soluble drug, together with one or more surfactants and/or solvents, optionally with one or more, co-surfactants or co-emulsifiers. 58. The lipid formulation of claim 32 in the form of a single phase. 59. Use of a lipid formulation according to claim 32 as a fill for a capsule. 60. A capsule, sachet, syringe or dropper device, ampoule, tube or bottle containing a lipid formulation according to claim 32. 61. A method for the manufacture of a lipid formulation of a poorly water soluble drug, according to claim 32, said method comprising the step of blending a low melting ionic salt of the poorly water soluble drug with a non-aqueous lipid vehicle. 62. The method of claim 61 wherein the resulting lipid formulation is a single phase liquid, solid or semi-solid. | The disclosure relates generally to ionic salts, particularly low-melting ionic salts such as ionic liquids, of poorly-water soluble drugs. The disclosure further relates to methods of preparing the ionic salts of poorly-water soluble drugs, lipid formulations comprising them and their use in drug delivery.1.-31. (canceled) 32. A lipid formulation of a poorly water soluble drug comprising a low melting ionic salt of the poorly water soluble drug, together with a substantially non-aqueous lipid vehicle. 33. The lipid formulation according to claim 32 wherein the low melting ionic salt is a ionic liquid salt of the poorly water soluble drug. 34. The lipid formulation according to claim 33 wherein the ionic liquid salt has a melting point of about 90° C. or less. 35. The lipid formulation according to claim 33 wherein the ionic liquid salt has a melting point of about 70° C. or less. 36. The lipid formulation according to claim 33 wherein the ionic liquid salt has a melting point of about 50° C. or less. 37. The lipid formulation according to claim 33 wherein the ionic liquid salt has a melting point of about 40° C. or less. 38. The lipid formulation according to claim 33 wherein the ionic liquid salt has a melting point of about 30° C. or less. 39. The lipid formulation according to claim 33 wherein the ionic liquid salt has a melting point of about 25° C. or less. 40. The lipid formulation according to claim 33 wherein the ionic liquid salt is an oil at room temperature. 41. The lipid formulation according to claim 32 wherein the low melting ionic salt of the poorly water soluble drug is at least twice as soluble in the non-aqueous lipid vehicle as the non-ionised drug. 42. The lipid formulation according to claim 41 wherein the low melting ionic salt of the poorly water soluble drug is at least 4-5 times as soluble in the non-aqueous lipid vehicle as the non-ionised drug. 43. The lipid formulation according to claim 32 wherein the poorly water soluble drug forms the cation of the low melting ionic salt and contains at least one basic ionisable nitrogen atom. 44. The lipid formulation according to claim 43 wherein the poorly water soluble drug forms a low melting ionic salt with an anion formed from carboxylic acids (RC(O)O−), phosphates (ROP(O)O2 −), phosphonates (RP(O)O2 −), sulfonates (RSO(O)2O−), sulfates (ROS(O)2O−), tetrazolys (R-tetrazolate) or bis(sulfonyl)imides (RSO2—N−—SO2R), where R is an optionally substituted hydrocarbon group having at least 2 carbon atoms. 45. The lipid formulation according to claim 44 wherein the poorly water soluble drug forms low melting ionic salt with an anion formed from phosphates (ROP(O)O2 −), or sulfates (ROS(O)2O−). 46. The lipid formulation according to claim 43 wherein R is optionally substituted and is selected from the group consisting of an alkyl, alkenyl or alkynl group, each having from 4-40 carbon atoms, and a cycloalkyl or unsaturated cyclic hydrocarbon group, each having from 3-10 carbon atoms. 47. The lipid formulation according to claim 46 wherein R is an optionally substituted alkyl group having 4-24 carbon atoms. 48. The lipid formulation according to claim 32 wherein the poorly water soluble drug forms the anion of the low melting ionic salt and contains at least one acidic group. 49. The lipid formulation according to claim 48 wherein the poorly water soluble drug forms a low melting ionic salt with a cation selected from +NR′4 and +PR′4, wherein each R′ is independently selected from hydrogen and R″ where R″ is selected from the group of an alkyl, alkenyl or alkynl group each having from 4-40 carbon atoms and a cycloalkyl or unsaturated cyclic hydrocarbon group each having from 3-10 carbon atoms. 50. The lipid formulation of claim 32, wherein the substantially non-aqueous lipid vehicle comprises at least one oil or lipid. 51. The lipid formulation of claim 32, wherein the substantially non-aqueous lipid vehicle consists essentially of at least one oil or lipid. 52. The lipid formulation of claim 50, wherein the substantially non-aqueous lipid vehicle comprises at least one oil or lipid and at least one surfactant. 53. The lipid formulation of claim 51, wherein the substantially non-aqueous lipid vehicle comprises at least one oil or lipid, at least one surfactant and at least one co-solvent. 54. The lipid formulation of claim 32, wherein the substantially non-aqueous lipid vehicle comprises at least one surfactant and, optionally, at least one co-solvent. 55. The lipid formulation of claim 32, wherein the substantially non-aqueous lipid vehicle consists essentially of at least one surfactant and/or solvent, optionally with one or more co-surfactants or co-emulsifiers. 56. The lipid formulation of claim 32 consisting essentially of an ionic liquid salt of the poorly water soluble drug, together with one or more oils and/or liquids. 57. The lipid formulation of claim 32 consisting essentially of an ionic liquid salt of the poorly water soluble drug, together with one or more surfactants and/or solvents, optionally with one or more, co-surfactants or co-emulsifiers. 58. The lipid formulation of claim 32 in the form of a single phase. 59. Use of a lipid formulation according to claim 32 as a fill for a capsule. 60. A capsule, sachet, syringe or dropper device, ampoule, tube or bottle containing a lipid formulation according to claim 32. 61. A method for the manufacture of a lipid formulation of a poorly water soluble drug, according to claim 32, said method comprising the step of blending a low melting ionic salt of the poorly water soluble drug with a non-aqueous lipid vehicle. 62. The method of claim 61 wherein the resulting lipid formulation is a single phase liquid, solid or semi-solid. | 1,600 |
852 | 14,402,590 | 1,624 | A composition is provided with a benzodiazepine and at least one hygroscopic excipient, in particular lactose and/or dextran. | 1-39. (canceled) 40. A lyophilized or spray-dried composition comprising at least one benzodiazepine according to formula (I)
with
W is H;
X is CH2; n is 1;
Y is CH2; m is 1;
Z is O; p is 0 or 1;
R1 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2 or CH2CH(CH3)2;
R2 is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl;
R3 is Cl or Br;
R4, R5 and R6 form the group-CR8═U—V═ wherein R8 is hydrogen, C1-4 alkyl or C1-3 hydroxyalkyl, U is N or CR9 wherein R9 is H, C1-4 alkyl, C1-3 hydroxyalkyl or C1-4 alkoxy, V is N or CH and p is zero
or a pharmaceutically acceptable salt thereof, wherein the composition
comprises at least one pharmaceutically acceptable hygroscopic excipient, wherein the hygroscopic excipient is a carbohydrate selected from the group consisting of disaccharides and dextran. 41. A composition according to claim 40, wherein the benzodiazepine according to formula (I) is methyl 3-[(4S)-8-bromo-1-methyl-6-(pyridine-2-yl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propanoate (remimazolam). 42. A composition according to claim 41, wherein in the pharmaceutically acceptable salt of the benzodiazepine is formulated in cationic form and the counter ion is benzene sulfonate (besylate). 43. A composition as in claim 40, wherein the dextran possesses a molecular weight of less than 150 kD. 44. A composition according to claim 40, wherein the disaccharide is selected from the group consisting of lactose, maltose, sucrose and trehalose. 45. A composition according to claim 40, wherein the composition comprises a mixture of a first hygroscopic excipient and a second hygroscopic excipient. 46. A composition according to claim 40, wherein the composition comprises a mixture of a disaccharide and dextran. 47. A composition according to claim 46, wherein the disaccharide is lactose, and wherein the lactose and dextran have a wt % ratio between 1:1.0 to 1:10. 48. A composition according to claim 40, wherein the total amount of hygroscopic excipients and the total amount of benzodiazepines or salts thereof, calculated for the base, in the composition have a wt % ratio between 20:1 to 1:1. 49. A composition according to claim 40, which is a pharmaceutical formulation. 50. A stable lyophilized or stable freeze-dried composition comprising at least one benzodiazepine according to formula (I)
with
W is H;
X is CH2; n is 1;
Y is CH2; m is 1;
Z is O; p is 0 or 1;
R1 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2 or CH2CH(CH3)2;
R2 is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl;
R3 is Cl or Br;
R4, R5 and R6 form the group-CR8═U—V═ wherein R8 is hydrogen, C1-4 alkyl or C1-3 hydroxyalkyl, U is N or CR9 wherein R9 is H, C1-4 alkyl, C1-3 hydroxyalkyl or C1-4 alkoxy, V is N or CH and p is zero.
or a pharmaceutically acceptable salt thereof, wherein the composition comprises at least one pharmaceutically acceptable hygroscopic excipient, wherein the hygroscopic excipient is a carbohydrate. 51. A composition comprising at least one benzodiazepine according to formula (I)
with
W is H;
X is CH2; n is 1;
Y is CH2; m is 1;
Z is O; p is 0 or 1;
R1 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2 or CH2CH(CH3)2;
R2 is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl;
R3 is Cl or Br;
R4, R5 and R6 form the group-CR8═U—V═ wherein R8 is hydrogen, C1-4 alkyl or C1-3 hydroxyalkyl, U is N or CR9 wherein R9 is H, C1-4 alkyl, C1-3 hydroxyalkyl or C1-4 alkoxy, V is N or CH and p is zero.
or a pharmaceutically acceptable salt thereof, wherein the composition comprises at least one pharmaceutically acceptable hygroscopic excipient, wherein the hygroscopic excipient is a carbohydrate. 52. The composition according to claim 50, wherein less than 1% of the carboxylic ester moiety of the benzodiazepine is hydrolysed during storage. 53. The composition according to claim 50, wherein the hygroscopic excipient is a substance which at 25° C. and 1013.25 hPa reversibly binds water molecules. 54. A Method of preparing a pharmaceutical composition comprising the steps of
a) providing a solution comprising a benzodiazepine according to claim 40; or a pharmaceutically acceptable salt thereof; b) adding a hygroscopic excipient, which comprises a carbohydrate selected from the group consisting of disaccharides and dextran or a mixture thereof with at least a second hygroscopic excipient; c) drying the solution from step b) by lyophilization or spray-drying. 55. A composition, as in claim 40, wherein the composition is at least in part amorphous. 56. A composition, as in claim 51, wherein less than 1% of the carboxylic ester moiety of the benzodiazepine is hydrolysed during storage. 57. A composition, as in claim 51, wherein the hygroscopic excipient is a substance which at 25° C. and 1013.25 hPa reversibly binds water molecules. | A composition is provided with a benzodiazepine and at least one hygroscopic excipient, in particular lactose and/or dextran.1-39. (canceled) 40. A lyophilized or spray-dried composition comprising at least one benzodiazepine according to formula (I)
with
W is H;
X is CH2; n is 1;
Y is CH2; m is 1;
Z is O; p is 0 or 1;
R1 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2 or CH2CH(CH3)2;
R2 is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl;
R3 is Cl or Br;
R4, R5 and R6 form the group-CR8═U—V═ wherein R8 is hydrogen, C1-4 alkyl or C1-3 hydroxyalkyl, U is N or CR9 wherein R9 is H, C1-4 alkyl, C1-3 hydroxyalkyl or C1-4 alkoxy, V is N or CH and p is zero
or a pharmaceutically acceptable salt thereof, wherein the composition
comprises at least one pharmaceutically acceptable hygroscopic excipient, wherein the hygroscopic excipient is a carbohydrate selected from the group consisting of disaccharides and dextran. 41. A composition according to claim 40, wherein the benzodiazepine according to formula (I) is methyl 3-[(4S)-8-bromo-1-methyl-6-(pyridine-2-yl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propanoate (remimazolam). 42. A composition according to claim 41, wherein in the pharmaceutically acceptable salt of the benzodiazepine is formulated in cationic form and the counter ion is benzene sulfonate (besylate). 43. A composition as in claim 40, wherein the dextran possesses a molecular weight of less than 150 kD. 44. A composition according to claim 40, wherein the disaccharide is selected from the group consisting of lactose, maltose, sucrose and trehalose. 45. A composition according to claim 40, wherein the composition comprises a mixture of a first hygroscopic excipient and a second hygroscopic excipient. 46. A composition according to claim 40, wherein the composition comprises a mixture of a disaccharide and dextran. 47. A composition according to claim 46, wherein the disaccharide is lactose, and wherein the lactose and dextran have a wt % ratio between 1:1.0 to 1:10. 48. A composition according to claim 40, wherein the total amount of hygroscopic excipients and the total amount of benzodiazepines or salts thereof, calculated for the base, in the composition have a wt % ratio between 20:1 to 1:1. 49. A composition according to claim 40, which is a pharmaceutical formulation. 50. A stable lyophilized or stable freeze-dried composition comprising at least one benzodiazepine according to formula (I)
with
W is H;
X is CH2; n is 1;
Y is CH2; m is 1;
Z is O; p is 0 or 1;
R1 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2 or CH2CH(CH3)2;
R2 is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl;
R3 is Cl or Br;
R4, R5 and R6 form the group-CR8═U—V═ wherein R8 is hydrogen, C1-4 alkyl or C1-3 hydroxyalkyl, U is N or CR9 wherein R9 is H, C1-4 alkyl, C1-3 hydroxyalkyl or C1-4 alkoxy, V is N or CH and p is zero.
or a pharmaceutically acceptable salt thereof, wherein the composition comprises at least one pharmaceutically acceptable hygroscopic excipient, wherein the hygroscopic excipient is a carbohydrate. 51. A composition comprising at least one benzodiazepine according to formula (I)
with
W is H;
X is CH2; n is 1;
Y is CH2; m is 1;
Z is O; p is 0 or 1;
R1 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2 or CH2CH(CH3)2;
R2 is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl;
R3 is Cl or Br;
R4, R5 and R6 form the group-CR8═U—V═ wherein R8 is hydrogen, C1-4 alkyl or C1-3 hydroxyalkyl, U is N or CR9 wherein R9 is H, C1-4 alkyl, C1-3 hydroxyalkyl or C1-4 alkoxy, V is N or CH and p is zero.
or a pharmaceutically acceptable salt thereof, wherein the composition comprises at least one pharmaceutically acceptable hygroscopic excipient, wherein the hygroscopic excipient is a carbohydrate. 52. The composition according to claim 50, wherein less than 1% of the carboxylic ester moiety of the benzodiazepine is hydrolysed during storage. 53. The composition according to claim 50, wherein the hygroscopic excipient is a substance which at 25° C. and 1013.25 hPa reversibly binds water molecules. 54. A Method of preparing a pharmaceutical composition comprising the steps of
a) providing a solution comprising a benzodiazepine according to claim 40; or a pharmaceutically acceptable salt thereof; b) adding a hygroscopic excipient, which comprises a carbohydrate selected from the group consisting of disaccharides and dextran or a mixture thereof with at least a second hygroscopic excipient; c) drying the solution from step b) by lyophilization or spray-drying. 55. A composition, as in claim 40, wherein the composition is at least in part amorphous. 56. A composition, as in claim 51, wherein less than 1% of the carboxylic ester moiety of the benzodiazepine is hydrolysed during storage. 57. A composition, as in claim 51, wherein the hygroscopic excipient is a substance which at 25° C. and 1013.25 hPa reversibly binds water molecules. | 1,600 |
853 | 15,069,672 | 1,699 | The present invention relates to a method for the generation of compact Transcription Activator-Like Effector Nucleases (TALENS) that can efficiently target and process double-stranded DNA. More specifically, the present invention concerns a method for the creation of TALENs that consist of a single TALE DNA binding domain fused to at least one catalytic domain such that the active entity is composed of a singe polypeptide chain for simple and efficient vectorization and does not require dimerization to target a specific single double-stranded DNA tar et sequence of interest and process DNA nearby said DNA target sequence. The present invention also relates to compact TALENs, vectors, compositions and kits used to implement the method. | 1) A method for targeting and processing a double-stranded DNA, comprising:
(a) selecting one DNA target sequence of interest on one strand of a double-stranded DNA; (b) providing a unique compact TALEN monomer comprising:
(i) one core TALE scaffold comprising Repeat Variable Dipeptide regions (RVDs) having DNA binding specificity onto said DNA target sequence of interest;
(ii) at least one catalytic domain wherein said catalytic domain is capable of processing DNA a few base pairs away from said DNA target sequence of interest when fused to the C and/or N terminal of said core TALE scaffold from (i);
(iii) optionally one peptidic linker to fuse said catalytic domain from (ii) to said core TALE scaffold from (i) when needed;
wherein said compact TALEN monomer is assembled to bind and process said double stranded DNA without requiring dimerization; (c) contacting said double-stranded DNA with said unique monomer such that the double-stranded is processed a few base pairs away in 3′ and/or 5′ direction(s) from said one strand target sequence. 2) A method according to claim 1, wherein said catalytic domain has cleavage activity on said double-stranded DNA. 3) A method according to claim 1, wherein said catalytic domain is fused to the C-terminal domain of said core TALE scaffold. 4) A method according to claim 1, wherein said catalytic domain is fused to the N-terminal domain of said core TALE scaffold. 5) A method according to claim 1, wherein one catalytic domain is fused to the C-terminal domain and another catalytic domain is fused to the N-terminal domain of said core TALE scaffold. 6) A method according to claim 1, wherein said catalytic domain is selected from the group consisting of proteins listed in Table 2 or a functional mutant thereof. 7) A method according to claim 1, wherein said catalytic domain is I-TevI (SEQ ID NO: 20) or a functional mutant thereof. 8) A method according to claim 7, wherein I-TevI (SEQ ID NO: 20) or said functional mutant thereof is fused to the N-terminal domain of said core TALE scaffold. 9) A method according to claim 8, comprising a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino add sequence identity with the protein sequences selected from the group of SEQ ID NO: 426-432. 10) A method according to claim 1, wherein said catalytic domain is ColE7 (SEQ ID NO: 11) or a functional mutant thereof. 11) A method according to claim 10, wherein ColE7 (SEQ ID NO: 11) or said functional mutant thereof is fused to the C-terminus part of said core TALE scaffold. 12) A method according to claim 10, wherein ColE7 (SEQ ID NO: 11) or said functional mutant thereof is fused to the N-terminus part of said core TALE scaffold. 13) A method according to claim 11, comprising a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino acid sequence identity with the protein sequences selected from the group of SEQ ID NO: 435-438. 14) A method according to claim 1, wherein said catalytic domain is NucA (SEQ ID NO: 26) or a functional mutant thereof. 15) A method according to claim 14, wherein NucA (SEQ ID NO: 26) or said functional mutant thereof is fused to the C-terminus part of said core TALE scaffold. 16) A method according to claim 14, wherein NucA (SEQ ID NO: 26) or said functional mutant thereof is fused to the N-terminus part of said core TALE scaffold. 17) A method according to claim 15, comprising a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino acid sequence identity with the protein sequences selected from the group of SEQ ID NO: 433-434. 18) A method according to claim 1, wherein said catalytic domain is I-CreI (SEQ ID NO: 1) or a functional mutant thereof. 19) A method according to claim 18, wherein I-CreI (SEQ ID NO: 1) or said functional mutant thereof is fused to the C-terminus part of said core TALE scaffold. 20) A method according to claim 18, wherein I-CreI (SEQ ID NO: 1) or said functional mutant thereof is fused to the N-terminus part of said core TALE scaffold. 21) A method according to claim 19, comprising a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino add sequence identity with the protein sequences selected from the group of SEQ ID NO: 439-441 and SEQ ID NO: 444-446. 22) A method according to claim 1, wherein said core TALE scaffold comprises a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino acid sequence identity with the protein sequences selected from the group consisting of SEQ ID NO: 134 and SEQ ID NO: 135. 23) A method according to claim 1, wherein said core TALE scaffold comprises a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino add sequence identity with the protein sequences selected from the group consisting of SEQ ID NO: 136 to SEQ ID NO: 139. 24) A method according to claim 1, wherein said unique compact TALEN monomer further comprises:
(i) at least one enhancer domain; (ii) Optionally one peptide linker to fuse said enhancer domain to one part of said unique compact TALEN monomer active entity. 25) A method according to claim 1, wherein said peptidic linker sequence can be selected from the group consisting of SEQ ID NO: 67-104 and SEQ ID NO 372 to SEQ ID NO: 415. 26) A method according to claim 5, wherein said unique compact TALEN monomer comprises a combination of two catalytic domains respectively fused to the C-terminus part and to the N-terminus part of said core TALE scaffold selected from the group consisting of:
(i) A Nuc A domain (SEQ ID NO: 26) in N-terminus and a Nuc A domain (SEQ ID NO: 26) in C-terminus; (ii) A ColE7 domain (SEQ ID NO: 11) in N-terminus and a ColE7 domain (SEQ ID NO: 11) in C-terminus; A TevI domain (SEQ ID NO: 20) in N-terminus and a ColE7 domain (SEQ ID NO: 11) in C-terminus; (iv) A TevI domain (SEQ ID NO: 20) in N-terminus and a NucA domain (SEQ ID NO: 26) in C-terminus; (v) A ColE7 domain (SEQ ID NO: 11) in N-terminus and a NucA domain (SEQ ID NO: 26) in C-terminus; (vi) A NucA domain (SEQ ID NO: 26) in N-terminus and a ColE7 domain (SEQ ID NO: 11) in C-terminus. 27) A method according to claim 29, comprising a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino acid sequence identity with the protein sequences selected from the group consisting of SEQ ID NO: 448 and 450. 28) A method according to claim 5, wherein said unique compact TALEN monomer comprises a combination of two catalytic domains respectively fused to the C-terminus part and to the N-terminus part of said core TALE scaffold selected from the group consisting of:
(i) A TevI domain (SEQ ID NO: 20) in N-terminus and a FokI domain (SEQ ID NO: 368) in C-terminus; (ii) A TevI domain (SEQ ID NO: 20) in N-terminus and a TevI domain (SEQ ID NO: 20) in C-terminus; (iii) A scTrex2 domain (SEQ ID NO: 451) in N-terminus and a FokI domain (SEQ ID NO: 368) in C-terminus. 29) A method according to claim 28, comprising a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino acid sequence identity with the protein sequences selected from the group consisting of SEQ ID NO: 447-450 and SEQ ID NO: 452. 30) A compact TALEN monomer comprising;
(i) one core TALE scaffold comprising Repeat Variable Dipeptide regions (RVDs) having DNA binding specificity onto a specific double-stranded DNA target sequence of interest; (ii) at least one catalytic domain wherein said catalytic domain is capable of processing DNA a few base pairs away from said double-stranded DNA target sequence of interest when fused to the C or N terminal of said core TALE scaffold from (i); (iii) optionally one peptidic linker to fuse said catalytic domain from (ii) to said engineered core TALE scaffold from (i) when needed;
wherein said compact TALEN monomer is assembled to bind said target DNA sequence and process double-stranded DNA without requiring dimerization. 31) A compact TALEN monomer according to claim 30, wherein said catalytic domain has cleavage activity on the double-stranded DNA. 32) A compact TALEN monomer according to claim 30, wherein said catalytic domain is fused to the C-terminal domain of said core TALE scaffold. 33) A compact TALEN monomer according to claim 30, wherein said catalytic domain is fused to the N-terminal domain of said core TALE scaffold. 34) A compact TALEN monomer according to claim 30, wherein one catalytic domain is fused to the C-terminal domain and another catalytic domain is fused to the N-terminal domain of said core TALE scaffold. 35) A compact TALEN monomer according to claim 30, wherein said catalytic domain is selected from the group consisting of proteins listed in Table 2 or a functional mutant thereof. 36) A compact TALEN monomer according to claim 30, wherein said catalytic domain is I-TevI (SEQ ID NO: 20) or a functional mutant thereof. 37) A compact TALEN monomer according to claim 36, wherein I-TevI (SEQ ID NO: 20) or said functional mutant thereof is fused to the N-terminal domain of said core TALE scaffold. 38) A compact TALEN monomer according to claim 37, comprising a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino add sequence identity with the protein sequences selected from the group of SEQ ID NO: 426-432. 39) A compact TALEN monomer according to claim 30, wherein said catalytic domain is ColE7 (SEQ ID NO: 11) or a functional mutant thereof. 40) A compact TALEN monomer according to claim 39, wherein ColE7 (SEQ ID NO: 11) or said functional mutant thereof is fused to the C-terminus part of said core TALE scaffold. 41) A compact TALEN monomer according to claim 39, wherein ColE7 (SEQ ID NO 11) or said functional mutant thereof is fused to the N-terminus part of said core TALE scaffold. 42) A compact TALEN monomer according to claim 40, comprising a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino acid sequence identity with the protein sequences selected from the group of SEQ ID NO: 435-438. 43) A compact TALEN monomer according to claim 30, wherein said catalytic domain is NucA (SEQ ID NO: 26) or a functional mutant thereof. 44) A compact TALEN monomer according to claim 43, wherein NucA (SEQ ID NO: 26) or said functional mutant thereof is fused to the C-terminus part of said core TALE scaffold. 45) A compact TALEN monomer according to claim 43, wherein NucA (SEQ ID NO: 26) or said functional mutant thereof is fused to the N-terminus part of said core TALE scaffold. 46) A compact TALEN monomer according to claim 44, comprising a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino acid sequence identity with the protein sequences selected from the group of SEQ ID NO: 433-434. 47) A compact TALEN monomer according to claim 30, wherein said catalytic domain is I-CreI (SEQ ID NO: 1) or a functional mutant thereof. 48) A compact TALEN monomer according to claim 47, wherein I-CreI (SEQ ID NO: 1) or said functional mutant thereof is fused to the C-terminus part of said core TALE scaffold. 49) A compact TALEN monomer according to claim 47, wherein I-CreI (SEQ ID NO: 1) or said functional mutant thereof is fused to the N-terminus part of said core TALE scaffold. 50) A compact TALEN monomer according to claim 48, comprising a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino acid sequence identity with the protein sequences selected from the group of SEQ ID NO: 444-446. 51) A compact TALEN monomer according to claim 30, wherein said core TALE scaffold comprises a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino acid sequence identity with the protein sequences selected from the group consisting of SEQ ID NO: 134 and SEQ ID NO: 135. 52) A compact TALEN monomer according to claim 30 wherein said core TALE scaffold comprises a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino acid sequence identity with the protein sequences selected from the group consisting of SEQ ID NO: 136 to SEQ ID NO: 139. 53) A compact TALEN monomer according to claim 30, wherein said unique compact TALEN monomer further comprises:
(i) At least one enhancer domain; (ii) Optionally one peptide linker to fuse said enhancer domain to one part of said unique compact TALEN monomer active entity. 54) A compact TALEN monomer according to claim 30, wherein said peptidic linker sequence can be selected from the group consisting of SEQ ID NO: 67-104 and SEQ ID NO: 372 to SEQ ID NO: 415. 55) A compact TALEN monomer according to claim 34, comprising a combination of two catalytic domains respectively fused to the C-terminus part and to the N-terminus part of said core TALE scaffold selected from the group consisting of:
(i) A Nuc A domain (SEQ ID NO: 26) in N-terminus and a Nuc A domain (SEQ ID NO: 26) in C-terminus; (ii) A ColE7 domain (SEQ ID NO: 11) in N-terminus and a ColE7 domain (SEQ ID NO: 11) in C-terminus; (iii) A TevI domain (SEQ ID NO: 20) in N-terminus and a ColE7 domain (SEQ ID NO: 11) in C-terminus; (iv) A TevI domain (SEQ ID NO: 20) in N-terminus and a NucA domain (SEQ ID NO: 26) in C-terminus; (v) A ColE7 domain (SEQ ID NO: 11) in N-terminus and a NucA domain (SEQ ID NO: 26) in C-terminus; (vi) A NucA domain (SEQ ID NO: 26) in N-terminus and a ColE7 domain (SEQ ID NO: 11) in C-terminus. 56) A compact TALEN monomer according to claim 55, comprising a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino acid sequence identity with the protein sequences selected from the group consisting of SEQ ID NO: 448 and 450. 57) A compact TALEN monomer according to claim 37, wherein said unique compact TALEN monomer comprises a combination of two catalytic domains respectively fused to the C-terminus part and to the N-terminus part of said core TALE scaffold selected from the group consisting of:
(i) A TevI domain (SEQ ID NO: 20) in N-terminus and a FokI domain (SEQ ID NO: 368) in C-terminus; (ii) A TevI domain (SEQ ID NO: 20) in N-terminus and a TevI domain (SEQ ID NO: 20) in C-terminus; (iii) A scTrex2 domain (SEQ ID NO: 451) in N-terminus and a FokI domain (SEQ ID NO: 368) in C-terminus. 58) A method according to claim 63, comprising a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino acid sequence identity with the protein sequences selected from the group consisting of SEQ ID NO: 447-450 and SEQ ID NO: 452. 59) A recombinant polynucleotide encoding a compact TALEN according to any one of claims 30 to 58. 60) A vector comprising a recombinant polynucleotide according to claim 59. 61) A composition comprising a compact TALEN according to claim 30 and a carrier. 62) A pharmaceutical composition comprising a compact TALEN according to claim 30 and a pharmaceutically active carrier. 63) A host cell which comprises a recombinant polynucleotide of claim 59. 64) A non-human transgenic animal which comprises a recombinant polynucleotide of claim 59. 65) A non-human transgenic animal which comprises a vector of claim 60. 66) A transgenic plant which comprises a recombinant polynucleotide of claim 59. 67) A transgenic plant which comprises a vector of claim 60. 68) A kit comprising a compact TALEN monomer according to claim 30 and instructions for use in enhancing DNA processing efficiency of a single double-stranded DNA target sequence of interest. 69) A method for increasing targeted Homologous Recombination comprising a compact TALEN monomer according to claim 30 wherein at least one catalytic domain has a cleavase activity. 70) A method for increasing targeted Homologous Recombination with less Non Homologous End-joining comprising a compact TALEN monomer according to claim 30 wherein at least one catalytic domain has a nickase activity. 71) A method for increasing excision of a single-strand of DNA spanning the binding region of a compact TALEN monomer according to claim 30 wherein:
(i) at least one catalytic domain has a cleavase activity;
(ii) at least one catalytic domain has a nickase activity. 72) A method of treatment of a genetic disease caused by a mutation in a specific single double-stranded DNA target sequence in a gene comprising administering to a subject in need thereof an effective amount of a compact TALEN of claim 30 or a variant thereof. 73) A method for inserting a transgene into a specific single double-stranded DNA target sequence of a genomic locus of a cell, tissue or non-human animal wherein at least one compact TALEN monomer of claim 30 is introduced in said cell tissue or non-human animal. 74) A method to modulate the activity of a compact TALEN monomer according to claim 30 when expressed in a cell wherein said method comprises the step of introducing in said cell an auxiliary domain modulating the activity of said compact TALEN. 75) A method according to claim 74 to inhibit the activity of a compact TALEN monomer comprising:
(iv) one core TALE scaffold comprising Repeat Variable Dipeptide regions (RVDs) having DNA binding specificity onto a specific double-stranded DNA target sequence of interest;
(v) at least one catalytic domain wherein said catalytic domain is capable of processing DNA a few base pairs away from said double-stranded DNA target sequence of interest when fused to the C or N terminal of said core TALE scaffold from (i);
(vi) optionally one peptidic linker to fuse said catalytic domain from (ii) to said engineered core TALE scaffold from (i) when needed;
wherein said compact TALEN monomer is assembled to bind said target DNA sequence and process double-stranded DNA without requiring dimerization. 76) A method according to claim 74 wherein the catalytic domain of said compact TALEN monomer is NucA (SEQ ID NO: 26) and said auxiliary domain is NuiA (SEQ ID NO: 229) or a functional mutant thereof. 77) A method according to claim 74 wherein the catalytic domain of said compact TALEN monomer is ColE7 (SEQ ID NO: 11) and said auxiliary domain is Im7 (SEQ ID NO: 230) or a functional mutant thereof. | The present invention relates to a method for the generation of compact Transcription Activator-Like Effector Nucleases (TALENS) that can efficiently target and process double-stranded DNA. More specifically, the present invention concerns a method for the creation of TALENs that consist of a single TALE DNA binding domain fused to at least one catalytic domain such that the active entity is composed of a singe polypeptide chain for simple and efficient vectorization and does not require dimerization to target a specific single double-stranded DNA tar et sequence of interest and process DNA nearby said DNA target sequence. The present invention also relates to compact TALENs, vectors, compositions and kits used to implement the method.1) A method for targeting and processing a double-stranded DNA, comprising:
(a) selecting one DNA target sequence of interest on one strand of a double-stranded DNA; (b) providing a unique compact TALEN monomer comprising:
(i) one core TALE scaffold comprising Repeat Variable Dipeptide regions (RVDs) having DNA binding specificity onto said DNA target sequence of interest;
(ii) at least one catalytic domain wherein said catalytic domain is capable of processing DNA a few base pairs away from said DNA target sequence of interest when fused to the C and/or N terminal of said core TALE scaffold from (i);
(iii) optionally one peptidic linker to fuse said catalytic domain from (ii) to said core TALE scaffold from (i) when needed;
wherein said compact TALEN monomer is assembled to bind and process said double stranded DNA without requiring dimerization; (c) contacting said double-stranded DNA with said unique monomer such that the double-stranded is processed a few base pairs away in 3′ and/or 5′ direction(s) from said one strand target sequence. 2) A method according to claim 1, wherein said catalytic domain has cleavage activity on said double-stranded DNA. 3) A method according to claim 1, wherein said catalytic domain is fused to the C-terminal domain of said core TALE scaffold. 4) A method according to claim 1, wherein said catalytic domain is fused to the N-terminal domain of said core TALE scaffold. 5) A method according to claim 1, wherein one catalytic domain is fused to the C-terminal domain and another catalytic domain is fused to the N-terminal domain of said core TALE scaffold. 6) A method according to claim 1, wherein said catalytic domain is selected from the group consisting of proteins listed in Table 2 or a functional mutant thereof. 7) A method according to claim 1, wherein said catalytic domain is I-TevI (SEQ ID NO: 20) or a functional mutant thereof. 8) A method according to claim 7, wherein I-TevI (SEQ ID NO: 20) or said functional mutant thereof is fused to the N-terminal domain of said core TALE scaffold. 9) A method according to claim 8, comprising a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino add sequence identity with the protein sequences selected from the group of SEQ ID NO: 426-432. 10) A method according to claim 1, wherein said catalytic domain is ColE7 (SEQ ID NO: 11) or a functional mutant thereof. 11) A method according to claim 10, wherein ColE7 (SEQ ID NO: 11) or said functional mutant thereof is fused to the C-terminus part of said core TALE scaffold. 12) A method according to claim 10, wherein ColE7 (SEQ ID NO: 11) or said functional mutant thereof is fused to the N-terminus part of said core TALE scaffold. 13) A method according to claim 11, comprising a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino acid sequence identity with the protein sequences selected from the group of SEQ ID NO: 435-438. 14) A method according to claim 1, wherein said catalytic domain is NucA (SEQ ID NO: 26) or a functional mutant thereof. 15) A method according to claim 14, wherein NucA (SEQ ID NO: 26) or said functional mutant thereof is fused to the C-terminus part of said core TALE scaffold. 16) A method according to claim 14, wherein NucA (SEQ ID NO: 26) or said functional mutant thereof is fused to the N-terminus part of said core TALE scaffold. 17) A method according to claim 15, comprising a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino acid sequence identity with the protein sequences selected from the group of SEQ ID NO: 433-434. 18) A method according to claim 1, wherein said catalytic domain is I-CreI (SEQ ID NO: 1) or a functional mutant thereof. 19) A method according to claim 18, wherein I-CreI (SEQ ID NO: 1) or said functional mutant thereof is fused to the C-terminus part of said core TALE scaffold. 20) A method according to claim 18, wherein I-CreI (SEQ ID NO: 1) or said functional mutant thereof is fused to the N-terminus part of said core TALE scaffold. 21) A method according to claim 19, comprising a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino add sequence identity with the protein sequences selected from the group of SEQ ID NO: 439-441 and SEQ ID NO: 444-446. 22) A method according to claim 1, wherein said core TALE scaffold comprises a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino acid sequence identity with the protein sequences selected from the group consisting of SEQ ID NO: 134 and SEQ ID NO: 135. 23) A method according to claim 1, wherein said core TALE scaffold comprises a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino add sequence identity with the protein sequences selected from the group consisting of SEQ ID NO: 136 to SEQ ID NO: 139. 24) A method according to claim 1, wherein said unique compact TALEN monomer further comprises:
(i) at least one enhancer domain; (ii) Optionally one peptide linker to fuse said enhancer domain to one part of said unique compact TALEN monomer active entity. 25) A method according to claim 1, wherein said peptidic linker sequence can be selected from the group consisting of SEQ ID NO: 67-104 and SEQ ID NO 372 to SEQ ID NO: 415. 26) A method according to claim 5, wherein said unique compact TALEN monomer comprises a combination of two catalytic domains respectively fused to the C-terminus part and to the N-terminus part of said core TALE scaffold selected from the group consisting of:
(i) A Nuc A domain (SEQ ID NO: 26) in N-terminus and a Nuc A domain (SEQ ID NO: 26) in C-terminus; (ii) A ColE7 domain (SEQ ID NO: 11) in N-terminus and a ColE7 domain (SEQ ID NO: 11) in C-terminus; A TevI domain (SEQ ID NO: 20) in N-terminus and a ColE7 domain (SEQ ID NO: 11) in C-terminus; (iv) A TevI domain (SEQ ID NO: 20) in N-terminus and a NucA domain (SEQ ID NO: 26) in C-terminus; (v) A ColE7 domain (SEQ ID NO: 11) in N-terminus and a NucA domain (SEQ ID NO: 26) in C-terminus; (vi) A NucA domain (SEQ ID NO: 26) in N-terminus and a ColE7 domain (SEQ ID NO: 11) in C-terminus. 27) A method according to claim 29, comprising a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino acid sequence identity with the protein sequences selected from the group consisting of SEQ ID NO: 448 and 450. 28) A method according to claim 5, wherein said unique compact TALEN monomer comprises a combination of two catalytic domains respectively fused to the C-terminus part and to the N-terminus part of said core TALE scaffold selected from the group consisting of:
(i) A TevI domain (SEQ ID NO: 20) in N-terminus and a FokI domain (SEQ ID NO: 368) in C-terminus; (ii) A TevI domain (SEQ ID NO: 20) in N-terminus and a TevI domain (SEQ ID NO: 20) in C-terminus; (iii) A scTrex2 domain (SEQ ID NO: 451) in N-terminus and a FokI domain (SEQ ID NO: 368) in C-terminus. 29) A method according to claim 28, comprising a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino acid sequence identity with the protein sequences selected from the group consisting of SEQ ID NO: 447-450 and SEQ ID NO: 452. 30) A compact TALEN monomer comprising;
(i) one core TALE scaffold comprising Repeat Variable Dipeptide regions (RVDs) having DNA binding specificity onto a specific double-stranded DNA target sequence of interest; (ii) at least one catalytic domain wherein said catalytic domain is capable of processing DNA a few base pairs away from said double-stranded DNA target sequence of interest when fused to the C or N terminal of said core TALE scaffold from (i); (iii) optionally one peptidic linker to fuse said catalytic domain from (ii) to said engineered core TALE scaffold from (i) when needed;
wherein said compact TALEN monomer is assembled to bind said target DNA sequence and process double-stranded DNA without requiring dimerization. 31) A compact TALEN monomer according to claim 30, wherein said catalytic domain has cleavage activity on the double-stranded DNA. 32) A compact TALEN monomer according to claim 30, wherein said catalytic domain is fused to the C-terminal domain of said core TALE scaffold. 33) A compact TALEN monomer according to claim 30, wherein said catalytic domain is fused to the N-terminal domain of said core TALE scaffold. 34) A compact TALEN monomer according to claim 30, wherein one catalytic domain is fused to the C-terminal domain and another catalytic domain is fused to the N-terminal domain of said core TALE scaffold. 35) A compact TALEN monomer according to claim 30, wherein said catalytic domain is selected from the group consisting of proteins listed in Table 2 or a functional mutant thereof. 36) A compact TALEN monomer according to claim 30, wherein said catalytic domain is I-TevI (SEQ ID NO: 20) or a functional mutant thereof. 37) A compact TALEN monomer according to claim 36, wherein I-TevI (SEQ ID NO: 20) or said functional mutant thereof is fused to the N-terminal domain of said core TALE scaffold. 38) A compact TALEN monomer according to claim 37, comprising a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino add sequence identity with the protein sequences selected from the group of SEQ ID NO: 426-432. 39) A compact TALEN monomer according to claim 30, wherein said catalytic domain is ColE7 (SEQ ID NO: 11) or a functional mutant thereof. 40) A compact TALEN monomer according to claim 39, wherein ColE7 (SEQ ID NO: 11) or said functional mutant thereof is fused to the C-terminus part of said core TALE scaffold. 41) A compact TALEN monomer according to claim 39, wherein ColE7 (SEQ ID NO 11) or said functional mutant thereof is fused to the N-terminus part of said core TALE scaffold. 42) A compact TALEN monomer according to claim 40, comprising a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino acid sequence identity with the protein sequences selected from the group of SEQ ID NO: 435-438. 43) A compact TALEN monomer according to claim 30, wherein said catalytic domain is NucA (SEQ ID NO: 26) or a functional mutant thereof. 44) A compact TALEN monomer according to claim 43, wherein NucA (SEQ ID NO: 26) or said functional mutant thereof is fused to the C-terminus part of said core TALE scaffold. 45) A compact TALEN monomer according to claim 43, wherein NucA (SEQ ID NO: 26) or said functional mutant thereof is fused to the N-terminus part of said core TALE scaffold. 46) A compact TALEN monomer according to claim 44, comprising a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino acid sequence identity with the protein sequences selected from the group of SEQ ID NO: 433-434. 47) A compact TALEN monomer according to claim 30, wherein said catalytic domain is I-CreI (SEQ ID NO: 1) or a functional mutant thereof. 48) A compact TALEN monomer according to claim 47, wherein I-CreI (SEQ ID NO: 1) or said functional mutant thereof is fused to the C-terminus part of said core TALE scaffold. 49) A compact TALEN monomer according to claim 47, wherein I-CreI (SEQ ID NO: 1) or said functional mutant thereof is fused to the N-terminus part of said core TALE scaffold. 50) A compact TALEN monomer according to claim 48, comprising a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino acid sequence identity with the protein sequences selected from the group of SEQ ID NO: 444-446. 51) A compact TALEN monomer according to claim 30, wherein said core TALE scaffold comprises a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino acid sequence identity with the protein sequences selected from the group consisting of SEQ ID NO: 134 and SEQ ID NO: 135. 52) A compact TALEN monomer according to claim 30 wherein said core TALE scaffold comprises a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino acid sequence identity with the protein sequences selected from the group consisting of SEQ ID NO: 136 to SEQ ID NO: 139. 53) A compact TALEN monomer according to claim 30, wherein said unique compact TALEN monomer further comprises:
(i) At least one enhancer domain; (ii) Optionally one peptide linker to fuse said enhancer domain to one part of said unique compact TALEN monomer active entity. 54) A compact TALEN monomer according to claim 30, wherein said peptidic linker sequence can be selected from the group consisting of SEQ ID NO: 67-104 and SEQ ID NO: 372 to SEQ ID NO: 415. 55) A compact TALEN monomer according to claim 34, comprising a combination of two catalytic domains respectively fused to the C-terminus part and to the N-terminus part of said core TALE scaffold selected from the group consisting of:
(i) A Nuc A domain (SEQ ID NO: 26) in N-terminus and a Nuc A domain (SEQ ID NO: 26) in C-terminus; (ii) A ColE7 domain (SEQ ID NO: 11) in N-terminus and a ColE7 domain (SEQ ID NO: 11) in C-terminus; (iii) A TevI domain (SEQ ID NO: 20) in N-terminus and a ColE7 domain (SEQ ID NO: 11) in C-terminus; (iv) A TevI domain (SEQ ID NO: 20) in N-terminus and a NucA domain (SEQ ID NO: 26) in C-terminus; (v) A ColE7 domain (SEQ ID NO: 11) in N-terminus and a NucA domain (SEQ ID NO: 26) in C-terminus; (vi) A NucA domain (SEQ ID NO: 26) in N-terminus and a ColE7 domain (SEQ ID NO: 11) in C-terminus. 56) A compact TALEN monomer according to claim 55, comprising a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino acid sequence identity with the protein sequences selected from the group consisting of SEQ ID NO: 448 and 450. 57) A compact TALEN monomer according to claim 37, wherein said unique compact TALEN monomer comprises a combination of two catalytic domains respectively fused to the C-terminus part and to the N-terminus part of said core TALE scaffold selected from the group consisting of:
(i) A TevI domain (SEQ ID NO: 20) in N-terminus and a FokI domain (SEQ ID NO: 368) in C-terminus; (ii) A TevI domain (SEQ ID NO: 20) in N-terminus and a TevI domain (SEQ ID NO: 20) in C-terminus; (iii) A scTrex2 domain (SEQ ID NO: 451) in N-terminus and a FokI domain (SEQ ID NO: 368) in C-terminus. 58) A method according to claim 63, comprising a protein sequence having at least 80%, more preferably 90%, again more preferably 95% amino acid sequence identity with the protein sequences selected from the group consisting of SEQ ID NO: 447-450 and SEQ ID NO: 452. 59) A recombinant polynucleotide encoding a compact TALEN according to any one of claims 30 to 58. 60) A vector comprising a recombinant polynucleotide according to claim 59. 61) A composition comprising a compact TALEN according to claim 30 and a carrier. 62) A pharmaceutical composition comprising a compact TALEN according to claim 30 and a pharmaceutically active carrier. 63) A host cell which comprises a recombinant polynucleotide of claim 59. 64) A non-human transgenic animal which comprises a recombinant polynucleotide of claim 59. 65) A non-human transgenic animal which comprises a vector of claim 60. 66) A transgenic plant which comprises a recombinant polynucleotide of claim 59. 67) A transgenic plant which comprises a vector of claim 60. 68) A kit comprising a compact TALEN monomer according to claim 30 and instructions for use in enhancing DNA processing efficiency of a single double-stranded DNA target sequence of interest. 69) A method for increasing targeted Homologous Recombination comprising a compact TALEN monomer according to claim 30 wherein at least one catalytic domain has a cleavase activity. 70) A method for increasing targeted Homologous Recombination with less Non Homologous End-joining comprising a compact TALEN monomer according to claim 30 wherein at least one catalytic domain has a nickase activity. 71) A method for increasing excision of a single-strand of DNA spanning the binding region of a compact TALEN monomer according to claim 30 wherein:
(i) at least one catalytic domain has a cleavase activity;
(ii) at least one catalytic domain has a nickase activity. 72) A method of treatment of a genetic disease caused by a mutation in a specific single double-stranded DNA target sequence in a gene comprising administering to a subject in need thereof an effective amount of a compact TALEN of claim 30 or a variant thereof. 73) A method for inserting a transgene into a specific single double-stranded DNA target sequence of a genomic locus of a cell, tissue or non-human animal wherein at least one compact TALEN monomer of claim 30 is introduced in said cell tissue or non-human animal. 74) A method to modulate the activity of a compact TALEN monomer according to claim 30 when expressed in a cell wherein said method comprises the step of introducing in said cell an auxiliary domain modulating the activity of said compact TALEN. 75) A method according to claim 74 to inhibit the activity of a compact TALEN monomer comprising:
(iv) one core TALE scaffold comprising Repeat Variable Dipeptide regions (RVDs) having DNA binding specificity onto a specific double-stranded DNA target sequence of interest;
(v) at least one catalytic domain wherein said catalytic domain is capable of processing DNA a few base pairs away from said double-stranded DNA target sequence of interest when fused to the C or N terminal of said core TALE scaffold from (i);
(vi) optionally one peptidic linker to fuse said catalytic domain from (ii) to said engineered core TALE scaffold from (i) when needed;
wherein said compact TALEN monomer is assembled to bind said target DNA sequence and process double-stranded DNA without requiring dimerization. 76) A method according to claim 74 wherein the catalytic domain of said compact TALEN monomer is NucA (SEQ ID NO: 26) and said auxiliary domain is NuiA (SEQ ID NO: 229) or a functional mutant thereof. 77) A method according to claim 74 wherein the catalytic domain of said compact TALEN monomer is ColE7 (SEQ ID NO: 11) and said auxiliary domain is Im7 (SEQ ID NO: 230) or a functional mutant thereof. | 1,600 |
854 | 14,783,295 | 1,658 | The present invention has an object of providing a novel drug inhibiting formation of leukocyte extracellular traps. The present invention provides a lactoferrin-containing inhibitor of formation of leukocyte extracellular traps, and a lactoferrin-containing composition for treating a disease associated with the formation of the leukocyte extracellular traps. | 1. A method for treating a disease associated with formation of leukocyte extracellular traps, comprising administering a composition for inhibiting formation of leukocyte extracellular traps to a patient in need thereof, wherein said composition comprises lactoferrin and pharmacologically acceptable carrier, and said disease is selected from the group consisting of ANCA associated vasculitis, systemic lupus erythematosus, local Shwartzman reaction, acute kidney injury (AKI) accompanied by ischemia reperfusion injury, and disseminated intravascular coagulation. 2. The method according to claim 1, wherein the lactoferrin is in an amount of 0.001 to 10 g/kg/day. 3. The method according to claim 1, wherein the lactoferrin is derived from human. 4. The method according to claim 1, wherein the lactoferrin is a protein selected from the group consisting of (a) to (c):
(a) a protein formed of either one of amino acid sequences of SEQ ID NOS: 1 to 5; (b) a protein formed of either one of amino acid sequences of SEQ ID NOS: 1 to 5, in which 1 to 66 amino acids are deleted, substituted, inserted and/or added, the protein having activity of inhibiting the formation of the leukocyte extracellular traps; and (c) a protein having an amino acid sequence having an amino acid sequence identity of 90% or greater with either one of amino acid sequences of SEQ ID NOS: 1 to 5, the protein having activity of inhibiting the formation of the leukocyte extracellular traps. 5. The method according to claim 1, wherein the leukocytes are one selected from the group consisting of neutrophils, eosinophil granulocytes, basophil granulocytes, monocytes, macrophages, and mast cells. 6. The method according to claim 5, wherein the leukocytes are neutrophils. 7. A method for treating a disease associated with formation of leukocyte extracellular traps, comprising administering lactoferrin to a patient in need thereof, said disease is selected from the group consisting of ANCA associated vasculitis, systemic lupus erythematosus, local Shwartzman reaction, acute kidney injury (AKI) accompanied by ischemia reperfusion injury, and disseminated intravascular coagulation. 8. The method according to claim 7, wherein the lactoferrin is administered in an amount of 0.001 to 10 g/kg/day. 9. The method according to claim 7, wherein the lactoferrin is derived from human. 10. The method according to claim 7, wherein the lactoferrin is a protein selected from the group consisting of (a) to (c):
(a) a protein formed of either one of amino acid sequences of SEQ ID NOS: 1 to 5; (b) a protein formed of either one of amino acid sequences of SEQ ID NOS: 1 to 5, in which 1 to 66 amino acids are deleted, substituted, inserted and/or added, the protein having activity of inhibiting the formation of the leukocyte extracellular traps; and (c) a protein having an amino acid sequence having an amino acid sequence identity of 90% or greater with either one of amino acid sequences of SEQ ID NOS: 1 to 5, the protein having activity of inhibiting the formation of the leukocyte extracellular traps. 11. The method according to claim 7, wherein the leukocytes are one selected from the group consisting of neutrophils, eosinophil granulocytes, basophil granulocytes, monocytes, macrophages, and mast cells. 12. (canceled) 13. The method according to claim 7, wherein the administration is made orally in a form of food. 14. The method according to claim 7, wherein the administration is in a form of injection. 15. The method according to claim 7, wherein the administration is oral administration. | The present invention has an object of providing a novel drug inhibiting formation of leukocyte extracellular traps. The present invention provides a lactoferrin-containing inhibitor of formation of leukocyte extracellular traps, and a lactoferrin-containing composition for treating a disease associated with the formation of the leukocyte extracellular traps.1. A method for treating a disease associated with formation of leukocyte extracellular traps, comprising administering a composition for inhibiting formation of leukocyte extracellular traps to a patient in need thereof, wherein said composition comprises lactoferrin and pharmacologically acceptable carrier, and said disease is selected from the group consisting of ANCA associated vasculitis, systemic lupus erythematosus, local Shwartzman reaction, acute kidney injury (AKI) accompanied by ischemia reperfusion injury, and disseminated intravascular coagulation. 2. The method according to claim 1, wherein the lactoferrin is in an amount of 0.001 to 10 g/kg/day. 3. The method according to claim 1, wherein the lactoferrin is derived from human. 4. The method according to claim 1, wherein the lactoferrin is a protein selected from the group consisting of (a) to (c):
(a) a protein formed of either one of amino acid sequences of SEQ ID NOS: 1 to 5; (b) a protein formed of either one of amino acid sequences of SEQ ID NOS: 1 to 5, in which 1 to 66 amino acids are deleted, substituted, inserted and/or added, the protein having activity of inhibiting the formation of the leukocyte extracellular traps; and (c) a protein having an amino acid sequence having an amino acid sequence identity of 90% or greater with either one of amino acid sequences of SEQ ID NOS: 1 to 5, the protein having activity of inhibiting the formation of the leukocyte extracellular traps. 5. The method according to claim 1, wherein the leukocytes are one selected from the group consisting of neutrophils, eosinophil granulocytes, basophil granulocytes, monocytes, macrophages, and mast cells. 6. The method according to claim 5, wherein the leukocytes are neutrophils. 7. A method for treating a disease associated with formation of leukocyte extracellular traps, comprising administering lactoferrin to a patient in need thereof, said disease is selected from the group consisting of ANCA associated vasculitis, systemic lupus erythematosus, local Shwartzman reaction, acute kidney injury (AKI) accompanied by ischemia reperfusion injury, and disseminated intravascular coagulation. 8. The method according to claim 7, wherein the lactoferrin is administered in an amount of 0.001 to 10 g/kg/day. 9. The method according to claim 7, wherein the lactoferrin is derived from human. 10. The method according to claim 7, wherein the lactoferrin is a protein selected from the group consisting of (a) to (c):
(a) a protein formed of either one of amino acid sequences of SEQ ID NOS: 1 to 5; (b) a protein formed of either one of amino acid sequences of SEQ ID NOS: 1 to 5, in which 1 to 66 amino acids are deleted, substituted, inserted and/or added, the protein having activity of inhibiting the formation of the leukocyte extracellular traps; and (c) a protein having an amino acid sequence having an amino acid sequence identity of 90% or greater with either one of amino acid sequences of SEQ ID NOS: 1 to 5, the protein having activity of inhibiting the formation of the leukocyte extracellular traps. 11. The method according to claim 7, wherein the leukocytes are one selected from the group consisting of neutrophils, eosinophil granulocytes, basophil granulocytes, monocytes, macrophages, and mast cells. 12. (canceled) 13. The method according to claim 7, wherein the administration is made orally in a form of food. 14. The method according to claim 7, wherein the administration is in a form of injection. 15. The method according to claim 7, wherein the administration is oral administration. | 1,600 |
855 | 15,259,862 | 1,612 | Provided is a non-aqueous formulation for oral teeth, which includes a source of a metal ion and a source of a phosphate ion. The metal ion is chosen from alkaline earth metals, Zn, Zr or any combination thereof, and a molar ratio of the metal ion to the phosphate ion in the formulation is between about 0.01 and about 1.0. The non-aqueous formulation can provide a therapeutic effect. | 1. A method for treating or preventing an exposed dentinal tubule-associated symptom or disease, comprising administering a non-aqueous formulation to dentinal tubules of a subject in need thereof, wherein the non-aqueous formulation comprises:
a source of a metal ion; and a source of a phosphate ion, wherein the metal ion is chosen from Mg, Ca, Sr, Zn, Zr or any combination thereof, and a molar ratio of the metal ion to the phosphate ion in the formulation is between about 0.01 and about 1.0, and wherein the metal ion and the phosphate ion form a precipitate in the dentinal tubules of the subject. 2. The method of claim 1, wherein the molar ratio of the metal ion to the phosphate ion in the formulation is between about 0.1 and about 1. 3. The method of claim 1, wherein the molar ratio of the metal ion to the phosphate ion in the formulation is between about 0.2 and about 1. 4. The method of claim 1, wherein the molar ratio of the metal ion to the phosphate ion in the formulation is between about 0.2 and about 0.6. 5. The method of claim 1, wherein the formulation is used in combination with water or saliva to form a mixture having a pH value between about 2 and about 6. 6. The method of claim 5, wherein the pH value of the mixture is between about 2.0 and about 5.5. 7. The method of claim 5, wherein the pH value of the mixture is between about 2.0 and about 5.0. 8. The method of claim 5, wherein the pH value of the mixture is between about 2.0 and about 4.0. 9. The method of claim 5, wherein the pH value of the mixture is between about 3.0 and about 4.0. 10. The method of claim 1, wherein the metal ion is selected from the group consisting of a magnesium ion, a calcium ion, and a strontium ion. 11. The method of claim 1, wherein the source of the metal ion is selected from the group consisting of carbonates, acetates, lactates, citrates, chlorides, oxides, nitrates and hydroxides. 12. The method of claim 1, wherein the source of the phosphate ion is at least one selected from the group consisting of disodium hydrogen phosphate, dipotassium hydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, ammonium phosphate and a phosphate-containing drug. 13. The method of claim 12, wherein the phosphate-containing drug is selected from the group consisting of tetracycline phosphate complex, oleadomycin phosphate, codeine phosphate, estramustine phosphate, primaquine phosphate, dimemorfan phosphate, pyrldoxal phosphate, pyridoxal phosphate, piperazine phosphate, clindamycin phosphate, sodium phosphate, dexamethasone sodium phosphate, oseltamivir phosphate, benproperine phosphate, prednisolone sodium phosphate, betamethasone sodium phosphate, chloroquine phosphate, disopyramide phosphate, etoposide phosphate, fludarabine phosphate, histamine phosphate, hydrocortisone sodium phosphate, sodium biphosphate, ruxolitinib phosphate, sitagliptin phosphate, anileridine phosphate, sonidegib phosphate, oritavancin diphosphate, tedizolid phosphate, antazoline phosphate, estramustine phosphate, toceranib phosphate and chromic phosphate P32. 14. The method of claim 1, further comprising an additive selected from the group consisting of a thickening agent, an adhesive, an excipient, a stabilizer, an emulsifier, a humectant, and a combination thereof. 15. The method of claim 14, wherein the thickening agent is selected from the group consisting of methyl cellulose, hydroxyethyl cellulose, carbomer, titanium dioxide, zinc phosphate, zinc oxide, silicon dioxide, silicoaluminate, aluminum oxide and calcium phosphate. 16. The method of claim 14, wherein the adhesive is selected from the group consisting of acacia, alginate, alginic acid, candelilla wax, carnuba wax, corn starch, copolyvidone, ethyl cellulose, gelatin, glyceryl behenate, hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, hypromellose, lactose hydrous, lactose anhydrous, lactose monohydrate, lactose spray dried, methyl cellulose, povidone, polyvinylpyrrolidone, polyethylene oxide, potato starch, starch pregelatinized, starch, sodium starch and sodium carboxy methyl cellulose. 17. The method of claim 14, wherein the excipient is pectin, eudragit or a combination thereof. 18. The method of claim 1, being in a form of a powder, a paste, a flake, a gel, a soft gel, a gum, a semi-solid, a slurry, a patch, an emulsion, a glue, a buccal tablet, a pill, a film, a cream, an aerosol, or an orabase. 19. (canceled) 20. The method of claim 1, wherein the exposed dentinal tubule-associated symptom is selected from the group consisting of dentin hypersensitivity, crack tooth syndrome, enamel loss, dentin loss and postoperative hypersensitivity. 21. The method of claim 1, wherein the exposed dentinal tubule-associated disease is selected from the group consisting of dental caries, root caries, tooth fracture, root fracture, cervical abrasion, tooth wearing, root perforation, radicular cyst, apicitis, pulpitis, periapical periodontitis, pulp necrosis and exposed dentinal associated pulp disease. 22. The method of claim 1,
wherein the non-aqueous formulation is administered to the dentinal tubules of the subject by smearing, pasting, attaching or brushing. 23. A method for treating or preventing dentin hypersensitivity, comprising administering a non-aqueous formulation to dentinal tubules of a subject in need thereof, wherein the non-aqueous formulation comprises:
a source of a metal ion; and a source of a phosphate ion,
wherein the metal ion is chosen from Mg, Ca, Sr, Zn, Zr or any combination thereof, and a molar ratio of the metal ion to the phosphate ion in the formulation is between about 0.01 and about 1.0, and wherein the metal ion and the phosphate ion form a precipitate in the dentinal tubules. | Provided is a non-aqueous formulation for oral teeth, which includes a source of a metal ion and a source of a phosphate ion. The metal ion is chosen from alkaline earth metals, Zn, Zr or any combination thereof, and a molar ratio of the metal ion to the phosphate ion in the formulation is between about 0.01 and about 1.0. The non-aqueous formulation can provide a therapeutic effect.1. A method for treating or preventing an exposed dentinal tubule-associated symptom or disease, comprising administering a non-aqueous formulation to dentinal tubules of a subject in need thereof, wherein the non-aqueous formulation comprises:
a source of a metal ion; and a source of a phosphate ion, wherein the metal ion is chosen from Mg, Ca, Sr, Zn, Zr or any combination thereof, and a molar ratio of the metal ion to the phosphate ion in the formulation is between about 0.01 and about 1.0, and wherein the metal ion and the phosphate ion form a precipitate in the dentinal tubules of the subject. 2. The method of claim 1, wherein the molar ratio of the metal ion to the phosphate ion in the formulation is between about 0.1 and about 1. 3. The method of claim 1, wherein the molar ratio of the metal ion to the phosphate ion in the formulation is between about 0.2 and about 1. 4. The method of claim 1, wherein the molar ratio of the metal ion to the phosphate ion in the formulation is between about 0.2 and about 0.6. 5. The method of claim 1, wherein the formulation is used in combination with water or saliva to form a mixture having a pH value between about 2 and about 6. 6. The method of claim 5, wherein the pH value of the mixture is between about 2.0 and about 5.5. 7. The method of claim 5, wherein the pH value of the mixture is between about 2.0 and about 5.0. 8. The method of claim 5, wherein the pH value of the mixture is between about 2.0 and about 4.0. 9. The method of claim 5, wherein the pH value of the mixture is between about 3.0 and about 4.0. 10. The method of claim 1, wherein the metal ion is selected from the group consisting of a magnesium ion, a calcium ion, and a strontium ion. 11. The method of claim 1, wherein the source of the metal ion is selected from the group consisting of carbonates, acetates, lactates, citrates, chlorides, oxides, nitrates and hydroxides. 12. The method of claim 1, wherein the source of the phosphate ion is at least one selected from the group consisting of disodium hydrogen phosphate, dipotassium hydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, ammonium phosphate and a phosphate-containing drug. 13. The method of claim 12, wherein the phosphate-containing drug is selected from the group consisting of tetracycline phosphate complex, oleadomycin phosphate, codeine phosphate, estramustine phosphate, primaquine phosphate, dimemorfan phosphate, pyrldoxal phosphate, pyridoxal phosphate, piperazine phosphate, clindamycin phosphate, sodium phosphate, dexamethasone sodium phosphate, oseltamivir phosphate, benproperine phosphate, prednisolone sodium phosphate, betamethasone sodium phosphate, chloroquine phosphate, disopyramide phosphate, etoposide phosphate, fludarabine phosphate, histamine phosphate, hydrocortisone sodium phosphate, sodium biphosphate, ruxolitinib phosphate, sitagliptin phosphate, anileridine phosphate, sonidegib phosphate, oritavancin diphosphate, tedizolid phosphate, antazoline phosphate, estramustine phosphate, toceranib phosphate and chromic phosphate P32. 14. The method of claim 1, further comprising an additive selected from the group consisting of a thickening agent, an adhesive, an excipient, a stabilizer, an emulsifier, a humectant, and a combination thereof. 15. The method of claim 14, wherein the thickening agent is selected from the group consisting of methyl cellulose, hydroxyethyl cellulose, carbomer, titanium dioxide, zinc phosphate, zinc oxide, silicon dioxide, silicoaluminate, aluminum oxide and calcium phosphate. 16. The method of claim 14, wherein the adhesive is selected from the group consisting of acacia, alginate, alginic acid, candelilla wax, carnuba wax, corn starch, copolyvidone, ethyl cellulose, gelatin, glyceryl behenate, hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, hypromellose, lactose hydrous, lactose anhydrous, lactose monohydrate, lactose spray dried, methyl cellulose, povidone, polyvinylpyrrolidone, polyethylene oxide, potato starch, starch pregelatinized, starch, sodium starch and sodium carboxy methyl cellulose. 17. The method of claim 14, wherein the excipient is pectin, eudragit or a combination thereof. 18. The method of claim 1, being in a form of a powder, a paste, a flake, a gel, a soft gel, a gum, a semi-solid, a slurry, a patch, an emulsion, a glue, a buccal tablet, a pill, a film, a cream, an aerosol, or an orabase. 19. (canceled) 20. The method of claim 1, wherein the exposed dentinal tubule-associated symptom is selected from the group consisting of dentin hypersensitivity, crack tooth syndrome, enamel loss, dentin loss and postoperative hypersensitivity. 21. The method of claim 1, wherein the exposed dentinal tubule-associated disease is selected from the group consisting of dental caries, root caries, tooth fracture, root fracture, cervical abrasion, tooth wearing, root perforation, radicular cyst, apicitis, pulpitis, periapical periodontitis, pulp necrosis and exposed dentinal associated pulp disease. 22. The method of claim 1,
wherein the non-aqueous formulation is administered to the dentinal tubules of the subject by smearing, pasting, attaching or brushing. 23. A method for treating or preventing dentin hypersensitivity, comprising administering a non-aqueous formulation to dentinal tubules of a subject in need thereof, wherein the non-aqueous formulation comprises:
a source of a metal ion; and a source of a phosphate ion,
wherein the metal ion is chosen from Mg, Ca, Sr, Zn, Zr or any combination thereof, and a molar ratio of the metal ion to the phosphate ion in the formulation is between about 0.01 and about 1.0, and wherein the metal ion and the phosphate ion form a precipitate in the dentinal tubules. | 1,600 |
856 | 14,629,859 | 1,662 | Materials and methods for gene targeting using Clustered Regularly Interspersed Short Palindromic Repeats/CRISPR-associated (CRISPR/Cas) systems are provided herein. | 1. A method for modifying the genomic material in a plant cell, comprising:
(a) introducing into the plant cell a nucleic acid molecule, wherein the nucleic acid molecule comprises a crRNA and a tracrRNA, a chimeric cr/tracrRNA hybrid, a sequence encoding the crRNA and the tracrRNA, or a sequence encoding the chimeric cr/tracrRNA hybrid, wherein the crRNA and tracrRNA, or the chimeric cr/tracrRNA hybrid, is targeted to a sequence that is endogenous to the plant cell; and (b) introducing into the plant cell a Cas9 endonuclease molecule or a nucleic acid molecule comprising a sequence encoding the Cas9 endonuclease molecule, wherein the Cas9 endonuclease molecule induces a double strand break at or near the sequence to which the crRNA and tracrRNA sequence is targeted, or at or near the sequence to which the chimeric cr/tracrRNA hybrid is targeted. 2. The method of claim 1, wherein step (a) comprises delivering to the plant cell the nucleic acid molecule encoding the crRNA and tracrRNA or the chimeric cr/tracrRNA hybrid, and step (b) comprises delivering to the plant cell the nucleic acid molecule comprising the sequence encoding the Cas9 endonuclease molecule. 3. The method of claim 2, wherein the delivering in step (a), step (b), or both steps (a) and (b) comprises delivery via a DNA virus. 4. The method of claim 3, wherein the DNA virus is a geminivirus. 5. The method of claim 2, wherein the delivering in step (a), step (b), or both steps (a) and (b) comprises delivery via RNA virus. 6. The method of claim 5, wherein the RNA virus is a tobravirus. 7. The method of claim 2, wherein the delivering in step (a), step (b), or both steps (a) and (b) comprises delivery to protoplasts. 8. The method of claim 2, wherein the delivering in step (a), step (b), or both steps (a) and (b) comprises T-DNA delivery. 9. The method of claim 8, wherein the T-DNA delivery is via Agrobacterium or Ensifer. 10. The method of claim 2, wherein the delivering in step (a), step (b), or both steps (a) and (b) comprises particle bombardment. 11. The method of claim 2, wherein the sequence encoding the Cas9 endonuclease molecule is operably linked to a promoter that is constitutive, cell specific, inducible, or activated by alternative splicing of a suicide exon. 12. The method of claim 1, wherein the plant is monocotyledonous. 13. The method of claim 12, wherein the plant is wheat, maize, or Setaria. 14. The method of claim 1, wherein the plant is dicotyledonous. 15. The method of claim 14, wherein the plant is tomato, soybean, tobacco, potato, or Arabidopsis. | Materials and methods for gene targeting using Clustered Regularly Interspersed Short Palindromic Repeats/CRISPR-associated (CRISPR/Cas) systems are provided herein.1. A method for modifying the genomic material in a plant cell, comprising:
(a) introducing into the plant cell a nucleic acid molecule, wherein the nucleic acid molecule comprises a crRNA and a tracrRNA, a chimeric cr/tracrRNA hybrid, a sequence encoding the crRNA and the tracrRNA, or a sequence encoding the chimeric cr/tracrRNA hybrid, wherein the crRNA and tracrRNA, or the chimeric cr/tracrRNA hybrid, is targeted to a sequence that is endogenous to the plant cell; and (b) introducing into the plant cell a Cas9 endonuclease molecule or a nucleic acid molecule comprising a sequence encoding the Cas9 endonuclease molecule, wherein the Cas9 endonuclease molecule induces a double strand break at or near the sequence to which the crRNA and tracrRNA sequence is targeted, or at or near the sequence to which the chimeric cr/tracrRNA hybrid is targeted. 2. The method of claim 1, wherein step (a) comprises delivering to the plant cell the nucleic acid molecule encoding the crRNA and tracrRNA or the chimeric cr/tracrRNA hybrid, and step (b) comprises delivering to the plant cell the nucleic acid molecule comprising the sequence encoding the Cas9 endonuclease molecule. 3. The method of claim 2, wherein the delivering in step (a), step (b), or both steps (a) and (b) comprises delivery via a DNA virus. 4. The method of claim 3, wherein the DNA virus is a geminivirus. 5. The method of claim 2, wherein the delivering in step (a), step (b), or both steps (a) and (b) comprises delivery via RNA virus. 6. The method of claim 5, wherein the RNA virus is a tobravirus. 7. The method of claim 2, wherein the delivering in step (a), step (b), or both steps (a) and (b) comprises delivery to protoplasts. 8. The method of claim 2, wherein the delivering in step (a), step (b), or both steps (a) and (b) comprises T-DNA delivery. 9. The method of claim 8, wherein the T-DNA delivery is via Agrobacterium or Ensifer. 10. The method of claim 2, wherein the delivering in step (a), step (b), or both steps (a) and (b) comprises particle bombardment. 11. The method of claim 2, wherein the sequence encoding the Cas9 endonuclease molecule is operably linked to a promoter that is constitutive, cell specific, inducible, or activated by alternative splicing of a suicide exon. 12. The method of claim 1, wherein the plant is monocotyledonous. 13. The method of claim 12, wherein the plant is wheat, maize, or Setaria. 14. The method of claim 1, wherein the plant is dicotyledonous. 15. The method of claim 14, wherein the plant is tomato, soybean, tobacco, potato, or Arabidopsis. | 1,600 |
857 | 14,774,886 | 1,619 | Methods and compositions are provided for treating or preventing a neurological disease or disorder using an inhibitor of Glyoxalase 1 (GLO1). In some embodiments, the inhibitor is a small molecule. In certain embodiments, the disease or disorder is a sleep disorder, a mood disorder such as depression, epilepsy, an anxiety disorder, substance abuse, substance dependence or substance such as an alcohol withdrawal syndrome. | 1. A method of treating a condition in a subject, comprising treating the condition by administering to the subject a composition comprising a Glo1 inhibitor, wherein the condition is a sleep disorder or mood disorder. 2. The method of claim 1, wherein the condition is a sleep disorder. 3. The method of claim 2, wherein the sleep disorder is rapid eye movement (REM) sleep behavior disorder (RBD), insomnia, circadian rhythm sleep disorder, dyssomnia NOS, parasomnias, or restless leg syndrome. 4. The method of any of claims 1-3, further comprising administering a second sleep disorder treatment. 5. The method of claim 4, wherein the second sleep disorder treatment is amitriptyline, amoxapine, bupropion, buspirone, carbidopa-levodopa, citalopram, clonazepam, clorazepate, desipramine, desmopressin, dextroamphetamine, diazepam, doxepin, estazolam, fluoxetine flurazepam, fluvoxamine, medroxyprogesterone, methylphenidate, mirtazapine, modafinil, nefazodone, nortriptyline, paroxetine, pemoline, pergolide, phenelzine, phenobarbital, pramipexole, protriptyline, ropinirole, selegiline, sertraline, temazepam, tranylcypromine, trazodone, triazolam), trimipramine, venlafaxine, zaleplon, and/or zolpidem. 6. The method of claim 1, wherein the condition is a mood disorder. 7. The method of claim 6, wherein the mood disorder is a depressive disorder, bipolar disorder, phobia, obsessive-compulsive disorder, or post-traumatic stress disorder. 8. The method of any of claims 6-7, wherein the mood disorder is a depressive disorder. 9. The method of any of claims 6-7, wherein the mood disorder is a bipolar disorder. 10. The method of any of claims 6-9, further comprising administering a second mood disorder treatment. 11. The method of claim 10, wherein the second mood disorder treatment is antipsychotics, mood stabilizers and/or lithium. 12. The method of any of claims 1-11, wherein the subject is a human. 13. The method of any of claims 1-12, wherein the Glo1 inhibitor is an antibody, an inhibitory nucleic acid, or a small molecule. 14. The method of any of claims 1-13, wherein the Glo1 inhibitor is a small molecule. 15. The method of any of claims 1-14, wherein the Glo1 inhibitor has a glutathione structure. 16. The method of any of claims 1-15, wherein the Glo1 inhibitor is S-bromobenzylglutathione cyclopentyl diester (BrBzGCp2). 17. The method of any of claims 1-14, wherein the Glo1 inhibitor is a 1-hydroxy-6,7-diphenylpyridin-2-one derivative (3d), a flavonoid, a curcumin, a benzothiazole derivative, a 4-(7-azaindole)-substituted 6-phenyl-N-hydroxypyridones, and/or 4,6-diphenyl-N-hydroxypyridon. 18. The method of any of claims 1-17, wherein the composition is administered orally, topically, nasally, intravascularly, intraperiotoneally, intrathecally, intratracheally, by inhalation or instillation. 19. The method of any of claims 1-18, wherein the composition is administered orally, topically, or intravenously. 20. The method of any of claims 1-19, wherein the subject has been determined to have a mood disorder or sleep disorder. 21. The method of any of claims 1-20, further comprising identifying the subject as having a sleep disorder or mood disorder. 22. The method of any of claims 1-21, further comprising selecting the subject after the subject is diagnosed with a sleep disorder or mood disorder. 23. The method of any of claims 1-22, further comprising testing the subject for a sleep disorder or mood disorder. 24. The method of any of claims 1-23, wherein the subject is administered the composition within 1 week of being determined to have a sleep disorder or mood disorder. 25. The method of any of claims 1-24, wherein the subject is at risk of a sleep disorder or mood disorder. 26. The method of any of claims 1-25, further comprising monitoring the subject for the sleep disorder or mood disorder within a week of first administering the composition. 27. A method of treating a condition in a subject, comprising treating the condition by administering to the subject a composition comprising a small molecule Glo1 inhibitor, wherein the condition is an anxiety disorder. 28. The method of claim 27, wherein the anxiety disorder is a generalized anxiety disorder, panic disorder, a phobia, obsessive compulsive disorder, posttraumatic stress disorder, or acute stress disorder. 29. The method of any of claims 27-28, further comprising administering a second anxiety disorder treatment. 30. The method of claim 29, wherein the second anxiety disorder treatment is selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), benzodiazepines and/or tricyclic antidepressants, 31. The method of any of claims 27-30, wherein the subject is a human. 32. The method of any of claims 27-31, wherein the Glo1 inhibitor is an antibody, an inhibitory nucleic acid, or a small molecule. 33. The method of any of claims 27-32, wherein the Glo1 inhibitor is a small molecule. 34. The method of any of claims 27-31, wherein the Glo1 inhibitor is a molecule having a glutahion structure, a 1-hydroxy-6,7-diphenylpyridin-2-one derivative (3d), a flavonoid, a curcumin, a benzothiazole derivative, a 4-(7-azaindole)-substituted 6-phenyl-N-hydroxypyridones, and/or 4,6-diphenyl-N-hydroxypyridon. 35. The method of any of claims 27-34, wherein the composition is administered orally, topically, nasally, intravascularly, intraperiotoneally, intrathecally, intratracheally, by inhalation or instillation. 36. The method of any of claims 27-35, wherein the composition is administered orally, topically, or intravenously. 37. The method of any of claims 27-36, wherein the subject has been determined to have an anxiety disorder. 38. The method of any of claims 27-37, further comprising identifying the subject as having an anxiety disorder. 39. The method of any of claims 27-38, further comprising selecting the subject after the subject is diagnosed with an anxiety disorder. 40. The method of any of claims 27-39, further comprising testing the subject for an anxiety disorder. 41. The method of any of claims 27-40, wherein the subject is administered the composition within 1 week of being determined to have an anxiety disorder. 42. The method of any of claims 27-41, wherein the subject is at risk of an anxiety disorder. 43. The method of any of claims 27-42, further comprising monitoring the subject for the anxiety disorder within a week of first administering the composition. 44. A method of treating a condition in a subject, comprising treating the condition by administering to the subject a composition comprising a Glo1 inhibitor, wherein the condition is epilepsy. 45. The method of claim 44, wherein the epilepsy is generalized anxiety disorder, panic disorder, a phobia, obsessive compulsive disorder, posttraumatic stress disorder, or acute stress disorder, 46. The method of any of claims 44-45, further comprising administering a second epilepsy disorder treatment. 47. The method of claim 46, wherein the second epilepsy treatment is carbamazepine (Tegretol), clorazepate (Tranxene), clonazepam (Klonopin), ethosuximide (Zarontin), felbamate (Felbatol), fosphenytoin (Cerebyx), gabapentin (Neurontin), lacosamide (Vimpat), lamotrigine (Lamictal), levetiracetam (Keppra), oxcarbazepine (Trileptal), phenobarbital (Luminal), phenytoin (Dilantin), pregabalin (Lyrica), primidone (Mysoline), tiagabine (Gabitril), topiramate (Topamax), valproate semisodium (Depakote), valproic acid (Depakene), and/or zonisamide (Zonegran). 48. The method of any of claims 44-47, wherein the subject is a human. 49. The method of any of claims 44-48, wherein the Glo1 inhibitor is an antibody, an inhibitory nucleic acid, or a small molecule. 50. The method of any of claims 44-49, wherein the Glo1 inhibitor is a small molecule. 51. The method of any of claims 44-50, wherein the Glo1 inhibitor is a molecule having a glutahion structure, a 1-hydroxy-6,7-diphenylpyridin-2-one derivative (3d), a flavonoid, a curcumin, a benzothiazole derivative, a 4-(7-azaindole)-substituted 6-phenyl-N-hydroxypyridones, and/or 4,6-diphenyl-N-hydroxypyridon. 52. The method of any of claims 44-51, wherein the composition is administered orally, topically, nasally, intravascularly, intraperiotoneally, intrathecally, intratracheally, by inhalation or instillation. 53. The method of any of claims 44-52, wherein the composition is administered orally, topically, or intravenously. 54. The method of any of claims 44-53, wherein the subject has been determined to have epilepsy. 55. The method of any of claims 44-54, further comprising identifying the subject as having epilepsy. 56. The method of any of claims 44-55, further comprising selecting the subject after the subject is diagnosed with epilepsy. 57. The method of any of claims 44-56, further comprising testing the subject for epilepsy. 58. The method of any of claims 44-57, wherein the subject is administered the composition within 1 week of being determined to have epilepsy. 59. The method of any of claims 44-58, wherein the subject is at risk of epilepsy. 60. The method of any of claims 44-59, further comprising monitoring the subject for the epilepsy within a week of first administering the composition. 61. A method of treating a condition in a subject, comprising treating the condition by administering to the subject a composition comprising a Glo1 inhibitor, wherein the condition is an alcohol withdrawal syndrome. 62. The method of claim 61, further comprising administering a second alcohol withdrawal syndrome treatment. 63. The method of claim 62, wherein the second alcohol withdrawal syndrome treatment is benzodiazepines, barbiturates, clonidine, topiramate carbamazepine, and/or clomethiazole (heminevrin). 64. The method of any of claims 61-63, wherein the subject is a human. 65. The method of any of claims 61-64, wherein the Glo1 inhibitor is an antibody, an inhibitory nucleic acid, or a small molecule. 66. The method of any of claims 61-65, wherein the Glo1 inhibitor is a small molecule. 67. The method of any of claims 61-66, wherein the Glo1 inhibitor is a molecule having a glutahion structure, a 1-hydroxy-6,7-diphenylpyridin-2-one derivative (3d), a flavonoid, a curcumin, a benzothiazole derivative, a 4-(7-azaindole)-substituted 6-phenyl-N-hydroxypyridones, and/or 4,6-diphenyl-N-hydroxypyridon. 68. The method of any of claims 61-67, wherein the composition is administered orally, topically, nasally, intravascularly, intraperiotoneally, intrathecally, intratracheally, by inhalation or instillation. 69. The method of any of claims 61-68, wherein the composition is administered orally, topically, or intravenously. 70. The method of any of claims 61-69, wherein the subject has been determined to have an alcohol withdrawal syndrome. 71. The method of any of claims 61-70, further comprising identifying the subject as having an alcohol withdrawal syndrome. 72. The method of any of claims 61-71, further comprising selecting the subject after the subject is diagnosed with an alcohol withdrawal syndrome. 73. The method of any of claims 61-72, further comprising testing the subject for an alcohol withdrawal syndrome. 74. The method of any of claims 61-73, wherein the subject is administered the composition within 1 week of being determined to have an alcohol withdrawal syndrome. 75. The method of any of claims 61-74, wherein the subject is at risk of an alcohol withdrawal syndrome. 76. The method of any of claims 61-75, further comprising monitoring the subject for the alcohol withdrawal syndrome within a week of first administering the composition. 77. A method of treating a condition in a subject, comprising treating the condition by administering to the subject a composition comprising a Glo1 inhibitor, wherein the condition is a depressive disorder. 78. The method of claim 77, further comprising administering a second treatment for the depressive disorder. 79. The method of claim 78, wherein the second treatment is an antidepressant, a psychotherapy, electroconvulsive therapy, vagus nerve stimulation, repetitive transcranial magnetic stimulation, or cranial electrotherapy stimulation. 80. The method of any of claims 77-79, wherein the subject is a human. 81. The method of any of claims 77-80, wherein the Glo1 inhibitor is an antibody, an inhibitory nucleic acid, or a small molecule. 82. The method of any of claims 77-81, wherein the Glo1 inhibitor is a small molecule. 83. The method of any of claims 77-82, wherein the Glo1 inhibitor is a molecule having a glutahion structure, a 1-hydroxy-6,7-diphenylpyridin-2-one derivative (3d), a flavonoid, a curcumin, a benzothiazole derivative, a 4-(7-azaindole)-substituted 6-phenyl-N-hydroxypyridones, and/or 4,6-diphenyl-N-hydroxypyridon. 84. The method of any of claims 77-83, wherein the composition is administered orally, topically, nasally, intravascularly, intraperiotoneally, intrathecally, intratracheally, by inhalation or instillation. 85. The method of any of claims 77-84, wherein the composition is administered orally, topically, or intravenously. 86. The method of any of claims 77-85, wherein the subject has been determined to have a depressive disorder. 87. The method of any of claims 77-86, further comprising identifying the subject as having a depressive disorder. 88. The method of any of claims 77-87, further comprising selecting the subject after the subject is diagnosed with a depressive disorder. 89. The method of any of claims 77-88, further comprising testing the subject for a depressive disorder. 90. The method of any of claims 77-89, wherein the subject is administered the composition within 1 week of being determined to have a depressive disorder. 91. The method of any of claims 77-90, wherein the subject is at risk of a depressive disorder. 92. The method of any of claims 77-91, further comprising monitoring the subject for the depressive disorder within a week of first administering the composition. | Methods and compositions are provided for treating or preventing a neurological disease or disorder using an inhibitor of Glyoxalase 1 (GLO1). In some embodiments, the inhibitor is a small molecule. In certain embodiments, the disease or disorder is a sleep disorder, a mood disorder such as depression, epilepsy, an anxiety disorder, substance abuse, substance dependence or substance such as an alcohol withdrawal syndrome.1. A method of treating a condition in a subject, comprising treating the condition by administering to the subject a composition comprising a Glo1 inhibitor, wherein the condition is a sleep disorder or mood disorder. 2. The method of claim 1, wherein the condition is a sleep disorder. 3. The method of claim 2, wherein the sleep disorder is rapid eye movement (REM) sleep behavior disorder (RBD), insomnia, circadian rhythm sleep disorder, dyssomnia NOS, parasomnias, or restless leg syndrome. 4. The method of any of claims 1-3, further comprising administering a second sleep disorder treatment. 5. The method of claim 4, wherein the second sleep disorder treatment is amitriptyline, amoxapine, bupropion, buspirone, carbidopa-levodopa, citalopram, clonazepam, clorazepate, desipramine, desmopressin, dextroamphetamine, diazepam, doxepin, estazolam, fluoxetine flurazepam, fluvoxamine, medroxyprogesterone, methylphenidate, mirtazapine, modafinil, nefazodone, nortriptyline, paroxetine, pemoline, pergolide, phenelzine, phenobarbital, pramipexole, protriptyline, ropinirole, selegiline, sertraline, temazepam, tranylcypromine, trazodone, triazolam), trimipramine, venlafaxine, zaleplon, and/or zolpidem. 6. The method of claim 1, wherein the condition is a mood disorder. 7. The method of claim 6, wherein the mood disorder is a depressive disorder, bipolar disorder, phobia, obsessive-compulsive disorder, or post-traumatic stress disorder. 8. The method of any of claims 6-7, wherein the mood disorder is a depressive disorder. 9. The method of any of claims 6-7, wherein the mood disorder is a bipolar disorder. 10. The method of any of claims 6-9, further comprising administering a second mood disorder treatment. 11. The method of claim 10, wherein the second mood disorder treatment is antipsychotics, mood stabilizers and/or lithium. 12. The method of any of claims 1-11, wherein the subject is a human. 13. The method of any of claims 1-12, wherein the Glo1 inhibitor is an antibody, an inhibitory nucleic acid, or a small molecule. 14. The method of any of claims 1-13, wherein the Glo1 inhibitor is a small molecule. 15. The method of any of claims 1-14, wherein the Glo1 inhibitor has a glutathione structure. 16. The method of any of claims 1-15, wherein the Glo1 inhibitor is S-bromobenzylglutathione cyclopentyl diester (BrBzGCp2). 17. The method of any of claims 1-14, wherein the Glo1 inhibitor is a 1-hydroxy-6,7-diphenylpyridin-2-one derivative (3d), a flavonoid, a curcumin, a benzothiazole derivative, a 4-(7-azaindole)-substituted 6-phenyl-N-hydroxypyridones, and/or 4,6-diphenyl-N-hydroxypyridon. 18. The method of any of claims 1-17, wherein the composition is administered orally, topically, nasally, intravascularly, intraperiotoneally, intrathecally, intratracheally, by inhalation or instillation. 19. The method of any of claims 1-18, wherein the composition is administered orally, topically, or intravenously. 20. The method of any of claims 1-19, wherein the subject has been determined to have a mood disorder or sleep disorder. 21. The method of any of claims 1-20, further comprising identifying the subject as having a sleep disorder or mood disorder. 22. The method of any of claims 1-21, further comprising selecting the subject after the subject is diagnosed with a sleep disorder or mood disorder. 23. The method of any of claims 1-22, further comprising testing the subject for a sleep disorder or mood disorder. 24. The method of any of claims 1-23, wherein the subject is administered the composition within 1 week of being determined to have a sleep disorder or mood disorder. 25. The method of any of claims 1-24, wherein the subject is at risk of a sleep disorder or mood disorder. 26. The method of any of claims 1-25, further comprising monitoring the subject for the sleep disorder or mood disorder within a week of first administering the composition. 27. A method of treating a condition in a subject, comprising treating the condition by administering to the subject a composition comprising a small molecule Glo1 inhibitor, wherein the condition is an anxiety disorder. 28. The method of claim 27, wherein the anxiety disorder is a generalized anxiety disorder, panic disorder, a phobia, obsessive compulsive disorder, posttraumatic stress disorder, or acute stress disorder. 29. The method of any of claims 27-28, further comprising administering a second anxiety disorder treatment. 30. The method of claim 29, wherein the second anxiety disorder treatment is selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), benzodiazepines and/or tricyclic antidepressants, 31. The method of any of claims 27-30, wherein the subject is a human. 32. The method of any of claims 27-31, wherein the Glo1 inhibitor is an antibody, an inhibitory nucleic acid, or a small molecule. 33. The method of any of claims 27-32, wherein the Glo1 inhibitor is a small molecule. 34. The method of any of claims 27-31, wherein the Glo1 inhibitor is a molecule having a glutahion structure, a 1-hydroxy-6,7-diphenylpyridin-2-one derivative (3d), a flavonoid, a curcumin, a benzothiazole derivative, a 4-(7-azaindole)-substituted 6-phenyl-N-hydroxypyridones, and/or 4,6-diphenyl-N-hydroxypyridon. 35. The method of any of claims 27-34, wherein the composition is administered orally, topically, nasally, intravascularly, intraperiotoneally, intrathecally, intratracheally, by inhalation or instillation. 36. The method of any of claims 27-35, wherein the composition is administered orally, topically, or intravenously. 37. The method of any of claims 27-36, wherein the subject has been determined to have an anxiety disorder. 38. The method of any of claims 27-37, further comprising identifying the subject as having an anxiety disorder. 39. The method of any of claims 27-38, further comprising selecting the subject after the subject is diagnosed with an anxiety disorder. 40. The method of any of claims 27-39, further comprising testing the subject for an anxiety disorder. 41. The method of any of claims 27-40, wherein the subject is administered the composition within 1 week of being determined to have an anxiety disorder. 42. The method of any of claims 27-41, wherein the subject is at risk of an anxiety disorder. 43. The method of any of claims 27-42, further comprising monitoring the subject for the anxiety disorder within a week of first administering the composition. 44. A method of treating a condition in a subject, comprising treating the condition by administering to the subject a composition comprising a Glo1 inhibitor, wherein the condition is epilepsy. 45. The method of claim 44, wherein the epilepsy is generalized anxiety disorder, panic disorder, a phobia, obsessive compulsive disorder, posttraumatic stress disorder, or acute stress disorder, 46. The method of any of claims 44-45, further comprising administering a second epilepsy disorder treatment. 47. The method of claim 46, wherein the second epilepsy treatment is carbamazepine (Tegretol), clorazepate (Tranxene), clonazepam (Klonopin), ethosuximide (Zarontin), felbamate (Felbatol), fosphenytoin (Cerebyx), gabapentin (Neurontin), lacosamide (Vimpat), lamotrigine (Lamictal), levetiracetam (Keppra), oxcarbazepine (Trileptal), phenobarbital (Luminal), phenytoin (Dilantin), pregabalin (Lyrica), primidone (Mysoline), tiagabine (Gabitril), topiramate (Topamax), valproate semisodium (Depakote), valproic acid (Depakene), and/or zonisamide (Zonegran). 48. The method of any of claims 44-47, wherein the subject is a human. 49. The method of any of claims 44-48, wherein the Glo1 inhibitor is an antibody, an inhibitory nucleic acid, or a small molecule. 50. The method of any of claims 44-49, wherein the Glo1 inhibitor is a small molecule. 51. The method of any of claims 44-50, wherein the Glo1 inhibitor is a molecule having a glutahion structure, a 1-hydroxy-6,7-diphenylpyridin-2-one derivative (3d), a flavonoid, a curcumin, a benzothiazole derivative, a 4-(7-azaindole)-substituted 6-phenyl-N-hydroxypyridones, and/or 4,6-diphenyl-N-hydroxypyridon. 52. The method of any of claims 44-51, wherein the composition is administered orally, topically, nasally, intravascularly, intraperiotoneally, intrathecally, intratracheally, by inhalation or instillation. 53. The method of any of claims 44-52, wherein the composition is administered orally, topically, or intravenously. 54. The method of any of claims 44-53, wherein the subject has been determined to have epilepsy. 55. The method of any of claims 44-54, further comprising identifying the subject as having epilepsy. 56. The method of any of claims 44-55, further comprising selecting the subject after the subject is diagnosed with epilepsy. 57. The method of any of claims 44-56, further comprising testing the subject for epilepsy. 58. The method of any of claims 44-57, wherein the subject is administered the composition within 1 week of being determined to have epilepsy. 59. The method of any of claims 44-58, wherein the subject is at risk of epilepsy. 60. The method of any of claims 44-59, further comprising monitoring the subject for the epilepsy within a week of first administering the composition. 61. A method of treating a condition in a subject, comprising treating the condition by administering to the subject a composition comprising a Glo1 inhibitor, wherein the condition is an alcohol withdrawal syndrome. 62. The method of claim 61, further comprising administering a second alcohol withdrawal syndrome treatment. 63. The method of claim 62, wherein the second alcohol withdrawal syndrome treatment is benzodiazepines, barbiturates, clonidine, topiramate carbamazepine, and/or clomethiazole (heminevrin). 64. The method of any of claims 61-63, wherein the subject is a human. 65. The method of any of claims 61-64, wherein the Glo1 inhibitor is an antibody, an inhibitory nucleic acid, or a small molecule. 66. The method of any of claims 61-65, wherein the Glo1 inhibitor is a small molecule. 67. The method of any of claims 61-66, wherein the Glo1 inhibitor is a molecule having a glutahion structure, a 1-hydroxy-6,7-diphenylpyridin-2-one derivative (3d), a flavonoid, a curcumin, a benzothiazole derivative, a 4-(7-azaindole)-substituted 6-phenyl-N-hydroxypyridones, and/or 4,6-diphenyl-N-hydroxypyridon. 68. The method of any of claims 61-67, wherein the composition is administered orally, topically, nasally, intravascularly, intraperiotoneally, intrathecally, intratracheally, by inhalation or instillation. 69. The method of any of claims 61-68, wherein the composition is administered orally, topically, or intravenously. 70. The method of any of claims 61-69, wherein the subject has been determined to have an alcohol withdrawal syndrome. 71. The method of any of claims 61-70, further comprising identifying the subject as having an alcohol withdrawal syndrome. 72. The method of any of claims 61-71, further comprising selecting the subject after the subject is diagnosed with an alcohol withdrawal syndrome. 73. The method of any of claims 61-72, further comprising testing the subject for an alcohol withdrawal syndrome. 74. The method of any of claims 61-73, wherein the subject is administered the composition within 1 week of being determined to have an alcohol withdrawal syndrome. 75. The method of any of claims 61-74, wherein the subject is at risk of an alcohol withdrawal syndrome. 76. The method of any of claims 61-75, further comprising monitoring the subject for the alcohol withdrawal syndrome within a week of first administering the composition. 77. A method of treating a condition in a subject, comprising treating the condition by administering to the subject a composition comprising a Glo1 inhibitor, wherein the condition is a depressive disorder. 78. The method of claim 77, further comprising administering a second treatment for the depressive disorder. 79. The method of claim 78, wherein the second treatment is an antidepressant, a psychotherapy, electroconvulsive therapy, vagus nerve stimulation, repetitive transcranial magnetic stimulation, or cranial electrotherapy stimulation. 80. The method of any of claims 77-79, wherein the subject is a human. 81. The method of any of claims 77-80, wherein the Glo1 inhibitor is an antibody, an inhibitory nucleic acid, or a small molecule. 82. The method of any of claims 77-81, wherein the Glo1 inhibitor is a small molecule. 83. The method of any of claims 77-82, wherein the Glo1 inhibitor is a molecule having a glutahion structure, a 1-hydroxy-6,7-diphenylpyridin-2-one derivative (3d), a flavonoid, a curcumin, a benzothiazole derivative, a 4-(7-azaindole)-substituted 6-phenyl-N-hydroxypyridones, and/or 4,6-diphenyl-N-hydroxypyridon. 84. The method of any of claims 77-83, wherein the composition is administered orally, topically, nasally, intravascularly, intraperiotoneally, intrathecally, intratracheally, by inhalation or instillation. 85. The method of any of claims 77-84, wherein the composition is administered orally, topically, or intravenously. 86. The method of any of claims 77-85, wherein the subject has been determined to have a depressive disorder. 87. The method of any of claims 77-86, further comprising identifying the subject as having a depressive disorder. 88. The method of any of claims 77-87, further comprising selecting the subject after the subject is diagnosed with a depressive disorder. 89. The method of any of claims 77-88, further comprising testing the subject for a depressive disorder. 90. The method of any of claims 77-89, wherein the subject is administered the composition within 1 week of being determined to have a depressive disorder. 91. The method of any of claims 77-90, wherein the subject is at risk of a depressive disorder. 92. The method of any of claims 77-91, further comprising monitoring the subject for the depressive disorder within a week of first administering the composition. | 1,600 |
858 | 15,192,708 | 1,631 | The present invention describes a method that is comprised of creating a set of synthetic samples that mimic a dynamic process or a specific process step or a variation thereof, to be used to develop multivariate monitoring calibrations and process supervisory control systems. | 1. A method for preparing at least one synthetic multicomponent biotechnological and/or chemical process sample for developing multivariate calibrations for monitoring systems and/or multivariate supervisory systems of increased robustness, wherein at least one synthetic sample mimicking a dynamic process or a specific process step or a variation thereof is prepared, the method comprising the steps of:
preparing historical process data of the dynamic process or the specific process step or the variation thereof to be mimicked and for which the at least one synthetic sample are to be prepared; creating a data matrix D of the historical process data; determining a plurality of main solutions of the data matrix D; determining which main solutions of the data matrix D are necessary to mimic the dynamic process or the specific process step or the variation thereof within a predetermined variance; determining the analyte composition of the necessary main solutions and the respective relative amount of the necessary main solutions with respect to the data matrix D; creating a matrix S comprising the determined analyte composition of the necessary main solutions; creating a matrix C comprising the relative amount of the necessary main solutions with respect to the data matrix D; determining whether the matrix product C×ST corresponds to the data matrix D within a predetermined tolerance; determining the relative amount of the necessary main solutions comprised in the matrix C for at least two instants of time; performing a regression between the relative amount of the necessary main solutions comprised in the matrix C and a respective time variable of the historical process data using the determined relative amount of the necessary main solutions for the at least two instants of time; estimating the relative amount of the necessary main solutions for at least one other instant of time between the at least two instants of time based on the regression; and creating an augmented time dependent matrix Caug comprising C and the estimated necessary main solutions for the at least one other instant of time, wherein the aforementioned steps are carried out on a computational unit; and wherein the method further comprises the step of: creating at least one sample by assembling the necessary main solutions according to the determined analyte composition. 2. The method according to claim 1, wherein if the matrix product C×ST does not correspond to the data matrix D within the predetermined tolerance repeating the steps of:
determining which main solutions of the data matrix D are necessary to mimic the dynamic process or the specific process step or the variation thereof within the predetermined variance;
determining the analyte composition of the necessary main solutions and the relative amount of each necessary main solution;
creating the matrix S;
creating the matrix C;
determining whether the matrix product C×ST corresponds to the data matrix D within the predetermined tolerance. 3. The method according to claim 1, wherein the relative amount of the necessary main solutions for creating the data matrix C and/or the determined analyte composition of the necessary main solutions for creating the matrix S is selected based on logical constraints and/or physical constraints and/or chemical constraints. 4. The method according to claim 2, wherein the relative amount of the necessary main solutions for creating the data matrix C and/or the determined analyte composition of the necessary main solutions for creating the matrix S is selected based on logical constraints and/or physical constraints and/or chemical constraints. 5. The method according to claim 1,
wherein the data matrix D is partitioned into a plurality of data matrices Di and wherein each matrix Di is individually processed in each step following the creating of the data matrix D, preferably if it is determined that only main solutions of the data matrix D can be determined which are configured to mimic the dynamic process or the specific process step or the variation thereof below the predetermined variance. 6. The method according to claim 1, wherein the historical data comprises at least one of the following: analytically determined composition values of the dynamic process or the specific process step or the variation thereof, physical information, process information, data of at least one further process variation corresponding to additional experimental and/or simulated runs of the process under similar or different process conditions and/or
wherein the historical data is organized in the matrix D according to the process time. 7. The method according to claim 1, wherein determining the necessary main solutions and/or determining the analyte composition of the necessary main solutions and/or determining the relative amount of the necessary main solutions with respect to the data matrix D is performed using an appropriate chemometric method, in particular at least one of the following chemometric methods:
a factor decomposition method, in particular principal component analysis (PCA), singular value decomposition (SVD) or evolving factor analysis, and/or a parallel factor analysis (PARAFAC), multivariate curve resolution-alternating least squares (MCR-ALS), evolving factor analysis. 8. The method according to claim 1, further comprising:
preprocessing the matrix D, preferably filtering, more preferably using at least one of: a Savitzky-Golay filter, a Kernel smoother, a smoothing spline, a moving average, or a weighted moving average. 9. The method according to claim 1, further comprising:
preparing at least one second sample being configured to break co-linearity between parameters or analytes comprised in the data matrix D using a co-linearity breaking method. 10. The method according to claim 9, wherein the co-linearity breaking method comprises at least one of the following: creating of an orthogonal design of experiments, random spiking of the specific compounds in the at least one sample, programmed spiking, random mixing of samples or any combination thereof. 11. The method according to claim 9, further comprising:
creating a third sample by grouping the sample with the at least one second sample. 12. The method according to claim 10, further comprising:
creating a third sample by grouping the sample with the at least one second sample. 13. A synthetic sample layout generation and sample handling system for preparing at least one synthetic sample mimicking a dynamic process or a specific process step or a variation thereof, the system comprising:
a computational unit; and a mixing unit; wherein the computational unit comprises: means for preparing historical process data of the dynamic process or the specific process step or the variation thereof to be mimicked and for which the set of synthetic samples are to be prepared; means for creating a data matrix D of the historical process data; means for determining a plurality of main solutions of the data matrix D; means for determining which main solutions of the data matrix D are necessary to mimic the dynamic process or the specific process step or the variation thereof within a predetermined variance; means for determining the analyte composition of the necessary main solutions and the respective relative amount of the necessary main solutions with respect to the data matrix D; and wherein the mixing unit is configured to create the at least one sample by assembling the necessary main solutions according to the determined analyte composition, wherein the computational unit further comprises: means for creating a matrix S comprising the determined analyte composition of the necessary main solutions; means for creating a matrix C comprising the relative amount of the necessary main solutions with respect to the data matrix D; means for determining whether the matrix product C×ST corresponds to the data matrix D within a predetermined tolerance; wherein the means for determining the respective relative amount of the necessary main solutions with respect to the data matrix D are configured to determine the relative amount of the necessary main solutions comprised in the matrix C for at least two instants of time; the computational unit further comprising: means for performing a regression between the relative amount of the necessary main solutions comprised in the matrix C and a respective time variable of the historical process data using the determined relative amount of the necessary main solutions for the at least two instants of time; means for estimating the relative amount of the necessary main solutions for at least one other instant of time between the at least two instants of time based on the regression; and means for creating an augmented time dependent matrix Caug comprising C and the estimated necessary main solutions for the at least one other instant of time. 14. The system according to claim 13, further comprising a measurement device having at least one sensor. 15. The system according to claim 14, wherein the at least one sensor of the measurement device is configured to measure at least one parameter in-situ in the dynamic process, the specific process step or the variation thereof and/or wherein the at least one sensor comprises at least one of the following: a pH probe, a temperature probe, a spectroscopic sensor, or a multichannel instrument. 16. The system according to claim 13, further comprising at least one control device comprising at least one temperature control structure and/or at least one pH control structure. 17. The system according to claim 16, wherein the at least one control device is configured to recreate respective conditions of the dynamic process or the specific process step or the variation thereof. 18. The system according to claim 15, wherein the at least one control device is configured to break the co-linearity between parameters or analytes comprised in the data matrix D using a co-linearity breaking method. 19. The system according to claim 16, wherein the at least one control device is configured to break the co-linearity between parameters or analytes comprised in the data matrix D using a co-linearity breaking method. 20. The system according to claim 18, wherein the at least one control device is configured to break the co-linearity using at least one of the following co-linearity breaking methods: creating of an orthogonal design of experiments, random spiking of the specific compounds in the at least one sample, programmed spiking, random mixing of samples or any combination thereof. 21. The system according to claim 19, wherein the at least one control device is configured to break the co-linearity using at least one of the following co-linearity breaking methods: creating of an orthogonal design of experiments, random spiking of the specific compounds in the at least one sample, programmed spiking, random mixing of samples or any combination thereof. 22. The system according to claim 13, further comprising an analytical device configured to analyze at least one of the main solutions and/or the at least one sample. 23. A computer program product comprising one or more computer readable media having computer executable instructions for performing the steps of the method of claim 1. | The present invention describes a method that is comprised of creating a set of synthetic samples that mimic a dynamic process or a specific process step or a variation thereof, to be used to develop multivariate monitoring calibrations and process supervisory control systems.1. A method for preparing at least one synthetic multicomponent biotechnological and/or chemical process sample for developing multivariate calibrations for monitoring systems and/or multivariate supervisory systems of increased robustness, wherein at least one synthetic sample mimicking a dynamic process or a specific process step or a variation thereof is prepared, the method comprising the steps of:
preparing historical process data of the dynamic process or the specific process step or the variation thereof to be mimicked and for which the at least one synthetic sample are to be prepared; creating a data matrix D of the historical process data; determining a plurality of main solutions of the data matrix D; determining which main solutions of the data matrix D are necessary to mimic the dynamic process or the specific process step or the variation thereof within a predetermined variance; determining the analyte composition of the necessary main solutions and the respective relative amount of the necessary main solutions with respect to the data matrix D; creating a matrix S comprising the determined analyte composition of the necessary main solutions; creating a matrix C comprising the relative amount of the necessary main solutions with respect to the data matrix D; determining whether the matrix product C×ST corresponds to the data matrix D within a predetermined tolerance; determining the relative amount of the necessary main solutions comprised in the matrix C for at least two instants of time; performing a regression between the relative amount of the necessary main solutions comprised in the matrix C and a respective time variable of the historical process data using the determined relative amount of the necessary main solutions for the at least two instants of time; estimating the relative amount of the necessary main solutions for at least one other instant of time between the at least two instants of time based on the regression; and creating an augmented time dependent matrix Caug comprising C and the estimated necessary main solutions for the at least one other instant of time, wherein the aforementioned steps are carried out on a computational unit; and wherein the method further comprises the step of: creating at least one sample by assembling the necessary main solutions according to the determined analyte composition. 2. The method according to claim 1, wherein if the matrix product C×ST does not correspond to the data matrix D within the predetermined tolerance repeating the steps of:
determining which main solutions of the data matrix D are necessary to mimic the dynamic process or the specific process step or the variation thereof within the predetermined variance;
determining the analyte composition of the necessary main solutions and the relative amount of each necessary main solution;
creating the matrix S;
creating the matrix C;
determining whether the matrix product C×ST corresponds to the data matrix D within the predetermined tolerance. 3. The method according to claim 1, wherein the relative amount of the necessary main solutions for creating the data matrix C and/or the determined analyte composition of the necessary main solutions for creating the matrix S is selected based on logical constraints and/or physical constraints and/or chemical constraints. 4. The method according to claim 2, wherein the relative amount of the necessary main solutions for creating the data matrix C and/or the determined analyte composition of the necessary main solutions for creating the matrix S is selected based on logical constraints and/or physical constraints and/or chemical constraints. 5. The method according to claim 1,
wherein the data matrix D is partitioned into a plurality of data matrices Di and wherein each matrix Di is individually processed in each step following the creating of the data matrix D, preferably if it is determined that only main solutions of the data matrix D can be determined which are configured to mimic the dynamic process or the specific process step or the variation thereof below the predetermined variance. 6. The method according to claim 1, wherein the historical data comprises at least one of the following: analytically determined composition values of the dynamic process or the specific process step or the variation thereof, physical information, process information, data of at least one further process variation corresponding to additional experimental and/or simulated runs of the process under similar or different process conditions and/or
wherein the historical data is organized in the matrix D according to the process time. 7. The method according to claim 1, wherein determining the necessary main solutions and/or determining the analyte composition of the necessary main solutions and/or determining the relative amount of the necessary main solutions with respect to the data matrix D is performed using an appropriate chemometric method, in particular at least one of the following chemometric methods:
a factor decomposition method, in particular principal component analysis (PCA), singular value decomposition (SVD) or evolving factor analysis, and/or a parallel factor analysis (PARAFAC), multivariate curve resolution-alternating least squares (MCR-ALS), evolving factor analysis. 8. The method according to claim 1, further comprising:
preprocessing the matrix D, preferably filtering, more preferably using at least one of: a Savitzky-Golay filter, a Kernel smoother, a smoothing spline, a moving average, or a weighted moving average. 9. The method according to claim 1, further comprising:
preparing at least one second sample being configured to break co-linearity between parameters or analytes comprised in the data matrix D using a co-linearity breaking method. 10. The method according to claim 9, wherein the co-linearity breaking method comprises at least one of the following: creating of an orthogonal design of experiments, random spiking of the specific compounds in the at least one sample, programmed spiking, random mixing of samples or any combination thereof. 11. The method according to claim 9, further comprising:
creating a third sample by grouping the sample with the at least one second sample. 12. The method according to claim 10, further comprising:
creating a third sample by grouping the sample with the at least one second sample. 13. A synthetic sample layout generation and sample handling system for preparing at least one synthetic sample mimicking a dynamic process or a specific process step or a variation thereof, the system comprising:
a computational unit; and a mixing unit; wherein the computational unit comprises: means for preparing historical process data of the dynamic process or the specific process step or the variation thereof to be mimicked and for which the set of synthetic samples are to be prepared; means for creating a data matrix D of the historical process data; means for determining a plurality of main solutions of the data matrix D; means for determining which main solutions of the data matrix D are necessary to mimic the dynamic process or the specific process step or the variation thereof within a predetermined variance; means for determining the analyte composition of the necessary main solutions and the respective relative amount of the necessary main solutions with respect to the data matrix D; and wherein the mixing unit is configured to create the at least one sample by assembling the necessary main solutions according to the determined analyte composition, wherein the computational unit further comprises: means for creating a matrix S comprising the determined analyte composition of the necessary main solutions; means for creating a matrix C comprising the relative amount of the necessary main solutions with respect to the data matrix D; means for determining whether the matrix product C×ST corresponds to the data matrix D within a predetermined tolerance; wherein the means for determining the respective relative amount of the necessary main solutions with respect to the data matrix D are configured to determine the relative amount of the necessary main solutions comprised in the matrix C for at least two instants of time; the computational unit further comprising: means for performing a regression between the relative amount of the necessary main solutions comprised in the matrix C and a respective time variable of the historical process data using the determined relative amount of the necessary main solutions for the at least two instants of time; means for estimating the relative amount of the necessary main solutions for at least one other instant of time between the at least two instants of time based on the regression; and means for creating an augmented time dependent matrix Caug comprising C and the estimated necessary main solutions for the at least one other instant of time. 14. The system according to claim 13, further comprising a measurement device having at least one sensor. 15. The system according to claim 14, wherein the at least one sensor of the measurement device is configured to measure at least one parameter in-situ in the dynamic process, the specific process step or the variation thereof and/or wherein the at least one sensor comprises at least one of the following: a pH probe, a temperature probe, a spectroscopic sensor, or a multichannel instrument. 16. The system according to claim 13, further comprising at least one control device comprising at least one temperature control structure and/or at least one pH control structure. 17. The system according to claim 16, wherein the at least one control device is configured to recreate respective conditions of the dynamic process or the specific process step or the variation thereof. 18. The system according to claim 15, wherein the at least one control device is configured to break the co-linearity between parameters or analytes comprised in the data matrix D using a co-linearity breaking method. 19. The system according to claim 16, wherein the at least one control device is configured to break the co-linearity between parameters or analytes comprised in the data matrix D using a co-linearity breaking method. 20. The system according to claim 18, wherein the at least one control device is configured to break the co-linearity using at least one of the following co-linearity breaking methods: creating of an orthogonal design of experiments, random spiking of the specific compounds in the at least one sample, programmed spiking, random mixing of samples or any combination thereof. 21. The system according to claim 19, wherein the at least one control device is configured to break the co-linearity using at least one of the following co-linearity breaking methods: creating of an orthogonal design of experiments, random spiking of the specific compounds in the at least one sample, programmed spiking, random mixing of samples or any combination thereof. 22. The system according to claim 13, further comprising an analytical device configured to analyze at least one of the main solutions and/or the at least one sample. 23. A computer program product comprising one or more computer readable media having computer executable instructions for performing the steps of the method of claim 1. | 1,600 |
859 | 14,785,548 | 1,618 | The invention relates to preparations for dietary, food supplement or medical purposes and more specifically to a safe and natural preparation or a composition useful in immunity regulation and/or stimulation and in particular in the building, reinforcement, efficiency, maintenance and regeneration of natural immune defences in a subject. The preparations comprise magnesium, zinc and/or iron, blackcurrent seed oil and/or palm oil, two plant extracts selected from thyme, chickpea and lentil, as well as algae (fucus, wakame, nori), mushroom (shiitake, maitake) and at least one hydrosoluble vitamin and/or vitamin E. | 1. A composition for immunity regulation and/or stimulation, per 100 g or 100 ml, comprising the combination of:
10 μg to 1000 μg of positively charged minerals consisting of magnesium, 10 μg to 1000 μg of metals selected from zinc and iron 7 μg to 700 μg of at least one plant oil selected from Ribes nigrum Oleum Acini (blackcurrant seed oil) and Elaeis guineensis Oleum (palm oil), 6 μg to 600 μg of at least two plant extracts selected from Thymus vulgaris (thyme), Cicer arietinum (chickpea), and Ervum lens (lentil), 6 μg to 600 μg of at least one alga chosen among Fucus vesiculosus (Fucus), Undaria pinnatfida (Wakame), Palmaria palmata (Dulse), and Porphyra umbilicalis (Nori), 7 μg to 700 μg of at least one mushroom chosen among Lentinula edodes (Shiitake) and Grifola frondosa (Maitake), 8 μg to 800 μg of at least one vitamin chosen among vitamins A, B1, B2, B5, B6, B9, C, E, PP(B3); optionally with a suitable excipient. 2. The composition for immunity regulation and/or stimulation of claim 1, wherein vitamin A is between 15% and 100% of the GDA (Guideline Daily Amounts). 3. The composition for immunity regulation and/or stimulation of claim 2, wherein the input weight of vitamin A represents from 120 to 800 μg/100 g of said composition. 4. The composition for immunity regulation and/or stimulation of claim 2, wherein zinc is between 15% and 100% of the GDA (Guideline Daily Amounts). 5. The composition for immunity regulation and/or stimulation of claim 4, wherein the weight of zinc represents from 0.225 to 1 mg/100 g of said composition. 6. The composition for immunity regulation and/or stimulation of claim 1, wherein the suitable excipient is a pharmaceutically acceptable excipient. 7. The composition for immunity regulation and/or stimulation according to claim 1, for use in a food preparation, a dietary supplement, a nutraceutical, or a beverage. 8. A medicament comprising the composition for immunity regulation and/or stimulation according to claim 1. 9-17. (canceled) 18. The composition according to claim 1, wherein said composition is a food preparation, a dietary supplement, a nutraceutical, or a beverage. 19. A method of immunity regulation and/or stimulation in a subject in need thereof comprising administering a composition according to claim 1 to the subject. 20. The method according to claim 19, wherein said method is a method of prevention and/or alleviation of the symptoms related to pathogenic infections comprising viral infections, bacterial infections, or parasitic infections. 21. The method according to claim 20, wherein the parasitic infections comprise malaria, fungal infections, superinfections or episodic infections. 22. The method according to claim 20, wherein the episodic infections comprise winter infections; flu syndromes; bronchitis; tuberculosis; lower or upper respiratory tract infections; or urinary; intestinal or skin infections. 23. The method according to claim 19, wherein said method is a method of potentiating antibiotics in pulmonary super infections comprising pulmonary, ENT, urinary or skin infections. 24. The method according to claim 19, wherein said method is a method of lowering secondary infections due to chronic pathologies. 25. The method according to claim 19, wherein said method is a method of increasing the mucosal immune defense. 26. The method according to claim 24, wherein said method is a method of treatment or prevention of chronic obstructive bronchopneumopathy disease (COPD) or Bronchiectasy. 27. The method according to claim 19, wherein said method is a method of alleviating HIV/AIDS disorders. 28. The method according to claim 19, wherein said method is a method of regulating inflammation due to an inappropriate immune response or to infections. 29. The method according to claim 19, wherein said method is a method of enhancing an immune response to antigenic proteins in vaccination protocols. | The invention relates to preparations for dietary, food supplement or medical purposes and more specifically to a safe and natural preparation or a composition useful in immunity regulation and/or stimulation and in particular in the building, reinforcement, efficiency, maintenance and regeneration of natural immune defences in a subject. The preparations comprise magnesium, zinc and/or iron, blackcurrent seed oil and/or palm oil, two plant extracts selected from thyme, chickpea and lentil, as well as algae (fucus, wakame, nori), mushroom (shiitake, maitake) and at least one hydrosoluble vitamin and/or vitamin E.1. A composition for immunity regulation and/or stimulation, per 100 g or 100 ml, comprising the combination of:
10 μg to 1000 μg of positively charged minerals consisting of magnesium, 10 μg to 1000 μg of metals selected from zinc and iron 7 μg to 700 μg of at least one plant oil selected from Ribes nigrum Oleum Acini (blackcurrant seed oil) and Elaeis guineensis Oleum (palm oil), 6 μg to 600 μg of at least two plant extracts selected from Thymus vulgaris (thyme), Cicer arietinum (chickpea), and Ervum lens (lentil), 6 μg to 600 μg of at least one alga chosen among Fucus vesiculosus (Fucus), Undaria pinnatfida (Wakame), Palmaria palmata (Dulse), and Porphyra umbilicalis (Nori), 7 μg to 700 μg of at least one mushroom chosen among Lentinula edodes (Shiitake) and Grifola frondosa (Maitake), 8 μg to 800 μg of at least one vitamin chosen among vitamins A, B1, B2, B5, B6, B9, C, E, PP(B3); optionally with a suitable excipient. 2. The composition for immunity regulation and/or stimulation of claim 1, wherein vitamin A is between 15% and 100% of the GDA (Guideline Daily Amounts). 3. The composition for immunity regulation and/or stimulation of claim 2, wherein the input weight of vitamin A represents from 120 to 800 μg/100 g of said composition. 4. The composition for immunity regulation and/or stimulation of claim 2, wherein zinc is between 15% and 100% of the GDA (Guideline Daily Amounts). 5. The composition for immunity regulation and/or stimulation of claim 4, wherein the weight of zinc represents from 0.225 to 1 mg/100 g of said composition. 6. The composition for immunity regulation and/or stimulation of claim 1, wherein the suitable excipient is a pharmaceutically acceptable excipient. 7. The composition for immunity regulation and/or stimulation according to claim 1, for use in a food preparation, a dietary supplement, a nutraceutical, or a beverage. 8. A medicament comprising the composition for immunity regulation and/or stimulation according to claim 1. 9-17. (canceled) 18. The composition according to claim 1, wherein said composition is a food preparation, a dietary supplement, a nutraceutical, or a beverage. 19. A method of immunity regulation and/or stimulation in a subject in need thereof comprising administering a composition according to claim 1 to the subject. 20. The method according to claim 19, wherein said method is a method of prevention and/or alleviation of the symptoms related to pathogenic infections comprising viral infections, bacterial infections, or parasitic infections. 21. The method according to claim 20, wherein the parasitic infections comprise malaria, fungal infections, superinfections or episodic infections. 22. The method according to claim 20, wherein the episodic infections comprise winter infections; flu syndromes; bronchitis; tuberculosis; lower or upper respiratory tract infections; or urinary; intestinal or skin infections. 23. The method according to claim 19, wherein said method is a method of potentiating antibiotics in pulmonary super infections comprising pulmonary, ENT, urinary or skin infections. 24. The method according to claim 19, wherein said method is a method of lowering secondary infections due to chronic pathologies. 25. The method according to claim 19, wherein said method is a method of increasing the mucosal immune defense. 26. The method according to claim 24, wherein said method is a method of treatment or prevention of chronic obstructive bronchopneumopathy disease (COPD) or Bronchiectasy. 27. The method according to claim 19, wherein said method is a method of alleviating HIV/AIDS disorders. 28. The method according to claim 19, wherein said method is a method of regulating inflammation due to an inappropriate immune response or to infections. 29. The method according to claim 19, wherein said method is a method of enhancing an immune response to antigenic proteins in vaccination protocols. | 1,600 |
860 | 13,989,351 | 1,644 | The invention describes a method and compounds for the prevention and treatment of infections with intracellular organisms, the treatment of tumors, and the prevention of infectious and allergic diseases by vaccination. | 1. A method of preparing a peptide or polypeptide comprising an artificial sequence able to activate NKT cells, said method comprising the steps of:
(a) identifying a peptide or polypeptide that does not activate NKT cells; (b) introducing into the peptide or polypeptide at least one CD1d binding motif by aminoacid addition, substitution and/or deletion. 2. The method according to claim 1, wherein the CD1d binding motif is [FWHY]-X2X3-[ILMV]-X5X6-[FWHY], wherein X2, X3, X5, and X6 stand for any amino acid. 3. The method according to claim 2, wherein said peptides or polypeptides which do not activate NKT cells comprise at least one putative CD1d binding motif of [FWHY]-R-[ILMV] or [ILMV]-R-[FWHY], wherein R represents an aminoacid or an aminoacid sequence. 4. The method according to claim 2, wherein said peptides or polypeptides which do not activate NKT cells comprise at least one putative CD1d binding motif of:
[FWHY]-X2X3-[ILMV],
[ILMV]-X2X3-[FWHY],
[FWHY]-X2X3X4-[ILMV],
[ILMV]X2X3X4-[FWHY],
[FWHY]-X2-[ILMV],
[ILMV]-X2-[FWHY],
or any combination thereof, wherein X2, X3, X4 stand for any amino acid. 5. The method according to claim 1 wherein said CD1d binding motif is derived from an intracellular pathogen, a tumor-associated antigen, an antigen from an infectious agent or an allergen. 6. A peptide or polypeptide prepared by the method of claim 1, wherein the at least one CD1d binding motif is obtained by chemical synthesis or by recombinant expression. 7. A peptide or polypeptide prepared by the method of claim 1, further comprising bulky aminoacid residues within flanking sequences of said CD1d binding motif. 8. A peptide or polypeptide prepared by the method of claim 1, further comprising at least one class II restricted T cell epitope within flanking sequences of said CD1d binding motif. 9. A protein comprising a peptide or polypeptide prepared by the method of claim 1. 10-13. (canceled) 14. A peptide or polypeptide comprising an artificial sequence that activates NKT cells, wherein the artificial sequence is a CD1d binding motif comprising [FWHY]-X2X3-[ILMV]-X5X6-[FWHY]. 15. A nucleic acid encoding a peptide or polypeptide of claim 14. 16. A method of treating in a subject an infection, a tumor, or an allergic disease, the method comprising administering to the subject the peptide or polypeptide of claim 14. 17. A method of activating NKT cells in a mammal, the method comprising administering to the mammal the peptide or polypeptide of claim 14. 18. A method of treating in a subject an infection, a tumor, or an allergic disease, the method comprising administering to the subject the nucleic acid of claim 15. 19. A method of activating NKT cells in a mammal, the method comprising administering to the mammal the nucleic acid of claim 15. | The invention describes a method and compounds for the prevention and treatment of infections with intracellular organisms, the treatment of tumors, and the prevention of infectious and allergic diseases by vaccination.1. A method of preparing a peptide or polypeptide comprising an artificial sequence able to activate NKT cells, said method comprising the steps of:
(a) identifying a peptide or polypeptide that does not activate NKT cells; (b) introducing into the peptide or polypeptide at least one CD1d binding motif by aminoacid addition, substitution and/or deletion. 2. The method according to claim 1, wherein the CD1d binding motif is [FWHY]-X2X3-[ILMV]-X5X6-[FWHY], wherein X2, X3, X5, and X6 stand for any amino acid. 3. The method according to claim 2, wherein said peptides or polypeptides which do not activate NKT cells comprise at least one putative CD1d binding motif of [FWHY]-R-[ILMV] or [ILMV]-R-[FWHY], wherein R represents an aminoacid or an aminoacid sequence. 4. The method according to claim 2, wherein said peptides or polypeptides which do not activate NKT cells comprise at least one putative CD1d binding motif of:
[FWHY]-X2X3-[ILMV],
[ILMV]-X2X3-[FWHY],
[FWHY]-X2X3X4-[ILMV],
[ILMV]X2X3X4-[FWHY],
[FWHY]-X2-[ILMV],
[ILMV]-X2-[FWHY],
or any combination thereof, wherein X2, X3, X4 stand for any amino acid. 5. The method according to claim 1 wherein said CD1d binding motif is derived from an intracellular pathogen, a tumor-associated antigen, an antigen from an infectious agent or an allergen. 6. A peptide or polypeptide prepared by the method of claim 1, wherein the at least one CD1d binding motif is obtained by chemical synthesis or by recombinant expression. 7. A peptide or polypeptide prepared by the method of claim 1, further comprising bulky aminoacid residues within flanking sequences of said CD1d binding motif. 8. A peptide or polypeptide prepared by the method of claim 1, further comprising at least one class II restricted T cell epitope within flanking sequences of said CD1d binding motif. 9. A protein comprising a peptide or polypeptide prepared by the method of claim 1. 10-13. (canceled) 14. A peptide or polypeptide comprising an artificial sequence that activates NKT cells, wherein the artificial sequence is a CD1d binding motif comprising [FWHY]-X2X3-[ILMV]-X5X6-[FWHY]. 15. A nucleic acid encoding a peptide or polypeptide of claim 14. 16. A method of treating in a subject an infection, a tumor, or an allergic disease, the method comprising administering to the subject the peptide or polypeptide of claim 14. 17. A method of activating NKT cells in a mammal, the method comprising administering to the mammal the peptide or polypeptide of claim 14. 18. A method of treating in a subject an infection, a tumor, or an allergic disease, the method comprising administering to the subject the nucleic acid of claim 15. 19. A method of activating NKT cells in a mammal, the method comprising administering to the mammal the nucleic acid of claim 15. | 1,600 |
861 | 15,315,557 | 1,644 | The present invention relates to a method for prevention and/or treatment of an autoimmune disease, comprising administering a composition, said composition comprising at least one beta cell autoantigen, to a subject The subject may have a serum vitamin-D level above 50 nanomole/liter or the composition may be administered by intralymphatic injection or injection directly into a lymph node, or over a period of weeks, months, or years. The invention also relates to a composition comprising a plurality of particles, each having immobilised on its surface at least one first and at least one second antigen, wherein the first antigen is a beta cell autoantigen, and the second antigen is either a tolerogen or a beta cell autoantigen, and to composition comprising i) at least one beta cell autoantigen, and at least one of iia) an IL-10 inducing compound selected from the group consisting of vitamin-D, vitamin-D analogs, tyrosine kinase inhibitors, gamma-amino butyric acid, and gamma-amino butyric acid analogs; and iib) a compound that reduces the dendritic cells' ability to activate naïve CD4+ Tcells, such as a cyclooxygenase inhibitor, a CTLA-4 compound or a TNF alpha inhibitor. The invention also relates to pharmaceutical kits and to medical use of beta cell autoantigens. | 1. A method for prevention and/or treatment of an autoimmune disease, comprising administering a composition, said composition comprising at least one beta cell autoantigen, to a subject having a serum vitamin-D level above 50 nanomole/liter. 2. The method according to claim 1, wherein the beta cell autoantigen is selected from the group consisting of glutamic acid decarboxylase (GAD), insulinoma antigen-2, ZnT8, islet-specific glucose-6-phosphate catalytic subunit-related protein (IGRP), chromogranin A, insulin, B chain insulin, proinsulin, or preproinsulin. 3. The method according to claim 1 or 2, wherein the subject has a serum D-vitamin level between 50-150 nanomole/liter, such as 60-100 nanomole/liter, 75-100 nanomole/liter or 100-1500 nanomole/liter. 4. The method according to any one of claims 1-3, further comprising a pretreatment of the subject to adjust the serum vitamin-D level. 5. The method according to claim 4, wherein the pre-treatment of the subject comprises administration of vitamin-D and/or vitamin-D analogs, and/or exposure to UVB-radiation, preferably for between 7 to 90 days before administration of the composition comprising at least one beta cell autoantigen to said subject. 6. The method according to any one of claims 1-5, wherein the method comprises administration of vitamin-D and/or vitamin-D analogs in an amount of 7000-70000 IU/week for 3-48 months. 7. The method according to any one of claims 1-6, further comprising administering a cyclooxygenase inhibitor to the subject. 8. The method according to claim 7, wherein the cyclooxygenase inhibitor is selected from the group consisting of Ibuprofen, Dexibuprofen, Naproxen, Fenoprofen, Ketoprofen, Dexketoprofen, Flurbiprofen, Oxaprozin, Loxoprofen, Indomethacin, Tolmetin, Sulindac, Etodolac, Ketorolac, Diclofenac, Aceclofenac, Nabumetone, acetylsalicylic acid, Diflunisal (Dolobid), Salicylic acid, Salsalate (Disalcid), Piroxicam, Meloxicam, Tenoxicam, Droxicam, Lornoxicam, Isoxicam, Mefenamic acid, Meclofenamic acid, Flufenamic acid, Tolfenamic acid, Celecoxib, Rofecoxib, Valdecoxib, Parecoxib, Lumiracoxib, Etoricoxib, and Nimesulide. 9. The method according to any one of claims 1-8, further comprising administering a CTLA4 compound, such as abatacept, to the subject. 10. The method according to any one of claims 1-9, further comprising administering a TNF-alpha inhibitor to the subject. 11. The method according to claim 10, wherein the TNF-alpha inhibitor is selected from the group consisting of Adalimumab, Certolizumab, Etanercept, Golimumab and Infliximab. 12. The method according to any one of claims 1-11, further comprising administering gamma-amino butyric acid or a gamma-amino butyric acid analog to the subject. 13. The method according to any one of claims 1-12, comprising administering to the subject a composition according to any one of claims 51-58. 14. The method according to any one of claims 1-13, comprising administering the composition containing the beta cell autoantigen by intralymphatic injection, injection directly into a lymph node, subcutaneous injection, intramuscular injection, intraperitoneal injection, intravenous injection, intranasal, transmucosal or sublingual application; or orally, including administration as tablets, pellets, granules, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, sprays or as reconstituted dry powdered form with a liquid medium. 15. The method according to claim 14, comprising administering the composition containing the beta cell autoantigen by intralymphatic injection or injection directly into a lymph node. 16. The method according to claim 15, wherein the beta cell autoantigen is administered in an amount of 1-15 μg, more preferred between 2-10 μg, and most preferred between 2-5 μg per injection and autoantigen used. 17. The method according to claim 15 or 16, comprising administering the composition comprising the beta cell autoantigen at least 2 times, more preferred at least 3 times and most preferred at least 4 times, each administration being at least 14 days apart, more preferably at least 30 days apart. 18. The method according to any one of claims 1-17, comprising administering the beta cell autoantigen in increased doses over a period of weeks, months, or years. 19. The method according to claim 18, wherein the composition containing the beta cell autoantigen is administered 1-4 weeks apart in an initial treatment period of 3 to 4 months, and optionally 2-3 months apart in a continued treatment period of 6-9 months. 20. The method according to claim 18 or 19, wherein the amount of beta cell autoantigen is increased from 1-5 μg per administration at the beginning of the treatment period to about 40-100 μg per administration in the final administrations. 21. A method for prevention and/or treatment of an autoimmune disease, comprising administering to a subject a composition, said composition comprising at least one beta cell autoantigen, by intralymphatic injection or injection directly into a lymph node. 22. The method according to claim 21, wherein the beta cella autoantigen is selected from the group consisting of glutamic acid decarboxylase (GAD), insulinoma antigen-2, ZnT8, islet-specific glucose-6-phosphate catalytic subunit-related protein (IGRP), chromogranin A, insulin, B chain insulin, preproinsulin or proinsulin. 23. The method according to claim 21, wherein the beta cell autoantigen is administered in an amount of 1-15 μg, more preferred between 2-10 μg, and most preferred between 2-5 μg per injection and autoantigen used. 24. The method according to claim 21, 22 or 23, comprising administering the composition comprising the beta cell autoantigen at least 2 times, more preferred at least 3 times and most preferred at least 4 times, each administration being at least 14 days apart, more preferably at least 30 days apart. 25. The method according to any one of claims 21-24, further comprising administering a cyclooxygenase inhibitor to the subject. 26. The method according to claim 25, wherein the cyclooxygenase inhibitor is selected from the group consisting of Ibuprofen, Dexibuprofen, Naproxen, Fenoprofen, Ketoprofen, Dexketoprofen, Flurbiprofen, Oxaprozin, Loxoprofen, Indomethacin, Tolmetin, Sulindac, Etodolac, Ketorolac, Diclofenac, Aceclofenac, Nabumetone, acetylsalicylic acid, Diflunisal (Dolobid), Salicylic acid, Salsalate (Disalcid), Piroxicam, Meloxicam, Tenoxicam, Droxicam, Lornoxicam, Isoxicam, Mefenamic acid, Meclofenamic acid, Flufenamic acid, Tolfenamic acid, Celecoxib, Rofecoxib, Valdecoxib, Parecoxib, Lumiracoxib, Etoricoxib, and Nimesulide. 27. The method according to any one of claims 21-26, further comprising administering a CTLA4 compound, such as abatacept, to the subject. 28. The method according to any one of claims 21-27, further comprising administering a TNF-alpha inhibitor to the subject. 29. The method according to claim 28, wherein the TNF-alpha inhibitor is selected from the group consisting of Adalimumab, Certolizumab, Etanercept, Golimumab and Infliximab. 30. The method according to any one of claims 21-29, further comprising administering vitamin-D, vitamin-D analogs, tyrosine kinase inhibitors, gamma-amino butyric acid or a gamma-amino butyric acid analog to the subject, and/or exposing the subject to UVB-radiation. 31. The method according to claim 30, wherein administration of vitamin-D and/or vitamin-D analogs and/or exposure to UVB-light, is performed for between 7 to 90 days before administration of the composition comprising at least one beta cell autoantigen to said subject. 32. The method according to claim 30 or 31, wherein the method comprises administration of vitamin-D and/or vitamin-D analogs in an amount of 7000-70000 IU/week for 3-48 months. 33. The method according to any one of claims 21-32, comprising administering to the subject a composition according to any one of claims 51-58. 34. A method for prevention and/or treatment of an autoimmune disease, comprising administering to a subject at least one beta cell autoantigen, in increasing doses over a period of weeks, months, or years. 35. The method according to claim 34, wherein the beta cella autoantigen is selected from the group consisting of glutamic acid decarboxylase (GAD), insulinoma antigen-2, ZnT8, islet-specific glucose-6-phosphate catalytic subunit-related protein (IGRP), chromogranin A, insulin, B chain insulin, preproinsulin or proinsulin. 36. The method according to claim 34, wherein a composition containing the beta cell autoantigen is administered 1-4 weeks apart in an initial treatment period of 3 to 4 months, and optionally 2-3 months apart in a continued treatment period of 6-9 months. 37. The method according to claim 34, 35 or 36, wherein the amount of beta cell autoantigen is increased from 1-5 μg per administration at the beginning of the treatment period to about 40-100 μg per administration in the final administration. 38. The method according to any one of claims 34-37, further comprising administering a cyclooxygenase inhibitor to the subject. 39. The method according to claim 38, wherein the cyclooxygenase inhibitor is selected from the group consisting of Ibuprofen, Dexibuprofen, Naproxen, Fenoprofen, Ketoprofen, Dexketoprofen, Flurbiprofen, Oxaprozin, Loxoprofen, Indomethacin, Tolmetin, Sulindac, Etodolac, Ketorolac, Diclofenac, Aceclofenac, Nabumetone, acetylsalicylic acid, Diflunisal (Dolobid), Salicylic acid, Salsalate (Disalcid), Piroxicam, Meloxicam, Tenoxicam, Droxicam, Lornoxicam, Isoxicam, Mefenamic acid, Meclofenamic acid, Flufenamic acid, Tolfenamic acid, Celecoxib, Rofecoxib, Valdecoxib, Parecoxib, Lumiracoxib, Etoricoxib, and Nimesulide. 40. The method according to any one of claims 34-39, further comprising administering a CTLA4 compound, such as abatacept, to the subject. 41. The method according to any one of claims 34-40, further comprising administering a TNF-alpha inhibitor to the subject. 42. The method according to claim 41, wherein the TNF-alpha inhibitor is selected from the group consisting of Adalimumab, Certolizumab, Etanercept, Golimumab and Infliximab. 43. The method according to any one of claims 34-42, further comprising administering vitamin-D, vitamin-D analogs, tyrosine kinase inhibitors, gamma-amino butyric acid or a gamma-amino butyric acid analog to the subject, and/or exposing the subject to UVB-radiation. 44. The method according to claim 43, wherein administration of vitamin-D and/or vitamin-D analogs and/or exposure to UVB-light, is performed for between 7 to 90 days before administration of the composition comprising at least one beta cell autoantigen to said subject, such as administration of vitamin-D and/or vitamin-D analogs in an amount of 7000-70000 IU/week for 3-48 months. 45. The method according to any one of claims 34-44, comprising administering to the subject a composition according to any one of claims 51-58. 46. The method according to any one of claims 34-45, comprising administering the composition containing the beta cell autoanigen by intralymphatic injection, injection directly into a lymph node, subcutaneous injection, intramuscular injection, intraperitoneal injection, intravenous injection, intranasal, transmucosal or sublingual application; or orally, including administration as tablets, pellets, granules, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, sprays or as reconstituted dry powdered form with a liquid medium. 47. The method according to claim 46, comprising administering the composition containing the beta cell autoanigen by intralymphatic injection or injection directly into a lymph node. 48. The method according to claim 47, wherein the beta cell autoantigen is administered in an amount of 1-15 μg, more preferred between 2-10 μg, and most preferred between 2-5 μg per injection and autoantigen used. 49. The method according to claim 47 or 48, comprising administering the composition comprising the beta cell autoantigen at least 2 times, more preferred at least 3 times and most preferred at least 4 times, each administration being at least 14 days apart, more preferably at least 30 days apart. 50. The method according to any one of claims 1-49, wherein the autoimmune disease is type 1 diabetes or autoimmune diabetes. 51. A composition comprising a plurality of particles, each having immobilised on its surface at least one first and at least one second antigen, wherein the first antigen is a beta cell autoantigen, and the second antigen is either a tolerogen or a beta cell autoantigen, the composition further optionally comprising pharmaceutically acceptable adjuvants, excipients, solvents, and/or buffers. 52. The composition according to claim 51, wherein all beta cell autoantigens are selected from the group consisting of glutamic acid decarboxylase (GAD), insulinoma antigen-2, ZnT8, islet-specific glucose-6-phosphate catalytic subunit-related protein (IGRP), chromogranin A, insulin, B chain insulin, preproinsulin or proinsulin. 53. The composition according to claim 51 or 52, wherein at least one beta cell autoantigen is glutamic acid decarboxylase (GAD). 54. The composition according to any one of claims 51-53, wherein at least one beta cell autoantigen is GAD-65. 55. The composition according to any one of claims 51-54, wherein a second antigen is a tolerogen. 56. The composition according to claim 55, wherein the the tolerogen is a native human protein, such as IL-10, Human Serum Albumin or hemoglobin, or gamma-amino butyric acid. 57. The composition according to any one of claims 51-56, wherein the particle is an aluminium hydroxide (alum) particle, a liposome, a nanoparticle, a gold particle, or a biodegradable particle. 58. The composition according to any one of claims 51-57, wherein each particle has immobilised on its surface 2, 3, 4, 5, 6, 7, 8, 9, or 10 different antigens selected from the group consisting of tolerogens and beta cell autoantigens. 59. A composition comprising
i) at least one beta cell autoantigen, and at least one of iia) an IL-10 inducing compound selected from the group consisting of vitamin-D, vitamin-D analogs, tyrosine kinase inhibitors, gamma-amino butyric acid, and gamma-amino butyric acid analogs; and iib) a compound that reduces the dendritic cells' ability to activate naïve CD4+ Tcells, such as a cyclooxygenase inhibitor, a CTLA-4 compound or a TNF alpha inhibitor; and optionally pharmaceutically acceptable adjuvants, excipients, solvents, and/or buffers. 60. The composition according to claim 59, wherein the at least one beta cell autoantigen is selected from the group consisting of glutamic acid decarboxylase (GAD), insulinoma antigen-2, ZnT8, islet-specific glucose-6-phosphate catalytic subunit-related protein (IGRP), chromogranin A, insulin, B chain insulin, preproinsulin or proinsulin. 61. The composition according to claim 59, wherein the at least one autoantigen is GAD-65. 62. The composition according to any one of claims 59-60, wherein the composition comprises
iia) an IL-10 inducing compound selected from the group consisting of vitamin-D, vitamin-D analogs, tyrosine kinase inhibitors, gamma-amino butyric acid, and gamma-amino butyric acid analogs. 63. The composition according to claim 62, wherein the IL-10 inducing compound is vitamin-D or a vitamin-D analog. 64. The composition according to claim 62, wherein the IL-10 inducing compound is a tyrosine kinase inhibitor, such as dasatinib, bosutinib, saracatinib, imatinib, sunitinib, or a combination thereof. 65. The composition according to any one of claims 59-64, wherein the composition comprises
iib) a compound that reduces the dendritic cells' ability to activate naïve CD4+ Tcells, such as a cyclooxygenase inhibitor, a CTLA-4 compound or a TNF alpha inhibitor. 66. The composition according to claim 65, wherein the compound that reduces the dendritic cells' ability to activate naïve CD4+ Tcells is a cyclooxygenase inhibitor. 67. The composition according to claim 66, wherein the cyclooxygenase inhibitor is selected from the group consisting of Ibuprofen, Dexibuprofen, Naproxen, Fenoprofen, Ketoprofen, Dexketoprofen, Flurbiprofen, Oxaprozin, Loxoprofen, Indomethacin, Tolmetin, Sulindac, Etodolac, Ketorolac, Diclofenac, Aceclofenac, Nabumetone, acetylsalicylic acid, Diflunisal (Dolobid), Salicylic acid, Salsalate (Disalcid), Piroxicam, Meloxicam, Tenoxicam, Droxicam, Lornoxicam, Isoxicam, Mefenamic acid, Meclofenamic acid, Flufenamic acid, Tolfenamic acid, Celecoxib, Rofecoxib, Valdecoxib, Parecoxib, Lumiracoxib, Etoricoxib, and Nimesulide. 68. The composition according to claim 65, wherein the compound that reduces the dendritic cells' ability to activate naïve CD4+ Tcells is a CTLA-4 compound, such as abatacept. 69. The composition according to claim 65, wherein the compound that reduces the dendritic cells' ability to activate naïve CD4+ Tcells is a TNF-alpha inhibitor. 70. The composition according to claim 69, wherein the TNF-alpha inhibitor is selected from the group consisting of Adalimumab, Certolizumab, Etanercept, Golimumab and Infliximab. 71. The composition according to any one of claims 59-70 comprising
iia) an IL-10 inducing compound selected from the group consisting of vitamin-D, vitamin-D analogs, tyrosine kinase inhibitors, gamma-amino butyric acid, and gamma-amino butyric acid analogs; and
iib) a compound that reduces the dendritic cells' ability to activate naïve CD4+ Tcells, such as a cyclooxygenase inhibitor, a CTLA-4 compound or a TNF alpha inhibitor. 72. The composition according to any one of claims 59-71 comprising a composition according to claims 51-58. 73. The composition according to any one of claims 51-72, for use as medicament. 74. The composition according to any one of claims 51-72 for use in a method for prevention and/or treatment of an autoimmune disease, such as type 1 diabetes or autoimmune diabetes. 75. The composition for use according to claim 74, wherein the method for prevention and/or treatment of an autoimmune disease is a method according to any one of claims 1-50. 76. A pharmaceutical kit comprising
i) a composition comprising a beta cell autoantigen, and at least one of iia) a composition comprising an IL-10 inducing compound selected from the group consisting of vitamin-D, vitamin-D analogs, tyrosine kinase inhibitors, gamma-amino butyric acid, and gamma-amino butyric acid analogs; and iib) a composition comprising a compound that reduces the dendritic cells' ability to activate naïve CD4+ Tcells, such as a cyclooxygenase inhibitor, a CTLA-4 compound or a TNF alpha inhibitor. 77. The pharmaceutical kit according to claim 76, wherein the beta cell autoantigen is selected from the group consisting of glutamic acid decarboxylase (GAD), insulinoma antigen-2, ZnT8, islet-specific glucose-6-phosphate catalytic subunit-related protein (IGRP), chromogranin A, insulin, B chain insulin, proinsulin, or preproinsulin. 78. The pharmaceutical kit according to claim 76 or 77, wherein the beta cell autoantigen is GAD-65. 79. The pharmaceutical kit according to any one of claims 76 to 78, wherein at least one composition comprises vitamin-D or a vitamin-D analog. 80. The pharmaceutical kit according to any one of claims 76 to 79, wherein at least one composition comprises a tyrosine kinase inhibitor such as dasatinib, bosutinib, saracatinib, imatinib, sunitinib or a combinations thereof. 81. The pharmaceutical kit according to any one of claims 76 to 80, wherein at least one composition comprises gamma-amino butyric acid, and gamma-amino butyric acid analogs. 82. The pharmaceutical kit according to any one of claims 76 to 81, wherein at least one composition comprises a cyclooxygenase inhibitor, such as Ibuprofen, Dexibuprofen, Naproxen, Fenoprofen, Ketoprofen, Dexketoprofen, Flurbiprofen, Oxaprozin, Loxoprofen, Indomethacin, Tolmetin, Sulindac, Etodolac, Ketorolac, Diclofenac, Aceclofenac, Nabumetone, acetylsalicylic acid, Diflunisal (Dolobid), Salicylic acid, Salsalate (Disalcid), Piroxicam, Meloxicam, Tenoxicam, Droxicam, Lornoxicam, Isoxicam, Mefenamic acid, Meclofenamic acid, Flufenamic acid, Tolfenamic acid, Celecoxib, Rofecoxib, Valdecoxib, Parecoxib, Lumiracoxib, Etoricoxib, and Nimesulide. 83. The pharmaceutical kit according to any one of claims 76 to 82, wherein at least one composition comprises a a CTLA-4 compound, such as abatacept. 84. The pharmaceutical kit according to any one of claims 76 to 83, wherein at least one composition comprises a TNF alpha inhibitor, such as of Adalimumab, Certolizumab, Etanercept, Golimumab and Infliximab. 85. The pharmaceutical kit according to any one of claims 76 to 84, wherein the composition comprising a beta cell autoantigen is a composition according to any one of claims 51-58. 86. A beta cell autoantigen for use in a method according to any one of claims 1 to 50. | The present invention relates to a method for prevention and/or treatment of an autoimmune disease, comprising administering a composition, said composition comprising at least one beta cell autoantigen, to a subject The subject may have a serum vitamin-D level above 50 nanomole/liter or the composition may be administered by intralymphatic injection or injection directly into a lymph node, or over a period of weeks, months, or years. The invention also relates to a composition comprising a plurality of particles, each having immobilised on its surface at least one first and at least one second antigen, wherein the first antigen is a beta cell autoantigen, and the second antigen is either a tolerogen or a beta cell autoantigen, and to composition comprising i) at least one beta cell autoantigen, and at least one of iia) an IL-10 inducing compound selected from the group consisting of vitamin-D, vitamin-D analogs, tyrosine kinase inhibitors, gamma-amino butyric acid, and gamma-amino butyric acid analogs; and iib) a compound that reduces the dendritic cells' ability to activate naïve CD4+ Tcells, such as a cyclooxygenase inhibitor, a CTLA-4 compound or a TNF alpha inhibitor. The invention also relates to pharmaceutical kits and to medical use of beta cell autoantigens.1. A method for prevention and/or treatment of an autoimmune disease, comprising administering a composition, said composition comprising at least one beta cell autoantigen, to a subject having a serum vitamin-D level above 50 nanomole/liter. 2. The method according to claim 1, wherein the beta cell autoantigen is selected from the group consisting of glutamic acid decarboxylase (GAD), insulinoma antigen-2, ZnT8, islet-specific glucose-6-phosphate catalytic subunit-related protein (IGRP), chromogranin A, insulin, B chain insulin, proinsulin, or preproinsulin. 3. The method according to claim 1 or 2, wherein the subject has a serum D-vitamin level between 50-150 nanomole/liter, such as 60-100 nanomole/liter, 75-100 nanomole/liter or 100-1500 nanomole/liter. 4. The method according to any one of claims 1-3, further comprising a pretreatment of the subject to adjust the serum vitamin-D level. 5. The method according to claim 4, wherein the pre-treatment of the subject comprises administration of vitamin-D and/or vitamin-D analogs, and/or exposure to UVB-radiation, preferably for between 7 to 90 days before administration of the composition comprising at least one beta cell autoantigen to said subject. 6. The method according to any one of claims 1-5, wherein the method comprises administration of vitamin-D and/or vitamin-D analogs in an amount of 7000-70000 IU/week for 3-48 months. 7. The method according to any one of claims 1-6, further comprising administering a cyclooxygenase inhibitor to the subject. 8. The method according to claim 7, wherein the cyclooxygenase inhibitor is selected from the group consisting of Ibuprofen, Dexibuprofen, Naproxen, Fenoprofen, Ketoprofen, Dexketoprofen, Flurbiprofen, Oxaprozin, Loxoprofen, Indomethacin, Tolmetin, Sulindac, Etodolac, Ketorolac, Diclofenac, Aceclofenac, Nabumetone, acetylsalicylic acid, Diflunisal (Dolobid), Salicylic acid, Salsalate (Disalcid), Piroxicam, Meloxicam, Tenoxicam, Droxicam, Lornoxicam, Isoxicam, Mefenamic acid, Meclofenamic acid, Flufenamic acid, Tolfenamic acid, Celecoxib, Rofecoxib, Valdecoxib, Parecoxib, Lumiracoxib, Etoricoxib, and Nimesulide. 9. The method according to any one of claims 1-8, further comprising administering a CTLA4 compound, such as abatacept, to the subject. 10. The method according to any one of claims 1-9, further comprising administering a TNF-alpha inhibitor to the subject. 11. The method according to claim 10, wherein the TNF-alpha inhibitor is selected from the group consisting of Adalimumab, Certolizumab, Etanercept, Golimumab and Infliximab. 12. The method according to any one of claims 1-11, further comprising administering gamma-amino butyric acid or a gamma-amino butyric acid analog to the subject. 13. The method according to any one of claims 1-12, comprising administering to the subject a composition according to any one of claims 51-58. 14. The method according to any one of claims 1-13, comprising administering the composition containing the beta cell autoantigen by intralymphatic injection, injection directly into a lymph node, subcutaneous injection, intramuscular injection, intraperitoneal injection, intravenous injection, intranasal, transmucosal or sublingual application; or orally, including administration as tablets, pellets, granules, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, sprays or as reconstituted dry powdered form with a liquid medium. 15. The method according to claim 14, comprising administering the composition containing the beta cell autoantigen by intralymphatic injection or injection directly into a lymph node. 16. The method according to claim 15, wherein the beta cell autoantigen is administered in an amount of 1-15 μg, more preferred between 2-10 μg, and most preferred between 2-5 μg per injection and autoantigen used. 17. The method according to claim 15 or 16, comprising administering the composition comprising the beta cell autoantigen at least 2 times, more preferred at least 3 times and most preferred at least 4 times, each administration being at least 14 days apart, more preferably at least 30 days apart. 18. The method according to any one of claims 1-17, comprising administering the beta cell autoantigen in increased doses over a period of weeks, months, or years. 19. The method according to claim 18, wherein the composition containing the beta cell autoantigen is administered 1-4 weeks apart in an initial treatment period of 3 to 4 months, and optionally 2-3 months apart in a continued treatment period of 6-9 months. 20. The method according to claim 18 or 19, wherein the amount of beta cell autoantigen is increased from 1-5 μg per administration at the beginning of the treatment period to about 40-100 μg per administration in the final administrations. 21. A method for prevention and/or treatment of an autoimmune disease, comprising administering to a subject a composition, said composition comprising at least one beta cell autoantigen, by intralymphatic injection or injection directly into a lymph node. 22. The method according to claim 21, wherein the beta cella autoantigen is selected from the group consisting of glutamic acid decarboxylase (GAD), insulinoma antigen-2, ZnT8, islet-specific glucose-6-phosphate catalytic subunit-related protein (IGRP), chromogranin A, insulin, B chain insulin, preproinsulin or proinsulin. 23. The method according to claim 21, wherein the beta cell autoantigen is administered in an amount of 1-15 μg, more preferred between 2-10 μg, and most preferred between 2-5 μg per injection and autoantigen used. 24. The method according to claim 21, 22 or 23, comprising administering the composition comprising the beta cell autoantigen at least 2 times, more preferred at least 3 times and most preferred at least 4 times, each administration being at least 14 days apart, more preferably at least 30 days apart. 25. The method according to any one of claims 21-24, further comprising administering a cyclooxygenase inhibitor to the subject. 26. The method according to claim 25, wherein the cyclooxygenase inhibitor is selected from the group consisting of Ibuprofen, Dexibuprofen, Naproxen, Fenoprofen, Ketoprofen, Dexketoprofen, Flurbiprofen, Oxaprozin, Loxoprofen, Indomethacin, Tolmetin, Sulindac, Etodolac, Ketorolac, Diclofenac, Aceclofenac, Nabumetone, acetylsalicylic acid, Diflunisal (Dolobid), Salicylic acid, Salsalate (Disalcid), Piroxicam, Meloxicam, Tenoxicam, Droxicam, Lornoxicam, Isoxicam, Mefenamic acid, Meclofenamic acid, Flufenamic acid, Tolfenamic acid, Celecoxib, Rofecoxib, Valdecoxib, Parecoxib, Lumiracoxib, Etoricoxib, and Nimesulide. 27. The method according to any one of claims 21-26, further comprising administering a CTLA4 compound, such as abatacept, to the subject. 28. The method according to any one of claims 21-27, further comprising administering a TNF-alpha inhibitor to the subject. 29. The method according to claim 28, wherein the TNF-alpha inhibitor is selected from the group consisting of Adalimumab, Certolizumab, Etanercept, Golimumab and Infliximab. 30. The method according to any one of claims 21-29, further comprising administering vitamin-D, vitamin-D analogs, tyrosine kinase inhibitors, gamma-amino butyric acid or a gamma-amino butyric acid analog to the subject, and/or exposing the subject to UVB-radiation. 31. The method according to claim 30, wherein administration of vitamin-D and/or vitamin-D analogs and/or exposure to UVB-light, is performed for between 7 to 90 days before administration of the composition comprising at least one beta cell autoantigen to said subject. 32. The method according to claim 30 or 31, wherein the method comprises administration of vitamin-D and/or vitamin-D analogs in an amount of 7000-70000 IU/week for 3-48 months. 33. The method according to any one of claims 21-32, comprising administering to the subject a composition according to any one of claims 51-58. 34. A method for prevention and/or treatment of an autoimmune disease, comprising administering to a subject at least one beta cell autoantigen, in increasing doses over a period of weeks, months, or years. 35. The method according to claim 34, wherein the beta cella autoantigen is selected from the group consisting of glutamic acid decarboxylase (GAD), insulinoma antigen-2, ZnT8, islet-specific glucose-6-phosphate catalytic subunit-related protein (IGRP), chromogranin A, insulin, B chain insulin, preproinsulin or proinsulin. 36. The method according to claim 34, wherein a composition containing the beta cell autoantigen is administered 1-4 weeks apart in an initial treatment period of 3 to 4 months, and optionally 2-3 months apart in a continued treatment period of 6-9 months. 37. The method according to claim 34, 35 or 36, wherein the amount of beta cell autoantigen is increased from 1-5 μg per administration at the beginning of the treatment period to about 40-100 μg per administration in the final administration. 38. The method according to any one of claims 34-37, further comprising administering a cyclooxygenase inhibitor to the subject. 39. The method according to claim 38, wherein the cyclooxygenase inhibitor is selected from the group consisting of Ibuprofen, Dexibuprofen, Naproxen, Fenoprofen, Ketoprofen, Dexketoprofen, Flurbiprofen, Oxaprozin, Loxoprofen, Indomethacin, Tolmetin, Sulindac, Etodolac, Ketorolac, Diclofenac, Aceclofenac, Nabumetone, acetylsalicylic acid, Diflunisal (Dolobid), Salicylic acid, Salsalate (Disalcid), Piroxicam, Meloxicam, Tenoxicam, Droxicam, Lornoxicam, Isoxicam, Mefenamic acid, Meclofenamic acid, Flufenamic acid, Tolfenamic acid, Celecoxib, Rofecoxib, Valdecoxib, Parecoxib, Lumiracoxib, Etoricoxib, and Nimesulide. 40. The method according to any one of claims 34-39, further comprising administering a CTLA4 compound, such as abatacept, to the subject. 41. The method according to any one of claims 34-40, further comprising administering a TNF-alpha inhibitor to the subject. 42. The method according to claim 41, wherein the TNF-alpha inhibitor is selected from the group consisting of Adalimumab, Certolizumab, Etanercept, Golimumab and Infliximab. 43. The method according to any one of claims 34-42, further comprising administering vitamin-D, vitamin-D analogs, tyrosine kinase inhibitors, gamma-amino butyric acid or a gamma-amino butyric acid analog to the subject, and/or exposing the subject to UVB-radiation. 44. The method according to claim 43, wherein administration of vitamin-D and/or vitamin-D analogs and/or exposure to UVB-light, is performed for between 7 to 90 days before administration of the composition comprising at least one beta cell autoantigen to said subject, such as administration of vitamin-D and/or vitamin-D analogs in an amount of 7000-70000 IU/week for 3-48 months. 45. The method according to any one of claims 34-44, comprising administering to the subject a composition according to any one of claims 51-58. 46. The method according to any one of claims 34-45, comprising administering the composition containing the beta cell autoanigen by intralymphatic injection, injection directly into a lymph node, subcutaneous injection, intramuscular injection, intraperitoneal injection, intravenous injection, intranasal, transmucosal or sublingual application; or orally, including administration as tablets, pellets, granules, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, sprays or as reconstituted dry powdered form with a liquid medium. 47. The method according to claim 46, comprising administering the composition containing the beta cell autoanigen by intralymphatic injection or injection directly into a lymph node. 48. The method according to claim 47, wherein the beta cell autoantigen is administered in an amount of 1-15 μg, more preferred between 2-10 μg, and most preferred between 2-5 μg per injection and autoantigen used. 49. The method according to claim 47 or 48, comprising administering the composition comprising the beta cell autoantigen at least 2 times, more preferred at least 3 times and most preferred at least 4 times, each administration being at least 14 days apart, more preferably at least 30 days apart. 50. The method according to any one of claims 1-49, wherein the autoimmune disease is type 1 diabetes or autoimmune diabetes. 51. A composition comprising a plurality of particles, each having immobilised on its surface at least one first and at least one second antigen, wherein the first antigen is a beta cell autoantigen, and the second antigen is either a tolerogen or a beta cell autoantigen, the composition further optionally comprising pharmaceutically acceptable adjuvants, excipients, solvents, and/or buffers. 52. The composition according to claim 51, wherein all beta cell autoantigens are selected from the group consisting of glutamic acid decarboxylase (GAD), insulinoma antigen-2, ZnT8, islet-specific glucose-6-phosphate catalytic subunit-related protein (IGRP), chromogranin A, insulin, B chain insulin, preproinsulin or proinsulin. 53. The composition according to claim 51 or 52, wherein at least one beta cell autoantigen is glutamic acid decarboxylase (GAD). 54. The composition according to any one of claims 51-53, wherein at least one beta cell autoantigen is GAD-65. 55. The composition according to any one of claims 51-54, wherein a second antigen is a tolerogen. 56. The composition according to claim 55, wherein the the tolerogen is a native human protein, such as IL-10, Human Serum Albumin or hemoglobin, or gamma-amino butyric acid. 57. The composition according to any one of claims 51-56, wherein the particle is an aluminium hydroxide (alum) particle, a liposome, a nanoparticle, a gold particle, or a biodegradable particle. 58. The composition according to any one of claims 51-57, wherein each particle has immobilised on its surface 2, 3, 4, 5, 6, 7, 8, 9, or 10 different antigens selected from the group consisting of tolerogens and beta cell autoantigens. 59. A composition comprising
i) at least one beta cell autoantigen, and at least one of iia) an IL-10 inducing compound selected from the group consisting of vitamin-D, vitamin-D analogs, tyrosine kinase inhibitors, gamma-amino butyric acid, and gamma-amino butyric acid analogs; and iib) a compound that reduces the dendritic cells' ability to activate naïve CD4+ Tcells, such as a cyclooxygenase inhibitor, a CTLA-4 compound or a TNF alpha inhibitor; and optionally pharmaceutically acceptable adjuvants, excipients, solvents, and/or buffers. 60. The composition according to claim 59, wherein the at least one beta cell autoantigen is selected from the group consisting of glutamic acid decarboxylase (GAD), insulinoma antigen-2, ZnT8, islet-specific glucose-6-phosphate catalytic subunit-related protein (IGRP), chromogranin A, insulin, B chain insulin, preproinsulin or proinsulin. 61. The composition according to claim 59, wherein the at least one autoantigen is GAD-65. 62. The composition according to any one of claims 59-60, wherein the composition comprises
iia) an IL-10 inducing compound selected from the group consisting of vitamin-D, vitamin-D analogs, tyrosine kinase inhibitors, gamma-amino butyric acid, and gamma-amino butyric acid analogs. 63. The composition according to claim 62, wherein the IL-10 inducing compound is vitamin-D or a vitamin-D analog. 64. The composition according to claim 62, wherein the IL-10 inducing compound is a tyrosine kinase inhibitor, such as dasatinib, bosutinib, saracatinib, imatinib, sunitinib, or a combination thereof. 65. The composition according to any one of claims 59-64, wherein the composition comprises
iib) a compound that reduces the dendritic cells' ability to activate naïve CD4+ Tcells, such as a cyclooxygenase inhibitor, a CTLA-4 compound or a TNF alpha inhibitor. 66. The composition according to claim 65, wherein the compound that reduces the dendritic cells' ability to activate naïve CD4+ Tcells is a cyclooxygenase inhibitor. 67. The composition according to claim 66, wherein the cyclooxygenase inhibitor is selected from the group consisting of Ibuprofen, Dexibuprofen, Naproxen, Fenoprofen, Ketoprofen, Dexketoprofen, Flurbiprofen, Oxaprozin, Loxoprofen, Indomethacin, Tolmetin, Sulindac, Etodolac, Ketorolac, Diclofenac, Aceclofenac, Nabumetone, acetylsalicylic acid, Diflunisal (Dolobid), Salicylic acid, Salsalate (Disalcid), Piroxicam, Meloxicam, Tenoxicam, Droxicam, Lornoxicam, Isoxicam, Mefenamic acid, Meclofenamic acid, Flufenamic acid, Tolfenamic acid, Celecoxib, Rofecoxib, Valdecoxib, Parecoxib, Lumiracoxib, Etoricoxib, and Nimesulide. 68. The composition according to claim 65, wherein the compound that reduces the dendritic cells' ability to activate naïve CD4+ Tcells is a CTLA-4 compound, such as abatacept. 69. The composition according to claim 65, wherein the compound that reduces the dendritic cells' ability to activate naïve CD4+ Tcells is a TNF-alpha inhibitor. 70. The composition according to claim 69, wherein the TNF-alpha inhibitor is selected from the group consisting of Adalimumab, Certolizumab, Etanercept, Golimumab and Infliximab. 71. The composition according to any one of claims 59-70 comprising
iia) an IL-10 inducing compound selected from the group consisting of vitamin-D, vitamin-D analogs, tyrosine kinase inhibitors, gamma-amino butyric acid, and gamma-amino butyric acid analogs; and
iib) a compound that reduces the dendritic cells' ability to activate naïve CD4+ Tcells, such as a cyclooxygenase inhibitor, a CTLA-4 compound or a TNF alpha inhibitor. 72. The composition according to any one of claims 59-71 comprising a composition according to claims 51-58. 73. The composition according to any one of claims 51-72, for use as medicament. 74. The composition according to any one of claims 51-72 for use in a method for prevention and/or treatment of an autoimmune disease, such as type 1 diabetes or autoimmune diabetes. 75. The composition for use according to claim 74, wherein the method for prevention and/or treatment of an autoimmune disease is a method according to any one of claims 1-50. 76. A pharmaceutical kit comprising
i) a composition comprising a beta cell autoantigen, and at least one of iia) a composition comprising an IL-10 inducing compound selected from the group consisting of vitamin-D, vitamin-D analogs, tyrosine kinase inhibitors, gamma-amino butyric acid, and gamma-amino butyric acid analogs; and iib) a composition comprising a compound that reduces the dendritic cells' ability to activate naïve CD4+ Tcells, such as a cyclooxygenase inhibitor, a CTLA-4 compound or a TNF alpha inhibitor. 77. The pharmaceutical kit according to claim 76, wherein the beta cell autoantigen is selected from the group consisting of glutamic acid decarboxylase (GAD), insulinoma antigen-2, ZnT8, islet-specific glucose-6-phosphate catalytic subunit-related protein (IGRP), chromogranin A, insulin, B chain insulin, proinsulin, or preproinsulin. 78. The pharmaceutical kit according to claim 76 or 77, wherein the beta cell autoantigen is GAD-65. 79. The pharmaceutical kit according to any one of claims 76 to 78, wherein at least one composition comprises vitamin-D or a vitamin-D analog. 80. The pharmaceutical kit according to any one of claims 76 to 79, wherein at least one composition comprises a tyrosine kinase inhibitor such as dasatinib, bosutinib, saracatinib, imatinib, sunitinib or a combinations thereof. 81. The pharmaceutical kit according to any one of claims 76 to 80, wherein at least one composition comprises gamma-amino butyric acid, and gamma-amino butyric acid analogs. 82. The pharmaceutical kit according to any one of claims 76 to 81, wherein at least one composition comprises a cyclooxygenase inhibitor, such as Ibuprofen, Dexibuprofen, Naproxen, Fenoprofen, Ketoprofen, Dexketoprofen, Flurbiprofen, Oxaprozin, Loxoprofen, Indomethacin, Tolmetin, Sulindac, Etodolac, Ketorolac, Diclofenac, Aceclofenac, Nabumetone, acetylsalicylic acid, Diflunisal (Dolobid), Salicylic acid, Salsalate (Disalcid), Piroxicam, Meloxicam, Tenoxicam, Droxicam, Lornoxicam, Isoxicam, Mefenamic acid, Meclofenamic acid, Flufenamic acid, Tolfenamic acid, Celecoxib, Rofecoxib, Valdecoxib, Parecoxib, Lumiracoxib, Etoricoxib, and Nimesulide. 83. The pharmaceutical kit according to any one of claims 76 to 82, wherein at least one composition comprises a a CTLA-4 compound, such as abatacept. 84. The pharmaceutical kit according to any one of claims 76 to 83, wherein at least one composition comprises a TNF alpha inhibitor, such as of Adalimumab, Certolizumab, Etanercept, Golimumab and Infliximab. 85. The pharmaceutical kit according to any one of claims 76 to 84, wherein the composition comprising a beta cell autoantigen is a composition according to any one of claims 51-58. 86. A beta cell autoantigen for use in a method according to any one of claims 1 to 50. | 1,600 |
862 | 12,640,861 | 1,653 | The present invention relates to apparatus, methods, and applications for treating wastewater, and more particularly to biological processes for removing pollutants from wastewater. This invention further relates to apparatus and methods for growing microbes on-site at a wastewater treatment facility, and for economically inoculating sufficient microbes to solve various treatment problems rapidly | 1-73. (canceled) 74. A method of reducing the time required for a wastewater treatment plant for coming into compliance with an environmental discharge regulation comprising:
providing an on-site system for growing of microbes at the wastewater treatment plant, the on-site system comprising: a main tank, an input for water, an output for a treatment batch, a mixing apparatus, and a temperature control apparatus; depositing nutrient, water and an inoculum comprising microbes into the on-site system; growing the inoculum in the on-site system to provide a treatment batch comprising an increased number of the microbes; and directly applying at least a portion of the treatment batch, said portion containing microbes, to the polluted wastewater, such that the microbes are not isolated, concentrated or freeze dried between the steps of growing and applying, and wherein the microbes reduce the pollutants in the wastewater as measured by at least one of biochemical oxygen demand, chemical oxygen demand, total organic carbon, or total carbon. 75. The method of claim 74, wherein a portion of the treatment batch is used as an inoculum to re-inoculate a subsequent growth to produce a subsequent treatment batch. 76. The method of claim 74, wherein the depositing, growing and directly applying are repeated at least once a day. 77. The method of claim 74, wherein depositing, growing and directly applying are repeated at least twice a day. 78. The method of claim 74, wherein the depositing, growing and directly applying are repeated at least three times a day. 79. The method of claim 74, wherein the depositing, growing and directly applying are repeated at least four times a day. 80. The method of claim 74, further comprising depositing additional inoculum; wherein the depositing, growing and directly applying are repeated for at least one week before the depositing of additional inoculum. 81. The method of claim 80, wherein the depositing, growing and directly applying are repeated for at least two weeks before the depositing of additional inoculum. 82. The method of claim 80, wherein the depositing, growing and directly applying are repeated for at least three weeks before the depositing of additional inoculum. 83. The method of claim 80, wherein the depositing, growing and directly applying are repeated for at least four weeks before the depositing of additional inoculum. 84. The method of claim 80, wherein the depositing, growing and directly applying are repeated for at least three months before the depositing of additional inoculum. 85. The method of claim 74, wherein the time required for coming into compliance with the environmental discharge regulation is reduced by at least about 25 percent. 86. The method of claim 74, wherein the time required for coming into compliance with the environmental discharge regulation is reduced by at least about 50 percent. 87. The method of claim 74, wherein the time required for coming into compliance with the environmental discharge regulation is reduced by at least about 75 percent. 88. The method of claim 74, wherein the time required for coming into compliance with the environmental discharge regulation is reduced by at least about 90 percent. 89-95. (canceled) 96. The method of claim 74, wherein growing the inoculum is for about 8 to 24 hours. 97. The method of claim 74, wherein the on-site system comprises at least one growth tank, aeration, and a controller. 98. The method of claim 97, wherein the on-site system comprises at least two growth tanks. 99. The method of claim 97, wherein the growth tank holds from about 250 gallons to about 1000 gallons. 100. The method of claim 97, wherein the growth tank holds from about 0.25 gallons to about 250 gallons. 101. The method of claim 97, wherein the growth tank holds about 1000 gallons. 102. The method of claim 74, wherein the step of applying comprises releasing the portion of the treatment batch from the on-site system directly into the polluted wastewater. 103. The method of claim 74, wherein the step of growing further comprises aerating the inoculum. 104. The method of claim 74, comprising depositing a defoamer. | The present invention relates to apparatus, methods, and applications for treating wastewater, and more particularly to biological processes for removing pollutants from wastewater. This invention further relates to apparatus and methods for growing microbes on-site at a wastewater treatment facility, and for economically inoculating sufficient microbes to solve various treatment problems rapidly1-73. (canceled) 74. A method of reducing the time required for a wastewater treatment plant for coming into compliance with an environmental discharge regulation comprising:
providing an on-site system for growing of microbes at the wastewater treatment plant, the on-site system comprising: a main tank, an input for water, an output for a treatment batch, a mixing apparatus, and a temperature control apparatus; depositing nutrient, water and an inoculum comprising microbes into the on-site system; growing the inoculum in the on-site system to provide a treatment batch comprising an increased number of the microbes; and directly applying at least a portion of the treatment batch, said portion containing microbes, to the polluted wastewater, such that the microbes are not isolated, concentrated or freeze dried between the steps of growing and applying, and wherein the microbes reduce the pollutants in the wastewater as measured by at least one of biochemical oxygen demand, chemical oxygen demand, total organic carbon, or total carbon. 75. The method of claim 74, wherein a portion of the treatment batch is used as an inoculum to re-inoculate a subsequent growth to produce a subsequent treatment batch. 76. The method of claim 74, wherein the depositing, growing and directly applying are repeated at least once a day. 77. The method of claim 74, wherein depositing, growing and directly applying are repeated at least twice a day. 78. The method of claim 74, wherein the depositing, growing and directly applying are repeated at least three times a day. 79. The method of claim 74, wherein the depositing, growing and directly applying are repeated at least four times a day. 80. The method of claim 74, further comprising depositing additional inoculum; wherein the depositing, growing and directly applying are repeated for at least one week before the depositing of additional inoculum. 81. The method of claim 80, wherein the depositing, growing and directly applying are repeated for at least two weeks before the depositing of additional inoculum. 82. The method of claim 80, wherein the depositing, growing and directly applying are repeated for at least three weeks before the depositing of additional inoculum. 83. The method of claim 80, wherein the depositing, growing and directly applying are repeated for at least four weeks before the depositing of additional inoculum. 84. The method of claim 80, wherein the depositing, growing and directly applying are repeated for at least three months before the depositing of additional inoculum. 85. The method of claim 74, wherein the time required for coming into compliance with the environmental discharge regulation is reduced by at least about 25 percent. 86. The method of claim 74, wherein the time required for coming into compliance with the environmental discharge regulation is reduced by at least about 50 percent. 87. The method of claim 74, wherein the time required for coming into compliance with the environmental discharge regulation is reduced by at least about 75 percent. 88. The method of claim 74, wherein the time required for coming into compliance with the environmental discharge regulation is reduced by at least about 90 percent. 89-95. (canceled) 96. The method of claim 74, wherein growing the inoculum is for about 8 to 24 hours. 97. The method of claim 74, wherein the on-site system comprises at least one growth tank, aeration, and a controller. 98. The method of claim 97, wherein the on-site system comprises at least two growth tanks. 99. The method of claim 97, wherein the growth tank holds from about 250 gallons to about 1000 gallons. 100. The method of claim 97, wherein the growth tank holds from about 0.25 gallons to about 250 gallons. 101. The method of claim 97, wherein the growth tank holds about 1000 gallons. 102. The method of claim 74, wherein the step of applying comprises releasing the portion of the treatment batch from the on-site system directly into the polluted wastewater. 103. The method of claim 74, wherein the step of growing further comprises aerating the inoculum. 104. The method of claim 74, comprising depositing a defoamer. | 1,600 |
863 | 14,764,488 | 1,618 | A method of treating a fungal infection in a subject includes topically administering to the subject a therapeutically effective amount of a fungal iron acquisition inhibitor to treat fungal infection in the subject. | 1-27. (canceled) 28. A method of treating a corneal fungal infection in a subject comprising:
topically administering to the subject a therapeutically effective amount of a fungal iron acquisition inhibitor to treat corneal fungal infection in the subject. 29. The method of claim 28, the fungal iron acquisition inhibitor selected from the group consisting of an iron chelator, a siderophore binding protein, and a siderophore biosynthesis inhibitor. 30. The method of claim 29, the fungal iron acquisition inhibitor comprising an iron chelator. 31. The method of claim 30, the iron chelator comprising lactoferrin. 32. The method of claim 30, the iron chelator comprising a 3,5-diphenyl-1,2,4-triazole derivative or a salt thereof. 33. The method of claim 32, the 3,5-diphenyl-l,2,4-triazole derivative selected from the group consisting of deferasirox, deferiprone, deferitrin, LlNAU, deferoxamine or salt thereof. 34. The method of claim 30, the iron chelator comprising deferiprone. 35. The method of claim 29, the fungal iron acquisition inhibitor comprising a siderophore biosynthesis inhibitor. 36. The method of claim 35, the siderophore biosynthesis inhibitor comprising an arginase inhibitor. 37. The method of claim 36, the arginase inhibitor selected from the group consisting of (S)-(2-Boronoethyl)-L-cysteine (BEC), 2(S)-amino-6-boronohexanoic acid (ABH), NG-Hydroxy-L-arginine (NOHA), Nω-Hydroxy-nor-L-arginine (nor-NOHA) and DL-alpfa-Difluoromethylornithine (DFMO). 38. The method of claim 36, the arginase inhibitor comprising (S)-(2-Boronoethyl)-L-cysteine (BEC). 39. The method of claim 35, the siderophore biosynthesis inhibitor comprising a statin. 40. The method of claim 39, the statin selected from the group consisting of simvastatin, mevistatin, lovastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin. 41. The method of claim 29, the fungal iron acquisition inhibitor comprising a siderophore binding protein. 42. The method of claim 41, the siderophore binding protein comprising lipocalin-1. 43. The method of claim 28, the corneal fungal infection comprising a corneal fungal infection related to Aspergillus, Fusarium, Curvularia, or Alternaria. 44. The method of claim 28, the subject not having a corneal fungal infection, but being at risk of developing a corneal fungal infection. 45. The method of claim 28, wherein the subject is a neutropenic subject. 46. The method of claim 28, the fungal iron acquisition inhibitor being administered to the subject in an ophthalmic preparation. 47. The method of claim 28, the fungal iron acquisition inhibitor being administered to the subject in conjunction with one or more additional therapeutic agents. 48. The method of claim 47, the one or more additional therapeutic agents comprising a second fungal iron acquisition inhibitor. 49. The method of claim 48, the fungal iron acquisition inhibitor comprising an iron chelator and the second fungal iron acquisition inhibitor comprising a siderophore biosynthesis inhibitor. 50. The method of claim 49, wherein the iron chelator is deferiprone and the siderophore biosynthesis inhibitor is a statin. 51. The method of claim 47, the one or more additional therapeutic agents comprising an antibiotic, antiviral or antifungal agent. | A method of treating a fungal infection in a subject includes topically administering to the subject a therapeutically effective amount of a fungal iron acquisition inhibitor to treat fungal infection in the subject.1-27. (canceled) 28. A method of treating a corneal fungal infection in a subject comprising:
topically administering to the subject a therapeutically effective amount of a fungal iron acquisition inhibitor to treat corneal fungal infection in the subject. 29. The method of claim 28, the fungal iron acquisition inhibitor selected from the group consisting of an iron chelator, a siderophore binding protein, and a siderophore biosynthesis inhibitor. 30. The method of claim 29, the fungal iron acquisition inhibitor comprising an iron chelator. 31. The method of claim 30, the iron chelator comprising lactoferrin. 32. The method of claim 30, the iron chelator comprising a 3,5-diphenyl-1,2,4-triazole derivative or a salt thereof. 33. The method of claim 32, the 3,5-diphenyl-l,2,4-triazole derivative selected from the group consisting of deferasirox, deferiprone, deferitrin, LlNAU, deferoxamine or salt thereof. 34. The method of claim 30, the iron chelator comprising deferiprone. 35. The method of claim 29, the fungal iron acquisition inhibitor comprising a siderophore biosynthesis inhibitor. 36. The method of claim 35, the siderophore biosynthesis inhibitor comprising an arginase inhibitor. 37. The method of claim 36, the arginase inhibitor selected from the group consisting of (S)-(2-Boronoethyl)-L-cysteine (BEC), 2(S)-amino-6-boronohexanoic acid (ABH), NG-Hydroxy-L-arginine (NOHA), Nω-Hydroxy-nor-L-arginine (nor-NOHA) and DL-alpfa-Difluoromethylornithine (DFMO). 38. The method of claim 36, the arginase inhibitor comprising (S)-(2-Boronoethyl)-L-cysteine (BEC). 39. The method of claim 35, the siderophore biosynthesis inhibitor comprising a statin. 40. The method of claim 39, the statin selected from the group consisting of simvastatin, mevistatin, lovastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin. 41. The method of claim 29, the fungal iron acquisition inhibitor comprising a siderophore binding protein. 42. The method of claim 41, the siderophore binding protein comprising lipocalin-1. 43. The method of claim 28, the corneal fungal infection comprising a corneal fungal infection related to Aspergillus, Fusarium, Curvularia, or Alternaria. 44. The method of claim 28, the subject not having a corneal fungal infection, but being at risk of developing a corneal fungal infection. 45. The method of claim 28, wherein the subject is a neutropenic subject. 46. The method of claim 28, the fungal iron acquisition inhibitor being administered to the subject in an ophthalmic preparation. 47. The method of claim 28, the fungal iron acquisition inhibitor being administered to the subject in conjunction with one or more additional therapeutic agents. 48. The method of claim 47, the one or more additional therapeutic agents comprising a second fungal iron acquisition inhibitor. 49. The method of claim 48, the fungal iron acquisition inhibitor comprising an iron chelator and the second fungal iron acquisition inhibitor comprising a siderophore biosynthesis inhibitor. 50. The method of claim 49, wherein the iron chelator is deferiprone and the siderophore biosynthesis inhibitor is a statin. 51. The method of claim 47, the one or more additional therapeutic agents comprising an antibiotic, antiviral or antifungal agent. | 1,600 |
864 | 14,113,740 | 1,644 | Embodiments of this invention include methods for detecting in vitro the presence in peripheral blood mononuclear cells (PBMCs), and in serum or plasma, of antibodies reactive to and of lymphocytes that are responsive to CNS antigens associated with Multiple Sclerosis (MS). These CNS antigens include, but are not limited to whole brain lysate and the myelin antigens myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), MOG peptides (MOGps), proteolipid protein (PLP), and PLP peptides (PLPps). Stimulating PBMCs from patients with MS by CNS antigens cause B-lymphocytes to produce antibodies specific for CNS antigen, and causes T-lymphocytes to produce T-lymphocyte-specific cytokines, including interferon gamma (IFN-y), interleukin-2 (IL-2), or interleukin-17 (IL-17). In contrast, stimulating PBMCs from subjects without MS do not produce such responses. | 1. A method for diagnosing a Multiple Sclerosis (MS) in a human being, comprising:
a). providing a sample of peripheral blood mononuclear cells (PBMCs) from blood, and serum or plasma of said human being; b). exposing said sample of PBMCs and serum or plasma to a CNS antigen associated with Multiple Sclerosis (MS); and c). determining the presence of a B-lymphocyte/plasma cell, T-lymphocyte, or CNS-antigen specific antibody in said sample, said lymphocyte producing a molecule in response to said CNS antigen or said antibody binding to said CNS antigen. 2. The method of claim 1, where said CNS antigen is either present in whole brain lysate or is selected from the group consisting of myelin antigens, proteolipid protein (PLP), myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), neuronal antigen, MP4 fusion protein, recombinant proteins, and analogues of these proteins, and peptides that contain sequences of the protein CNS antigen. 3. The method of claim 1, where said step of determining includes a step of detecting a T-lymphocyte cytokine. 4. The method of claim 1, where said T-lymphocyte cytokine is interferon gamma (IFN-γ), interleukin-2 (IL-2), or interleukin-17 (IL-17). 5. The method of claim 1, where said step of determining includes a step of detecting an antibody specific for said CNS antigen. 6. The method of claim 1, where said CNS antigen is either present in whole brain lysate or is selected from the group consisting of myelin antigens such as proteolipid protein (PLP), myelin basic protein (MBP) or myelin oligodendrocyte glycoprotein (MOG), but also neuronal antigens and additionally, fusion proteins, recombinant proteins or analogues of these proteins, the analogues being defined by their cross-reactivity with the respective antigen-specific antibodies. CNS antigens also include peptides that contain sequences of the protein CNS antigens. 7. The method of claim 1, where said step of detecting is carried out using enzyme-linked immuno assay (ELISA), enzyme-linked immune spot assay (ELISPOT). 8. A method of determining whether a patient is likely to develop a symptom of MS, comprising the steps:
a. providing a sample of peripheral blood mononuclear cells (PBMC), and serum or plasma from blood of a patient with clinically-isolated syndrome (CIS) or radiologically-isolated syndrome (RIS), or MS; b. exposing said sample of PBMCs and serum or plasma to a CNS antigen associated with Multiple Sclerosis; and c. determining the presence of a B-lymphocyte or plasma cell or a T-lymphocyte or a CNS-specific antibody in said sample, said lymphocyte producing a molecule in response to said CNS antigen or said antibody binding to said CNS antigen; where if a response to said CNS antigen is detected, said patient is likely to develop MS. 9. A method of determining whether a patient with MS is likely to develop a relapse, comprising:
a. providing a sample of peripheral blood mononuclear cells (PBMCs) from blood, and serum or plasma of a patient with clinically-isolated syndrome (CIS), radiologically-isolated syndrome (RIS) or MS; b. exposing said sample of PBMCs and serum or plasma to a CNS antigen associated with Multiple Sclerosis; and c. determining the magnitude of a B-lymphocyte/plasma cell or a T-lymphocyte or antibody response to CNS antigen, said lymphocyte or plasma cell producing a molecule in response to said CNS antigen or said antibody binding to said CNS antigen, where an increase in response to said CNS antigen indicates an upcoming relapse. 10. A method for predicting whether a patient is likely to respond to immune modulatory therapy, comprising:
a. providing a sample of PBMCs, and serum or plasma from blood of said patient having MS, CIS or RIS; b. exposing said sample of PBMCs and serum or plasma to a CNS antigen associated with MS, and c. determining the presence of a B-lymphocyte, plasma cell, T-lymphocyte or antibody in said sample, said lymphocyte or plasma cell producing a molecule in response to said CNS antigen or said antibody binding to said CNS antigen; where if a response to said CNS antigen is detected, said patient is likely to respond to immune modulating therapy. 11. The method of claim 1, said method being carried out in vitro. 12. A method for detecting a cell that produces an antibody against a CNS-specific antigen, comprising the steps:
a) providing a cell culture well having a surface and a cell culture medium therein; b) attaching a CNS-specific antigen to said surface; c) introducing a sample of peripheral blood mononuclear cells (PBMCs), CNS cells, or cell liquor from a human being into said cell culture medium; d) permitting said PBMCs to produce an antibody against said CNS-specific antigen; and e) detecting the presence of said antibody using an anti-antibody specific reagent. 13. The method of claim 12, said step of detection being carried out using a method selected from the group consisting of enzyme linked immune spot assay (ELISPOT), enzyme-linked immunoassay (ELISA), bead array, or protein array. 14. The method of claim 12, said method performed with PBMCs or cells isolated from the CNS. 15. The method of claim 1 further comprising the step of stimulating production of said cell to produce said antibody. 16. The method of claim 1, said step of stimulating comprising use of a polyclonal stimulating agent. 17. The method of claim 16, said polyclonal stimulating agent being R848, interleukin-2 (IL-2) and/or β-mercaptoethanol. 18. The method of claim 12, said antibody being directed to a CNS-specific antigen selected from the group of human myelin basic protein (MBP), human myelin oligodendrocyte glycoprotein (hMOG), a peptide from hMOG (hMOGp), a proteolipid protein, CNS lysate, human proteolipid protein, and a MOG/PLP fusion protein. 19. The method of claim 1 where said hMOG is SEQ ID NO.1. 20. The method of claim 1, where said MOGp is human MOG 35-55 (SEQ ID NO.2). 21. The method of claim 1, where said MBP is MBP isoform 3, 21.5 kDa (SEQ ID NO.3). 22. The method of claim 1, where said proteolipid protein is ΔPLP4 (SEQ ID NO.4). 23. The method of claim 1, where said MOG/PLP fusion protein is MP4 (SEQ ID NO.6). 24. The method of claim 1, where said CNS-specific antigen response of a T-lymphocyte is detected via measurement of interleukin-17 (IL-17), interferon-γ (IFN-γ), or interleukin-2 (IL-2). 25. A method for predicting disease progression in a patient with remitting-relapsing MS (RRMS) comprising the steps:
a). providing a sample of PBMCs from blood of said patient having RRMS; b). exposing said sample of PBMCs to a CNS antigen associated with MS, and c). determining the presence of a B-lymphocyte or plasma cell or a T-lymphocyte in said sample, said lymphocyte producing a molecule in response to said CNS antigen; where if a response to said CNS antigen is detected, said patient is likely to show disease progression, to secondary progressive MS (SPMS). 26. A method for predicting whether a patient is likely to respond to B cell-specific therapy, comprising:
a. providing a sample of PBMCs from blood of said patient having MS, CIS or RIS; b. exposing said sample of PBMCs to a CNS antigen associated with MS, and c. determining the presence of a B-lymphocyte or plasma cell in said sample, said lymphocyte producing a molecule in response to said CNS antigen; where if a response to said CNS antigen is detected, said patient is likely to respond to B cell-specific therapy. 27. The method of claim 26, further comprising administering to said patient, a B-cell depleting agent. 28. The method of claim 27, where said B-cell depleting agent is anti-CD20 antibody. 29. The method of claim 26, further comprising administering to said patient, a therapeutic agent selected from the group consisting of glatiramer acetate, interferon beta-1a, interferon beta-1b, mitoxantrone, natalizumab, and FTY720 fingolimod. 30. A method for treating a patient having a symptom of multiple sclerosis (MS), comprising:
a) determining said patient's B lymphocyte (B cell) responsiveness using a direct B cell test in vitro to a CNS antigen; b) determining said patient's B cell responsiveness using an indirect B cell test in vitro to a CNS antigen; c) determining said patient's T lymphocytes (TH1 or TH17 cell) responsiveness in vitro to a CNS antigen; d) determining in vitro the presence of a serum antibody against a CNS antigen in said patient's serum; e) if said patient has a positive indirect B cell response, a positive serum antibody and a negative direct B cell response, said patient has clinically definite MS (ODMS); and f) said patient receives immune modulatory therapy to decrease the number of B cells or T cells; and optionally g) said patient receives a neuroprotective agent. 31. The method of claim 30, where if said patient's indirect B cell test is positive and direct B cell test is negative, said patient is diagnosed with remitting relapsing MS (RRMS), and said patient is treated with an immune modulating agent. 32. The method of claim 30, where is said patient's serum antibody test is positive, said TH17 test is positive, and said indirect B cell test is positive, said patient has clinically isolated syndrome (CIS), and
said patient is treated with an immune modulating agent. | Embodiments of this invention include methods for detecting in vitro the presence in peripheral blood mononuclear cells (PBMCs), and in serum or plasma, of antibodies reactive to and of lymphocytes that are responsive to CNS antigens associated with Multiple Sclerosis (MS). These CNS antigens include, but are not limited to whole brain lysate and the myelin antigens myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), MOG peptides (MOGps), proteolipid protein (PLP), and PLP peptides (PLPps). Stimulating PBMCs from patients with MS by CNS antigens cause B-lymphocytes to produce antibodies specific for CNS antigen, and causes T-lymphocytes to produce T-lymphocyte-specific cytokines, including interferon gamma (IFN-y), interleukin-2 (IL-2), or interleukin-17 (IL-17). In contrast, stimulating PBMCs from subjects without MS do not produce such responses.1. A method for diagnosing a Multiple Sclerosis (MS) in a human being, comprising:
a). providing a sample of peripheral blood mononuclear cells (PBMCs) from blood, and serum or plasma of said human being; b). exposing said sample of PBMCs and serum or plasma to a CNS antigen associated with Multiple Sclerosis (MS); and c). determining the presence of a B-lymphocyte/plasma cell, T-lymphocyte, or CNS-antigen specific antibody in said sample, said lymphocyte producing a molecule in response to said CNS antigen or said antibody binding to said CNS antigen. 2. The method of claim 1, where said CNS antigen is either present in whole brain lysate or is selected from the group consisting of myelin antigens, proteolipid protein (PLP), myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), neuronal antigen, MP4 fusion protein, recombinant proteins, and analogues of these proteins, and peptides that contain sequences of the protein CNS antigen. 3. The method of claim 1, where said step of determining includes a step of detecting a T-lymphocyte cytokine. 4. The method of claim 1, where said T-lymphocyte cytokine is interferon gamma (IFN-γ), interleukin-2 (IL-2), or interleukin-17 (IL-17). 5. The method of claim 1, where said step of determining includes a step of detecting an antibody specific for said CNS antigen. 6. The method of claim 1, where said CNS antigen is either present in whole brain lysate or is selected from the group consisting of myelin antigens such as proteolipid protein (PLP), myelin basic protein (MBP) or myelin oligodendrocyte glycoprotein (MOG), but also neuronal antigens and additionally, fusion proteins, recombinant proteins or analogues of these proteins, the analogues being defined by their cross-reactivity with the respective antigen-specific antibodies. CNS antigens also include peptides that contain sequences of the protein CNS antigens. 7. The method of claim 1, where said step of detecting is carried out using enzyme-linked immuno assay (ELISA), enzyme-linked immune spot assay (ELISPOT). 8. A method of determining whether a patient is likely to develop a symptom of MS, comprising the steps:
a. providing a sample of peripheral blood mononuclear cells (PBMC), and serum or plasma from blood of a patient with clinically-isolated syndrome (CIS) or radiologically-isolated syndrome (RIS), or MS; b. exposing said sample of PBMCs and serum or plasma to a CNS antigen associated with Multiple Sclerosis; and c. determining the presence of a B-lymphocyte or plasma cell or a T-lymphocyte or a CNS-specific antibody in said sample, said lymphocyte producing a molecule in response to said CNS antigen or said antibody binding to said CNS antigen; where if a response to said CNS antigen is detected, said patient is likely to develop MS. 9. A method of determining whether a patient with MS is likely to develop a relapse, comprising:
a. providing a sample of peripheral blood mononuclear cells (PBMCs) from blood, and serum or plasma of a patient with clinically-isolated syndrome (CIS), radiologically-isolated syndrome (RIS) or MS; b. exposing said sample of PBMCs and serum or plasma to a CNS antigen associated with Multiple Sclerosis; and c. determining the magnitude of a B-lymphocyte/plasma cell or a T-lymphocyte or antibody response to CNS antigen, said lymphocyte or plasma cell producing a molecule in response to said CNS antigen or said antibody binding to said CNS antigen, where an increase in response to said CNS antigen indicates an upcoming relapse. 10. A method for predicting whether a patient is likely to respond to immune modulatory therapy, comprising:
a. providing a sample of PBMCs, and serum or plasma from blood of said patient having MS, CIS or RIS; b. exposing said sample of PBMCs and serum or plasma to a CNS antigen associated with MS, and c. determining the presence of a B-lymphocyte, plasma cell, T-lymphocyte or antibody in said sample, said lymphocyte or plasma cell producing a molecule in response to said CNS antigen or said antibody binding to said CNS antigen; where if a response to said CNS antigen is detected, said patient is likely to respond to immune modulating therapy. 11. The method of claim 1, said method being carried out in vitro. 12. A method for detecting a cell that produces an antibody against a CNS-specific antigen, comprising the steps:
a) providing a cell culture well having a surface and a cell culture medium therein; b) attaching a CNS-specific antigen to said surface; c) introducing a sample of peripheral blood mononuclear cells (PBMCs), CNS cells, or cell liquor from a human being into said cell culture medium; d) permitting said PBMCs to produce an antibody against said CNS-specific antigen; and e) detecting the presence of said antibody using an anti-antibody specific reagent. 13. The method of claim 12, said step of detection being carried out using a method selected from the group consisting of enzyme linked immune spot assay (ELISPOT), enzyme-linked immunoassay (ELISA), bead array, or protein array. 14. The method of claim 12, said method performed with PBMCs or cells isolated from the CNS. 15. The method of claim 1 further comprising the step of stimulating production of said cell to produce said antibody. 16. The method of claim 1, said step of stimulating comprising use of a polyclonal stimulating agent. 17. The method of claim 16, said polyclonal stimulating agent being R848, interleukin-2 (IL-2) and/or β-mercaptoethanol. 18. The method of claim 12, said antibody being directed to a CNS-specific antigen selected from the group of human myelin basic protein (MBP), human myelin oligodendrocyte glycoprotein (hMOG), a peptide from hMOG (hMOGp), a proteolipid protein, CNS lysate, human proteolipid protein, and a MOG/PLP fusion protein. 19. The method of claim 1 where said hMOG is SEQ ID NO.1. 20. The method of claim 1, where said MOGp is human MOG 35-55 (SEQ ID NO.2). 21. The method of claim 1, where said MBP is MBP isoform 3, 21.5 kDa (SEQ ID NO.3). 22. The method of claim 1, where said proteolipid protein is ΔPLP4 (SEQ ID NO.4). 23. The method of claim 1, where said MOG/PLP fusion protein is MP4 (SEQ ID NO.6). 24. The method of claim 1, where said CNS-specific antigen response of a T-lymphocyte is detected via measurement of interleukin-17 (IL-17), interferon-γ (IFN-γ), or interleukin-2 (IL-2). 25. A method for predicting disease progression in a patient with remitting-relapsing MS (RRMS) comprising the steps:
a). providing a sample of PBMCs from blood of said patient having RRMS; b). exposing said sample of PBMCs to a CNS antigen associated with MS, and c). determining the presence of a B-lymphocyte or plasma cell or a T-lymphocyte in said sample, said lymphocyte producing a molecule in response to said CNS antigen; where if a response to said CNS antigen is detected, said patient is likely to show disease progression, to secondary progressive MS (SPMS). 26. A method for predicting whether a patient is likely to respond to B cell-specific therapy, comprising:
a. providing a sample of PBMCs from blood of said patient having MS, CIS or RIS; b. exposing said sample of PBMCs to a CNS antigen associated with MS, and c. determining the presence of a B-lymphocyte or plasma cell in said sample, said lymphocyte producing a molecule in response to said CNS antigen; where if a response to said CNS antigen is detected, said patient is likely to respond to B cell-specific therapy. 27. The method of claim 26, further comprising administering to said patient, a B-cell depleting agent. 28. The method of claim 27, where said B-cell depleting agent is anti-CD20 antibody. 29. The method of claim 26, further comprising administering to said patient, a therapeutic agent selected from the group consisting of glatiramer acetate, interferon beta-1a, interferon beta-1b, mitoxantrone, natalizumab, and FTY720 fingolimod. 30. A method for treating a patient having a symptom of multiple sclerosis (MS), comprising:
a) determining said patient's B lymphocyte (B cell) responsiveness using a direct B cell test in vitro to a CNS antigen; b) determining said patient's B cell responsiveness using an indirect B cell test in vitro to a CNS antigen; c) determining said patient's T lymphocytes (TH1 or TH17 cell) responsiveness in vitro to a CNS antigen; d) determining in vitro the presence of a serum antibody against a CNS antigen in said patient's serum; e) if said patient has a positive indirect B cell response, a positive serum antibody and a negative direct B cell response, said patient has clinically definite MS (ODMS); and f) said patient receives immune modulatory therapy to decrease the number of B cells or T cells; and optionally g) said patient receives a neuroprotective agent. 31. The method of claim 30, where if said patient's indirect B cell test is positive and direct B cell test is negative, said patient is diagnosed with remitting relapsing MS (RRMS), and said patient is treated with an immune modulating agent. 32. The method of claim 30, where is said patient's serum antibody test is positive, said TH17 test is positive, and said indirect B cell test is positive, said patient has clinically isolated syndrome (CIS), and
said patient is treated with an immune modulating agent. | 1,600 |
865 | 14,703,337 | 1,627 | Antimicrobial diferulates, compositions containing same, and uses of same for inhibiting growth of microorganisms. The antimicrobial diferulates can be used alone or in combination with other antimicrobial agents to inhibit growth of microorganisms such as fungi, oomycetes, and other microorganisms having a glucan-containing cell wall. The antimicrobial diferulates can be included in pharmaceutical compositions for treatment of animals or included in agricultural compositions for treatment of plants, crops, and soils. | 1. An antimicrobial composition comprising an antimicrobial-effective amount of a substantially purified compound selected from the group consisting of a compound of Formula I, a compound of Formula II, and combinations thereof, in combination with an inert carrier, wherein:
the compound of Formula I is selected from the group consisting of:
wherein R1-R5 are each independently selected from the group consisting of hydrogen, C1-C6 linear, branched, or cyclic alkyl, and C6 aryl; and a salt thereof; and
the compound of Formula II is selected from the group consisting of:
wherein R6-R10 are each independently selected from the group consisting of hydrogen, C1-C6 linear, branched, or cyclic alkyl, and C6 aryl; and a salt thereof. 2. The composition of claim 1 wherein the substantially purified compound comprises the compound of Formula I and the compound of Formula II. 3. The composition of claim 1 wherein the compound of Formula I is selected from the group consisting of:
and a salt thereof. 4. The composition of claim 1 wherein the compound of Formula II is selected from the group consisting of:
and a salt thereof. 5. The composition of claim 1 wherein the composition is substantially devoid of one or more diferulate compounds selected from the group consisting of 5-5 diferulate, 8-5-O diferulate, 8-8-C diferulate, 8-8-THF diferulate, 4-O-5 diferulate, 8-O-4 diferulate, and 8-8-O diferulate. 6. The composition of claim 1 wherein the composition comprises from about 0.01% to about 95% by mass of the substantially purified compound. 7. The composition of claim 1 wherein the composition comprises at least 5% water by mass. 8. The composition of claim 1 wherein the inert carrier comprises a solid carrier. 9. The composition of claim 1 wherein the inert carrier comprises a semi-solid carrier. 10. The composition of claim 1 wherein the inert carrier comprises a liquid carrier including at least 5% water by mass. 11. The composition of claim 1 further comprising an additional antimicrobial compound. 12. The composition of claim 11 wherein the additional antimicrobial compound comprises an antifungal compound. 13. The composition of claim 12 wherein the antifungal compound comprises a cell-wall targeting agent. 14. A method of inhibiting growth of a microorganism comprising contacting the microorganism with a composition as recited in claim 1. 15. The method of claim 14 wherein the microorganism comprises a glucan-containing cell wall. 16. The method of claim 14 wherein the microorganism is selected from the group consisting of a fungus and an oomycete. 17. A method of inhibiting microbial infection in a host comprising administering to the host a composition as recited in claim 1. 18. The method of claim 17 wherein the administering inhibits growth of a microorganism comprising a glucan-containing cell wall. 19. The method of claim 17 wherein the administering inhibits growth of a microorganism selected from the group consisting of a fungus and an oomycete. 20. The method of claim 17 wherein the host is an animal. 21. The method of claim 17 wherein the host is a plant. 22. A method of inhibiting growth of a microorganism comprising contacting the microorganism with an effective amount of a substantially purified compound selected from the group consisting of a compound of Formula I, a compound of Formula II, and combinations thereof, wherein:
the compound of Formula I is selected from the group consisting of:
wherein R1-R5 are each independently selected from the group consisting of hydrogen, C1-C6 linear, branched, or cyclic alkyl, and C6 aryl; and a salt thereof; and
the compound of Formula II is selected from the group consisting of:
wherein R6-R10 are each independently selected from the group consisting of hydrogen, C1-C6 linear, branched, or cyclic alkyl, and C6 aryl; and a salt thereof. | Antimicrobial diferulates, compositions containing same, and uses of same for inhibiting growth of microorganisms. The antimicrobial diferulates can be used alone or in combination with other antimicrobial agents to inhibit growth of microorganisms such as fungi, oomycetes, and other microorganisms having a glucan-containing cell wall. The antimicrobial diferulates can be included in pharmaceutical compositions for treatment of animals or included in agricultural compositions for treatment of plants, crops, and soils.1. An antimicrobial composition comprising an antimicrobial-effective amount of a substantially purified compound selected from the group consisting of a compound of Formula I, a compound of Formula II, and combinations thereof, in combination with an inert carrier, wherein:
the compound of Formula I is selected from the group consisting of:
wherein R1-R5 are each independently selected from the group consisting of hydrogen, C1-C6 linear, branched, or cyclic alkyl, and C6 aryl; and a salt thereof; and
the compound of Formula II is selected from the group consisting of:
wherein R6-R10 are each independently selected from the group consisting of hydrogen, C1-C6 linear, branched, or cyclic alkyl, and C6 aryl; and a salt thereof. 2. The composition of claim 1 wherein the substantially purified compound comprises the compound of Formula I and the compound of Formula II. 3. The composition of claim 1 wherein the compound of Formula I is selected from the group consisting of:
and a salt thereof. 4. The composition of claim 1 wherein the compound of Formula II is selected from the group consisting of:
and a salt thereof. 5. The composition of claim 1 wherein the composition is substantially devoid of one or more diferulate compounds selected from the group consisting of 5-5 diferulate, 8-5-O diferulate, 8-8-C diferulate, 8-8-THF diferulate, 4-O-5 diferulate, 8-O-4 diferulate, and 8-8-O diferulate. 6. The composition of claim 1 wherein the composition comprises from about 0.01% to about 95% by mass of the substantially purified compound. 7. The composition of claim 1 wherein the composition comprises at least 5% water by mass. 8. The composition of claim 1 wherein the inert carrier comprises a solid carrier. 9. The composition of claim 1 wherein the inert carrier comprises a semi-solid carrier. 10. The composition of claim 1 wherein the inert carrier comprises a liquid carrier including at least 5% water by mass. 11. The composition of claim 1 further comprising an additional antimicrobial compound. 12. The composition of claim 11 wherein the additional antimicrobial compound comprises an antifungal compound. 13. The composition of claim 12 wherein the antifungal compound comprises a cell-wall targeting agent. 14. A method of inhibiting growth of a microorganism comprising contacting the microorganism with a composition as recited in claim 1. 15. The method of claim 14 wherein the microorganism comprises a glucan-containing cell wall. 16. The method of claim 14 wherein the microorganism is selected from the group consisting of a fungus and an oomycete. 17. A method of inhibiting microbial infection in a host comprising administering to the host a composition as recited in claim 1. 18. The method of claim 17 wherein the administering inhibits growth of a microorganism comprising a glucan-containing cell wall. 19. The method of claim 17 wherein the administering inhibits growth of a microorganism selected from the group consisting of a fungus and an oomycete. 20. The method of claim 17 wherein the host is an animal. 21. The method of claim 17 wherein the host is a plant. 22. A method of inhibiting growth of a microorganism comprising contacting the microorganism with an effective amount of a substantially purified compound selected from the group consisting of a compound of Formula I, a compound of Formula II, and combinations thereof, wherein:
the compound of Formula I is selected from the group consisting of:
wherein R1-R5 are each independently selected from the group consisting of hydrogen, C1-C6 linear, branched, or cyclic alkyl, and C6 aryl; and a salt thereof; and
the compound of Formula II is selected from the group consisting of:
wherein R6-R10 are each independently selected from the group consisting of hydrogen, C1-C6 linear, branched, or cyclic alkyl, and C6 aryl; and a salt thereof. | 1,600 |
866 | 15,096,214 | 1,633 | An improved method to kill pathogenic microbes in a patient is disclosed and claimed. The improved method includes transducing eukaryotic cells of the patient with a first viral vector that will not transfect the pathogenic microbes. The first viral vector is replication defective and encodes in its recombinant genome a first antimicrobial resistance gene and a promoter. An antimicrobial medication is administered to the patient. | 1. A method to kill pathogenic microbes in a patient, comprising:
transducing eukaryotic cells of the patient with a first viral vector that will not transfect the pathogenic microbes, the first viral vector is replication defective and encodes in its recombinant genome a first antimicrobial resistance gene and a first promoter; and administering an antimicrobial medication to the patient. 2. The method of claim 1 wherein the first viral vector is chosen to generally transduce the patient's eukaryotic cells. 3. The method of claim 2 wherein the first viral vector is a human adenovirus vector serotype 5 that encodes a bsr gene downstream of a CMV promoter. 4. The method of claim 1 wherein the first viral vector is selected to primarily transduce one or more specific types of eukaryotic cells of the patient. 5. The method of claim 4 wherein the first viral vector is modified to have a different tropism. 6. The method of claim 4 wherein the specific type of eukaryotic cells of the patient belongs to the group consisting of neural, cardiac, skeletal, or pulmonary cells. 7. The method of claim 4 wherein the first viral vector is a self-complementary adeno-associated virus serotype 9 vector (scAAV9), with Hb9 promoter enhancer elements and a synapsin 1 (SYN1) promoter that are upstream of pfmdr1, that primarily transduces CNS tissue of the patient. 8. The method of claim 7 wherein administering the antimicrobial medication to the patient comprises mefloquine administration. 9. The method of claim 1 further comprising transducing eukaryotic cells of the patient with a second viral vector that will not transfect the pathogenic microbes, the second viral vector encoding in its recombinant genome a second antimicrobial resistance gene and a second promoter, the second viral vector being replication defective. 10. The method of claim 9 wherein the second promoter is the same as the first promoter. 11. The method of claim 9 wherein the first viral vector is chosen to generally transduce the patient's eukaryotic cells, and the second viral vector is chosen to primarily transduce one or more specific types of eukaryotic cells of the patient. 12. The method of claim 11 wherein the first viral vector is a lentivirus vector with a VSV-G pseudotype, and the second viral vector is an adeno-associated virus serotype 1 that primarily transduces skeletal muscle cells, cardiac muscle cells, and central nervous system cells of the patient. 13. The method of claim 1 wherein the first viral vector is chosen from the group consisting of the adenoviridae, arenaviridae, bunyaviridae, flaviviridae, hepadnaviridae, herpesviridae, orthomyxoviridae, papovaviridae, paramyxoviridae, parvoviridae, picornaviridae, poxviridae, reoviridae, retroviridae, rhabdoviridae, and togaviridae families. 14. The method of claim 1 wherein the antimicrobial medication is an antibiotic medication, and the pathogenic microbes are bacteria. 15. The method of claim 14 wherein the first viral vector is a human adenovirus serotype 35 vector, containing a human PGP gene downstream of a human EF-1 promoter. 16. The method of claim 15 wherein administering the antimicrobial medication to the patient comprises ciprofloxacin administration. 17. The method of claim 1 wherein the pathogenic microbes are fungi, and the antimicrobial medication is an antifungal agent selected from the group consisting of azoles, polyenes, echinocandins, and flucytosine. 18. The method of claim 17 wherein the first viral vector is an adeno-associated virus serotype 1 vector containing a CDR1 antifungal resistance gene downstream of a synthetic CAG promoter. 19. The method of claim 18 wherein administering the antimicrobial medication to the patient comprises voriconazole administration. 20. The method of claim 1 wherein the antimicrobial medication is an antiparasitic agent, and the pathogenic microbes are parasites. 21. The method of claim 1 wherein the first promoter is selected from the group consisting of ubiquitous promoters, tissue-specific promoters, inducible promoters, and synthetic promoters. 22. The method of claim 21 wherein the first viral vector is a HIV-1 lentivirus vector, containing a tetX tetracycline resistance gene downstream of a TetOn inducible promoter. 23. The method of claim 22 wherein administering the antimicrobial medication to the patient comprises tetracycline administration. 24. The method of claim 1 wherein the first viral vector is administered intravenously to the patient before the antimicrobial medication is administered to the patient. 25. The method of claim 9 wherein the patient is a human, the first viral vector is a herpes simplex virus 1 vector containing a mefE macrolide resistance gene downstream of a neural-specific SYN promoter, and the second viral vector is an adeno-associated virus serotype 6 vector containing mefE downstream of a cardiac-specific a-myosin heavy chain promoter, and wherein administering the antimicrobial medication to the patient comprises azithromycin administration. 26. The method of claim 11 wherein the patient is a mouse. 27. The method of claim 26 wherein the first viral vector is a replication incompetent Venezuelan equine encephalitis virus vector containing a hph gene downstream of a murine ROSA promoter and the second viral vector is a pulmonary-specific influenza hemagglutinin-pseudotyped equine infectious anemia virus vector containing a hph gene downstream of a murine PGK1 promoter. 28. The method of claim 27 wherein administering the antimicrobial medication to the patient comprises hygromycin B administration. 29. The method of claim 1 wherein the first viral vector is a human adenovirus serotype 11 vector, containing both the vgb and ermA antimicrobial resistance genes, each downstream of a GAPDH promoter. 30. The method of claim 29 wherein administering the antimicrobial medication to the patient comprises quinupristin administration and dalfopristin administration. | An improved method to kill pathogenic microbes in a patient is disclosed and claimed. The improved method includes transducing eukaryotic cells of the patient with a first viral vector that will not transfect the pathogenic microbes. The first viral vector is replication defective and encodes in its recombinant genome a first antimicrobial resistance gene and a promoter. An antimicrobial medication is administered to the patient.1. A method to kill pathogenic microbes in a patient, comprising:
transducing eukaryotic cells of the patient with a first viral vector that will not transfect the pathogenic microbes, the first viral vector is replication defective and encodes in its recombinant genome a first antimicrobial resistance gene and a first promoter; and administering an antimicrobial medication to the patient. 2. The method of claim 1 wherein the first viral vector is chosen to generally transduce the patient's eukaryotic cells. 3. The method of claim 2 wherein the first viral vector is a human adenovirus vector serotype 5 that encodes a bsr gene downstream of a CMV promoter. 4. The method of claim 1 wherein the first viral vector is selected to primarily transduce one or more specific types of eukaryotic cells of the patient. 5. The method of claim 4 wherein the first viral vector is modified to have a different tropism. 6. The method of claim 4 wherein the specific type of eukaryotic cells of the patient belongs to the group consisting of neural, cardiac, skeletal, or pulmonary cells. 7. The method of claim 4 wherein the first viral vector is a self-complementary adeno-associated virus serotype 9 vector (scAAV9), with Hb9 promoter enhancer elements and a synapsin 1 (SYN1) promoter that are upstream of pfmdr1, that primarily transduces CNS tissue of the patient. 8. The method of claim 7 wherein administering the antimicrobial medication to the patient comprises mefloquine administration. 9. The method of claim 1 further comprising transducing eukaryotic cells of the patient with a second viral vector that will not transfect the pathogenic microbes, the second viral vector encoding in its recombinant genome a second antimicrobial resistance gene and a second promoter, the second viral vector being replication defective. 10. The method of claim 9 wherein the second promoter is the same as the first promoter. 11. The method of claim 9 wherein the first viral vector is chosen to generally transduce the patient's eukaryotic cells, and the second viral vector is chosen to primarily transduce one or more specific types of eukaryotic cells of the patient. 12. The method of claim 11 wherein the first viral vector is a lentivirus vector with a VSV-G pseudotype, and the second viral vector is an adeno-associated virus serotype 1 that primarily transduces skeletal muscle cells, cardiac muscle cells, and central nervous system cells of the patient. 13. The method of claim 1 wherein the first viral vector is chosen from the group consisting of the adenoviridae, arenaviridae, bunyaviridae, flaviviridae, hepadnaviridae, herpesviridae, orthomyxoviridae, papovaviridae, paramyxoviridae, parvoviridae, picornaviridae, poxviridae, reoviridae, retroviridae, rhabdoviridae, and togaviridae families. 14. The method of claim 1 wherein the antimicrobial medication is an antibiotic medication, and the pathogenic microbes are bacteria. 15. The method of claim 14 wherein the first viral vector is a human adenovirus serotype 35 vector, containing a human PGP gene downstream of a human EF-1 promoter. 16. The method of claim 15 wherein administering the antimicrobial medication to the patient comprises ciprofloxacin administration. 17. The method of claim 1 wherein the pathogenic microbes are fungi, and the antimicrobial medication is an antifungal agent selected from the group consisting of azoles, polyenes, echinocandins, and flucytosine. 18. The method of claim 17 wherein the first viral vector is an adeno-associated virus serotype 1 vector containing a CDR1 antifungal resistance gene downstream of a synthetic CAG promoter. 19. The method of claim 18 wherein administering the antimicrobial medication to the patient comprises voriconazole administration. 20. The method of claim 1 wherein the antimicrobial medication is an antiparasitic agent, and the pathogenic microbes are parasites. 21. The method of claim 1 wherein the first promoter is selected from the group consisting of ubiquitous promoters, tissue-specific promoters, inducible promoters, and synthetic promoters. 22. The method of claim 21 wherein the first viral vector is a HIV-1 lentivirus vector, containing a tetX tetracycline resistance gene downstream of a TetOn inducible promoter. 23. The method of claim 22 wherein administering the antimicrobial medication to the patient comprises tetracycline administration. 24. The method of claim 1 wherein the first viral vector is administered intravenously to the patient before the antimicrobial medication is administered to the patient. 25. The method of claim 9 wherein the patient is a human, the first viral vector is a herpes simplex virus 1 vector containing a mefE macrolide resistance gene downstream of a neural-specific SYN promoter, and the second viral vector is an adeno-associated virus serotype 6 vector containing mefE downstream of a cardiac-specific a-myosin heavy chain promoter, and wherein administering the antimicrobial medication to the patient comprises azithromycin administration. 26. The method of claim 11 wherein the patient is a mouse. 27. The method of claim 26 wherein the first viral vector is a replication incompetent Venezuelan equine encephalitis virus vector containing a hph gene downstream of a murine ROSA promoter and the second viral vector is a pulmonary-specific influenza hemagglutinin-pseudotyped equine infectious anemia virus vector containing a hph gene downstream of a murine PGK1 promoter. 28. The method of claim 27 wherein administering the antimicrobial medication to the patient comprises hygromycin B administration. 29. The method of claim 1 wherein the first viral vector is a human adenovirus serotype 11 vector, containing both the vgb and ermA antimicrobial resistance genes, each downstream of a GAPDH promoter. 30. The method of claim 29 wherein administering the antimicrobial medication to the patient comprises quinupristin administration and dalfopristin administration. | 1,600 |
867 | 15,784,487 | 1,619 | Disclosed herein are foamable gritty foam compositions that can suspend particulate mechanical scrubbers with particles sized from about 100 microns to about 800 microns that is capable of being foamed through a non-aerosol, or unpressurized pump dispenser. | 1. A non-aerosol dispenser containing a foamable gritty composition, the non-aerosol dispenser comprising an unpressurized container having a dispenser pump configured to mix air with the foamable gritty composition under low pressure conditions during dispensing to form a gritty foam; and the foamable gritty composition comprising:
a) constituents including a solvent present in a range from about 0.5% w/w to about 30.0% w/w, said solvent including any one or combination of D'limonene and sunflower oil methyl ester; a particulate scrubbing agent present in a range from about 1.0% w/w to about 8% w/w; a surfactant present in a range from about 0.5% w/w to about 30.0% w/w; skin conditioner present in a range from 0.01% w/w to about 5.00% w/w; and a non-Newtonian thickening agent present in a range from about 0.05% w/w to about 10% w/w; water; and b) wherein the non-Newtonian thickening agent is selected to give the foamable gritty formulation a critical strain force greater than or equal to about 30 dynes/cm2, and a viscosity in a range from about 500 cPoise to about 4000 cPoise such that said foamable gritty composition is dispensible as a foam from a non-aerosol foam dispenser. 2. The non-aerosol dispenser containing a foamable gritty composition according to claim 1 wherein the surfactant includes any one or combination of
i) an anionic surfactant present in a range from about 1% w/w to about 20% w/w if present alone;
ii) an amphoteric surfactant present in a range from about 0.5% w/w to about 5.0% w/w if present alone;
iii) a non-ionic surfactant present in a range from about 0.5% w/w to about 20% w/w if present alone; and
wherein a total amount of surfactant of any combination of surfactants present is in a range from about 0.5% w/w to about 30.0% w/w. 3. The non-aerosol dispenser containing a foamable gritty composition according to claim 2 wherein the anionic surfactant is selected from the group consisting of lauryl sulphates, lauryl ether sulphates, sulphosuccinates, carboxylates (i.e. sodium oleate), carboxylic acid esters (i.e. sodium dilaureth citrate), alkyl sulfate (i.e. sodium lauryl ether sulfate, ammonium alkyl sulfate, alkyl and alkyl-aryl sulfonates (i.e. sodium dodecyl benzene sulfonate), sulfosuccinates (i.e. disodium laurylether sulfosuccinate), isethionates (i.e. sodium cocoyl isethionate, ammonium cocoyl isethionate), taurates (i.e. sodium methyl cocoyl taurate, sodium methyl oleoyl taurate), acyl glutamates (i.e. sodium lauroyl glutamate, sodium cocoyl glutamate, disodium cocoyl glutamate), sarcosinate (i.e. cocoyl sarcosinate), alkylpolyglucosides (i.e. decyl glucoside, sodium lauryl glucose carboxylate, caprylyl/capryl glucoside). 4. The non-aerosol dispenser containing a foamable gritty composition according to claim 2 wherein the amphoteric surfactant is any one or combination of betaines, acyl ethylene diamines, amino-acids derivates, imidazolines. 5. The non-aerosol dispenser containing a foamable gritty composition according to claim 2 wherein the amphoteric surfactant is any one or combination of acylamphoacetate, acylamphodiacetate, acylamphodipropionate, sodium cocoglycinate, sodium alkyliminodipropionate, cocamidopropyl betaine, sodium cocoamphoacetate. 6. The non-aerosol dispenser containing a foamable gritty composition according to claim 4 wherein said betaine is selected from the group consisting of coco betaine and cocamidopropyl betaine. 7. The non-aerosol dispenser containing a foamable gritty composition according to claim 2 wherein the non-ionic surfactant is any one or combination of of glucosides, ethoxylated fatty alcohols, ethoxylated fatty acids, saccharose esters, sorbitan esters, alkanolamides, glycerol alkyl esters and polyoxyethylene glycol alkylphenol ethers. 8. The non-aerosol dispenser containing a foamable gritty composition according to claim 1 wherein the solvent further includes any one or combination of glycol ethers, esters, alcohols, terpenes other than D'Limonene, aromatic-free white spirit, and wherein a total amount of solvent present is in said range from about 0.5% w/w to about 30.0% w/w. 9. The non-aerosol dispenser containing a foamable gritty composition according to claim 1 wherein the particulate scrubbing agent is any one or combination of a vegetable based scrubbing agent, a synthetic based scrubbing agent and a mineral based scrubbing agent, and wherein the scrubbing agent has a size in a range from about 100 microns to about 800 microns. 10. The non-aerosol dispenser containing a foamable gritty composition according to claim 9 wherein the vegetable based scrubbing agent is any one or combination of cornmeal, olive stone, walnut shells, ground fruit stones, ground corn meal, ground fruit shells. 11. The non-aerosol dispenser containing a foamable gritty composition according to claim 9 wherein the synthetic based scrubbing agent is any one or combination of polyethylene and polypropylene. 12. The non-aerosol dispenser containing a foamable gritty composition according to claim 9 wherein the mineral based scrubbing agent is any one or combination of ground shellfish, pumice, and silica. 13. The non-aerosol dispenser containing a foamable gritty composition according to claim 1 wherein said skin conditioner is any one or combination of a polyol, an anionic surfactant, a non-ionic surfactant, a cationic surfactant, an amphoteric surfactant, a cationic polymer, a quaternised gum, and a polyol. 14. The non-aerosol dispenser containing a foamable gritty composition according to claim 13 wherein said polyol is any one or combination of glycerine and polyglycerin-6, propylene glycol, sorbitol, mannitol, erythritol, xylitol, arabitol, ribitol, dulcitol, lactitol, and maltitol. 15. The non-aerosol dispenser containing a foamable gritty composition according to claim 1 wherein said thickening agent is any one or combination of synthetic polymers and natural thickeners. 16. The non-aerosol dispenser containing a foamable gritty composition according to claim 15 wherein said synthetic polymer is selected from the group consisting of acrylate copolymers. 17. The non-aerosol dispenser containing a foamable gritty composition according to claim 15 wherein said synthetic polymer is selected from the group consisting of acrylates/C10-30 alkyl acrylate crosspolymer, carbomers, and combinations thereof. 18. The non-aerosol dispenser containing a foamable gritty composition according to claim 15 wherein said natural thickener is selected from the group consisting of xanthan gum, guar gum, quaternised guar gum, alginate, bentonite and fumed silica. 19. The non-aerosol dispenser containing a foamable gritty composition according to claim 1 including an antioxidant present in a range from about 0.01 to about 1.0% w/w. 20. The non-aerosol dispenser containing a foamable gritty composition according to claim 19 wherein said antioxidant is any one or combination of butylhydroxytoluene (BHT), butylhydroxyanizole, 1,2-dihydroxybenzene, p-coumarine acid, caffeic acid, sodium sulfite, sodium metasulfite, ferrulic acid, tyrosol, quercetin, chlorogenic acid, oleuropein hydroxytyrosol, ascorbic acid, phenolic acid, propyl gallate, α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, and tetradibutyl-pentaerithrityl hydroxyhydrocinnamate. 21. A method of producing and dispensing a gritty foam, the method comprising;
dispensing a foamable gritty composition from a non-aerosol dispenser containing the foamable gritty composition, the non-aerosol disperser comprising an unpressurized container having a dispenser pump configured to mix air with the foamable gritty composition under low pressure conditions during dispensing to form a gritty foam; and the foamable gritty composition comprising
a) constituents including
a solvent present in a range from about 0.5% w/w to about 30.0% w/w, said solvent including any one or combination of D'limonene and sunflower oil methyl ester;
a particulate scrubbing agent present in a range from about 1.0% w/w to about 8% w/w;
a surfactant present in a range from about 0.5% w/w to about 30.0% w/w;
skin conditioner present in a range from 0.01% w/w to about 5.00% w/w; and
a non-Newtonian thickening agent present in a range from about 0.05% w/w to about 10% w/w; water; and
b) wherein the non-Newtonian thickening agent is selected to give the foamable gritty composition a critical strain force greater than or equal to about 30 dynes/cm2, and a viscosity in a range from about 500 cPoise to about 4000 cPoise such that said foamable gritty composition is dispensible as a foam from a an unpressurized foam dispenser. 22. The method of claim 21 including
introducing a predetermined quantity of air under pressure to a first side of a microporous air sparging element located upstream from an outlet;
introducing, concurrently with the introduction of the air, a predetermined amount of said foamable gritty composition under pressure to a foamable gritty composition inlet of a mixing chamber located on a second side of the microporous air sparging element that is located upstream from said outlet, such that a ratio of air to foamable gritty composition has a greater proportion of air to foamable gritty composition;
forcing the air through the microporous sparging element into the mixing chamber to form a plurality of bubbles;
mixing the plurality of bubbles and the foamable gritty composition in the mixing chamber thereby creating a gritty foam; and
dispensing the gritty foam to a user in shots through said outlet from the mixing chamber. 23. A method as claimed in claim 22 wherein the air is introduced a predetermined quantity and the foamable gritty composition is introduced in a predetermined quantity. | Disclosed herein are foamable gritty foam compositions that can suspend particulate mechanical scrubbers with particles sized from about 100 microns to about 800 microns that is capable of being foamed through a non-aerosol, or unpressurized pump dispenser.1. A non-aerosol dispenser containing a foamable gritty composition, the non-aerosol dispenser comprising an unpressurized container having a dispenser pump configured to mix air with the foamable gritty composition under low pressure conditions during dispensing to form a gritty foam; and the foamable gritty composition comprising:
a) constituents including a solvent present in a range from about 0.5% w/w to about 30.0% w/w, said solvent including any one or combination of D'limonene and sunflower oil methyl ester; a particulate scrubbing agent present in a range from about 1.0% w/w to about 8% w/w; a surfactant present in a range from about 0.5% w/w to about 30.0% w/w; skin conditioner present in a range from 0.01% w/w to about 5.00% w/w; and a non-Newtonian thickening agent present in a range from about 0.05% w/w to about 10% w/w; water; and b) wherein the non-Newtonian thickening agent is selected to give the foamable gritty formulation a critical strain force greater than or equal to about 30 dynes/cm2, and a viscosity in a range from about 500 cPoise to about 4000 cPoise such that said foamable gritty composition is dispensible as a foam from a non-aerosol foam dispenser. 2. The non-aerosol dispenser containing a foamable gritty composition according to claim 1 wherein the surfactant includes any one or combination of
i) an anionic surfactant present in a range from about 1% w/w to about 20% w/w if present alone;
ii) an amphoteric surfactant present in a range from about 0.5% w/w to about 5.0% w/w if present alone;
iii) a non-ionic surfactant present in a range from about 0.5% w/w to about 20% w/w if present alone; and
wherein a total amount of surfactant of any combination of surfactants present is in a range from about 0.5% w/w to about 30.0% w/w. 3. The non-aerosol dispenser containing a foamable gritty composition according to claim 2 wherein the anionic surfactant is selected from the group consisting of lauryl sulphates, lauryl ether sulphates, sulphosuccinates, carboxylates (i.e. sodium oleate), carboxylic acid esters (i.e. sodium dilaureth citrate), alkyl sulfate (i.e. sodium lauryl ether sulfate, ammonium alkyl sulfate, alkyl and alkyl-aryl sulfonates (i.e. sodium dodecyl benzene sulfonate), sulfosuccinates (i.e. disodium laurylether sulfosuccinate), isethionates (i.e. sodium cocoyl isethionate, ammonium cocoyl isethionate), taurates (i.e. sodium methyl cocoyl taurate, sodium methyl oleoyl taurate), acyl glutamates (i.e. sodium lauroyl glutamate, sodium cocoyl glutamate, disodium cocoyl glutamate), sarcosinate (i.e. cocoyl sarcosinate), alkylpolyglucosides (i.e. decyl glucoside, sodium lauryl glucose carboxylate, caprylyl/capryl glucoside). 4. The non-aerosol dispenser containing a foamable gritty composition according to claim 2 wherein the amphoteric surfactant is any one or combination of betaines, acyl ethylene diamines, amino-acids derivates, imidazolines. 5. The non-aerosol dispenser containing a foamable gritty composition according to claim 2 wherein the amphoteric surfactant is any one or combination of acylamphoacetate, acylamphodiacetate, acylamphodipropionate, sodium cocoglycinate, sodium alkyliminodipropionate, cocamidopropyl betaine, sodium cocoamphoacetate. 6. The non-aerosol dispenser containing a foamable gritty composition according to claim 4 wherein said betaine is selected from the group consisting of coco betaine and cocamidopropyl betaine. 7. The non-aerosol dispenser containing a foamable gritty composition according to claim 2 wherein the non-ionic surfactant is any one or combination of of glucosides, ethoxylated fatty alcohols, ethoxylated fatty acids, saccharose esters, sorbitan esters, alkanolamides, glycerol alkyl esters and polyoxyethylene glycol alkylphenol ethers. 8. The non-aerosol dispenser containing a foamable gritty composition according to claim 1 wherein the solvent further includes any one or combination of glycol ethers, esters, alcohols, terpenes other than D'Limonene, aromatic-free white spirit, and wherein a total amount of solvent present is in said range from about 0.5% w/w to about 30.0% w/w. 9. The non-aerosol dispenser containing a foamable gritty composition according to claim 1 wherein the particulate scrubbing agent is any one or combination of a vegetable based scrubbing agent, a synthetic based scrubbing agent and a mineral based scrubbing agent, and wherein the scrubbing agent has a size in a range from about 100 microns to about 800 microns. 10. The non-aerosol dispenser containing a foamable gritty composition according to claim 9 wherein the vegetable based scrubbing agent is any one or combination of cornmeal, olive stone, walnut shells, ground fruit stones, ground corn meal, ground fruit shells. 11. The non-aerosol dispenser containing a foamable gritty composition according to claim 9 wherein the synthetic based scrubbing agent is any one or combination of polyethylene and polypropylene. 12. The non-aerosol dispenser containing a foamable gritty composition according to claim 9 wherein the mineral based scrubbing agent is any one or combination of ground shellfish, pumice, and silica. 13. The non-aerosol dispenser containing a foamable gritty composition according to claim 1 wherein said skin conditioner is any one or combination of a polyol, an anionic surfactant, a non-ionic surfactant, a cationic surfactant, an amphoteric surfactant, a cationic polymer, a quaternised gum, and a polyol. 14. The non-aerosol dispenser containing a foamable gritty composition according to claim 13 wherein said polyol is any one or combination of glycerine and polyglycerin-6, propylene glycol, sorbitol, mannitol, erythritol, xylitol, arabitol, ribitol, dulcitol, lactitol, and maltitol. 15. The non-aerosol dispenser containing a foamable gritty composition according to claim 1 wherein said thickening agent is any one or combination of synthetic polymers and natural thickeners. 16. The non-aerosol dispenser containing a foamable gritty composition according to claim 15 wherein said synthetic polymer is selected from the group consisting of acrylate copolymers. 17. The non-aerosol dispenser containing a foamable gritty composition according to claim 15 wherein said synthetic polymer is selected from the group consisting of acrylates/C10-30 alkyl acrylate crosspolymer, carbomers, and combinations thereof. 18. The non-aerosol dispenser containing a foamable gritty composition according to claim 15 wherein said natural thickener is selected from the group consisting of xanthan gum, guar gum, quaternised guar gum, alginate, bentonite and fumed silica. 19. The non-aerosol dispenser containing a foamable gritty composition according to claim 1 including an antioxidant present in a range from about 0.01 to about 1.0% w/w. 20. The non-aerosol dispenser containing a foamable gritty composition according to claim 19 wherein said antioxidant is any one or combination of butylhydroxytoluene (BHT), butylhydroxyanizole, 1,2-dihydroxybenzene, p-coumarine acid, caffeic acid, sodium sulfite, sodium metasulfite, ferrulic acid, tyrosol, quercetin, chlorogenic acid, oleuropein hydroxytyrosol, ascorbic acid, phenolic acid, propyl gallate, α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, and tetradibutyl-pentaerithrityl hydroxyhydrocinnamate. 21. A method of producing and dispensing a gritty foam, the method comprising;
dispensing a foamable gritty composition from a non-aerosol dispenser containing the foamable gritty composition, the non-aerosol disperser comprising an unpressurized container having a dispenser pump configured to mix air with the foamable gritty composition under low pressure conditions during dispensing to form a gritty foam; and the foamable gritty composition comprising
a) constituents including
a solvent present in a range from about 0.5% w/w to about 30.0% w/w, said solvent including any one or combination of D'limonene and sunflower oil methyl ester;
a particulate scrubbing agent present in a range from about 1.0% w/w to about 8% w/w;
a surfactant present in a range from about 0.5% w/w to about 30.0% w/w;
skin conditioner present in a range from 0.01% w/w to about 5.00% w/w; and
a non-Newtonian thickening agent present in a range from about 0.05% w/w to about 10% w/w; water; and
b) wherein the non-Newtonian thickening agent is selected to give the foamable gritty composition a critical strain force greater than or equal to about 30 dynes/cm2, and a viscosity in a range from about 500 cPoise to about 4000 cPoise such that said foamable gritty composition is dispensible as a foam from a an unpressurized foam dispenser. 22. The method of claim 21 including
introducing a predetermined quantity of air under pressure to a first side of a microporous air sparging element located upstream from an outlet;
introducing, concurrently with the introduction of the air, a predetermined amount of said foamable gritty composition under pressure to a foamable gritty composition inlet of a mixing chamber located on a second side of the microporous air sparging element that is located upstream from said outlet, such that a ratio of air to foamable gritty composition has a greater proportion of air to foamable gritty composition;
forcing the air through the microporous sparging element into the mixing chamber to form a plurality of bubbles;
mixing the plurality of bubbles and the foamable gritty composition in the mixing chamber thereby creating a gritty foam; and
dispensing the gritty foam to a user in shots through said outlet from the mixing chamber. 23. A method as claimed in claim 22 wherein the air is introduced a predetermined quantity and the foamable gritty composition is introduced in a predetermined quantity. | 1,600 |
868 | 13,131,506 | 1,629 | A human oral care composition, includes safe and effective amounts of the fluoride ion and stabilized chlorine dioxide, that may take the form of a paste, gel, rinse, spray, powder, varnish or similar that reduces demineralization and promotes remineralization of teeth. The method includes the topical application of the composition to the human oral cavity (including but not limited to the teeth, gingiva, and tongue), preferably at least once daily, to enhance the anti-caries effect of fluoride by released chlorine dioxido compromising any biofilm present. | 1. A composition for reducing demineralization and promoting remineralization of teeth, said compensation comprising in combination:
a) a chlorine dioxide source; b) a fluoride ion source; and c) a buffer. 2. The composition as set forth in claim 1 wherein said chlorine dioxide source is stabilized chlorine dioxide. 3. The composition as set forth in claim 1 wherein said fluoride ion is selected from a group consisting of sodium fluoride and sodium monoflourophosphate. 4. The composition as set forth in claim 1 wherein said buffer is selected from a group consisting of acetate, citrate and phosphate buffers. 5. The composition as set forth in claim 2 wherein said fluoride ion is selected from a group consisting of sodium fluoride and sodium monoflourophosphate. 6. The composition as set forth in claim 3 wherein said buffer is selected from a group consisting of acetate, citrate and phosphate buffers. 7. The composition as set forth in claim 2 wherein said buffer is selected from a group consisting of acetate, citrate and phosphate buffers. 8. The composition as set forth in claim 5 wherein said buffer is selected from a group consisting of acetate, citrate and phosphate buffers. 9. The composition as set forth in claim 1 wherein said composition is in the form of a paste and the concentration of chlorine dioxide is in the range of about 0.005% to about 0.800% (w/w). 10. The composition as set forth in claim 9 wherein concentration of the fluoride ion is in the range of about 45 ppm to about 5000 ppm. 11. The composition as set forth in claim 9 wherein the buffer provides a pH in the range of about 6.0 to about 7.5. 12. The composition as set forth in claim 10 wherein concentration of the fluoride ion is in the range of about 45 ppm to about 5000 ppm. 13. The composition as set forth in claim 1 wherein said composition is in the form of a solution and the concentration of chlorine dioxide is in the range of about 0.005% to about 0.800% (w/v). 14. The composition as set forth in claim 13 wherein concentration of the fluoride ion is in the range of about 45 ppm to about 5000 ppm. 15. The composition as set forth in claim 13 wherein the buffer provides a pH in the range of about 6.0 to about 7.5. 16. The composition as set forth in claim 15 wherein concentration of the fluoride ion is in the range of about 45 ppm to about 5000 ppm. 17. The composition as set forth in claim 1 wherein said composition is a single phase composition. 18. The composition as set forth in claim 9 wherein said composition is a single phase composition. 19. A method for reducing demineralization of teeth, said method including the steps of:
a) applying a composition including stabilization chlorine dioxide for reaction with the acidic elements/biofilm to produce chlorine dioxide for the benefit of its bactericidal properties on the biofilm; b) applying a fluoride ion as part of the composition to reduce demineralization and promote remineralization of the teeth as a result of the bactericidal effect of the chlorine dioxide on any biofilm present; and c) establishing the effective pH range of the composition with a buffer. 20. The method as set forth in claim 19 wherein said steps of applying is carried out by chlorine dioxide in a concentration range of about 0.005% to about 0.800% (w/w if the composition is not a liquid and w/v if the composition is not a solid). 21. The method as set forth in claim 19 wherein said step of applying is carried out by the fluoride ion in the range of about 45 ppm to about 5000 ppm. 22. The method as set forth in claim 19 wherein said step of establishing is carried out by the buffer setting the pH range of the composition in the range of about 6.0 to about 7.5. 23. The method as set forth in claim 20 wherein said step of applying is carried out by the fluoride ion in the range of about 45 ppm to about 5000 ppm. 24. The method as set forth in claim 20 wherein said step of establishing is carried out by the buffer setting the pH range of the composition in the range of about 6.0 to about 7.5. 25. The method as set forth in claim 21 wherein said step of establishing is carried out by the buffer setting the pH range of said composition in the range of about 6.0 to about 7.5. 26. The method as set forth in claim 23 wherein said step of establishing is carried out by the buffer setting the pH range of said composition in the range of about 6.0 to about 7.5 | A human oral care composition, includes safe and effective amounts of the fluoride ion and stabilized chlorine dioxide, that may take the form of a paste, gel, rinse, spray, powder, varnish or similar that reduces demineralization and promotes remineralization of teeth. The method includes the topical application of the composition to the human oral cavity (including but not limited to the teeth, gingiva, and tongue), preferably at least once daily, to enhance the anti-caries effect of fluoride by released chlorine dioxido compromising any biofilm present.1. A composition for reducing demineralization and promoting remineralization of teeth, said compensation comprising in combination:
a) a chlorine dioxide source; b) a fluoride ion source; and c) a buffer. 2. The composition as set forth in claim 1 wherein said chlorine dioxide source is stabilized chlorine dioxide. 3. The composition as set forth in claim 1 wherein said fluoride ion is selected from a group consisting of sodium fluoride and sodium monoflourophosphate. 4. The composition as set forth in claim 1 wherein said buffer is selected from a group consisting of acetate, citrate and phosphate buffers. 5. The composition as set forth in claim 2 wherein said fluoride ion is selected from a group consisting of sodium fluoride and sodium monoflourophosphate. 6. The composition as set forth in claim 3 wherein said buffer is selected from a group consisting of acetate, citrate and phosphate buffers. 7. The composition as set forth in claim 2 wherein said buffer is selected from a group consisting of acetate, citrate and phosphate buffers. 8. The composition as set forth in claim 5 wherein said buffer is selected from a group consisting of acetate, citrate and phosphate buffers. 9. The composition as set forth in claim 1 wherein said composition is in the form of a paste and the concentration of chlorine dioxide is in the range of about 0.005% to about 0.800% (w/w). 10. The composition as set forth in claim 9 wherein concentration of the fluoride ion is in the range of about 45 ppm to about 5000 ppm. 11. The composition as set forth in claim 9 wherein the buffer provides a pH in the range of about 6.0 to about 7.5. 12. The composition as set forth in claim 10 wherein concentration of the fluoride ion is in the range of about 45 ppm to about 5000 ppm. 13. The composition as set forth in claim 1 wherein said composition is in the form of a solution and the concentration of chlorine dioxide is in the range of about 0.005% to about 0.800% (w/v). 14. The composition as set forth in claim 13 wherein concentration of the fluoride ion is in the range of about 45 ppm to about 5000 ppm. 15. The composition as set forth in claim 13 wherein the buffer provides a pH in the range of about 6.0 to about 7.5. 16. The composition as set forth in claim 15 wherein concentration of the fluoride ion is in the range of about 45 ppm to about 5000 ppm. 17. The composition as set forth in claim 1 wherein said composition is a single phase composition. 18. The composition as set forth in claim 9 wherein said composition is a single phase composition. 19. A method for reducing demineralization of teeth, said method including the steps of:
a) applying a composition including stabilization chlorine dioxide for reaction with the acidic elements/biofilm to produce chlorine dioxide for the benefit of its bactericidal properties on the biofilm; b) applying a fluoride ion as part of the composition to reduce demineralization and promote remineralization of the teeth as a result of the bactericidal effect of the chlorine dioxide on any biofilm present; and c) establishing the effective pH range of the composition with a buffer. 20. The method as set forth in claim 19 wherein said steps of applying is carried out by chlorine dioxide in a concentration range of about 0.005% to about 0.800% (w/w if the composition is not a liquid and w/v if the composition is not a solid). 21. The method as set forth in claim 19 wherein said step of applying is carried out by the fluoride ion in the range of about 45 ppm to about 5000 ppm. 22. The method as set forth in claim 19 wherein said step of establishing is carried out by the buffer setting the pH range of the composition in the range of about 6.0 to about 7.5. 23. The method as set forth in claim 20 wherein said step of applying is carried out by the fluoride ion in the range of about 45 ppm to about 5000 ppm. 24. The method as set forth in claim 20 wherein said step of establishing is carried out by the buffer setting the pH range of the composition in the range of about 6.0 to about 7.5. 25. The method as set forth in claim 21 wherein said step of establishing is carried out by the buffer setting the pH range of said composition in the range of about 6.0 to about 7.5. 26. The method as set forth in claim 23 wherein said step of establishing is carried out by the buffer setting the pH range of said composition in the range of about 6.0 to about 7.5 | 1,600 |
869 | 15,484,509 | 1,699 | A method for detecting soluble oligomeric amyloid β in a subject using, e.g., PET is provided. | 1. A kit for detecting soluble oligomeric amyloid β comprising
(a) an antibody or fragment thereof that selectively binds soluble oligomeric amyloid β, and either
(b) a labeling moiety selected from the group of:
(i) a chelating agent, and
(ii) a fluorescent label; or
(c) a labeled secondary antibody. 2. The kit of claim 1, further comprising a radioisotope. 3. The kit of claim 1, further comprising a standard curve. 4. A method for quantitatively detecting soluble oligomeric amyloid β in a biological sample comprising
(a) contacting a biological sample from a subject comprising soluble oligomeric amyloid β with an antibody or fragment thereof exhibiting selective cross-reactivity with soluble oligomeric amyloid β over monomer and fibrillar amyloid; and
(b) quantitatively measuring binding of the antibody or fragment thereof to the soluble oligomeric amyloid β to obtain a concentration of soluble oligomeric amyloid β in the biological sample thereby quantitatively detecting soluble oligomeric amyloid β in the biological sample. 5. The method of claim 4, further comprising (c) correlating the concentration of soluble oligomeric amyloid β with the subject's cognitive function. 6. The method of claim 4, wherein the antibody is a monoclonal antibody or fragment thereof. 7. The method of claim 4, wherein the antibody is a humanized monoclonal antibody or fragment thereof. | A method for detecting soluble oligomeric amyloid β in a subject using, e.g., PET is provided.1. A kit for detecting soluble oligomeric amyloid β comprising
(a) an antibody or fragment thereof that selectively binds soluble oligomeric amyloid β, and either
(b) a labeling moiety selected from the group of:
(i) a chelating agent, and
(ii) a fluorescent label; or
(c) a labeled secondary antibody. 2. The kit of claim 1, further comprising a radioisotope. 3. The kit of claim 1, further comprising a standard curve. 4. A method for quantitatively detecting soluble oligomeric amyloid β in a biological sample comprising
(a) contacting a biological sample from a subject comprising soluble oligomeric amyloid β with an antibody or fragment thereof exhibiting selective cross-reactivity with soluble oligomeric amyloid β over monomer and fibrillar amyloid; and
(b) quantitatively measuring binding of the antibody or fragment thereof to the soluble oligomeric amyloid β to obtain a concentration of soluble oligomeric amyloid β in the biological sample thereby quantitatively detecting soluble oligomeric amyloid β in the biological sample. 5. The method of claim 4, further comprising (c) correlating the concentration of soluble oligomeric amyloid β with the subject's cognitive function. 6. The method of claim 4, wherein the antibody is a monoclonal antibody or fragment thereof. 7. The method of claim 4, wherein the antibody is a humanized monoclonal antibody or fragment thereof. | 1,600 |
870 | 14,771,192 | 1,612 | The present invention relates to a non-aqueous composition that comprises a permeation enhancer such as a terpene, for delivering an active ingredient transdermally. The composition comprises at least on one active ingredient, a terpene, and a solvent, such as a non-hydroxyl containing solvent, non-heterocyclic ester solvent and/or a tripropylene glycol alkyl ether. The composition can be used to deliver a range of actives, such as anthelmintics. The present invention provides a platform composition and can be used to deliver a wide variety of active ingredients and combinations thereof transdermally to mammals. | 1. An anhydrous transdermal composition comprising
at least one active ingredient optionally (a) having a log P in hexane and water of less than about 8 at pH 7.4, or (b) being an anthelmintic, a terpene optionally present at, at least 20% by weight, and a solvent selected from
i) a non-hydroxyl containing solvent,
ii) a non-heterocyclic ester solvent,
iii) a tripropylene glycol alkyl ether, or
iv) a combination thereof. 2-3. (canceled) 4. A composition of claim 1 wherein at least one of the active ingredients is selected from the group consisting of an anthelmintic, a non-steroidal anti-inflammatory, a steroidal anti-inflammatory, a steroid hormone, an anti-histamine, an anti-emetic, a metabolic regulator, a productivity regulator, a hypothyroidism treatment, a behavioural treatment, an analgesic, a parasiticide, an insecticide, an anti-biotic, an anti-microbial, an anti-fungal, an anti-viral, a coccidostat, a skin-treatment agent, or any combination of two or more thereof. 5-6. (canceled) 7. A composition of claim 1 wherein the anthelmintic is an imidazothiazole. 8. (canceled) 9. A composition of claim 1, wherein the anthelmintic is levamisole base. 10-14. (canceled) 15. A composition of claim 1 wherein the non-hydroxyl containing solvent or the non-heterocyclic ester solvent is a fatty acid ester. 16. A composition of claim 1 wherein the non-hydroxyl containing solvent or the non-heterocyclic ester solvent is selected from a triglyceride, glycerol ester or combination thereof. 17. (canceled) 18. A composition of claim 1 wherein the non-heterocyclic ester solvent is selected from a triglyceride, glycerol ester or combination thereof. 19-21. (canceled) 22. A composition of claim 1 wherein the composition comprises at least about 10% or at least about 20% w/w terpene. 23-26. (canceled) 27. A composition of claim 1 wherein the terpene is limonene or phellandrene. 28. (canceled) 29. A composition of claim 1 further comprising at least one surfactant. 30. A composition of claim 29 wherein at least one of the surfactants has the following structure:
Z—(O—CR1R2CR3R4)n—OH
where
z is an optionally substituted C14 to C22 linear alkenyl,
R1, R2, R3 and R4 are each independently selected from methyl or hydrogen, and
n is an integer from 1 to 10. 31. A composition of claim 30 wherein
at least two of R1, R2, R3 and R4 are hydrogen, or
R1, R2, R3 and R4 are all hydrogen, or
n is an integer from 1 to 5. 32-33. (canceled) 34. A composition of any one of claim 30 wherein at least one of the carbon-carbon double bonds in Z has a cis configuration. 35. A composition of claim 30 wherein Z is C16 to C22 linear alkenyl. 36-39. (canceled) 39. A composition of claim 30 wherein the composition is stable at 4° C. for at least 72 hrs. 40-41. (canceled) 42. A composition of claim 1, comprising a macrocyclic lactone. 43-44. (canceled) 45. A composition of claim 1 comprising
optionally about 1 to about 60% w/w levamisole base,
optionally about 0.1 to about 20% w/w macrocyclic lactone,
optionally about 1 to about 40% w/w fatty acid ester,
optionally about 1 to about 60% w/w terpene, and
optionally about 1 to about 25% w/w non-aqueous solvent. 46-49. (canceled) 50. A composition of claim 1 wherein the composition delivers levamisol base transdermally at an average flux rate of at least 300 μg/cm2/h. 51. A composition of claim 1, wherein the composition is administered in an amount less than about 0.1 mL/kg of live animal; and wherein the composition delivers levamisole base within its therapeutically effective does range to the target animal. 52. A method of manufacturing a composition comprising
i) mixing a first composition comprising an active ingredient that is substantially insoluble in water, and a terpene, with a fatty acid ester, or ii) mixing a first composition comprising a terpene, with a second composition comprising an active ingredient that is substantially insoluble in water and a fatty acid ester, or iii) mixing a first composition comprising a first active ingredient that is substantially insoluble in water, and a terpene, with a second composition comprising a second active ingredient that is substantially insoluble in water, and a fatty acid ester, thereby providing the transdermal composition. 53. A method of claim 52 wherein the first composition is formed from a mix of at least one active ingredient that is substantially insoluble in water, a terpene and a non-aqueous solvent. 54. (canceled) 55. A method of claim 52 wherein the non-aqueous solvent is a glycol ether. 56. A method of claim 55 wherein the glycol ether is a tripropylene glycol alkyl ether. 57. A method of claim 56 wherein the tripropylene glycol alkyl ether is selected from tripropylene glycol methyl ether, tripropylene glycol mono-n-propyl ether or tripropylene glycol mono-n-butyl ether. 58-64. (canceled) | The present invention relates to a non-aqueous composition that comprises a permeation enhancer such as a terpene, for delivering an active ingredient transdermally. The composition comprises at least on one active ingredient, a terpene, and a solvent, such as a non-hydroxyl containing solvent, non-heterocyclic ester solvent and/or a tripropylene glycol alkyl ether. The composition can be used to deliver a range of actives, such as anthelmintics. The present invention provides a platform composition and can be used to deliver a wide variety of active ingredients and combinations thereof transdermally to mammals.1. An anhydrous transdermal composition comprising
at least one active ingredient optionally (a) having a log P in hexane and water of less than about 8 at pH 7.4, or (b) being an anthelmintic, a terpene optionally present at, at least 20% by weight, and a solvent selected from
i) a non-hydroxyl containing solvent,
ii) a non-heterocyclic ester solvent,
iii) a tripropylene glycol alkyl ether, or
iv) a combination thereof. 2-3. (canceled) 4. A composition of claim 1 wherein at least one of the active ingredients is selected from the group consisting of an anthelmintic, a non-steroidal anti-inflammatory, a steroidal anti-inflammatory, a steroid hormone, an anti-histamine, an anti-emetic, a metabolic regulator, a productivity regulator, a hypothyroidism treatment, a behavioural treatment, an analgesic, a parasiticide, an insecticide, an anti-biotic, an anti-microbial, an anti-fungal, an anti-viral, a coccidostat, a skin-treatment agent, or any combination of two or more thereof. 5-6. (canceled) 7. A composition of claim 1 wherein the anthelmintic is an imidazothiazole. 8. (canceled) 9. A composition of claim 1, wherein the anthelmintic is levamisole base. 10-14. (canceled) 15. A composition of claim 1 wherein the non-hydroxyl containing solvent or the non-heterocyclic ester solvent is a fatty acid ester. 16. A composition of claim 1 wherein the non-hydroxyl containing solvent or the non-heterocyclic ester solvent is selected from a triglyceride, glycerol ester or combination thereof. 17. (canceled) 18. A composition of claim 1 wherein the non-heterocyclic ester solvent is selected from a triglyceride, glycerol ester or combination thereof. 19-21. (canceled) 22. A composition of claim 1 wherein the composition comprises at least about 10% or at least about 20% w/w terpene. 23-26. (canceled) 27. A composition of claim 1 wherein the terpene is limonene or phellandrene. 28. (canceled) 29. A composition of claim 1 further comprising at least one surfactant. 30. A composition of claim 29 wherein at least one of the surfactants has the following structure:
Z—(O—CR1R2CR3R4)n—OH
where
z is an optionally substituted C14 to C22 linear alkenyl,
R1, R2, R3 and R4 are each independently selected from methyl or hydrogen, and
n is an integer from 1 to 10. 31. A composition of claim 30 wherein
at least two of R1, R2, R3 and R4 are hydrogen, or
R1, R2, R3 and R4 are all hydrogen, or
n is an integer from 1 to 5. 32-33. (canceled) 34. A composition of any one of claim 30 wherein at least one of the carbon-carbon double bonds in Z has a cis configuration. 35. A composition of claim 30 wherein Z is C16 to C22 linear alkenyl. 36-39. (canceled) 39. A composition of claim 30 wherein the composition is stable at 4° C. for at least 72 hrs. 40-41. (canceled) 42. A composition of claim 1, comprising a macrocyclic lactone. 43-44. (canceled) 45. A composition of claim 1 comprising
optionally about 1 to about 60% w/w levamisole base,
optionally about 0.1 to about 20% w/w macrocyclic lactone,
optionally about 1 to about 40% w/w fatty acid ester,
optionally about 1 to about 60% w/w terpene, and
optionally about 1 to about 25% w/w non-aqueous solvent. 46-49. (canceled) 50. A composition of claim 1 wherein the composition delivers levamisol base transdermally at an average flux rate of at least 300 μg/cm2/h. 51. A composition of claim 1, wherein the composition is administered in an amount less than about 0.1 mL/kg of live animal; and wherein the composition delivers levamisole base within its therapeutically effective does range to the target animal. 52. A method of manufacturing a composition comprising
i) mixing a first composition comprising an active ingredient that is substantially insoluble in water, and a terpene, with a fatty acid ester, or ii) mixing a first composition comprising a terpene, with a second composition comprising an active ingredient that is substantially insoluble in water and a fatty acid ester, or iii) mixing a first composition comprising a first active ingredient that is substantially insoluble in water, and a terpene, with a second composition comprising a second active ingredient that is substantially insoluble in water, and a fatty acid ester, thereby providing the transdermal composition. 53. A method of claim 52 wherein the first composition is formed from a mix of at least one active ingredient that is substantially insoluble in water, a terpene and a non-aqueous solvent. 54. (canceled) 55. A method of claim 52 wherein the non-aqueous solvent is a glycol ether. 56. A method of claim 55 wherein the glycol ether is a tripropylene glycol alkyl ether. 57. A method of claim 56 wherein the tripropylene glycol alkyl ether is selected from tripropylene glycol methyl ether, tripropylene glycol mono-n-propyl ether or tripropylene glycol mono-n-butyl ether. 58-64. (canceled) | 1,600 |
871 | 14,428,350 | 1,618 | The present invention relates to contrast agent enhanced medical ultrasound imaging. In particular, the contrast agents provided are useful for cell imaging and cell therapy, as well as in vivo targeting, drug delivery and perfusion or vascular imaging applications. More specifically, it provides a particle comprising a fluorinated organic compound and a metal. Such particles may be advantageously employed in qualitative or quantitative imaging such as acoustic imaging including photoacoustic and ultra-sound imaging, MRI imaging, such as 19F imaging, 1H imaging including T1 and T2 weighted imaging, SPECT, PET, scintigraphy, fluorescence imaging and optical coherence imaging and tomographic applications. This may then be employed in cell labeling, microscopy, histology or for imaging vasculature or perfusion in vivo and in vitro. | 1. A poly(lactic-co-glycolic) acid (PLGA) particle comprising a perfluoro crown ether and a gadolinium chelate. 2. The particle of claim 1, wherein the perfluoro crown ether is selected from the group consisting of perfluoro-15-crown-5-ether, perfluoro-12-crown-4-ether, and perfluoro-18-crown-6-ether. 3. The particle of claim 1, wherein the gadolinium chelate is gadoteridol. 4. The particle of claim 1, wherein the particle comprises a therapeutic agent or a targeting agent, such as a drug, a receptor ligand or an antibody. 5. The particle of claim 1, wherein the particle comprises a detecting agent, such as a dye, such as a fluorescent dye or a radionuclide. 6. Particulate matter comprising a number of particles of claim 1, wherein the mean particle diameter is of a value of between 100 and 300 nanometers. 7. The particle of claim 1, wherein the particle is essentially surfactant free or surfactant free. 8. A method of in vitro imaging of a subject, the method comprising:
providing the particle of claim 1 to the subject; and imaging the particle; wherein the imaging is selected from the group consisting of diagnostic imaging, imaging of metastases and vasculature, quantitative imaging, qualitative imaging, therapeutic imaging, imaging of cellular vaccines, imaging of cellular therapeutics, imaging of dendritic cell vaccines, imaging of stem cells, imaging of beta islet cells, acoustic imaging, photo acoustic imaging, ultrasound imaging, optical coherence imaging, MRI imaging, multinuclear MRI imaging, 19F imaging, 1H imaging, T1, T2 and T2* weighted imaging, proton density weighted imaging, SPECT, PET, scintigraphy, bioluminescence imaging and fluorescence imaging. 9. A method of in vivo imaging of a subject, the method comprising:
providing the particle of claim 1 to the subject; and imaging the particle; wherein the imaging is selected from the group consisting of diagnostic imaging, imaging of metastases or vasculature, quantitative imaging, qualitative imaging, therapeutic imaging, imaging of cellular vaccines, imaging of cellular therapeutics, imaging of dendritic cell vaccines, imaging of stem cells, imaging of beta islet cells, acoustic imaging, photo acoustic imaging, ultrasound imaging, MRI imaging, multinuclear MRI imaging, 19F imaging, 1H imaging, T1, T2 and T2* weighted imaging, proton density weighted imaging, SPECT, PET, scintigraphy, bioluminescence imaging and fluorescence imaging. 10. A method for in vitro cell labeling, in vitro microscopy, in vitro imaging of vasculature or perfusion, or in vitro histology, the method comprising:
utilizing the particle of claim 1 for in vitro cell labeling, in vitro microscopy, in vitro imaging of vasculature or perfusion, or in vitro histology. 11. (canceled) 12. A method for delivering a therapeutic agent, wherein the improvement comprises delivering to a subject a therapeutic agent comprising the particle of claim 1. 13. A method for treating a disease, wherein the improvement comprises delivering to a subject suffering from the disease the particle of claim 1. 14. The method according to claim 13, wherein the disease is selected from the group consisting of cancer, cardiovascular diseases, heart disease, stroke and perfusion issues, graft rejection after transplant, immune diseases, autoimmune diseases and vascular diseases. 15. The particulate matter of claim 6, wherein the particulate matter is essentially surfactant free or surfactant free. 16. The method according to claim 8, wherein the particle forms part of a particulate matter wherein the mean particle diameter is of a value of between 100 and 300 nanomters. 17. The method according to claim 9, wherein the particle forms part of a particulate matter wherein the mean particle diameter is of a value of between 100 and 300 nanomters. 18. The method according to claim 10, wherein the particle forms part of a particulate matter wherein the mean particle diameter is of a value of between 100 and 300 nanomters. 19. The method according to claim 12, wherein the particle forms part of a particulate matter wherein the mean particle diameter is of a value of between 100 and 300 nanomters. 20. The method according to claim 13, wherein the particle forms part of a particulate matter wherein the mean particle diameter is of a value of between 100 and 300 nanomters. 21. The method according to claim 14, wherein the particle forms part of a particulate matter wherein the mean particle diameter is of a value of between 100 and 300 nanomters. | The present invention relates to contrast agent enhanced medical ultrasound imaging. In particular, the contrast agents provided are useful for cell imaging and cell therapy, as well as in vivo targeting, drug delivery and perfusion or vascular imaging applications. More specifically, it provides a particle comprising a fluorinated organic compound and a metal. Such particles may be advantageously employed in qualitative or quantitative imaging such as acoustic imaging including photoacoustic and ultra-sound imaging, MRI imaging, such as 19F imaging, 1H imaging including T1 and T2 weighted imaging, SPECT, PET, scintigraphy, fluorescence imaging and optical coherence imaging and tomographic applications. This may then be employed in cell labeling, microscopy, histology or for imaging vasculature or perfusion in vivo and in vitro.1. A poly(lactic-co-glycolic) acid (PLGA) particle comprising a perfluoro crown ether and a gadolinium chelate. 2. The particle of claim 1, wherein the perfluoro crown ether is selected from the group consisting of perfluoro-15-crown-5-ether, perfluoro-12-crown-4-ether, and perfluoro-18-crown-6-ether. 3. The particle of claim 1, wherein the gadolinium chelate is gadoteridol. 4. The particle of claim 1, wherein the particle comprises a therapeutic agent or a targeting agent, such as a drug, a receptor ligand or an antibody. 5. The particle of claim 1, wherein the particle comprises a detecting agent, such as a dye, such as a fluorescent dye or a radionuclide. 6. Particulate matter comprising a number of particles of claim 1, wherein the mean particle diameter is of a value of between 100 and 300 nanometers. 7. The particle of claim 1, wherein the particle is essentially surfactant free or surfactant free. 8. A method of in vitro imaging of a subject, the method comprising:
providing the particle of claim 1 to the subject; and imaging the particle; wherein the imaging is selected from the group consisting of diagnostic imaging, imaging of metastases and vasculature, quantitative imaging, qualitative imaging, therapeutic imaging, imaging of cellular vaccines, imaging of cellular therapeutics, imaging of dendritic cell vaccines, imaging of stem cells, imaging of beta islet cells, acoustic imaging, photo acoustic imaging, ultrasound imaging, optical coherence imaging, MRI imaging, multinuclear MRI imaging, 19F imaging, 1H imaging, T1, T2 and T2* weighted imaging, proton density weighted imaging, SPECT, PET, scintigraphy, bioluminescence imaging and fluorescence imaging. 9. A method of in vivo imaging of a subject, the method comprising:
providing the particle of claim 1 to the subject; and imaging the particle; wherein the imaging is selected from the group consisting of diagnostic imaging, imaging of metastases or vasculature, quantitative imaging, qualitative imaging, therapeutic imaging, imaging of cellular vaccines, imaging of cellular therapeutics, imaging of dendritic cell vaccines, imaging of stem cells, imaging of beta islet cells, acoustic imaging, photo acoustic imaging, ultrasound imaging, MRI imaging, multinuclear MRI imaging, 19F imaging, 1H imaging, T1, T2 and T2* weighted imaging, proton density weighted imaging, SPECT, PET, scintigraphy, bioluminescence imaging and fluorescence imaging. 10. A method for in vitro cell labeling, in vitro microscopy, in vitro imaging of vasculature or perfusion, or in vitro histology, the method comprising:
utilizing the particle of claim 1 for in vitro cell labeling, in vitro microscopy, in vitro imaging of vasculature or perfusion, or in vitro histology. 11. (canceled) 12. A method for delivering a therapeutic agent, wherein the improvement comprises delivering to a subject a therapeutic agent comprising the particle of claim 1. 13. A method for treating a disease, wherein the improvement comprises delivering to a subject suffering from the disease the particle of claim 1. 14. The method according to claim 13, wherein the disease is selected from the group consisting of cancer, cardiovascular diseases, heart disease, stroke and perfusion issues, graft rejection after transplant, immune diseases, autoimmune diseases and vascular diseases. 15. The particulate matter of claim 6, wherein the particulate matter is essentially surfactant free or surfactant free. 16. The method according to claim 8, wherein the particle forms part of a particulate matter wherein the mean particle diameter is of a value of between 100 and 300 nanomters. 17. The method according to claim 9, wherein the particle forms part of a particulate matter wherein the mean particle diameter is of a value of between 100 and 300 nanomters. 18. The method according to claim 10, wherein the particle forms part of a particulate matter wherein the mean particle diameter is of a value of between 100 and 300 nanomters. 19. The method according to claim 12, wherein the particle forms part of a particulate matter wherein the mean particle diameter is of a value of between 100 and 300 nanomters. 20. The method according to claim 13, wherein the particle forms part of a particulate matter wherein the mean particle diameter is of a value of between 100 and 300 nanomters. 21. The method according to claim 14, wherein the particle forms part of a particulate matter wherein the mean particle diameter is of a value of between 100 and 300 nanomters. | 1,600 |
872 | 14,130,718 | 1,629 | The present invention relates to a product comprising capsaicin or a capsaicinoid for use in the treatment of cough, in particular chronic persistent unexplained cough or increased cough reflex sensitivity. More precisely, the invention concerns oral formulations for reducing and relieving coughing from other irritants than capsaicin itself. The capsaicin formulations are stated to down-regulate coughing following a regular consumption. Said products can also be used in the treatment of rhinitis and other conditions known to have cough symptoms. | 1-10. (canceled) 11. A method of treating cough symptoms in a patient in need thereof, comprising administering to said patient a formulation comprising capsaicin and/or a capsaicinoid. 12. The method of claim 11, wherein cough symptoms comprise chronic persistent unexplained cough or increased cough reflex sensitivity. 13. The method of claim 11, wherein the capsaicin and/or capsaicinoid is administered to the patient in a dose of between 0.01 mg to 100 mg. 14. The method of claim 11, wherein the capsaicin and/or capsaicinoid is administered to the patient in a dose of between 0.05 mg to 10 mg. 15. The method of claim 11, wherein the capsaicin and/or capsaicinoid is administered to the patient in a dose of between 0.2 mg to 4 mg. 16. The method of claim 11, wherein the capsaicin and/or capsaicinoid is administered to the patient by nasal or bronchial inhaling of a powder and/or nasal or bronchial spraying of a powder and/or an aerosol. 17. The method of claim 11, wherein the capsaicin and/or capsaicinoid is administered to the patient by oral ingestion of a capsule, liquid, or tablet. 18. The method of claim 11, wherein the capsaicin and/or capsaicinoid is administered to the patient locally as a liquid for gargling and/or chewing gum for chewing. 19. A method of treating non-allergic rhinitis, asthma-like symptoms, eye irritation, burning mouth syndrome and/or other symptoms resulting from environmental sensitivity in a patient in need thereof, comprising administering to said patient a formulation comprising capsaicin and/or a capsaicinoid. 20. The method of claim 19, wherein other symptoms resulting from environmental sensitivity comprise headache, nausea and/or fatigue. 21. The method of claim 19, wherein the capsaicin and/or capsaicinoid is administered to the patient in a dose of between 0.01 mg to 100 mg. 22. The method of claim 19, wherein the capsaicin and/or capsaicinoid is administered to the patient in a dose of between 0.05 mg to 10 mg. 23. The method of claim 19, wherein the capsaicin and/or capsaicinoid is administered to the patient in a dose of between 0.2 mg to 4 mg. 24, (New) The method of claim 19, wherein the capsaicin and/or capsaicinoid is administered to the patient by nasal or bronchial inhaling of a powder and/or nasal or bronchial spraying of a powder and/or an aerosol. 25. The method of claim 19, wherein the capsaicin and/or capsaicinoid is administered to the patient by oral ingestion of a capsule, liquid, or tablet. 26. The method of claim 24, wherein the capsaicin and/or capsaicinoid is administered to the patient locally as a liquid for gargling and/or chewing gum for chewing. | The present invention relates to a product comprising capsaicin or a capsaicinoid for use in the treatment of cough, in particular chronic persistent unexplained cough or increased cough reflex sensitivity. More precisely, the invention concerns oral formulations for reducing and relieving coughing from other irritants than capsaicin itself. The capsaicin formulations are stated to down-regulate coughing following a regular consumption. Said products can also be used in the treatment of rhinitis and other conditions known to have cough symptoms.1-10. (canceled) 11. A method of treating cough symptoms in a patient in need thereof, comprising administering to said patient a formulation comprising capsaicin and/or a capsaicinoid. 12. The method of claim 11, wherein cough symptoms comprise chronic persistent unexplained cough or increased cough reflex sensitivity. 13. The method of claim 11, wherein the capsaicin and/or capsaicinoid is administered to the patient in a dose of between 0.01 mg to 100 mg. 14. The method of claim 11, wherein the capsaicin and/or capsaicinoid is administered to the patient in a dose of between 0.05 mg to 10 mg. 15. The method of claim 11, wherein the capsaicin and/or capsaicinoid is administered to the patient in a dose of between 0.2 mg to 4 mg. 16. The method of claim 11, wherein the capsaicin and/or capsaicinoid is administered to the patient by nasal or bronchial inhaling of a powder and/or nasal or bronchial spraying of a powder and/or an aerosol. 17. The method of claim 11, wherein the capsaicin and/or capsaicinoid is administered to the patient by oral ingestion of a capsule, liquid, or tablet. 18. The method of claim 11, wherein the capsaicin and/or capsaicinoid is administered to the patient locally as a liquid for gargling and/or chewing gum for chewing. 19. A method of treating non-allergic rhinitis, asthma-like symptoms, eye irritation, burning mouth syndrome and/or other symptoms resulting from environmental sensitivity in a patient in need thereof, comprising administering to said patient a formulation comprising capsaicin and/or a capsaicinoid. 20. The method of claim 19, wherein other symptoms resulting from environmental sensitivity comprise headache, nausea and/or fatigue. 21. The method of claim 19, wherein the capsaicin and/or capsaicinoid is administered to the patient in a dose of between 0.01 mg to 100 mg. 22. The method of claim 19, wherein the capsaicin and/or capsaicinoid is administered to the patient in a dose of between 0.05 mg to 10 mg. 23. The method of claim 19, wherein the capsaicin and/or capsaicinoid is administered to the patient in a dose of between 0.2 mg to 4 mg. 24, (New) The method of claim 19, wherein the capsaicin and/or capsaicinoid is administered to the patient by nasal or bronchial inhaling of a powder and/or nasal or bronchial spraying of a powder and/or an aerosol. 25. The method of claim 19, wherein the capsaicin and/or capsaicinoid is administered to the patient by oral ingestion of a capsule, liquid, or tablet. 26. The method of claim 24, wherein the capsaicin and/or capsaicinoid is administered to the patient locally as a liquid for gargling and/or chewing gum for chewing. | 1,600 |
873 | 15,795,873 | 1,627 | Solid dispersions and dosage forms comprising the hydrobromide salt of a diarylpyrimidine derivative, useful as an anti-HIV agent. | 1-10. (canceled) 11. A solid dispersion comprising a compound of formula (I):
in a water-soluble polymer selected from hydroxypropylmethyl cellulose and vitamin E TGPS. 12. The solid dispersion according to claim 11, wherein the polymer is hydroxypropylmethyl cellulose 2910 5 mPa·s. 13. The solid dispersion according to claim 11, wherein the weight:weight ratio of the polymer to the pharmaceutical agent is in the range from 9:1 to 1:1. 14. A dosage form comprising the solid dispersion of claim 11. 15. The dosage form of claim 14 wherein the dosage form is selected from a tablet and a capsule. 16. The solid dispersion according to claim 11 obtainable by spray-drying. 17. The solid dispersion according to claim 16, further containing microcrystalline cellulose. 18. A solid dispersion comprising a compound of formula (I):
in a water-soluble polymer selected from hydroxypropylmethyl cellulose 2910 5 mPa·s and vitamin E TGPS, wherein the weight:weight ratio of polymer to pharmaceutical agent is in the range from 9:1 to 1:1. 19. A dosage form comprising the solid dispersion of claim 18. 20. The dosage form of claim 19 wherein the dosage form is selected from a tablet and a capsule. 21. The solid dispersion according to claim 18 obtainable by spray-drying. 22. The solid dispersion according to claim 21, further containing microcrystalline cellulose. 23. A solid dispersion comprising a compound of formula (I):
in a water-soluble polymer selected from hydroxypropylmethyl cellulose 2910 5 mPa·s and vitamin E TGPS, wherein the weight:weight ratio of polymer to pharmaceutical agent is in the range from 3:1 to 1:1. 24. A dosage form comprising the solid dispersion of claim 23. 25. The dosage form of claim 24 wherein the dosage form is selected from a tablet and a capsule. 26. The solid dispersion according to claim 23 obtainable by spray-drying. 27. The solid dispersion according to claim 26, further containing microcrystalline cellulose. | Solid dispersions and dosage forms comprising the hydrobromide salt of a diarylpyrimidine derivative, useful as an anti-HIV agent.1-10. (canceled) 11. A solid dispersion comprising a compound of formula (I):
in a water-soluble polymer selected from hydroxypropylmethyl cellulose and vitamin E TGPS. 12. The solid dispersion according to claim 11, wherein the polymer is hydroxypropylmethyl cellulose 2910 5 mPa·s. 13. The solid dispersion according to claim 11, wherein the weight:weight ratio of the polymer to the pharmaceutical agent is in the range from 9:1 to 1:1. 14. A dosage form comprising the solid dispersion of claim 11. 15. The dosage form of claim 14 wherein the dosage form is selected from a tablet and a capsule. 16. The solid dispersion according to claim 11 obtainable by spray-drying. 17. The solid dispersion according to claim 16, further containing microcrystalline cellulose. 18. A solid dispersion comprising a compound of formula (I):
in a water-soluble polymer selected from hydroxypropylmethyl cellulose 2910 5 mPa·s and vitamin E TGPS, wherein the weight:weight ratio of polymer to pharmaceutical agent is in the range from 9:1 to 1:1. 19. A dosage form comprising the solid dispersion of claim 18. 20. The dosage form of claim 19 wherein the dosage form is selected from a tablet and a capsule. 21. The solid dispersion according to claim 18 obtainable by spray-drying. 22. The solid dispersion according to claim 21, further containing microcrystalline cellulose. 23. A solid dispersion comprising a compound of formula (I):
in a water-soluble polymer selected from hydroxypropylmethyl cellulose 2910 5 mPa·s and vitamin E TGPS, wherein the weight:weight ratio of polymer to pharmaceutical agent is in the range from 3:1 to 1:1. 24. A dosage form comprising the solid dispersion of claim 23. 25. The dosage form of claim 24 wherein the dosage form is selected from a tablet and a capsule. 26. The solid dispersion according to claim 23 obtainable by spray-drying. 27. The solid dispersion according to claim 26, further containing microcrystalline cellulose. | 1,600 |
874 | 14,810,858 | 1,615 | Biomaterials, implants made therefrom, methods of making the biomaterial and implants, methods of promoting bone or wound healing in a mammal by administering the biomaterial or implant to the mammal, and kits that include such biomaterials, implants, or components thereof. The biomaterials may be designed to exhibit osteogenic, osteoinductive, osteoconductive, and/or osteostimulative properties. | 1. A method of making an implantable biomaterial for aiding bone regeneration, the method comprising:
obtaining demineralized bone in particulate form; adding the demineralized, particulate bone to a mold; compressing the demineralized, particulate bone in the mold for a time and pressure sufficient to form a molded biomaterial composition of a given shape; and freeze-drying the molded biomaterial composition to form the implantable biomaterial, wherein the shape of the implantable biomaterial is determined by the mold. 2. The method of claim 1 further comprising adding bioactive glass, tricalcium phosphate, or a combination thereof to the demineralized, particulate bone. 3. The method of claim 1, wherein the demineralized bone is in the form of demineralized cortical or cancellous fibers. 4. The method of claim 1, wherein the implantable biomaterial is multi-layered. 5. The method of claim 4, wherein adjoining layers of the multi-layered implantable biomaterial are different compositionally from one another. 6. The method of claim 1, wherein the implantable biomaterial includes a plurality of complimentary shapes assembled together. 7. The method of claim 6, wherein the plurality of complimentary shapes include a first portion having a mortise interlocked with a second portion having a tenon received in the mortise of the first portion. 8. The method of claim 6, wherein the plurality of complimentary shapes include a plurality of substantially concentric rings interlocked together. 9. The method of claim 1, wherein the implantable biomaterial includes one or more openings sized and configured to receive one or more bone graft materials. 10. The method of claim 1, wherein the implantable biomaterial includes one or more notches configured to receive a portion of a bone fastener. 11. A method of making an implantable biomaterial for aiding bone regeneration, the method comprising:
obtaining demineralized bone in particulate form; adding a first layer of the demineralized, particulate bone to a mold; adding a second layer of the demineralized, particulate bone to the mold; compressing the layers of demineralized, particulate bone in the mold for a time and pressure sufficient to form a molded biomaterial composition of a given shape having separate and distinct layers; and freeze-drying the molded biomaterial composition to form the implantable biomaterial, wherein the shape of the implantable biomaterial is determined by the mold. 12. The method of claim 11, wherein the first and second layers are different compositionally. 13. The method of claim 11 further comprising adding a third layer of the demineralized, particulate bone to the mold, wherein the third layer is the same compositionally as the first layer. 14. The method of claim 11 further comprising adding a plurality of additional layers to the mold, wherein the resulting layered implantable biomaterial comprises alternating layers of different materials. 15. A method of promoting bone or wound healing in a mammal, the method comprising:
providing a compressed, multi-layered implantable biomaterial comprised of demineralized bone in particulate form; and administering the implantable biomaterial into a target repair site to facilitate repair or regeneration of bone at the target repair site. 16. The method of claim 15, wherein the implantable biomaterial is positioned and retained within a frame formed of a different material than the implantable biomaterial. 17. The method of claim 16, wherein the implantable biomaterial and the frame form a standalone implant configured to be secured to adjacent vertebrae with one or more bone fasteners. 18. The method of claim 15, wherein the implantable biomaterial includes one or more openings sized and configured to receive one or more bone graft materials. 19. The method of claim 15, wherein the implantable biomaterial includes one or more notches configured to receive a portion of a bone fastener. 20. The method of claim 15 wherein the target repair site is an injury or defect in the spine. | Biomaterials, implants made therefrom, methods of making the biomaterial and implants, methods of promoting bone or wound healing in a mammal by administering the biomaterial or implant to the mammal, and kits that include such biomaterials, implants, or components thereof. The biomaterials may be designed to exhibit osteogenic, osteoinductive, osteoconductive, and/or osteostimulative properties.1. A method of making an implantable biomaterial for aiding bone regeneration, the method comprising:
obtaining demineralized bone in particulate form; adding the demineralized, particulate bone to a mold; compressing the demineralized, particulate bone in the mold for a time and pressure sufficient to form a molded biomaterial composition of a given shape; and freeze-drying the molded biomaterial composition to form the implantable biomaterial, wherein the shape of the implantable biomaterial is determined by the mold. 2. The method of claim 1 further comprising adding bioactive glass, tricalcium phosphate, or a combination thereof to the demineralized, particulate bone. 3. The method of claim 1, wherein the demineralized bone is in the form of demineralized cortical or cancellous fibers. 4. The method of claim 1, wherein the implantable biomaterial is multi-layered. 5. The method of claim 4, wherein adjoining layers of the multi-layered implantable biomaterial are different compositionally from one another. 6. The method of claim 1, wherein the implantable biomaterial includes a plurality of complimentary shapes assembled together. 7. The method of claim 6, wherein the plurality of complimentary shapes include a first portion having a mortise interlocked with a second portion having a tenon received in the mortise of the first portion. 8. The method of claim 6, wherein the plurality of complimentary shapes include a plurality of substantially concentric rings interlocked together. 9. The method of claim 1, wherein the implantable biomaterial includes one or more openings sized and configured to receive one or more bone graft materials. 10. The method of claim 1, wherein the implantable biomaterial includes one or more notches configured to receive a portion of a bone fastener. 11. A method of making an implantable biomaterial for aiding bone regeneration, the method comprising:
obtaining demineralized bone in particulate form; adding a first layer of the demineralized, particulate bone to a mold; adding a second layer of the demineralized, particulate bone to the mold; compressing the layers of demineralized, particulate bone in the mold for a time and pressure sufficient to form a molded biomaterial composition of a given shape having separate and distinct layers; and freeze-drying the molded biomaterial composition to form the implantable biomaterial, wherein the shape of the implantable biomaterial is determined by the mold. 12. The method of claim 11, wherein the first and second layers are different compositionally. 13. The method of claim 11 further comprising adding a third layer of the demineralized, particulate bone to the mold, wherein the third layer is the same compositionally as the first layer. 14. The method of claim 11 further comprising adding a plurality of additional layers to the mold, wherein the resulting layered implantable biomaterial comprises alternating layers of different materials. 15. A method of promoting bone or wound healing in a mammal, the method comprising:
providing a compressed, multi-layered implantable biomaterial comprised of demineralized bone in particulate form; and administering the implantable biomaterial into a target repair site to facilitate repair or regeneration of bone at the target repair site. 16. The method of claim 15, wherein the implantable biomaterial is positioned and retained within a frame formed of a different material than the implantable biomaterial. 17. The method of claim 16, wherein the implantable biomaterial and the frame form a standalone implant configured to be secured to adjacent vertebrae with one or more bone fasteners. 18. The method of claim 15, wherein the implantable biomaterial includes one or more openings sized and configured to receive one or more bone graft materials. 19. The method of claim 15, wherein the implantable biomaterial includes one or more notches configured to receive a portion of a bone fastener. 20. The method of claim 15 wherein the target repair site is an injury or defect in the spine. | 1,600 |
875 | 15,314,674 | 1,653 | The invention relates to a method for a photochemical process, such as a photocatalytic and/or photosynthetic process, in particular for the culture and production or the hydroculture of microorganisms. A reaction medium ( 6 ) is conducted in a meandering manner in a reactor element ( 2 ) which is made of at least two upright and connected pipes ( 3 ) or chambers ( 13 ). Multiple reactor elements ( 2 ) are serially connected into a bio solar reactor ( 1 ), and a reaction medium ( 6 ) flow which is stress-free for the microorganisms is generated in the bio solar reactor ( 1 ) using hydrostatic pressure and level compensation. Inlet and outlet openings ( 4, 5 ) are arranged on the lower face ( 8 ) of each individual reactor element ( 2 ) on each of the outermost pipes ( 3 ) or chambers ( 13 ). The reaction medium ( 6 ) flows around all of the connections in the lower region, in particular the inlet opening ( 4 ), the outlet opening ( 5 ), and the introduction inlet ( 17 ). The invention also relates to a device for carrying out the method and to a bio solar reactor. | 1-15. (canceled) 16. A method of culturing phototropic microorganisms in a reaction medium in a bioreactor, wherein the bioreactor comprises at least one reactor element, wherein the reactor element comprises an inlet for the reaction medium from outside of the reactor element, an outlet for the reaction medium to outside of the reactor element, and at least two pipes or chambers for the reaction medium, wherein the at least two pipes or chambers are upright and fluidly connected to each other, and wherein a first pipe or chamber of the at least two pipes or chambers has the inlet and a second pipe or chamber of the at least two pipes or chambers has the outlet, and wherein the inlet and the outlet are arranged on or close to a lower face of the reactor element, said method comprising:
conducting the reaction medium containing the phototrophic microorganisms in a meandering manner through the at least two pipes or chambers, such that the first pipe or chamber has a reaction medium flow against the direction of gravity, and the second pipe or chamber has a reaction medium flow in the direction of gravity, and such that an entirety of an inner surface of the inlet and an entirety of an inner surface of the outlet come into contact with the reaction medium during said conducting; and exposing, during the conducting, at least a portion of the phototrophic microorganisms to an amount of light sufficient for growth of the portion of the phototrophic microorganisms; and introducing, into the reaction medium during the conducting, at least one of a liquid additive and a gaseous additive at or close to a lower face of the reactor element. 17. The method of claim 16, further comprising, during the conducting:
detecting a filling level of the reaction medium in the reactor element with a filling level control; and maintaining the filling level at a predetermined value, wherein a liquid is added to the reaction medium if a fall of the filling level is detected. 18. The method of claim 16, further comprising, during said conducting:
transporting a gaseous product produced by the phototrophic microorganisms in the reaction medium via an exhaust system out of the reactor element, wherein the gaseous product traverses a surface of the reaction medium in the reactor element, and wherein the exhaust system is on or close to an upper face of the reactor element. 19. The method of claim 16, wherein said introducing comprises introducing gas bubbles at or close to the lower face of the reactor element into the reaction medium in each of the at least two pipes or chambers. 20. The method of claim 16, wherein the at least one reactor element comprises first and second reactor elements, wherein an outlet of the first reactor element is fluidly connected to an inlet of the second reactor element. 21. The method of claim 16, wherein said at least two pipes or chambers are substantially translucent or transparent. 22. The method of claim 16, wherein said at least two pipes or chambers comprise a glass material. 23. The method of claim 19, wherein said at least two pipes or chambers comprise a glass material. 24. A method of culturing phototropic microorganisms in a reaction medium in a bioreactor, wherein the bioreactor comprises a reactor element having an inlet open to an outside, an outlet open to an outside, and first and second pipes or elongate chambers oriented upright and fluidly connected to each other, wherein the inlet is coupled to a lower end of the first pipe or elongate chamber and the outlet is coupled to a lower end of the second pipe or elongate chamber, said method comprising:
conducting the reaction medium containing the phototrophic microorganisms in a meandering manner through the first and second pipes or elongate chambers, such that the first pipe or elongate chamber has a reaction medium flow against the direction of gravity, and the second pipe or elongate chamber has a reaction medium flow in the direction of gravity, and such that an entirety of an inner surface of the inlet and an entirety of an inner surface of the outlet come into contact with the reaction medium during said conducting; and exposing, during the conducting, at least a portion of the phototrophic microorganisms to an amount of light sufficient for growth of the portion of the phototrophic microorganisms; and introducing into the reaction medium, during the conducting, at least one of a liquid additive and a gaseous additive, said introducing occurring at or close to a lower end of the reactor element. 25. A method of culturing phototropic microorganisms in a reaction medium in a bioreactor, wherein the bioreactor comprises an inlet, an outlet, and reactor elements, with each reactor element comprising first and second pipes or elongate chambers oriented upright and fluidly connected to each other, wherein the inlet is located at a lower end of the bioreactor and on one side of the bioreactor and the outlet is located at a lower end of the bioreactor and on an opposite side of the bioreactor, said method comprising:
conducting the reaction medium containing the phototrophic microorganisms in a meandering manner through each reactor element, such that each first pipe or elongate chamber has a reaction medium flow against the direction of gravity, and each second pipe or elongate chamber has a reaction medium flow in the direction of gravity, and such that an entirety of an inner surface of the inlet and an entirety of an inner surface of the outlet come into contact with the reaction medium during said conducting; and exposing, during the conducting, at least a portion of the phototrophic microorganisms to an amount of light sufficient for growth of the portion of the phototrophic microorganisms; and introducing into the reaction medium, during the conducting, at least one of a liquid additive and a gaseous additive. | The invention relates to a method for a photochemical process, such as a photocatalytic and/or photosynthetic process, in particular for the culture and production or the hydroculture of microorganisms. A reaction medium ( 6 ) is conducted in a meandering manner in a reactor element ( 2 ) which is made of at least two upright and connected pipes ( 3 ) or chambers ( 13 ). Multiple reactor elements ( 2 ) are serially connected into a bio solar reactor ( 1 ), and a reaction medium ( 6 ) flow which is stress-free for the microorganisms is generated in the bio solar reactor ( 1 ) using hydrostatic pressure and level compensation. Inlet and outlet openings ( 4, 5 ) are arranged on the lower face ( 8 ) of each individual reactor element ( 2 ) on each of the outermost pipes ( 3 ) or chambers ( 13 ). The reaction medium ( 6 ) flows around all of the connections in the lower region, in particular the inlet opening ( 4 ), the outlet opening ( 5 ), and the introduction inlet ( 17 ). The invention also relates to a device for carrying out the method and to a bio solar reactor.1-15. (canceled) 16. A method of culturing phototropic microorganisms in a reaction medium in a bioreactor, wherein the bioreactor comprises at least one reactor element, wherein the reactor element comprises an inlet for the reaction medium from outside of the reactor element, an outlet for the reaction medium to outside of the reactor element, and at least two pipes or chambers for the reaction medium, wherein the at least two pipes or chambers are upright and fluidly connected to each other, and wherein a first pipe or chamber of the at least two pipes or chambers has the inlet and a second pipe or chamber of the at least two pipes or chambers has the outlet, and wherein the inlet and the outlet are arranged on or close to a lower face of the reactor element, said method comprising:
conducting the reaction medium containing the phototrophic microorganisms in a meandering manner through the at least two pipes or chambers, such that the first pipe or chamber has a reaction medium flow against the direction of gravity, and the second pipe or chamber has a reaction medium flow in the direction of gravity, and such that an entirety of an inner surface of the inlet and an entirety of an inner surface of the outlet come into contact with the reaction medium during said conducting; and exposing, during the conducting, at least a portion of the phototrophic microorganisms to an amount of light sufficient for growth of the portion of the phototrophic microorganisms; and introducing, into the reaction medium during the conducting, at least one of a liquid additive and a gaseous additive at or close to a lower face of the reactor element. 17. The method of claim 16, further comprising, during the conducting:
detecting a filling level of the reaction medium in the reactor element with a filling level control; and maintaining the filling level at a predetermined value, wherein a liquid is added to the reaction medium if a fall of the filling level is detected. 18. The method of claim 16, further comprising, during said conducting:
transporting a gaseous product produced by the phototrophic microorganisms in the reaction medium via an exhaust system out of the reactor element, wherein the gaseous product traverses a surface of the reaction medium in the reactor element, and wherein the exhaust system is on or close to an upper face of the reactor element. 19. The method of claim 16, wherein said introducing comprises introducing gas bubbles at or close to the lower face of the reactor element into the reaction medium in each of the at least two pipes or chambers. 20. The method of claim 16, wherein the at least one reactor element comprises first and second reactor elements, wherein an outlet of the first reactor element is fluidly connected to an inlet of the second reactor element. 21. The method of claim 16, wherein said at least two pipes or chambers are substantially translucent or transparent. 22. The method of claim 16, wherein said at least two pipes or chambers comprise a glass material. 23. The method of claim 19, wherein said at least two pipes or chambers comprise a glass material. 24. A method of culturing phototropic microorganisms in a reaction medium in a bioreactor, wherein the bioreactor comprises a reactor element having an inlet open to an outside, an outlet open to an outside, and first and second pipes or elongate chambers oriented upright and fluidly connected to each other, wherein the inlet is coupled to a lower end of the first pipe or elongate chamber and the outlet is coupled to a lower end of the second pipe or elongate chamber, said method comprising:
conducting the reaction medium containing the phototrophic microorganisms in a meandering manner through the first and second pipes or elongate chambers, such that the first pipe or elongate chamber has a reaction medium flow against the direction of gravity, and the second pipe or elongate chamber has a reaction medium flow in the direction of gravity, and such that an entirety of an inner surface of the inlet and an entirety of an inner surface of the outlet come into contact with the reaction medium during said conducting; and exposing, during the conducting, at least a portion of the phototrophic microorganisms to an amount of light sufficient for growth of the portion of the phototrophic microorganisms; and introducing into the reaction medium, during the conducting, at least one of a liquid additive and a gaseous additive, said introducing occurring at or close to a lower end of the reactor element. 25. A method of culturing phototropic microorganisms in a reaction medium in a bioreactor, wherein the bioreactor comprises an inlet, an outlet, and reactor elements, with each reactor element comprising first and second pipes or elongate chambers oriented upright and fluidly connected to each other, wherein the inlet is located at a lower end of the bioreactor and on one side of the bioreactor and the outlet is located at a lower end of the bioreactor and on an opposite side of the bioreactor, said method comprising:
conducting the reaction medium containing the phototrophic microorganisms in a meandering manner through each reactor element, such that each first pipe or elongate chamber has a reaction medium flow against the direction of gravity, and each second pipe or elongate chamber has a reaction medium flow in the direction of gravity, and such that an entirety of an inner surface of the inlet and an entirety of an inner surface of the outlet come into contact with the reaction medium during said conducting; and exposing, during the conducting, at least a portion of the phototrophic microorganisms to an amount of light sufficient for growth of the portion of the phototrophic microorganisms; and introducing into the reaction medium, during the conducting, at least one of a liquid additive and a gaseous additive. | 1,600 |
876 | 11,668,148 | 1,653 | Semen and sperm cell processing and preservation systems, and methods of producing a mammal and methods of producing mammalian embryos are disclosed. The present invention is directed to sperm cell preservation, fertilization, and insemination, maintaining or enhancing sperm quality and addressing one or more sperm cell characteristics, such as viability, motility, functionality, fertilization rates, and pregnancy rates. Further, sperm cell characteristics may be addressed within the context of various collection, handling, separation, storage, transportation, usage, fertilization, or insemination techniques. | 1. A method of producing a mammal comprising the steps of:
obtaining sperm cells from a male of a nonhuman mammalian species; cryopreserving said obtained sperm cells; thawing said cryopreserved sperm cells; processing said thawed sperm cells; cryopreserving said processed sperm cells to yield twice-cryopreserved processed sperm cells, wherein an increased percentage of said twice-cryopreserved processed sperm cells, when thawed, are motile, compared to said thawed sperm cells; thawing said twice-cryopreserved processed sperm cells to yield thawed twice-cryopreserved processed sperm cells; fertilizing at least one egg from a female of said non-human mammalian species with said thawed twice-cryopreserved processed sperm cells; producing a mammal from said at least one fertilized egg. 2. A method of producing a mammal as described in claim 1 wherein said step of processing comprises sorting said thawed sperm cells. 3. A method of producing a mammal as described in claim 2, wherein said step of sorting comprises selecting said thawed sperm cells based upon at least one desired sperm cell characteristic. 4. A method of producing a mammal as described in claim 3, wherein said step of selecting comprises staining said thawed sperm cells based upon at least one desired sperm cell characteristic. 5. A method of producing a mammal as described in claim 4, wherein said step of selecting further comprises differentiating said thawed sperm cells based upon said at least one desired sperm cell characteristic. 6. A method of producing a mammal as described in claim 5, wherein said step of differentiating comprises differentiating said thawed sperm cells as either an X chromosome bearing sperm cell or a Y chromosome bearing sperm cell. 7. A method of producing a mammal as described in claim 5, wherein said step of selecting further comprises separating said thawed sperm cells having said at least one desired sperm cell characteristic. 8. A method of producing a mammal as described in claims 5 or 7, further comprising the step of collecting said thawed twice-cryopreserved processed sperm cells. 9. A method of producing a mammal as described in claim 8, wherein said step of collecting comprises the step of maintaining sperm quality. 10. A method of producing a mammal as described in claim 2, wherein said step of sorting comprises flow cytometer sorting. 11. A method of producing a mammal as described in claim 2, further comprising the step of establishing a sperm sample from said sorted sperm cells. 12. A method of producing a mammal as described in claim 11, wherein said second step of cryopreserving comprises cryopreserving said sperm sample. 13. A method of producing a mammal as described in claim 11, wherein said step of establishing a sperm sample comprises establishing a plurality of sperm samples and wherein said second step of cryopreserving comprises cryopreserving said plurality of samples. 14. A method of producing a mammal as described in claim 1, further comprising the step of establishing a sperm sample from said thawed twice-cryopreserved processed sperm cells. 15. A method of producing a mammal as described in claim 14, wherein said step of establishing a sperm sample comprises establishing a plurality of sperm samples. 16. A sperm sample established in accordance with the method of claim 11. 17. A sperm sample established in accordance with the method of claim 12, 13, 14, or 15. 18. A sperm sample as described in claim 16, wherein said sperm sample comprises a straw. 19. A sperm sample as described in claim 16, wherein said sperm sample comprises a pellet. 20. A sperm sample as described in claim 16, wherein said sperm sample comprises an insemination dose. 21. A sperm sample as described in claim 16, wherein said sperm sample comprises a prepared sperm sample. 22. A method of producing a mammal as described in claim 1, wherein said step of obtaining comprises obtaining semen having a concentration of sperm cells, wherein said first step of cryopreserving comprises cryopreserving said semen, and wherein said first step of thawing comprises thawing said cryopreserved semen. 23. A method of producing a mammal as described in claim 1, wherein said step of obtaining comprises obtaining sperm cells from zoological specimens. 24. A mammal produced from the thawed twice-cryopreserved processed sperm cells of claim 1. 25. A mammal produced from the thawed twice-cryopreserved processed sperm cells of claim 22. 26. A mammal produced from the sperm sample of claim 16. 27. A mammal as described in claims 24, 25, or 26, wherein said mammal comprises a mammal selected from the group consisting of equids, bovids, felids, ovids, canids, buffalo, oxen, elk, and porcine. 28. A mammal as described in claims 24, 25, or 26, wherein said mammal comprises a mammal selected from the group consisting of prized mammal species, endangered mammal species, and rare individuals of a mammal species. 29. A mammal produced from a sperm sample established in accordance with the method of claim 11, 12, 13, 14, 15, 18, 19, 20, or 21. 30. A method of producing a mammal as described in claim 1, further comprising the step of maintaining sperm quality of said thawed twice-cryopreserved processed sperm cells. 31. A method of producing a mammal as described in claim 30, wherein said step of maintaining sperm quality comprises enhancing motility of said thawed twice-cryopreserved processed sperm cells. 32. A method of producing a mammal as described in claim 30, wherein said step of maintaining sperm quality comprises enhancing viability of said thawed twice-cryopreserved processed sperm cells. 33. A method of producing a mammal as described in claim 30, wherein said step of maintaining sperm quality comprises enhancing functionality of said thawed twice-cryopreserved processed sperm cells. 34. A method of producing a mammal as described in claim 1, further comprising the step of maintaining fertilization rates with said thawed twice-cryopreserved processed sperm cells. 35. A method of producing a mammal as described in claim 1, further comprising the step of enhancing blastocyst development rates with said thawed twice-cryopreserved processed sperm cells. 36. A method of producing a mammal as described in claim 1, further comprising the step of maintaining monospermic fertilization with said thawed twice-cryopreserved processed sperm cells. 37. A method of producing a mammal as described in claim 1, further comprising the step of maintaining cleavage rates with said thawed twice-cryopreserved processed sperm cells. 38. A method of producing a mammal as described in claim 31, wherein said step of enhancing motility comprises achieving at least about 83.4 percent motility of said thawed twice-cryopreserved processed sperm cells. 39. A method of producing a mammal as described in claim 30, wherein said step of maintaining sperm quality comprises enhancing an insemination rate with said thawed twice-cryopreserved processed sperm cells. 40. A method of producing a mammal, comprising the steps of:
obtaining sperm cells; cryopreserving said sperm cells; thawing said sperm cells; cryopreserving said sperm cells; fertilizing at least one egg with said sperm cells; and producing a mammal from said at least one fertilized egg. 41. A method of producing a mammal as described in claim 40, further comprising the step of inseminating at least one female of a species of said mammal with said sperm cells. 42. A method of producing a mammal as described in claim 41, wherein said step of inseminating comprises inseminating with said sperm cells in an unthawed condition. 43. A method of producing a mammal as described in claim 41, wherein said step of inseminating a female comprises inseminating a superovulated female with said sperm cells. 44. A method of producing a mammal as described in claim 41, further comprising the step of superovulating a female of said species of said mammal and wherein said step of inseminating a female comprises inseminating said superovulated female. 45. A method of producing a mammal as described in claim 40, further comprising the step of obtaining at least one egg of a superovulated female of a species of said mammal and wherein said step of fertilizing comprises fertilizing in vitro said at least one egg. 46. A method of producing a mammal as described in claims 43, 44, or 45, further comprising the step of transferring said at least one fertilized egg to a recipient female. 47. A method of producing a mammal as described in claim 40, wherein said step of fertilizing comprises fertilizing in vitro said at least one egg. 48. A method of producing a mammal as described in claim 47, further comprising the step of transferring said at least one fertilized egg to a recipient female. 49. A method of producing a mammal as described in claim 40, further comprising the step of sorting said sperm cells. 50. A method of producing a mammal as described in claim 40, further comprising the step of thawing said sperm cells. 51. A method of producing a mammalian embryo, comprising the steps of:
obtaining sperm cells; cryopreserving said sperm cells; thawing said sperm cells; cryopreserving said sperm cells; fertilizing at least one egg with said sperm cells; and producing a mammalian embryo from said at least one fertilized egg. 52. A method of producing a mammal, comprising the steps of:
obtaining sperm cells; cryopreserving said sperm cells; thawing said sperm cells; cryopreserving said sperm cells; fertilizing in vitro said at least one egg with said sperm cells; transferring said at least one fertilized egg to a recipient female; and producing a mammal from said at least one fertilized egg. 53. A method of producing a mammal, comprising the steps of:
obtaining sperm cells; cryopreserving said sperm cells; thawing said sperm cells; cryopreserving said sperm cells; inseminating at least one female of a species of said mammal with said sperm cells; fertilizing at least one egg with said sperm cells; and producing a mammal from said at least one fertilized egg. | Semen and sperm cell processing and preservation systems, and methods of producing a mammal and methods of producing mammalian embryos are disclosed. The present invention is directed to sperm cell preservation, fertilization, and insemination, maintaining or enhancing sperm quality and addressing one or more sperm cell characteristics, such as viability, motility, functionality, fertilization rates, and pregnancy rates. Further, sperm cell characteristics may be addressed within the context of various collection, handling, separation, storage, transportation, usage, fertilization, or insemination techniques.1. A method of producing a mammal comprising the steps of:
obtaining sperm cells from a male of a nonhuman mammalian species; cryopreserving said obtained sperm cells; thawing said cryopreserved sperm cells; processing said thawed sperm cells; cryopreserving said processed sperm cells to yield twice-cryopreserved processed sperm cells, wherein an increased percentage of said twice-cryopreserved processed sperm cells, when thawed, are motile, compared to said thawed sperm cells; thawing said twice-cryopreserved processed sperm cells to yield thawed twice-cryopreserved processed sperm cells; fertilizing at least one egg from a female of said non-human mammalian species with said thawed twice-cryopreserved processed sperm cells; producing a mammal from said at least one fertilized egg. 2. A method of producing a mammal as described in claim 1 wherein said step of processing comprises sorting said thawed sperm cells. 3. A method of producing a mammal as described in claim 2, wherein said step of sorting comprises selecting said thawed sperm cells based upon at least one desired sperm cell characteristic. 4. A method of producing a mammal as described in claim 3, wherein said step of selecting comprises staining said thawed sperm cells based upon at least one desired sperm cell characteristic. 5. A method of producing a mammal as described in claim 4, wherein said step of selecting further comprises differentiating said thawed sperm cells based upon said at least one desired sperm cell characteristic. 6. A method of producing a mammal as described in claim 5, wherein said step of differentiating comprises differentiating said thawed sperm cells as either an X chromosome bearing sperm cell or a Y chromosome bearing sperm cell. 7. A method of producing a mammal as described in claim 5, wherein said step of selecting further comprises separating said thawed sperm cells having said at least one desired sperm cell characteristic. 8. A method of producing a mammal as described in claims 5 or 7, further comprising the step of collecting said thawed twice-cryopreserved processed sperm cells. 9. A method of producing a mammal as described in claim 8, wherein said step of collecting comprises the step of maintaining sperm quality. 10. A method of producing a mammal as described in claim 2, wherein said step of sorting comprises flow cytometer sorting. 11. A method of producing a mammal as described in claim 2, further comprising the step of establishing a sperm sample from said sorted sperm cells. 12. A method of producing a mammal as described in claim 11, wherein said second step of cryopreserving comprises cryopreserving said sperm sample. 13. A method of producing a mammal as described in claim 11, wherein said step of establishing a sperm sample comprises establishing a plurality of sperm samples and wherein said second step of cryopreserving comprises cryopreserving said plurality of samples. 14. A method of producing a mammal as described in claim 1, further comprising the step of establishing a sperm sample from said thawed twice-cryopreserved processed sperm cells. 15. A method of producing a mammal as described in claim 14, wherein said step of establishing a sperm sample comprises establishing a plurality of sperm samples. 16. A sperm sample established in accordance with the method of claim 11. 17. A sperm sample established in accordance with the method of claim 12, 13, 14, or 15. 18. A sperm sample as described in claim 16, wherein said sperm sample comprises a straw. 19. A sperm sample as described in claim 16, wherein said sperm sample comprises a pellet. 20. A sperm sample as described in claim 16, wherein said sperm sample comprises an insemination dose. 21. A sperm sample as described in claim 16, wherein said sperm sample comprises a prepared sperm sample. 22. A method of producing a mammal as described in claim 1, wherein said step of obtaining comprises obtaining semen having a concentration of sperm cells, wherein said first step of cryopreserving comprises cryopreserving said semen, and wherein said first step of thawing comprises thawing said cryopreserved semen. 23. A method of producing a mammal as described in claim 1, wherein said step of obtaining comprises obtaining sperm cells from zoological specimens. 24. A mammal produced from the thawed twice-cryopreserved processed sperm cells of claim 1. 25. A mammal produced from the thawed twice-cryopreserved processed sperm cells of claim 22. 26. A mammal produced from the sperm sample of claim 16. 27. A mammal as described in claims 24, 25, or 26, wherein said mammal comprises a mammal selected from the group consisting of equids, bovids, felids, ovids, canids, buffalo, oxen, elk, and porcine. 28. A mammal as described in claims 24, 25, or 26, wherein said mammal comprises a mammal selected from the group consisting of prized mammal species, endangered mammal species, and rare individuals of a mammal species. 29. A mammal produced from a sperm sample established in accordance with the method of claim 11, 12, 13, 14, 15, 18, 19, 20, or 21. 30. A method of producing a mammal as described in claim 1, further comprising the step of maintaining sperm quality of said thawed twice-cryopreserved processed sperm cells. 31. A method of producing a mammal as described in claim 30, wherein said step of maintaining sperm quality comprises enhancing motility of said thawed twice-cryopreserved processed sperm cells. 32. A method of producing a mammal as described in claim 30, wherein said step of maintaining sperm quality comprises enhancing viability of said thawed twice-cryopreserved processed sperm cells. 33. A method of producing a mammal as described in claim 30, wherein said step of maintaining sperm quality comprises enhancing functionality of said thawed twice-cryopreserved processed sperm cells. 34. A method of producing a mammal as described in claim 1, further comprising the step of maintaining fertilization rates with said thawed twice-cryopreserved processed sperm cells. 35. A method of producing a mammal as described in claim 1, further comprising the step of enhancing blastocyst development rates with said thawed twice-cryopreserved processed sperm cells. 36. A method of producing a mammal as described in claim 1, further comprising the step of maintaining monospermic fertilization with said thawed twice-cryopreserved processed sperm cells. 37. A method of producing a mammal as described in claim 1, further comprising the step of maintaining cleavage rates with said thawed twice-cryopreserved processed sperm cells. 38. A method of producing a mammal as described in claim 31, wherein said step of enhancing motility comprises achieving at least about 83.4 percent motility of said thawed twice-cryopreserved processed sperm cells. 39. A method of producing a mammal as described in claim 30, wherein said step of maintaining sperm quality comprises enhancing an insemination rate with said thawed twice-cryopreserved processed sperm cells. 40. A method of producing a mammal, comprising the steps of:
obtaining sperm cells; cryopreserving said sperm cells; thawing said sperm cells; cryopreserving said sperm cells; fertilizing at least one egg with said sperm cells; and producing a mammal from said at least one fertilized egg. 41. A method of producing a mammal as described in claim 40, further comprising the step of inseminating at least one female of a species of said mammal with said sperm cells. 42. A method of producing a mammal as described in claim 41, wherein said step of inseminating comprises inseminating with said sperm cells in an unthawed condition. 43. A method of producing a mammal as described in claim 41, wherein said step of inseminating a female comprises inseminating a superovulated female with said sperm cells. 44. A method of producing a mammal as described in claim 41, further comprising the step of superovulating a female of said species of said mammal and wherein said step of inseminating a female comprises inseminating said superovulated female. 45. A method of producing a mammal as described in claim 40, further comprising the step of obtaining at least one egg of a superovulated female of a species of said mammal and wherein said step of fertilizing comprises fertilizing in vitro said at least one egg. 46. A method of producing a mammal as described in claims 43, 44, or 45, further comprising the step of transferring said at least one fertilized egg to a recipient female. 47. A method of producing a mammal as described in claim 40, wherein said step of fertilizing comprises fertilizing in vitro said at least one egg. 48. A method of producing a mammal as described in claim 47, further comprising the step of transferring said at least one fertilized egg to a recipient female. 49. A method of producing a mammal as described in claim 40, further comprising the step of sorting said sperm cells. 50. A method of producing a mammal as described in claim 40, further comprising the step of thawing said sperm cells. 51. A method of producing a mammalian embryo, comprising the steps of:
obtaining sperm cells; cryopreserving said sperm cells; thawing said sperm cells; cryopreserving said sperm cells; fertilizing at least one egg with said sperm cells; and producing a mammalian embryo from said at least one fertilized egg. 52. A method of producing a mammal, comprising the steps of:
obtaining sperm cells; cryopreserving said sperm cells; thawing said sperm cells; cryopreserving said sperm cells; fertilizing in vitro said at least one egg with said sperm cells; transferring said at least one fertilized egg to a recipient female; and producing a mammal from said at least one fertilized egg. 53. A method of producing a mammal, comprising the steps of:
obtaining sperm cells; cryopreserving said sperm cells; thawing said sperm cells; cryopreserving said sperm cells; inseminating at least one female of a species of said mammal with said sperm cells; fertilizing at least one egg with said sperm cells; and producing a mammal from said at least one fertilized egg. | 1,600 |
877 | 15,678,823 | 1,635 | The present invention relates to a siRNA structure and the use thereof. More particularly, the invention relates to a double-stranded small interfering RNA molecule (siRNA molecule) comprising a 19-21 nucleotide (nt) antisense strand and a 15-19 nt sense strand having a sequence complementary to the antisense sequence, wherein the 5′ end of the antisense strand has a blunt end and the 3′ end of the antisense strand has an overhang, and to a method for silencing the expression of a target gene using the siRNA molecule. | 1. A small interfering RNA molecule (siRNA molecule) comprising: a 19-21 nucleotide (nt) antisense strand; and a 15-19 nt sense strand having a sequence complementary to the antisense strand, wherein the 5′ end of the antisense strand has a blunt end and the 3′ end of the antisense strand has an overhang. 2. The siRNA molecule according to claim 1, wherein the length of the antisense strand is 19 nt, the length of the sense strand is 15-17 nt, and the length of the overhang is 2-4 nt. 3. The siRNA molecule according to claim 2, wherein the length of the sense strand is 16 nt, and the length of the overhang is 3 nt. 4. The siRNA molecule according to claim 2, wherein the length of the sense strand is 15 nt, and the length of the overhang is 4 nt. 5. A method for silencing the expression of a target gene in a cell using said siRNA molecule of claim 1. 6. The method for silencing the expression of a target gene in a cell according to claim 5, wherein the antisense strand of the siRNA molecule is complementary to the mRNA sequence of a target gene. | The present invention relates to a siRNA structure and the use thereof. More particularly, the invention relates to a double-stranded small interfering RNA molecule (siRNA molecule) comprising a 19-21 nucleotide (nt) antisense strand and a 15-19 nt sense strand having a sequence complementary to the antisense sequence, wherein the 5′ end of the antisense strand has a blunt end and the 3′ end of the antisense strand has an overhang, and to a method for silencing the expression of a target gene using the siRNA molecule.1. A small interfering RNA molecule (siRNA molecule) comprising: a 19-21 nucleotide (nt) antisense strand; and a 15-19 nt sense strand having a sequence complementary to the antisense strand, wherein the 5′ end of the antisense strand has a blunt end and the 3′ end of the antisense strand has an overhang. 2. The siRNA molecule according to claim 1, wherein the length of the antisense strand is 19 nt, the length of the sense strand is 15-17 nt, and the length of the overhang is 2-4 nt. 3. The siRNA molecule according to claim 2, wherein the length of the sense strand is 16 nt, and the length of the overhang is 3 nt. 4. The siRNA molecule according to claim 2, wherein the length of the sense strand is 15 nt, and the length of the overhang is 4 nt. 5. A method for silencing the expression of a target gene in a cell using said siRNA molecule of claim 1. 6. The method for silencing the expression of a target gene in a cell according to claim 5, wherein the antisense strand of the siRNA molecule is complementary to the mRNA sequence of a target gene. | 1,600 |
878 | 14,901,617 | 1,644 | Methods and compositions for treating multiple sclerosis using dendritic cell anti-ASGPR antibodies fused to myelin basic protein or myelin oligodendrocyte glycoprotein provided. | 1. A method of inducing immune tolerance to at least one myelin sheath protein in a patient comprising administering to the patient an effective amount of a composition comprising a dendritic cell targeting complex comprising a dendritic cell antibody, or targeting fragment thereof, attached to the at least one myelin sheath protein, or antigenic fragment thereof. 2. The method of claim 1, wherein at least one myelin sheath protein is myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), proteolipid protein (PLP), or myelin associated glycoprotein (MAG). 3. The method of claim 2, wherein at least one myelin sheath protein is MBP. 4. The method of claim 2, wherein at least one myelin sheath protein is MOG. 5. The method of any of claims 1-4, wherein the dendritic cell antibody specifically binds asialoglycoprotein receptor (ASGPR). 6. The method of any of claims 1-5, wherein the composition comprises multiple dendritic cell targeting complexes. 7. The method of claim 6, wherein the multiple dendritic cell targeting complexes comprise different myelin sheath proteins or different antigenic fragments of one or more myelin sheath proteins. 8. The method of claim 6 or 7, wherein each myelin sheath protein or antigen fragment is separately attached to a dendritic cell antibody, or a targeting fragment thereof. 9. The method of any of claims 1-8, wherein the dendritic cell antibody is attached to the myelin sheath protein using a peptide linker. 10. The method of any of claims 1-9, wherein the composition further comprises at least one tolerogenic adjuvant. 11. The method of claim 10, wherein the tolerogenic adjuvant is attached to the dendritic cell targeting complex. 12. The method of claim 11, wherein the tolerogenic adjuvant is conjugated to the dendritic cell targeting complex. 13. The method of claim 11, wherein the tolerogenic adjuvant is fused to the dendritic cell antibody, or targeting fragment thereof, and/or to the at least one myelin sheath protein. 14. The method of any of claims 10-13, wherein the tolerogenic adjuvant is selected from IL-10, dexamethasone, FK506 (Tacrolimus), cholera toxin B subunit, Escherichia coli heat-labile enterotoxin B subunit, IFN-beta, glucocorticoids, vitamin D3, and vitamin D3 analogues. 15. The method of any of claims 1-14, wherein the dendritic cell antibody is attached to at least one myelin sheath protein through binding polypeptides. 16. The method of claim 15, wherein the binding polypeptides are dockerin and cohesin. 17. The method of any of claims 1-16, comprising more than one administration of the composition. 18. The method of any of claims 1-16, wherein the composition is administered orally, intravenously, subcutaneously, intradermally, intramuscularly, nasally, by injection, by inhalation, mucosally, and/or using a nebulizer. 19. The method of any of claims 1-18, wherein the subject exhibits one or more symptoms of a demyelinating disease. 20. The method of any of claims 1-19, wherein the subject has been diagnosed with a demyelinating disease. 21. The method of any of claims 1-20, wherein the subject is at risk for a demyelinating disease. 22. The method of any of claims 19-21, wherein the demyelinating disease affects the central nervous system. 23. The method of claim 22, wherein the demyelinating disease is an idiopathic inflammatory demyelinating disease. 24. The method of claim 22, wherein the demyelinating disease is multiple sclerosis, neuropathy, central pontine myelinolysis, tabes dorsalis, transverse myelitis, Devic's disease, progressive multifocal leukoencephalopathy, optic neuritis, or leukodystrophy. 25. The method of claim 24, wherein the demyelinating disease is multiple sclerosis. 26. The method of any of claims 19-21, wherein the demyelinating disease affects the peripheral nervous system. 27. The method of claim 26, wherein the demyelinating disease is Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, anti-MAG peripheral neuropathy, Charcot-Marie-Tooth Disease, copper deficiency, or progressive inflammatory neuropathy. 28. The method of any of claims 1-24, further comprising preparing the composition. 29. The method of any of claims 1-28, further comprising measuring antibodies against the at least one myelin sheath protein in the subject after administering the composition. 30. A method for treating a demyelinating disease in a subject comprising administering to the subject a pharmaceutically acceptable vaccine composition comprising at least a first ASGPR antibody, or binding fragment thereof, attached to myelin basic protein (MBP) and/or myelin oligodendrocyte glycoprotein (MOG), or antigenic fragment thereof. 31. The method of claim 30, wherein the ASGPR antibody, or binding fragment thereof, is fused to MBP or MOG, or an antigenic fragment thereof. 32. The method of claim 30 or 31, wherein the subject is administered the vaccine composition multiple times. 33. The method of claim 32, wherein the composition is administered orally, intravenously, subcutaneously, intradermally, intramuscularly, nasally, by injection, by inhalation, muscosally, and/or using a nebulizer. 34. The method of any of claims 30-33, wherein the subject exhibits one or more symptoms of a demyelinating disease. 35. The method of any of claims 30-33, wherein the subject has been diagnosed with a demyelinating disease. 36. The method of any of claims 30-33, wherein the subject is at risk for a demyelinating disease. 37. The method of any of claims 34-36, wherein the demyelinating disease affects the central nervous system. 38. The method of claim 37, wherein the demyelinating disease is an idiopathic inflammatory demyelinating disease. 39. The method of claim 38, wherein the demyelinating disease is multiple sclerosis, neuropathy, central pontine myelinolysis, tabes dorsalis, transverse myelitis, Devic's disease, progressive multifocal leukoencephalopathy, optic neuritis, or leukodystrophy. 40. The method of claim 39, wherein the demyelinating disease is multiple sclerosis. 41. The method of any of claims 34-36, wherein the demyelinating disease affects the peripheral nervous system. 42. The method of claim 41, wherein the demyelinating disease is Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, anti-MAG peripheral neuropathy. Charcot-Marie-Tooth Disease, copper deficiency, or progressive inflammatory neuropathy. 43. The method of any of claims 30-42, further comprising preparing the composition. 44. The method of any of claims 30-43, further comprising measuring antibodies against the at least one myelin sheath protein in the subject after administering the composition. 45. A composition comprising at least a first ASGPR antibody, or binding fragment thereof, attached to myelin basic protein (MBP) and/or myelin oligodendrocyte glycoprotein (MOG), or antigenic fragment thereof. 46. The composition of claim 45, wherein the dendritic cell antibody is attached to the myelin sheath protein or antigenic fragment thereof using a peptide linker. 47. The composition of any of claims 45-46, wherein the composition further comprises at least one tolerogenic adjuvant. 48. The composition of claim 47, wherein the tolerogenic adjuvant is attached to the dendritic cell targeting complex. 49. The composition of claim 48, wherein the tolerogenic adjuvant is conjugated to the dendritic cell targeting complex. 50. The composition of claim 48, wherein the tolerogenic adjuvant is fused to the dendritic cell antibody, or targeting fragment thereof, and/or to the at least one myelin sheath protein. 51. The composition of any of claims 47-50, wherein the tolerogenic adjuvant is selected from IL-10, dexamethasone, FK506 (Tacrolimus), cholera toxin B subunit, Escherichia coli heat-labile enterotoxin B subunit, IFN-beta, glucocorticoids, vitamin D3, and vitamin D3 analogues. 52. The composition of any of claims 45-51, wherein the dendritic cell antibody is attached to at least one myelin sheath protein or antigenic fragment thereof through binding polypeptides. 53. The composition of claim 52, wherein the binding polypeptides are dockerin and cohesin. | Methods and compositions for treating multiple sclerosis using dendritic cell anti-ASGPR antibodies fused to myelin basic protein or myelin oligodendrocyte glycoprotein provided.1. A method of inducing immune tolerance to at least one myelin sheath protein in a patient comprising administering to the patient an effective amount of a composition comprising a dendritic cell targeting complex comprising a dendritic cell antibody, or targeting fragment thereof, attached to the at least one myelin sheath protein, or antigenic fragment thereof. 2. The method of claim 1, wherein at least one myelin sheath protein is myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), proteolipid protein (PLP), or myelin associated glycoprotein (MAG). 3. The method of claim 2, wherein at least one myelin sheath protein is MBP. 4. The method of claim 2, wherein at least one myelin sheath protein is MOG. 5. The method of any of claims 1-4, wherein the dendritic cell antibody specifically binds asialoglycoprotein receptor (ASGPR). 6. The method of any of claims 1-5, wherein the composition comprises multiple dendritic cell targeting complexes. 7. The method of claim 6, wherein the multiple dendritic cell targeting complexes comprise different myelin sheath proteins or different antigenic fragments of one or more myelin sheath proteins. 8. The method of claim 6 or 7, wherein each myelin sheath protein or antigen fragment is separately attached to a dendritic cell antibody, or a targeting fragment thereof. 9. The method of any of claims 1-8, wherein the dendritic cell antibody is attached to the myelin sheath protein using a peptide linker. 10. The method of any of claims 1-9, wherein the composition further comprises at least one tolerogenic adjuvant. 11. The method of claim 10, wherein the tolerogenic adjuvant is attached to the dendritic cell targeting complex. 12. The method of claim 11, wherein the tolerogenic adjuvant is conjugated to the dendritic cell targeting complex. 13. The method of claim 11, wherein the tolerogenic adjuvant is fused to the dendritic cell antibody, or targeting fragment thereof, and/or to the at least one myelin sheath protein. 14. The method of any of claims 10-13, wherein the tolerogenic adjuvant is selected from IL-10, dexamethasone, FK506 (Tacrolimus), cholera toxin B subunit, Escherichia coli heat-labile enterotoxin B subunit, IFN-beta, glucocorticoids, vitamin D3, and vitamin D3 analogues. 15. The method of any of claims 1-14, wherein the dendritic cell antibody is attached to at least one myelin sheath protein through binding polypeptides. 16. The method of claim 15, wherein the binding polypeptides are dockerin and cohesin. 17. The method of any of claims 1-16, comprising more than one administration of the composition. 18. The method of any of claims 1-16, wherein the composition is administered orally, intravenously, subcutaneously, intradermally, intramuscularly, nasally, by injection, by inhalation, mucosally, and/or using a nebulizer. 19. The method of any of claims 1-18, wherein the subject exhibits one or more symptoms of a demyelinating disease. 20. The method of any of claims 1-19, wherein the subject has been diagnosed with a demyelinating disease. 21. The method of any of claims 1-20, wherein the subject is at risk for a demyelinating disease. 22. The method of any of claims 19-21, wherein the demyelinating disease affects the central nervous system. 23. The method of claim 22, wherein the demyelinating disease is an idiopathic inflammatory demyelinating disease. 24. The method of claim 22, wherein the demyelinating disease is multiple sclerosis, neuropathy, central pontine myelinolysis, tabes dorsalis, transverse myelitis, Devic's disease, progressive multifocal leukoencephalopathy, optic neuritis, or leukodystrophy. 25. The method of claim 24, wherein the demyelinating disease is multiple sclerosis. 26. The method of any of claims 19-21, wherein the demyelinating disease affects the peripheral nervous system. 27. The method of claim 26, wherein the demyelinating disease is Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, anti-MAG peripheral neuropathy, Charcot-Marie-Tooth Disease, copper deficiency, or progressive inflammatory neuropathy. 28. The method of any of claims 1-24, further comprising preparing the composition. 29. The method of any of claims 1-28, further comprising measuring antibodies against the at least one myelin sheath protein in the subject after administering the composition. 30. A method for treating a demyelinating disease in a subject comprising administering to the subject a pharmaceutically acceptable vaccine composition comprising at least a first ASGPR antibody, or binding fragment thereof, attached to myelin basic protein (MBP) and/or myelin oligodendrocyte glycoprotein (MOG), or antigenic fragment thereof. 31. The method of claim 30, wherein the ASGPR antibody, or binding fragment thereof, is fused to MBP or MOG, or an antigenic fragment thereof. 32. The method of claim 30 or 31, wherein the subject is administered the vaccine composition multiple times. 33. The method of claim 32, wherein the composition is administered orally, intravenously, subcutaneously, intradermally, intramuscularly, nasally, by injection, by inhalation, muscosally, and/or using a nebulizer. 34. The method of any of claims 30-33, wherein the subject exhibits one or more symptoms of a demyelinating disease. 35. The method of any of claims 30-33, wherein the subject has been diagnosed with a demyelinating disease. 36. The method of any of claims 30-33, wherein the subject is at risk for a demyelinating disease. 37. The method of any of claims 34-36, wherein the demyelinating disease affects the central nervous system. 38. The method of claim 37, wherein the demyelinating disease is an idiopathic inflammatory demyelinating disease. 39. The method of claim 38, wherein the demyelinating disease is multiple sclerosis, neuropathy, central pontine myelinolysis, tabes dorsalis, transverse myelitis, Devic's disease, progressive multifocal leukoencephalopathy, optic neuritis, or leukodystrophy. 40. The method of claim 39, wherein the demyelinating disease is multiple sclerosis. 41. The method of any of claims 34-36, wherein the demyelinating disease affects the peripheral nervous system. 42. The method of claim 41, wherein the demyelinating disease is Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, anti-MAG peripheral neuropathy. Charcot-Marie-Tooth Disease, copper deficiency, or progressive inflammatory neuropathy. 43. The method of any of claims 30-42, further comprising preparing the composition. 44. The method of any of claims 30-43, further comprising measuring antibodies against the at least one myelin sheath protein in the subject after administering the composition. 45. A composition comprising at least a first ASGPR antibody, or binding fragment thereof, attached to myelin basic protein (MBP) and/or myelin oligodendrocyte glycoprotein (MOG), or antigenic fragment thereof. 46. The composition of claim 45, wherein the dendritic cell antibody is attached to the myelin sheath protein or antigenic fragment thereof using a peptide linker. 47. The composition of any of claims 45-46, wherein the composition further comprises at least one tolerogenic adjuvant. 48. The composition of claim 47, wherein the tolerogenic adjuvant is attached to the dendritic cell targeting complex. 49. The composition of claim 48, wherein the tolerogenic adjuvant is conjugated to the dendritic cell targeting complex. 50. The composition of claim 48, wherein the tolerogenic adjuvant is fused to the dendritic cell antibody, or targeting fragment thereof, and/or to the at least one myelin sheath protein. 51. The composition of any of claims 47-50, wherein the tolerogenic adjuvant is selected from IL-10, dexamethasone, FK506 (Tacrolimus), cholera toxin B subunit, Escherichia coli heat-labile enterotoxin B subunit, IFN-beta, glucocorticoids, vitamin D3, and vitamin D3 analogues. 52. The composition of any of claims 45-51, wherein the dendritic cell antibody is attached to at least one myelin sheath protein or antigenic fragment thereof through binding polypeptides. 53. The composition of claim 52, wherein the binding polypeptides are dockerin and cohesin. | 1,600 |
879 | 13,865,121 | 1,639 | A method of tissue analysis integrates a pathology diagnostic step (subjective human inspection of a stained tissue section or image of it) with one or more gene/biomarker tests to enable perform of both procedures side-by-side on the same instrument. | 1. A method of operating an automated microscopy system for measuring biomarker labels, comprising:
labeling tissue sections with fluorescent labels for molecules; an automated microscopy-executed step of acquiring images of the fluorescently-labeled tissue sections; an automated microscopy-executed step of labeling the same tissue sections with classical diagnostic bright field dyes; an automated microscopy-executed step of scanning the classically-labeled tissue sections to acquire images of them; and an automated microscopy-executed step of generating and displaying measurements of biomarker labels. 2. The method of claim 1, further including an automated microscopy-executed step of displaying the fluorescent images and the bright field images together. 3. The method of claim 1, an automated microscopy-executed step of generating cell-by-cell measurements. 4. The method of claim 3, wherein the measurements include distances of cells from a region or regions within the tissue, further including an automated microscopy-executed step of generating gradients from the distances for detecting the presence of tumor outside the tissue section. 5. The method of claim 2, further including an automated microscopy-executed step of displaying the images and the measurements of the biomarkers together. 6. The method of claim 2, further including an automated microscopy-executed step of displaying multiple labels and stains together in response to a user selection. 7. The method of claim 6, further including an automated microscopy-executed step of associating the multiple labels in subpopulations of cells with specific combinations of biomarkers. 8. The method of claim 2, further including an automated microscopy-executed step of receiving specification of one or more regions of the images for obtaining biomarker measurements on those regions. 9. The method of claim 8, further including an automated microscopy-executed step of comparing the measures of biomarkers derived from different regions of the tissue. 10. The method of claim 2, further including an automated microscopy-executed step of displaying the images and measures from the on-slide standard for normalizing the measures of the biomarkers of other tissues. 11. The method of claim 10, further including an automated microscopy-executed step of comparing the measures of biomarkers in the on-slide standard with measures of biomarkers from the on-slide standards from other slides in order for normalizing the measurements across slides. 12. The method of claim 11, further including an automated microscopy-executed steps of comparing the measures of biomarkers from on-slide standards on slide to the measures of the on-slide standards on a reference slide or reference slides and normalizing measures of biomarkers. 13. The method of claim 12, further including an automated microscopy-executed step of accessing the measures of the on-slide standards on the reference slides through a web site. 14. The method of claim 12, wherein a database of patient laboratory results of measurements of biomarkers utilizes the measures of the on-slide standards as a reference to compare and normalize measures of biomarkers on tissues stored in the database. | A method of tissue analysis integrates a pathology diagnostic step (subjective human inspection of a stained tissue section or image of it) with one or more gene/biomarker tests to enable perform of both procedures side-by-side on the same instrument.1. A method of operating an automated microscopy system for measuring biomarker labels, comprising:
labeling tissue sections with fluorescent labels for molecules; an automated microscopy-executed step of acquiring images of the fluorescently-labeled tissue sections; an automated microscopy-executed step of labeling the same tissue sections with classical diagnostic bright field dyes; an automated microscopy-executed step of scanning the classically-labeled tissue sections to acquire images of them; and an automated microscopy-executed step of generating and displaying measurements of biomarker labels. 2. The method of claim 1, further including an automated microscopy-executed step of displaying the fluorescent images and the bright field images together. 3. The method of claim 1, an automated microscopy-executed step of generating cell-by-cell measurements. 4. The method of claim 3, wherein the measurements include distances of cells from a region or regions within the tissue, further including an automated microscopy-executed step of generating gradients from the distances for detecting the presence of tumor outside the tissue section. 5. The method of claim 2, further including an automated microscopy-executed step of displaying the images and the measurements of the biomarkers together. 6. The method of claim 2, further including an automated microscopy-executed step of displaying multiple labels and stains together in response to a user selection. 7. The method of claim 6, further including an automated microscopy-executed step of associating the multiple labels in subpopulations of cells with specific combinations of biomarkers. 8. The method of claim 2, further including an automated microscopy-executed step of receiving specification of one or more regions of the images for obtaining biomarker measurements on those regions. 9. The method of claim 8, further including an automated microscopy-executed step of comparing the measures of biomarkers derived from different regions of the tissue. 10. The method of claim 2, further including an automated microscopy-executed step of displaying the images and measures from the on-slide standard for normalizing the measures of the biomarkers of other tissues. 11. The method of claim 10, further including an automated microscopy-executed step of comparing the measures of biomarkers in the on-slide standard with measures of biomarkers from the on-slide standards from other slides in order for normalizing the measurements across slides. 12. The method of claim 11, further including an automated microscopy-executed steps of comparing the measures of biomarkers from on-slide standards on slide to the measures of the on-slide standards on a reference slide or reference slides and normalizing measures of biomarkers. 13. The method of claim 12, further including an automated microscopy-executed step of accessing the measures of the on-slide standards on the reference slides through a web site. 14. The method of claim 12, wherein a database of patient laboratory results of measurements of biomarkers utilizes the measures of the on-slide standards as a reference to compare and normalize measures of biomarkers on tissues stored in the database. | 1,600 |
880 | 14,430,724 | 1,631 | The present invention provides a device, method, and program for detection of a biomarker candidate that may be used in a diagnosis of a pre-disease state indicating a transition from a healthy state to a disease state. Biological samples are collected from a subject to be measured at different times. Statistical data is obtained by aggregating measurement data obtained in measurement on collected biological samples. Thereafter, a process of obtaining high-throughput data (s 1 ), a process of choosing differential biological molecules (s 2 ), a process of clustering (s 3 ), a process of choosing a DNB candidate (s 4 ), and a process of identifying a DNB by significance analysis (s 5 ) are carried out. | 1. A device for detecting a candidate for a biomarker based on measurement data on a plurality of factors obtained in measurement on a biological object to be measured, the biomarker being an index of a symptom of the biological object, said device comprising:
classification means for classifying factors into clusters based on a correlation of time-dependent changes of measurement data for each factor; choosing means for choosing one of the clusters that satisfies choice conditions that are predetermined based on a correlation of time-dependent changes of measurement data for each factor and time-dependent changes of measurement data among different factors; and detection means for detecting a factor in the chosen cluster as a candidate for a biomarker. 2. The device as set forth in claim 1, wherein the choosing means includes: means for calculating, as a first index, an average of values representing a correlation of measurement data for each factor in a cluster; means for calculating, as a second index, an average of values representing a correlation of measurement data on a factor inside the cluster with measurement data on a factor outside the cluster; and means for calculating, as a third index, an average standard deviation of measurement data for each factor in a cluster,
said device choosing one of the clusters that contains a factor to be a biomarker based on the first, second, and third indices. 3. The device as set forth in claim 2, wherein the choosing means chooses one of the clusters that has a maximum composite index based on a product of the first index, the second index, and a reciprocal of the third index. 4. The device as set forth in claim 2, further comprising difference verification means for verifying whether or not the measurement data for each factor has significantly changed with time,
wherein the classification means classifies factors that are verified to have changed significantly with time. 5. The device as set forth in claim 4, wherein the difference verification means verifies, based on a comparison of the measurement data for each factor and reference data that is predetermined for each factor and each time series, whether or not the measurement data for each factor has significantly changed with time. 6. The device as set forth in claim 5, further comprising means for calculating, for each factor, a reference standard deviation representing an average standard deviation of corresponding reference data and a reference correlation value representing an average of values representing a correlation among different factors,
wherein the detection means detects an item in one of the clusters as a candidate for a biomarker if the first index has increased significantly over the reference standard deviation, the second index has decreased significantly over the reference correlation value, and the third index has increased significantly over the reference standard deviation. 7. The device as set forth in claim 1, wherein the detection means includes means for verifying significance of a plurality of factors in a cluster based on a statistical value of measurement data and if the significance is verified, detects an item in that cluster as a candidate for a biomarker. 8. The device as set forth in claim 1, wherein the plurality of factors include a gene-related measured item, a protein-related measured item, a metabolite-related measured item, or a measured item related to an image obtained from the biological object. 9. A detection method using a device for detecting a candidate for a biomarker based on measurement data on a plurality of factors obtained in measurement on a biological object to be measured, the biomarker being an index of a symptom of the biological object, said device implementing:
the classification step of classifying factors into clusters based on a correlation of time-dependent changes of measurement data for each factor; the choosing step of choosing one of the clusters that satisfies choice conditions that are predetermined based on a correlation of time-dependent changes of measurement data for each factor and time-dependent changes of measurement data among different factors; and the detection step of detecting a factor in the chosen cluster as a candidate for a biomarker. 10. A method for detecting a candidate for a biomarker based on measurement data on a plurality of factors obtained in measurement on a biological object to be measured, the biomarker being an index of a symptom of the biological object, said method comprising:
the molecular screening step of calculating differential biological molecules from high-throughput data obtained from individual biological samples collected at different times; the clustering step of classifying the differential biological molecules chosen in the molecular screening step into clusters so that closely correlated biological molecules are in a single cluster; the candidate choosing step of prefetching, as the candidate of a biomarker, one of the clusters obtained in the clustering step in which there are a maximum increase in a correlation among biological molecules, a maximum increase in a standard deviation of biological molecules, and a maximum decrease in a correlation of a biological molecule with another biological molecule; and the determination step of determining by a significance test whether or not the candidate for a biomarker chosen in the candidate choosing step is the biomarker. 11. A detection program for causing a computer to implement a process of detecting a candidate for a biomarker based on measurement data on a plurality of factors obtained in measurement on a biological object to be measured, the biomarker being an index of a symptom of the biological object, said program causing a computer to implement the detection method of claim 9. 12. The device as set forth in claim 3, further comprising difference verification means for verifying whether or not the measurement data for each factor has significantly changed with time,
wherein the classification means classifies factors that are verified to have changed significantly with time. 13. The device as set forth in claim 12, wherein the difference verification means verifies, based on a comparison of the measurement data for each factor and reference data that is predetermined for each factor and each time series, whether or not the measurement data for each factor has significantly changed with time. 14. The device as set forth in claim 13, further comprising means for calculating, for each factor, a reference standard deviation representing an average standard deviation of corresponding reference data and a reference correlation value representing an average of values representing a correlation among different factors,
wherein the detection means detects an item in one of the clusters as a candidate for a biomarker if the first index has increased significantly over the reference standard deviation, the second index has decreased significantly over the reference correlation value, and the third index has increased significantly over the reference standard deviation. 15. The device as set forth in claim 2, wherein the detection means includes means for verifying significance of a plurality of factors in a cluster based on a statistical value of measurement data and if the significance is verified, detects an item in that cluster as a candidate for a biomarker. 16. The device as set forth in claim 3, wherein the detection means includes means for verifying significance of a plurality of factors in a cluster based on a statistical value of measurement data and if the significance is verified, detects an item in that cluster as a candidate for a biomarker. 17. The device as set forth in claim 4, wherein the detection means includes means for verifying significance of a plurality of factors in a cluster based on a statistical value of measurement data and if the significance is verified, detects an item in that cluster as a candidate for a biomarker. 18. The device as set forth in claim 2, wherein the plurality of factors include a gene-related measured item, a protein-related measured item, a metabolite-related measured item, or a measured item related to an image obtained from the biological object. 19. The device as set forth in claim 3, wherein the plurality of factors include a gene-related measured item, a protein-related measured item, a metabolite-related measured item, or a measured item related to an image obtained from the biological object. 20. The device as set forth in claim 4, wherein the plurality of factors include a gene-related measured item, a protein-related measured item, a metabolite-related measured item, or a measured item related to an image obtained from the biological object. | The present invention provides a device, method, and program for detection of a biomarker candidate that may be used in a diagnosis of a pre-disease state indicating a transition from a healthy state to a disease state. Biological samples are collected from a subject to be measured at different times. Statistical data is obtained by aggregating measurement data obtained in measurement on collected biological samples. Thereafter, a process of obtaining high-throughput data (s 1 ), a process of choosing differential biological molecules (s 2 ), a process of clustering (s 3 ), a process of choosing a DNB candidate (s 4 ), and a process of identifying a DNB by significance analysis (s 5 ) are carried out.1. A device for detecting a candidate for a biomarker based on measurement data on a plurality of factors obtained in measurement on a biological object to be measured, the biomarker being an index of a symptom of the biological object, said device comprising:
classification means for classifying factors into clusters based on a correlation of time-dependent changes of measurement data for each factor; choosing means for choosing one of the clusters that satisfies choice conditions that are predetermined based on a correlation of time-dependent changes of measurement data for each factor and time-dependent changes of measurement data among different factors; and detection means for detecting a factor in the chosen cluster as a candidate for a biomarker. 2. The device as set forth in claim 1, wherein the choosing means includes: means for calculating, as a first index, an average of values representing a correlation of measurement data for each factor in a cluster; means for calculating, as a second index, an average of values representing a correlation of measurement data on a factor inside the cluster with measurement data on a factor outside the cluster; and means for calculating, as a third index, an average standard deviation of measurement data for each factor in a cluster,
said device choosing one of the clusters that contains a factor to be a biomarker based on the first, second, and third indices. 3. The device as set forth in claim 2, wherein the choosing means chooses one of the clusters that has a maximum composite index based on a product of the first index, the second index, and a reciprocal of the third index. 4. The device as set forth in claim 2, further comprising difference verification means for verifying whether or not the measurement data for each factor has significantly changed with time,
wherein the classification means classifies factors that are verified to have changed significantly with time. 5. The device as set forth in claim 4, wherein the difference verification means verifies, based on a comparison of the measurement data for each factor and reference data that is predetermined for each factor and each time series, whether or not the measurement data for each factor has significantly changed with time. 6. The device as set forth in claim 5, further comprising means for calculating, for each factor, a reference standard deviation representing an average standard deviation of corresponding reference data and a reference correlation value representing an average of values representing a correlation among different factors,
wherein the detection means detects an item in one of the clusters as a candidate for a biomarker if the first index has increased significantly over the reference standard deviation, the second index has decreased significantly over the reference correlation value, and the third index has increased significantly over the reference standard deviation. 7. The device as set forth in claim 1, wherein the detection means includes means for verifying significance of a plurality of factors in a cluster based on a statistical value of measurement data and if the significance is verified, detects an item in that cluster as a candidate for a biomarker. 8. The device as set forth in claim 1, wherein the plurality of factors include a gene-related measured item, a protein-related measured item, a metabolite-related measured item, or a measured item related to an image obtained from the biological object. 9. A detection method using a device for detecting a candidate for a biomarker based on measurement data on a plurality of factors obtained in measurement on a biological object to be measured, the biomarker being an index of a symptom of the biological object, said device implementing:
the classification step of classifying factors into clusters based on a correlation of time-dependent changes of measurement data for each factor; the choosing step of choosing one of the clusters that satisfies choice conditions that are predetermined based on a correlation of time-dependent changes of measurement data for each factor and time-dependent changes of measurement data among different factors; and the detection step of detecting a factor in the chosen cluster as a candidate for a biomarker. 10. A method for detecting a candidate for a biomarker based on measurement data on a plurality of factors obtained in measurement on a biological object to be measured, the biomarker being an index of a symptom of the biological object, said method comprising:
the molecular screening step of calculating differential biological molecules from high-throughput data obtained from individual biological samples collected at different times; the clustering step of classifying the differential biological molecules chosen in the molecular screening step into clusters so that closely correlated biological molecules are in a single cluster; the candidate choosing step of prefetching, as the candidate of a biomarker, one of the clusters obtained in the clustering step in which there are a maximum increase in a correlation among biological molecules, a maximum increase in a standard deviation of biological molecules, and a maximum decrease in a correlation of a biological molecule with another biological molecule; and the determination step of determining by a significance test whether or not the candidate for a biomarker chosen in the candidate choosing step is the biomarker. 11. A detection program for causing a computer to implement a process of detecting a candidate for a biomarker based on measurement data on a plurality of factors obtained in measurement on a biological object to be measured, the biomarker being an index of a symptom of the biological object, said program causing a computer to implement the detection method of claim 9. 12. The device as set forth in claim 3, further comprising difference verification means for verifying whether or not the measurement data for each factor has significantly changed with time,
wherein the classification means classifies factors that are verified to have changed significantly with time. 13. The device as set forth in claim 12, wherein the difference verification means verifies, based on a comparison of the measurement data for each factor and reference data that is predetermined for each factor and each time series, whether or not the measurement data for each factor has significantly changed with time. 14. The device as set forth in claim 13, further comprising means for calculating, for each factor, a reference standard deviation representing an average standard deviation of corresponding reference data and a reference correlation value representing an average of values representing a correlation among different factors,
wherein the detection means detects an item in one of the clusters as a candidate for a biomarker if the first index has increased significantly over the reference standard deviation, the second index has decreased significantly over the reference correlation value, and the third index has increased significantly over the reference standard deviation. 15. The device as set forth in claim 2, wherein the detection means includes means for verifying significance of a plurality of factors in a cluster based on a statistical value of measurement data and if the significance is verified, detects an item in that cluster as a candidate for a biomarker. 16. The device as set forth in claim 3, wherein the detection means includes means for verifying significance of a plurality of factors in a cluster based on a statistical value of measurement data and if the significance is verified, detects an item in that cluster as a candidate for a biomarker. 17. The device as set forth in claim 4, wherein the detection means includes means for verifying significance of a plurality of factors in a cluster based on a statistical value of measurement data and if the significance is verified, detects an item in that cluster as a candidate for a biomarker. 18. The device as set forth in claim 2, wherein the plurality of factors include a gene-related measured item, a protein-related measured item, a metabolite-related measured item, or a measured item related to an image obtained from the biological object. 19. The device as set forth in claim 3, wherein the plurality of factors include a gene-related measured item, a protein-related measured item, a metabolite-related measured item, or a measured item related to an image obtained from the biological object. 20. The device as set forth in claim 4, wherein the plurality of factors include a gene-related measured item, a protein-related measured item, a metabolite-related measured item, or a measured item related to an image obtained from the biological object. | 1,600 |
881 | 13,985,536 | 1,612 | Flavour components for use in oral care compositions containing a metal salt, compositions comprising the flavour components, and methods of making and using the same. The flavour components comprise a taste -masking agent comprising cinnamic aldehyde, eugenol and eucalyptol and one or more flavouring agents selected from L-menthol, N-ethyl-p-menthane-3-carboxamide, anethole, peppermint oil, spearmint oil and corn mint oil. In particular the metal salt is zinc citrate. | 1. A flavor component for use in an oral care composition containing a metal salt, comprising:
a taste-masking agent comprising: cinnamic aldehyde; eugenol; and eucalyptol; and one or more flavoring agents selected from: L-menthol; N-ethyl-para-menthan-3-carboxamide; anethole; peppermint oil; spearmint oil; corn mint oil; and a combination of two or more thereof. 2. The flavor component of claim 1, comprising greater than 0.1%, by weight, cinnamic aldehyde. 3. The flavor component of claim 1 or claim 2, comprising greater than 0.1%, by weight, eugenol. 4. The flavor component of any one of claims 1 to 3, comprising greater than 0.5%, by weight, eucalyptol. 5. The flavor component of any one of claims 1 to 4, wherein at least one of the one or more flavoring agents is L-menthol. 6. The flavor component of any one of claims 1 to 5, wherein at least one of the one or more flavoring agents is N-ethyl-para-menthan-3-carboxamide. 7. The flavor component of any one of claims 1 to 6, wherein at least one of the one or more flavoring agents is anethole. 8. The flavor component of any one of claims 1 to 7, wherein at least one of the one or more flavoring agents is peppermint oil. 9. The flavor component of any one of claims 1 to 8, wherein at least one of the one or more flavoring agents is spearmint oil. 10. The flavor component of any one of claims 1 to 9, wherein at least one of the one or more flavoring agents is corn mint oil. 11. The flavor component of any one of claims 5 to 10, comprising greater than 29.5%, by weight, L-menthol. 12. The flavor component of any one of claims 6 to 11, comprising greater than 4.5%, by weight, N-ethyl-para-menthan-3-carboxamide. 13. The flavor component of any one of claims 7 to 12, comprising less than 14.5%, by weight, anethole. 14. The flavor component of any one of claims 8 to 13, comprising less than 40.5%, by weight, peppermint oil. 15. The flavor component of any one of claims 9 to 14, comprising less than 5.5%, by weight, spearmint oil. 16. The flavor component of any one of claims 10 to 15, comprising greater than 4.5%, by weight; corn mint oil. 17. A flavor component for use in an oral care composition containing a metal salt, comprising:
greater than 29.5%, by weight, L-menthol; greater than 4.5%, by weight, N-ethyl-para-menthan-3-carboxamide; less than 14.5%, by weight, anethole; greater than 0.1%, by weight, cinnamic aldehyde; greater than 0.1%, by weight, eugenol; greater than 0.5%, by weight, eucalyptol; less than 40.5%, by weight, peppermint oil; less than 5.5%, by weight, spearmint oil; and greater than 4.5%, by weight, corn mint oil. 18. The flavor component of claim 17, comprising:
from about 30 to about 50%, by weight, L-menthol; from about 5 to about 10%, by weight, N-ethyl-para-menthan-3-carboxamide; from about 5 to about 14%, by weight, anethole; from about 0.1 to about 1%, by weight, cinnamic aldehyde; from about 0.1 to about 1%, by weight, eugenol; from about 1 to about 5%, by weight, eucalyptol; from about 20 to about 40%, by weight, peppermint oil; from about 1 to about 5%, by weight, spearmint oil; and from about 5 to about 10%, by weight, corn mint oil. 19. The flavor component of claim 17 or claim 18, comprising:
from about 35 to about 45%, by weight, L-menthol;
from about 5 to about 8%, by weight, N-ethyl-para-menthan-3-carboxamide;
from about 8 to about 12%, by weight, anethole;
from about 0.5 to about 0.9%, by weight, cinnamic aldehyde;
from about 0.5 to about 0.9%, by weight, eugenol;
from about 2 to about 4%, by weight, eucalyptol; and
from about 22 to about 27%, by weight, peppermint oil. 20. An oral care composition comprising:
the flavor component of any one of claims 1 to 19; one or more metal salts selected from: a zinc salt; a calcium salt; a copper salt; an iron salt; a magnesium salt; a manganese salt; and a combination of two or more thereof; and an orally acceptable carrier;
wherein the total concentration of said one or more metal salts is from about 0.01 to about 5%, by weight of the composition. 21. The composition of claim 20, wherein at least one of said one or more metal salts is a zinc salt selected from: zinc oxide; zinc sulfate; zinc chloride; zinc citrate; zinc lactate; zinc gluconate; zinc malate; zinc tartrate; zinc carbonate; zinc phosphate; and a combination of two or more thereof. 22. The composition of claim 20 or claim 21, wherein the zinc salt is selected from: zinc oxide; zinc citrate; zinc gluconate; zinc glycinate; zinc lactate; and a combination of two or more thereof. 23. The composition of any one of claims 20 to 22, wherein the zinc salt is selected from: zinc oxide; zinc citrate; and a combination of two or more thereof. 24. The composition of any one of claims 20 to 23, wherein the zinc salt is zinc citrate. 25. The composition of any one of claims 20 to 24, wherein the metal salt is present at a concentration of from about 0.1 to about 4%, by weight. 26. The composition of any one of claims 20 to 25, wherein the metal salt is present at a concentration of from about 1 to about 3%, by weight. 27. The composition of any one of claims 20 to 26, wherein the metal salt is present at a concentration of about 2%, by weight. 28. The composition of any one of claims 20 to 27, wherein the flavor oil component is present at a concentration of from about 0.5 to about 2.5%, by weight. 29. The composition of any one of claims 20 to 28, wherein the flavor oil component is present at a concentration of from about 0.8 to about 1.5%, by weight. 30. The composition of any one of claims 20 to 29, wherein the flavor oil component is present at a concentration of about 1%, by weight. 31. The composition of any one of claims 20 to 30, further comprising one or more components selected from: a fluoride ion source; a tartar control agent; a buffering agent; an abrasive; and a combination of two or more thereof. 32. The composition according to any one of claims 20 to 31, wherein at least one of said one or more components is a fluoride ion source selected from: stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate, amine fluoride, ammonium fluoride, and a combination of two or more thereof. | Flavour components for use in oral care compositions containing a metal salt, compositions comprising the flavour components, and methods of making and using the same. The flavour components comprise a taste -masking agent comprising cinnamic aldehyde, eugenol and eucalyptol and one or more flavouring agents selected from L-menthol, N-ethyl-p-menthane-3-carboxamide, anethole, peppermint oil, spearmint oil and corn mint oil. In particular the metal salt is zinc citrate.1. A flavor component for use in an oral care composition containing a metal salt, comprising:
a taste-masking agent comprising: cinnamic aldehyde; eugenol; and eucalyptol; and one or more flavoring agents selected from: L-menthol; N-ethyl-para-menthan-3-carboxamide; anethole; peppermint oil; spearmint oil; corn mint oil; and a combination of two or more thereof. 2. The flavor component of claim 1, comprising greater than 0.1%, by weight, cinnamic aldehyde. 3. The flavor component of claim 1 or claim 2, comprising greater than 0.1%, by weight, eugenol. 4. The flavor component of any one of claims 1 to 3, comprising greater than 0.5%, by weight, eucalyptol. 5. The flavor component of any one of claims 1 to 4, wherein at least one of the one or more flavoring agents is L-menthol. 6. The flavor component of any one of claims 1 to 5, wherein at least one of the one or more flavoring agents is N-ethyl-para-menthan-3-carboxamide. 7. The flavor component of any one of claims 1 to 6, wherein at least one of the one or more flavoring agents is anethole. 8. The flavor component of any one of claims 1 to 7, wherein at least one of the one or more flavoring agents is peppermint oil. 9. The flavor component of any one of claims 1 to 8, wherein at least one of the one or more flavoring agents is spearmint oil. 10. The flavor component of any one of claims 1 to 9, wherein at least one of the one or more flavoring agents is corn mint oil. 11. The flavor component of any one of claims 5 to 10, comprising greater than 29.5%, by weight, L-menthol. 12. The flavor component of any one of claims 6 to 11, comprising greater than 4.5%, by weight, N-ethyl-para-menthan-3-carboxamide. 13. The flavor component of any one of claims 7 to 12, comprising less than 14.5%, by weight, anethole. 14. The flavor component of any one of claims 8 to 13, comprising less than 40.5%, by weight, peppermint oil. 15. The flavor component of any one of claims 9 to 14, comprising less than 5.5%, by weight, spearmint oil. 16. The flavor component of any one of claims 10 to 15, comprising greater than 4.5%, by weight; corn mint oil. 17. A flavor component for use in an oral care composition containing a metal salt, comprising:
greater than 29.5%, by weight, L-menthol; greater than 4.5%, by weight, N-ethyl-para-menthan-3-carboxamide; less than 14.5%, by weight, anethole; greater than 0.1%, by weight, cinnamic aldehyde; greater than 0.1%, by weight, eugenol; greater than 0.5%, by weight, eucalyptol; less than 40.5%, by weight, peppermint oil; less than 5.5%, by weight, spearmint oil; and greater than 4.5%, by weight, corn mint oil. 18. The flavor component of claim 17, comprising:
from about 30 to about 50%, by weight, L-menthol; from about 5 to about 10%, by weight, N-ethyl-para-menthan-3-carboxamide; from about 5 to about 14%, by weight, anethole; from about 0.1 to about 1%, by weight, cinnamic aldehyde; from about 0.1 to about 1%, by weight, eugenol; from about 1 to about 5%, by weight, eucalyptol; from about 20 to about 40%, by weight, peppermint oil; from about 1 to about 5%, by weight, spearmint oil; and from about 5 to about 10%, by weight, corn mint oil. 19. The flavor component of claim 17 or claim 18, comprising:
from about 35 to about 45%, by weight, L-menthol;
from about 5 to about 8%, by weight, N-ethyl-para-menthan-3-carboxamide;
from about 8 to about 12%, by weight, anethole;
from about 0.5 to about 0.9%, by weight, cinnamic aldehyde;
from about 0.5 to about 0.9%, by weight, eugenol;
from about 2 to about 4%, by weight, eucalyptol; and
from about 22 to about 27%, by weight, peppermint oil. 20. An oral care composition comprising:
the flavor component of any one of claims 1 to 19; one or more metal salts selected from: a zinc salt; a calcium salt; a copper salt; an iron salt; a magnesium salt; a manganese salt; and a combination of two or more thereof; and an orally acceptable carrier;
wherein the total concentration of said one or more metal salts is from about 0.01 to about 5%, by weight of the composition. 21. The composition of claim 20, wherein at least one of said one or more metal salts is a zinc salt selected from: zinc oxide; zinc sulfate; zinc chloride; zinc citrate; zinc lactate; zinc gluconate; zinc malate; zinc tartrate; zinc carbonate; zinc phosphate; and a combination of two or more thereof. 22. The composition of claim 20 or claim 21, wherein the zinc salt is selected from: zinc oxide; zinc citrate; zinc gluconate; zinc glycinate; zinc lactate; and a combination of two or more thereof. 23. The composition of any one of claims 20 to 22, wherein the zinc salt is selected from: zinc oxide; zinc citrate; and a combination of two or more thereof. 24. The composition of any one of claims 20 to 23, wherein the zinc salt is zinc citrate. 25. The composition of any one of claims 20 to 24, wherein the metal salt is present at a concentration of from about 0.1 to about 4%, by weight. 26. The composition of any one of claims 20 to 25, wherein the metal salt is present at a concentration of from about 1 to about 3%, by weight. 27. The composition of any one of claims 20 to 26, wherein the metal salt is present at a concentration of about 2%, by weight. 28. The composition of any one of claims 20 to 27, wherein the flavor oil component is present at a concentration of from about 0.5 to about 2.5%, by weight. 29. The composition of any one of claims 20 to 28, wherein the flavor oil component is present at a concentration of from about 0.8 to about 1.5%, by weight. 30. The composition of any one of claims 20 to 29, wherein the flavor oil component is present at a concentration of about 1%, by weight. 31. The composition of any one of claims 20 to 30, further comprising one or more components selected from: a fluoride ion source; a tartar control agent; a buffering agent; an abrasive; and a combination of two or more thereof. 32. The composition according to any one of claims 20 to 31, wherein at least one of said one or more components is a fluoride ion source selected from: stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate, amine fluoride, ammonium fluoride, and a combination of two or more thereof. | 1,600 |
882 | 15,661,658 | 1,644 | The present invention relates to anti-human OX40L antibodies, new medical uses and methods. | 1-30. (canceled) 31. A method of decreasing IL-2 secretion in a human subject, comprising administering to the subject an anti-OX40L antibody or antibody fragment that:
i. antagonizes specific binding of OX40 to OX40L; and ii. comprises an IgG4 constant region; wherein the anti-OX40L antibody or antibody fragment is administered intravenously to said subject in an amount effective to decrease secretion of IL-2; and wherein IL-2 secretion is reduced by at least 50% as compared to IL-2 secretion in the absence of the anti-OX40L antibody or antibody fragment, wherein IL-2 secretion is measured in an allogeneic mixed lymphocyte reaction (MLR) assay. 32. The method according to claim 31, wherein IL-2 secretion is reduced by at least 60% as compared to IL-2 secretion in the absence of an anti-OX40L antibody or antibody fragment. 33. The method of claim 31, where the anti-OX40L antibody or antibody fragment binds specifically to hOX40L with a Kd of from 1 nM to 0.01 nM, wherein the specific binding of OX40 to OX40L is measured by surface plasmon resonance (SPR). 34. The method according to claim 31, wherein the IgG4 constant region comprises a Leu235Glu mutation and a Ser228Pro mutation relative to the wild-type IgG4 constant region. 35. The method according to claim 31, wherein the anti-OX40L antibody or antibody fragment comprises the IgG4 constant region of SEQ ID No:128. 36. The method according to claim 31, wherein the human subject has or is at risk of a disease or condition selected from an autoimmune disease or condition, a systemic inflammatory disease or condition, or transplant rejection. 37. The method according to claim 36, wherein the disease or condition is selected from the group consisting of inflammatory bowel disease (IBD), Crohn's disease, rheumatoid arthritis, allogenic transplant rejection, graft-versus-host disease (GvHD), ulcerative colitis, systemic lupus erythematosus (SLE), diabetes, uveitis, ankylosing spondylitis, contact hypersensitivity, psoriasis, multiple sclerosis, and atherosclerosis. 38. The method according to claim 31, wherein the anti-OX40L antibody or antibody fragment is humanized or human. 39. The method according to claim 31, wherein the anti-OX40L antibody or antibody fragment is selected from the group consisting of multispecific antibodies, bi-specific antibodies, single-chain Fv antibodies (scFv), camelized antibodies, Fab fragments, F(ab′) fragments, disulfide-linked Fvs (sdFv), and epitope-binding fragments thereof. 40. The method according to claim 31, wherein the anti-OX40L antibody or antibody fragment competes for binding to OX40L with a second antibody or antibody fragment;
wherein the anti-OX40L antibody or antibody fragment comprises a CDR selected from:
i. the HCDR3 sequence of SEQ ID No:40 or SEQ ID No:46;
ii. the HCDR3 sequence of SEQ ID No:8 or SEQ ID No:14;
iii. the HCDR3 sequence of SEQ ID No:72 or SEQ ID No:78; and
iv. the HCDR3 sequence of SEQ ID No:100 or SEQ ID No:106;
and wherein the second antibody or antibody fragment comprises:
i. a heavy chain amino acid sequence of SEQ ID No:34 and a light chain amino acid sequence of SEQ ID No:48;
ii. a heavy chain amino acid sequence of SEQ ID No:62 and a light chain amino acid sequence of SEQ ID No:64; or
iii. a heavy chain amino acid sequence of SEQ ID No:30 and a light chain amino acid sequence of SEQ ID No:32. 41. The method of claim 31, wherein the anti-OX40L antibody or fragment thereof comprises an HCDR3 of from 16 to 27 amino acids and derived from the recombination of a human VH gene segment, a human D gene segment, and a human JH gene segment; wherein the human JH gene segment is IGHJ6 or IGHJ6*02. 42. A method of decreasing IL-13 secretion in a human subject, comprising administering to the subject an anti-OX40L antibody or antibody fragment that:
i. antagonizes specific binding of OX40 to OX40L; and ii. comprises an IgG4 constant region; wherein the anti-OX40L antibody or antibody fragment is administered intravenously to said subject in an amount effective to decrease secretion of IL-13; and wherein IL-13 secretion is reduced by at least 50% as compared to IL-13 secretion in the absence of the anti-OX40L antibody or antibody fragment, wherein IL-13 secretion is measured in an allogeneic mixed lymphocyte reaction (MLR) assay. 43. The method according to claim 42, wherein IL-13 secretion is reduced by at least 60% as compared to IL-13 secretion in the absence of an anti-OX40L antibody or antibody fragment. 44. The method of claim 42, where the anti-OX40L antibody or antibody fragment binds specifically to hOX40L with a Kd of from 1 nM to 0.01 nM, wherein the specific binding of OX40 to OX40L is measured by surface plasmon resonance (SPR). 45. The method of claim 42, wherein IL-13 secretion is reduced by at least 70% as compared to IL-13 secretion in the absence of the anti-OX40L antibody or antibody fragment, wherein IL-13 secretion is measured in an allogeneic mixed lymphocyte reaction (MLR) assay. 46. The method according to claim 42, wherein the IgG4 constant region comprises a Leu235Glu mutation and a Ser228Pro mutation relative to the wild-type IgG4 constant region. 47. The method according to claim 42, wherein the anti-OX40L antibody or antibody fragment comprises the IgG4 constant region of SEQ ID No:128. 48. The method according to claim 42, wherein the human subject has or is at risk of a disease or condition selected from an autoimmune disease or condition, a systemic inflammatory disease or condition, or transplant rejection. 49. The method according to claim 48, wherein the disease or condition is selected from the group consisting of inflammatory bowel disease (IBD), Crohn's disease, rheumatoid arthritis, allogenic transplant rejection, graft-versus-host disease (GvHD), ulcerative colitis, systemic lupus erythematosus (SLE), diabetes, uveitis, ankylosing spondylitis, contact hypersensitivity, psoriasis, multiple sclerosis, and atherosclerosis. 50. The method according to claim 42, wherein the anti-OX40L antibody or antibody fragment is humanized or human. 51. The method according to claim 42, wherein the anti-OX40L antibody or antibody fragment is selected from the group consisting of multispecific antibodies, bi-specific antibodies, single-chain Fv antibodies (scFv), camelized antibodies, Fab fragments, F(ab′) fragments, disulfide-linked Fvs (sdFv), and epitope-binding fragments thereof. 52. The method according to claim 42, wherein the anti-OX40L antibody or antibody fragment competes for binding to OX40L with a second antibody or antibody fragment;
wherein the anti-OX40L antibody or antibody fragment comprises a CDR selected from:
i. the HCDR3 sequence of SEQ ID No:40 or SEQ ID No:46;
ii. the HCDR3 sequence of SEQ ID No:8 or SEQ ID No:14;
iii. the HCDR3 sequence of SEQ ID No:72 or SEQ ID No:78; and
iv. the HCDR3 sequence of SEQ ID No:100 or SEQ ID No:106;
and wherein the second antibody or antibody fragment comprises:
i. a heavy chain amino acid sequence of SEQ ID No:34 and a light chain amino acid sequence of SEQ ID No:48;
ii. a heavy chain amino acid sequence of SEQ ID No:62 and a light chain amino acid sequence of SEQ ID No:64; or
iii. a heavy chain amino acid sequence of SEQ ID No:30 and a light chain amino acid sequence of SEQ ID No:32. 53. The method of claim 42, wherein the anti-OX40L antibody or fragment thereof comprises an HCDR3 of from 16 to 27 amino acids and derived from the recombination of a human VH gene segment, a human D gene segment, and a human JH gene segment; wherein the human JH gene segment is IGHJ6 or IGHJ6*02. 54. A method of treating a disease or condition selected from an autoimmune disease or condition, a systemic inflammatory disease or condition, or transplant rejection in a human subject in need thereof, comprising administering an anti-OX40L antibody or antibody fragment that:
i. antagonizes specific binding of OX40 to OX40L; and ii. comprises an IgG4 constant region; wherein the anti-OX40L antibody or antibody fragment is administered intravenously to said subject in an amount effective to decrease secretion of IL-2; and wherein IL-2 secretion is reduced by at least 50% as compared to IL-2 secretion in the absence of the anti-OX40L antibody or antibody fragment, wherein IL-2 secretion is measured in an allogeneic mixed lymphocyte reaction (MLR) assay. 55. The method of claim 54, where the anti-OX40L antibody or antibody fragment binds specifically to hOX40L with a Kd of from 1 nM to 0.01 nM, wherein the specific binding of OX40 to OX40L is measured by surface plasmon resonance (SPR). 56. The method according to claim 54, wherein the anti-OX40L antibody or antibody fragment competes for binding to OX40L with a second antibody or antibody fragment;
wherein the anti-OX40L antibody or antibody fragment comprises a CDR selected from:
i. the HCDR3 sequence of SEQ ID No:40 or SEQ ID No:46;
ii. the HCDR3 sequence of SEQ ID No:8 or SEQ ID No:14;
iii. the HCDR3 sequence of SEQ ID No:72 or SEQ ID No:78; and
iv. the HCDR3 sequence of SEQ ID No:100 or SEQ ID No:106;
and wherein the second antibody or antibody fragment comprises:
i. a heavy chain amino acid sequence of SEQ ID No:34 and a light chain amino acid sequence of SEQ ID No:48;
ii. a heavy chain amino acid sequence of SEQ ID No:62 and a light chain amino acid sequence of SEQ ID No:64; or
iii. a heavy chain amino acid sequence of SEQ ID No:30 and a light chain amino acid sequence of SEQ ID No:32. 57. A method of decreasing IL-2 secretion in a human subject, comprising administering to the subject an anti-OX40L antibody or antibody fragment that:
i. antagonizes specific binding of OX40 to OX40L; and ii. comprises an IgG4 constant region; wherein the anti-OX40L antibody or antibody fragment is administered intravenously to said subject in an amount effective to decrease secretion of IL-2; and wherein the anti-OX40L antibody or antibody fragment is produced in CHO cells. 58. The method of claim 57, wherein IL-2 secretion is reduced by at least 50% as compared to IL-2 secretion in the absence of the anti-OX40L antibody or antibody fragment, wherein IL-2 secretion is measured in an allogeneic mixed lymphocyte reaction (MLR) assay. 59. The method of claim 57, where in the in the CHO cells are from the GS-CHO cell line. | The present invention relates to anti-human OX40L antibodies, new medical uses and methods.1-30. (canceled) 31. A method of decreasing IL-2 secretion in a human subject, comprising administering to the subject an anti-OX40L antibody or antibody fragment that:
i. antagonizes specific binding of OX40 to OX40L; and ii. comprises an IgG4 constant region; wherein the anti-OX40L antibody or antibody fragment is administered intravenously to said subject in an amount effective to decrease secretion of IL-2; and wherein IL-2 secretion is reduced by at least 50% as compared to IL-2 secretion in the absence of the anti-OX40L antibody or antibody fragment, wherein IL-2 secretion is measured in an allogeneic mixed lymphocyte reaction (MLR) assay. 32. The method according to claim 31, wherein IL-2 secretion is reduced by at least 60% as compared to IL-2 secretion in the absence of an anti-OX40L antibody or antibody fragment. 33. The method of claim 31, where the anti-OX40L antibody or antibody fragment binds specifically to hOX40L with a Kd of from 1 nM to 0.01 nM, wherein the specific binding of OX40 to OX40L is measured by surface plasmon resonance (SPR). 34. The method according to claim 31, wherein the IgG4 constant region comprises a Leu235Glu mutation and a Ser228Pro mutation relative to the wild-type IgG4 constant region. 35. The method according to claim 31, wherein the anti-OX40L antibody or antibody fragment comprises the IgG4 constant region of SEQ ID No:128. 36. The method according to claim 31, wherein the human subject has or is at risk of a disease or condition selected from an autoimmune disease or condition, a systemic inflammatory disease or condition, or transplant rejection. 37. The method according to claim 36, wherein the disease or condition is selected from the group consisting of inflammatory bowel disease (IBD), Crohn's disease, rheumatoid arthritis, allogenic transplant rejection, graft-versus-host disease (GvHD), ulcerative colitis, systemic lupus erythematosus (SLE), diabetes, uveitis, ankylosing spondylitis, contact hypersensitivity, psoriasis, multiple sclerosis, and atherosclerosis. 38. The method according to claim 31, wherein the anti-OX40L antibody or antibody fragment is humanized or human. 39. The method according to claim 31, wherein the anti-OX40L antibody or antibody fragment is selected from the group consisting of multispecific antibodies, bi-specific antibodies, single-chain Fv antibodies (scFv), camelized antibodies, Fab fragments, F(ab′) fragments, disulfide-linked Fvs (sdFv), and epitope-binding fragments thereof. 40. The method according to claim 31, wherein the anti-OX40L antibody or antibody fragment competes for binding to OX40L with a second antibody or antibody fragment;
wherein the anti-OX40L antibody or antibody fragment comprises a CDR selected from:
i. the HCDR3 sequence of SEQ ID No:40 or SEQ ID No:46;
ii. the HCDR3 sequence of SEQ ID No:8 or SEQ ID No:14;
iii. the HCDR3 sequence of SEQ ID No:72 or SEQ ID No:78; and
iv. the HCDR3 sequence of SEQ ID No:100 or SEQ ID No:106;
and wherein the second antibody or antibody fragment comprises:
i. a heavy chain amino acid sequence of SEQ ID No:34 and a light chain amino acid sequence of SEQ ID No:48;
ii. a heavy chain amino acid sequence of SEQ ID No:62 and a light chain amino acid sequence of SEQ ID No:64; or
iii. a heavy chain amino acid sequence of SEQ ID No:30 and a light chain amino acid sequence of SEQ ID No:32. 41. The method of claim 31, wherein the anti-OX40L antibody or fragment thereof comprises an HCDR3 of from 16 to 27 amino acids and derived from the recombination of a human VH gene segment, a human D gene segment, and a human JH gene segment; wherein the human JH gene segment is IGHJ6 or IGHJ6*02. 42. A method of decreasing IL-13 secretion in a human subject, comprising administering to the subject an anti-OX40L antibody or antibody fragment that:
i. antagonizes specific binding of OX40 to OX40L; and ii. comprises an IgG4 constant region; wherein the anti-OX40L antibody or antibody fragment is administered intravenously to said subject in an amount effective to decrease secretion of IL-13; and wherein IL-13 secretion is reduced by at least 50% as compared to IL-13 secretion in the absence of the anti-OX40L antibody or antibody fragment, wherein IL-13 secretion is measured in an allogeneic mixed lymphocyte reaction (MLR) assay. 43. The method according to claim 42, wherein IL-13 secretion is reduced by at least 60% as compared to IL-13 secretion in the absence of an anti-OX40L antibody or antibody fragment. 44. The method of claim 42, where the anti-OX40L antibody or antibody fragment binds specifically to hOX40L with a Kd of from 1 nM to 0.01 nM, wherein the specific binding of OX40 to OX40L is measured by surface plasmon resonance (SPR). 45. The method of claim 42, wherein IL-13 secretion is reduced by at least 70% as compared to IL-13 secretion in the absence of the anti-OX40L antibody or antibody fragment, wherein IL-13 secretion is measured in an allogeneic mixed lymphocyte reaction (MLR) assay. 46. The method according to claim 42, wherein the IgG4 constant region comprises a Leu235Glu mutation and a Ser228Pro mutation relative to the wild-type IgG4 constant region. 47. The method according to claim 42, wherein the anti-OX40L antibody or antibody fragment comprises the IgG4 constant region of SEQ ID No:128. 48. The method according to claim 42, wherein the human subject has or is at risk of a disease or condition selected from an autoimmune disease or condition, a systemic inflammatory disease or condition, or transplant rejection. 49. The method according to claim 48, wherein the disease or condition is selected from the group consisting of inflammatory bowel disease (IBD), Crohn's disease, rheumatoid arthritis, allogenic transplant rejection, graft-versus-host disease (GvHD), ulcerative colitis, systemic lupus erythematosus (SLE), diabetes, uveitis, ankylosing spondylitis, contact hypersensitivity, psoriasis, multiple sclerosis, and atherosclerosis. 50. The method according to claim 42, wherein the anti-OX40L antibody or antibody fragment is humanized or human. 51. The method according to claim 42, wherein the anti-OX40L antibody or antibody fragment is selected from the group consisting of multispecific antibodies, bi-specific antibodies, single-chain Fv antibodies (scFv), camelized antibodies, Fab fragments, F(ab′) fragments, disulfide-linked Fvs (sdFv), and epitope-binding fragments thereof. 52. The method according to claim 42, wherein the anti-OX40L antibody or antibody fragment competes for binding to OX40L with a second antibody or antibody fragment;
wherein the anti-OX40L antibody or antibody fragment comprises a CDR selected from:
i. the HCDR3 sequence of SEQ ID No:40 or SEQ ID No:46;
ii. the HCDR3 sequence of SEQ ID No:8 or SEQ ID No:14;
iii. the HCDR3 sequence of SEQ ID No:72 or SEQ ID No:78; and
iv. the HCDR3 sequence of SEQ ID No:100 or SEQ ID No:106;
and wherein the second antibody or antibody fragment comprises:
i. a heavy chain amino acid sequence of SEQ ID No:34 and a light chain amino acid sequence of SEQ ID No:48;
ii. a heavy chain amino acid sequence of SEQ ID No:62 and a light chain amino acid sequence of SEQ ID No:64; or
iii. a heavy chain amino acid sequence of SEQ ID No:30 and a light chain amino acid sequence of SEQ ID No:32. 53. The method of claim 42, wherein the anti-OX40L antibody or fragment thereof comprises an HCDR3 of from 16 to 27 amino acids and derived from the recombination of a human VH gene segment, a human D gene segment, and a human JH gene segment; wherein the human JH gene segment is IGHJ6 or IGHJ6*02. 54. A method of treating a disease or condition selected from an autoimmune disease or condition, a systemic inflammatory disease or condition, or transplant rejection in a human subject in need thereof, comprising administering an anti-OX40L antibody or antibody fragment that:
i. antagonizes specific binding of OX40 to OX40L; and ii. comprises an IgG4 constant region; wherein the anti-OX40L antibody or antibody fragment is administered intravenously to said subject in an amount effective to decrease secretion of IL-2; and wherein IL-2 secretion is reduced by at least 50% as compared to IL-2 secretion in the absence of the anti-OX40L antibody or antibody fragment, wherein IL-2 secretion is measured in an allogeneic mixed lymphocyte reaction (MLR) assay. 55. The method of claim 54, where the anti-OX40L antibody or antibody fragment binds specifically to hOX40L with a Kd of from 1 nM to 0.01 nM, wherein the specific binding of OX40 to OX40L is measured by surface plasmon resonance (SPR). 56. The method according to claim 54, wherein the anti-OX40L antibody or antibody fragment competes for binding to OX40L with a second antibody or antibody fragment;
wherein the anti-OX40L antibody or antibody fragment comprises a CDR selected from:
i. the HCDR3 sequence of SEQ ID No:40 or SEQ ID No:46;
ii. the HCDR3 sequence of SEQ ID No:8 or SEQ ID No:14;
iii. the HCDR3 sequence of SEQ ID No:72 or SEQ ID No:78; and
iv. the HCDR3 sequence of SEQ ID No:100 or SEQ ID No:106;
and wherein the second antibody or antibody fragment comprises:
i. a heavy chain amino acid sequence of SEQ ID No:34 and a light chain amino acid sequence of SEQ ID No:48;
ii. a heavy chain amino acid sequence of SEQ ID No:62 and a light chain amino acid sequence of SEQ ID No:64; or
iii. a heavy chain amino acid sequence of SEQ ID No:30 and a light chain amino acid sequence of SEQ ID No:32. 57. A method of decreasing IL-2 secretion in a human subject, comprising administering to the subject an anti-OX40L antibody or antibody fragment that:
i. antagonizes specific binding of OX40 to OX40L; and ii. comprises an IgG4 constant region; wherein the anti-OX40L antibody or antibody fragment is administered intravenously to said subject in an amount effective to decrease secretion of IL-2; and wherein the anti-OX40L antibody or antibody fragment is produced in CHO cells. 58. The method of claim 57, wherein IL-2 secretion is reduced by at least 50% as compared to IL-2 secretion in the absence of the anti-OX40L antibody or antibody fragment, wherein IL-2 secretion is measured in an allogeneic mixed lymphocyte reaction (MLR) assay. 59. The method of claim 57, where in the in the CHO cells are from the GS-CHO cell line. | 1,600 |
883 | 14,649,109 | 1,612 | Described herein are oral care compositions comprising a zinc ion source, a fluoride ion source, and a basic amino acid; along with methods of making and using the same. | 1. An oral care composition comprising:
from about 0.05 to about 5% by weight, of a zinc ion source; a fluoride ion source in an amount effective to deliver from about 500 to about 5,000 ppm fluoride, and from about 0.1 to about 10%, by weight, of a basic amino acid. 2. The composition of claim 1 wherein the zinc ion source is selected from zinc citrate, zinc sulfate, zinc silicate, zinc lactate, zinc phosphate, zinc oxide, and combinations thereof, in an amount effective to inhibit erosion. 3. The composition according to any of the preceding claims wherein the basic amino acid is arginine. 4. The composition according to any of the preceding claims in the form of a dentifrice comprising an abrasive. 5. The composition according to any of the preceding claims wherein the amount of zinc is 0.5 to 4% by weight. 6. The composition of any of the foregoing claims comprising one or more abrasives, one or more humectants, and one or more surfactants. 7. The composition of any of the foregoing claims further comprising an effective amount of one or more alkali phosphate salts. 8. The composition of any of the foregoing claims further comprising an effective amount of one or more antibacterial agents. 9. The composition of any of the foregoing claims further comprising a whitening agent. 10. The composition of any of the foregoing claims further comprising one or more sources of zinc ion in addition to the zinc phosphate. 11. The composition of any of the foregoing claims wherein the pH of the composition is basic. 12. The composition of any of the foregoing claims comprising 1 to 3% zinc citrate;
1 to 8% arginine; 2 to 8% alkali phosphate salts selected from sodium phosphate dibasic, potassium phosphate dibasic, dicalcium phosphate dihydrate, tetrasodium pyrophosphate, tetrapotassium pyrophosphate, calcium pyrophosphate, sodium tripolyphosphate, and a combination of two or more thereof; 700 to 2000 ppm fluoride; in a silica abrasive dentifrice base. 13. Use of a basic amino acid to enhance fluoride delivery in an oral care composition comprising a zinc ion source and a fluoride ion source. 14. A method of treating or reducing dental enamel erosion comprising administering a composition according to any of claims 1 to 12 to the oral cavity of a subject in need thereof. 15. The composition according to any of claims 1 to 12 for use in treating or reducing dental enamel erosion. | Described herein are oral care compositions comprising a zinc ion source, a fluoride ion source, and a basic amino acid; along with methods of making and using the same.1. An oral care composition comprising:
from about 0.05 to about 5% by weight, of a zinc ion source; a fluoride ion source in an amount effective to deliver from about 500 to about 5,000 ppm fluoride, and from about 0.1 to about 10%, by weight, of a basic amino acid. 2. The composition of claim 1 wherein the zinc ion source is selected from zinc citrate, zinc sulfate, zinc silicate, zinc lactate, zinc phosphate, zinc oxide, and combinations thereof, in an amount effective to inhibit erosion. 3. The composition according to any of the preceding claims wherein the basic amino acid is arginine. 4. The composition according to any of the preceding claims in the form of a dentifrice comprising an abrasive. 5. The composition according to any of the preceding claims wherein the amount of zinc is 0.5 to 4% by weight. 6. The composition of any of the foregoing claims comprising one or more abrasives, one or more humectants, and one or more surfactants. 7. The composition of any of the foregoing claims further comprising an effective amount of one or more alkali phosphate salts. 8. The composition of any of the foregoing claims further comprising an effective amount of one or more antibacterial agents. 9. The composition of any of the foregoing claims further comprising a whitening agent. 10. The composition of any of the foregoing claims further comprising one or more sources of zinc ion in addition to the zinc phosphate. 11. The composition of any of the foregoing claims wherein the pH of the composition is basic. 12. The composition of any of the foregoing claims comprising 1 to 3% zinc citrate;
1 to 8% arginine; 2 to 8% alkali phosphate salts selected from sodium phosphate dibasic, potassium phosphate dibasic, dicalcium phosphate dihydrate, tetrasodium pyrophosphate, tetrapotassium pyrophosphate, calcium pyrophosphate, sodium tripolyphosphate, and a combination of two or more thereof; 700 to 2000 ppm fluoride; in a silica abrasive dentifrice base. 13. Use of a basic amino acid to enhance fluoride delivery in an oral care composition comprising a zinc ion source and a fluoride ion source. 14. A method of treating or reducing dental enamel erosion comprising administering a composition according to any of claims 1 to 12 to the oral cavity of a subject in need thereof. 15. The composition according to any of claims 1 to 12 for use in treating or reducing dental enamel erosion. | 1,600 |
884 | 16,223,940 | 1,617 | Packaged formulations of gamma-hydroxybutyrate having improved dissolution and chemical stability, packaging for supporting said stability, and therapeutic uses thereof. | 1. A packaged pharmaceutical composition comprising a pharmaceutical composition within a package, the pharmaceutical composition comprising:
a. an immediate release component comprising gamma-hydroxybutyrate or a pharmaceutically acceptable salt thereof; and b. a modified release component comprising gamma-hydroxybutyrate or a pharmaceutically acceptable salt thereof; wherein the package has an interior volume having a relative humidity from 29% to 54%; and the pharmaceutical composition has a stable dissolution profile over time. 2. The packaged pharmaceutical composition of claim 1, wherein the relative humidity of the package is from 29% to 54% for a period of at least 2 months when stored at 40° C. and 75% relative humidity. 3. The packaged pharmaceutical composition of claim 1, wherein the relative humidity of the package is greater than 29% at 1 week and less than 54% at 2 months when stored at 40° C. and 75% relative humidity. 4. The packaged pharmaceutical composition of claim 1, wherein the relative humidity of the package is greater than 29% and less than 44% at one week and less than 54% at 2 months when stored at 40° C. and 75% relative humidity. 5. The packaged pharmaceutical composition of claim 1, wherein the relative humidity of the package is from 35% to 39% after one week and from 39% to 48% after 2 months when stored at 40° C. and 75% relative humidity. 6. The packaged pharmaceutical composition of claim 1, wherein no more than 0.4% of gamma-hydroxybutyrate in the pharmaceutical composition is converted to gamma-butyrolactone (GBL) when stored two months at 40° C. and 75% relative humidity. 7. The packaged pharmaceutical composition of claim 1, wherein the package has a water vapor transmission rate of less than 7 mg/day/liter when measured according to USP 38 <671>. 8. The packaged pharmaceutical composition of claim 1, wherein, after a two-month 40° C./75% relative humidity storage period, the pharmaceutical composition exhibits a lag time that is less than 70 minutes different than the lag time at the beginning of the storage period, wherein the lag time is determined from testing in a dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm. 9. The packaged pharmaceutical composition of claim 1, wherein, after a two-month 40° C./75% relative humidity storage period, the pharmaceutical composition has a dissolution of gamma-hydroxybutyrate that differs by less than 10% than the dissolution of gamma-hydroxybutyrate before the storage period when tested for at least four consecutive hourly time points in a dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm. 10. The packaged pharmaceutical composition of claim 1, wherein the modified release component comprises a core comprising gamma-hydroxybutyrate or a pharmaceutically acceptable salt thereof and a coating comprising a hydrophobic compound and a mixture of methacrylic acid copolymers. 11. The packaged pharmaceutical composition of claim 10, wherein the hydrophobic compound is glyceryl tristearate or hydrogenated vegetable oil, and the mixture of methacrylic acid copolymers comprises methacrylic acid and ethyl acrylate copolymer NF and methacrylic acid and methyl methacrylate copolymer (1:2) NF. 12. The packaged pharmaceutical composition of claim 10, wherein the coating comprises from 40 to 70 weight parts of the hydrophobic compound and from 30 to 60 weight parts of the mixture of methacrylic acid copolymers. 13. The packaged pharmaceutical composition of claim 10, wherein the coating is from 10% to 50% of the weight of the modified release component. 14. The packaged pharmaceutical composition of claim 10, wherein the hydrophobic compound has a melting point equal to or greater than 40° C. and the mixture of methacrylic acid copolymers has a pH trigger greater than 5.6. 15. The packaged pharmaceutical composition of claim 10, wherein the modified release component is devoid of a barrier coat between the core and the coating. 16. The packaged pharmaceutical composition of claim 1, wherein the modified release component comprises particles having an average diameter from 200 to 800 micrometers. 17. The packaged pharmaceutical composition of claim 1, wherein the pharmaceutical composition further comprises an acidifying agent and a suspending or viscosifying agent. 18. The packaged pharmaceutical composition of claim 17, wherein the acidifying agent is chosen from malic acid, citric acid, tartaric acid, adipic acid, boric acid, maleic acid, phosphoric acid, ascorbic acid, oleic acid, capric acid, caprylic acid, benzoic acid, or mixtures thereof; and the suspending or viscosifying agent is chosen from xanthan gum, medium viscosity sodium carboxymethyl cellulose, mixtures of microcrystalline cellulose and sodium carboxymethyl cellulose, mixtures of microcrystalline cellulose and guar gum, medium viscosity hydroxyethyl cellulose, agar, sodium alginate, mixtures of sodium alginate and calcium alginate, gellan gum, carrageenan gum grade iota, kappa or lambda, medium viscosity hydroxypropylmethyl cellulose, or mixtures thereof. 19. The packaged pharmaceutical composition of claim 17, wherein the acidifying agent is malic acid or tartaric acid and is present in an amount from 1.2% to 15% by weight; and the suspending or viscosifying agent is a mixture of xanthan gum, carrageenan gum, and hydroxyethylcellulose or a mixture of xanthan gum and carrageenan gum and is present in an amount from 1% to 15% by weight. 20. The packaged pharmaceutical composition of claim 1, wherein gamma-hydroxybutyrate is present in a weight ratio from 10/90 to 65/35 in the immediate release and modified release components. 21. The packaged pharmaceutical composition of claim 1, wherein the package comprises from 0.5 gram to 12.0 grams of sodium salt of gamma-hydroxybutyrate. 22. The packaged pharmaceutical composition of claim 1, wherein the package is a pouch or sachet. 23. The packaged pharmaceutical composition of claim 1, wherein the package is an aluminum foil pouch or sachet having an aluminum foil thickness of at least 6 micrometers. | Packaged formulations of gamma-hydroxybutyrate having improved dissolution and chemical stability, packaging for supporting said stability, and therapeutic uses thereof.1. A packaged pharmaceutical composition comprising a pharmaceutical composition within a package, the pharmaceutical composition comprising:
a. an immediate release component comprising gamma-hydroxybutyrate or a pharmaceutically acceptable salt thereof; and b. a modified release component comprising gamma-hydroxybutyrate or a pharmaceutically acceptable salt thereof; wherein the package has an interior volume having a relative humidity from 29% to 54%; and the pharmaceutical composition has a stable dissolution profile over time. 2. The packaged pharmaceutical composition of claim 1, wherein the relative humidity of the package is from 29% to 54% for a period of at least 2 months when stored at 40° C. and 75% relative humidity. 3. The packaged pharmaceutical composition of claim 1, wherein the relative humidity of the package is greater than 29% at 1 week and less than 54% at 2 months when stored at 40° C. and 75% relative humidity. 4. The packaged pharmaceutical composition of claim 1, wherein the relative humidity of the package is greater than 29% and less than 44% at one week and less than 54% at 2 months when stored at 40° C. and 75% relative humidity. 5. The packaged pharmaceutical composition of claim 1, wherein the relative humidity of the package is from 35% to 39% after one week and from 39% to 48% after 2 months when stored at 40° C. and 75% relative humidity. 6. The packaged pharmaceutical composition of claim 1, wherein no more than 0.4% of gamma-hydroxybutyrate in the pharmaceutical composition is converted to gamma-butyrolactone (GBL) when stored two months at 40° C. and 75% relative humidity. 7. The packaged pharmaceutical composition of claim 1, wherein the package has a water vapor transmission rate of less than 7 mg/day/liter when measured according to USP 38 <671>. 8. The packaged pharmaceutical composition of claim 1, wherein, after a two-month 40° C./75% relative humidity storage period, the pharmaceutical composition exhibits a lag time that is less than 70 minutes different than the lag time at the beginning of the storage period, wherein the lag time is determined from testing in a dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm. 9. The packaged pharmaceutical composition of claim 1, wherein, after a two-month 40° C./75% relative humidity storage period, the pharmaceutical composition has a dissolution of gamma-hydroxybutyrate that differs by less than 10% than the dissolution of gamma-hydroxybutyrate before the storage period when tested for at least four consecutive hourly time points in a dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm. 10. The packaged pharmaceutical composition of claim 1, wherein the modified release component comprises a core comprising gamma-hydroxybutyrate or a pharmaceutically acceptable salt thereof and a coating comprising a hydrophobic compound and a mixture of methacrylic acid copolymers. 11. The packaged pharmaceutical composition of claim 10, wherein the hydrophobic compound is glyceryl tristearate or hydrogenated vegetable oil, and the mixture of methacrylic acid copolymers comprises methacrylic acid and ethyl acrylate copolymer NF and methacrylic acid and methyl methacrylate copolymer (1:2) NF. 12. The packaged pharmaceutical composition of claim 10, wherein the coating comprises from 40 to 70 weight parts of the hydrophobic compound and from 30 to 60 weight parts of the mixture of methacrylic acid copolymers. 13. The packaged pharmaceutical composition of claim 10, wherein the coating is from 10% to 50% of the weight of the modified release component. 14. The packaged pharmaceutical composition of claim 10, wherein the hydrophobic compound has a melting point equal to or greater than 40° C. and the mixture of methacrylic acid copolymers has a pH trigger greater than 5.6. 15. The packaged pharmaceutical composition of claim 10, wherein the modified release component is devoid of a barrier coat between the core and the coating. 16. The packaged pharmaceutical composition of claim 1, wherein the modified release component comprises particles having an average diameter from 200 to 800 micrometers. 17. The packaged pharmaceutical composition of claim 1, wherein the pharmaceutical composition further comprises an acidifying agent and a suspending or viscosifying agent. 18. The packaged pharmaceutical composition of claim 17, wherein the acidifying agent is chosen from malic acid, citric acid, tartaric acid, adipic acid, boric acid, maleic acid, phosphoric acid, ascorbic acid, oleic acid, capric acid, caprylic acid, benzoic acid, or mixtures thereof; and the suspending or viscosifying agent is chosen from xanthan gum, medium viscosity sodium carboxymethyl cellulose, mixtures of microcrystalline cellulose and sodium carboxymethyl cellulose, mixtures of microcrystalline cellulose and guar gum, medium viscosity hydroxyethyl cellulose, agar, sodium alginate, mixtures of sodium alginate and calcium alginate, gellan gum, carrageenan gum grade iota, kappa or lambda, medium viscosity hydroxypropylmethyl cellulose, or mixtures thereof. 19. The packaged pharmaceutical composition of claim 17, wherein the acidifying agent is malic acid or tartaric acid and is present in an amount from 1.2% to 15% by weight; and the suspending or viscosifying agent is a mixture of xanthan gum, carrageenan gum, and hydroxyethylcellulose or a mixture of xanthan gum and carrageenan gum and is present in an amount from 1% to 15% by weight. 20. The packaged pharmaceutical composition of claim 1, wherein gamma-hydroxybutyrate is present in a weight ratio from 10/90 to 65/35 in the immediate release and modified release components. 21. The packaged pharmaceutical composition of claim 1, wherein the package comprises from 0.5 gram to 12.0 grams of sodium salt of gamma-hydroxybutyrate. 22. The packaged pharmaceutical composition of claim 1, wherein the package is a pouch or sachet. 23. The packaged pharmaceutical composition of claim 1, wherein the package is an aluminum foil pouch or sachet having an aluminum foil thickness of at least 6 micrometers. | 1,600 |
885 | 15,109,746 | 1,641 | Methods and devices electrochemically detect analytes. The methods employ metal particles conjugated to the analytes. The metal particles can serve as an electrochemical label for the analyte to which they are conjugated. The metal particles can be oxidized to form metal ions that can subsequently be electrochemically detected and/or quantified. The metal ions can be electrodeposited as metal on a working electrode. The potential applied at the working electrode can then be varied to reoxidize the deposited metal to metal ions. The intensity of the resulting voltammetric peak reflects the amount of metal deposited on the working electrode, and therefore the amount of metal nanoparticle label and analyte. Sensitivity can tie improved by selectively localizing the analyte-metal particle conjugate in the vicinity of the working electrode. Analytes can be detected at concentrations as low as 767 fM via anodic stripping voltammetry, with no washing steps or electrode modifications. | 1. A method for detecting an analyte comprising:
(a) flowing fluid along a channel while applying a magnetic field to a region of the channel in electrochemical contact with a working electrode in order to accumulate the analyte conjugated to a metal particle and a magnetic particle in the region of the channel; (b) oxidizing the metal particle to form metal ions; and (c) electrochemically detecting the metal ions. 2. The method of claim 1, wherein step (a) comprises flowing fluid comprising the analyte conjugated to the metal particle and the magnetic particle along the channel, and applying the magnetic field to accumulate the analyte conjugated to the metal particle and the magnetic particle in the region of the channel. 3. The method of claim 1 or 2, further comprising interrupting fluid flow along the channel between steps (a) and (b). 4. The method of any of claims 1-3, wherein oxidizing the metal particle comprises contacting the metal particle with an oxidant. 5. The method of any of claims 1-4, wherein electrochemically detecting the metal ions comprises quantifying the concentration of the analyte. 6. The method of any of claims 1-5, wherein the analyte is selected from the group consisting of antibodies, peptides, proteins, polynucleotides, lipids, polysaccharides, small molecule organic compounds, pathogens, and combinations thereof. 7. The method of any of claims 1-6, wherein the analyte is bound to the metal particle by a recognition element. 8. The method of claim 7, wherein the recognition element comprises an antibody, polynucleotide, receptor, ligand, antigen, protein, small molecule organic compound, or combination thereof. 9. The method of any of claims 1-8, wherein the analyte is bound to the magnetic particle by a recognition element. 10. The method of claim 9, wherein the recognition element comprises an antibody, polynucleotide, receptor, ligand, antigen, protein, small molecule organic compound, or combination thereof. 11. The method of any of claims 1-10, wherein the analyte is bound to a first antibody and a second antibody, and wherein the metal particle is bound to the first antibody and the magnetic particle is bound to the second antibody. 12. The method of any of claims 1-10, wherein the analyte is bound to a first polynucleotide and a second polynucleotide, and wherein the metal particle is bound to the first polynucleotide and the magnetic particle is bound to the second polynucleotide. 13. The method of claim 12, wherein the analyte is a polynucleotide or a polynucleotide. 14. The method of any of claims 1-13, wherein the metal particle comprises a metal nanoparticle. 15. The method of any of claims 1-14, wherein the channel defines a path for fluid flow from a fluid inlet to a fluid outlet, and wherein the method further comprises injecting a sample comprising a molecule of interest into the fluid inlet. 16. The method of claim 15, wherein the molecule of interest is the analyte. 17. The method of claim 16, wherein the sample comprises the analyte conjugated to a metal particle and a magnetic particle. 18. The method of claim 15, wherein the analyte comprises a surrogate for the molecule of interest. 19. The method of claim 18, wherein the surrogate is conjugated to a fixed analyte support, the metal particle, the magnetic particle, or combinations thereof, and wherein the surrogate is displaced by the molecule of interest. 20. The method of any of claims 1-19, wherein the method further comprises flowing fluid along the channel while applying a magnetic field to the region of the channel in order to accumulate a second analyte conjugated to a second metal particle and a second magnetic particle in the region of the channel. 21. The method of claim 20, wherein the second metal particle comprises a different metal than the first metal particle. 22. The method of claim 20 or 21, wherein electrochemically detecting the metal ions comprises quantifying the concentration of the first analyte and the second analyte. 23. The method of any of claims 20-22, wherein electrochemically detecting the metal ions comprises quantifying the ratio of the first analyte to the second analyte. 24. A device comprising:
a channel defining a path for fluid flow from a fluid inlet to a fluid outlet; a working electrode positioned in electrochemical contact with a region of the channel; and a magnet configured to apply a magnetic field to the region of the channel. 25. The device of claim 24, further comprising an engageable platform;
wherein the engageable platform can be translocated from a retracted position to a deployed position; wherein in the retracted position the engageable platform is fluidly independent from the channel; and wherein in the deployed position the engageable platform is in fluid contact with the region of the channel. 26. The device of claim 25, wherein when the engageable platform is in the deployed position, the path for fluid flow from the fluid inlet to the fluid outlet is interrupted, such that fluid cannot flow from the fluid inlet to the fluid outlet. 27. The device of claim 25 or 26, wherein the engageable platform comprises an oxidant. 28. The device of claim 27, wherein the oxidant comprises potassium permanganate. 29. The device of any of claims 24-28, wherein the device is paper based. 30. The device of any of claims 24-29, wherein the channel comprises a hollow channel 31. The device of any of claims 24-30, further comprising a second working electrode in electrochemical contact with a second region of the channel, and a second magnet configured to apply a magnetic field to the second region of the channel. 32. The device of any of claims 24-31, further comprising a counter electrode, a reference electrode, or combinations thereof in electrochemical contact with the channel. 33. A device comprising:
a first layer comprising a top surface, a bottom surface, a fluid inlet defining a path for fluid flow from the top surface of the first layer to the bottom surface of the first layer, a fluid outlet defining a path for fluid flow from the bottom surface of the first layer to the top surface of the first layer, and a working electrode disposed on the bottom surface of the first layer; a second layer, comprising a top surface, a bottom surface, a hydrophobic boundary defining a channel for fluid flow within the second layer, and a port defining a path for fluid flow from the bottom surface of the second layer to the top surface of the second layer; a third layer, comprising a top surface, a bottom surface, a hydrophobic boundary defining a channel for fluid flow within the third layer, a port defining a path for fluid flow from the bottom surface of the third layer to the top surface of the third layer, and an engageable platform disposed within the third layer; a fourth layer, comprising a top surface, a bottom surface, a channel defining a path for fluid flow within the fourth layer formed from a porous hydrophilic material, and a sink fluidly connected to the channel and formed from a porous hydrophilic material; and a magnet; wherein the bottom surface of the first layer is in contact with the top surface of the second layer, the bottom surface of the second layer is in contact with the top surface of the third layer, and the bottom surface of the third layer is in contact with the top surface of the fourth layer; wherein the working electrode is in electrochemical contact with a region of the channel in the second layer; wherein the magnet is aligned with the working electrode so as to apply a magnetic field within the region of the channel in the second layer in electrochemical contact with the working electrode; wherein the first layer, the second layer, the third layer, and the fourth layer are aligned so as to form a path for fluid flow from the fluid inlet to the channel for fluid flow within the second layer, the channel for fluid flow within the third layer, and the channel within the fourth layer to the sink to the port in the third layer to the port in the second layer to the fluid outlet, and wherein the third layer can be translocated from a retracted position to a deployed position such that:
when the third layer is in the retracted position, the port of the third layer fluidly connects the port of the second layer and the sink and the engageable platform is fluidly independent from the channel for fluid flow within the second layer; and
when the third layer is in the deployed position, the engageable platform is in fluid contact with the region of the channel for fluid flow within the second layer and the port of the third layer is not aligned with the port of the second layer and the sink such that the path for fluid flow from the sink to the port of the second layer is interrupted. 34. The device of claim 33, wherein the engagable platform comprises an oxidant. 35. The device of claim 34, wherein the oxidant comprises potassium permanganate. 36. The device of any of claims 33-35, wherein the device is paper based. 37. The device of any of claims 33-36, wherein the first layer, the second layer, and the fourth layer are fabricated from a single piece of paper that is folded to form the device. 38. The device of any of the claims 33-37, further comprising a second working electrode disposed on the bottom surface of the first layer and a second magnet,
wherein the second working electrode is in electrochemical contact with a second region of channel in the second layer, and wherein the second magnet is aligned with the second working electrode so as to apply a magnetic field within the second region of the channel in the second layer in electrochemical contact with the second working electrode. 39. The device of any of claims 33-38, further comprising a counter electrode, a reference electrode, or combinations thereof disposed on the bottom surface of the first layer, wherein the counter electrode, the reference electrode, or the combinations thereof is in electrochemical with the channel in the second layer. 40. The device of any of claims 33-39, further comprising an indicator disposed on the sink, the port in the third layer, the port in the second layer, or combinations thereof. 41. The device of any of claims 33-40, wherein the fluid inlet comprises a reagent for the detection of a molecule of interest. 42. A method for detecting an analyte comprising:
(a) flowing fluid along a channel to accumulate the analyte conjugated to a metal particle in a region of the channel in electrochemical contact with a working electrode, wherein the analyte conjugated to the metal particle is accumulated in the region of the channel by a localization element; (b) oxidizing the metal particle to form metal ions; and (c) electrochemically detecting the metal ions, wherein the localization element is selected from the group consisting of a physical barrier disposed in the region of the channel, a localization electrode configured to apply an electric field to the region of the channel, a magnet configured to apply a magnetic field the region of the channel, or a combination thereof. 43. The method of claim 42, wherein the analyte comprises an analyte conjugated to a metal particle and a magnetic particle, and wherein the localization element comprises a magnet configured to apply a magnetic field to the region of the channel. 44. The method of claim 43, wherein step (a) comprises flowing fluid comprising the analyte conjugated to the metal particle and the magnetic particle along the channel, and applying the magnetic field to accumulate the analyte conjugated to the metal particle and the magnetic particle in the region of the channel. 45. The method of claim 42, wherein the analyte is charged, and wherein the localization element comprises a localization electrode configured to apply an electric field to the region of the channel. 46. The method of claim 45, wherein step (a) comprises flowing fluid comprising the charged analyte conjugated to the metal particle along the channel, and applying electric field to accumulate the charged analyte conjugated to the metal particle in the region of the channel. 47. The method of claim 42, the localization element comprises a physical barrier disposed in the region of the channel, and wherein step (a) comprises flowing fluid comprising the analyte conjugated to the metal particle along the channel to contact the physical barrier such that the analyte accumulates in the region of the channel. 48. The method of any of claims 42-47, further comprising interrupting fluid flow along the channel between steps (a) and (b). 49. The method of any of claims 42-48, wherein oxidizing the metal particle comprises contacting the metal particle with an oxidant. 50. The method of any of claims 42-49, wherein electrochemically detecting the metal ions comprises quantifying the concentration of the analyte. 51. The method of any of claims 42-50, wherein the analyte is selected from the group consisting of antibodies, peptides, proteins, polynucleotides, lipids, polysaccharides, small molecule organic compounds, pathogens, and combinations thereof. 52. The method of any of claims 42-51, wherein the analyte is bound to the metal particle by a recognition element. 53. The method of claim 52, wherein the recognition element comprises an antibody, polynucleotide, receptor, ligand, antigen, or combination thereof. 54. The method of any of claims 42-53, wherein the metal particle comprises a metal nanoparticle. 55. The method of any of claims 42-54, wherein the channel defines a path for fluid flow from a fluid inlet to a fluid outlet, and wherein the method further comprises injecting a sample comprising a molecule of interest into the fluid inlet. 56. The method of claim 55, wherein the molecule of interest is the analyte. 57. The method of claim 56, wherein the sample comprises the analyte conjugated to a metal particle. 58. The method of claim 55, wherein the analyte comprises a surrogate for the molecule of interest. 59. The method of claim 58, wherein the surrogate is conjugated to a fixed analyte support and wherein the analyte is displaced by the molecule of interest. 60. The method of any of claims 42-59, wherein the method further comprises flowing fluid along a channel to accumulate a second analyte conjugated to a second metal particle in the region of the channel in electrochemical contact with the working electrode, wherein the second analyte conjugated to the second metal particle is accumulated in the region of the channel by a localization element. 61. The method of claim 60, wherein the second metal particle comprises a different metal than the first metal particle. 62. The method of claim 60 or 61, wherein electrochemically detecting the metal ions comprises quantifying the concentration of the first analyte and the second analyte. 63. The method of any of claims 60-62, wherein electrochemically detecting the metal ions comprises quantifying the ratio of the first analyte to the second analyte. 64. A device for the detection of an analyte conjugated to a metal particle comprising:
a channel defining a path for fluid flow from a fluid inlet to a fluid outlet; a working electrode positioned in electrochemical contact with a region of the channel; and a localization element configured to accumulate the analyte conjugated to the metal particle in the region of the channel in electrochemical contact with the working electrode, wherein the localization element is selected from the group consisting of a physical barrier disposed in the region of the channel, a localization electrode configured to apply an electric field to the region of the channel, a magnet configured to apply a magnetic field the region of the channel, or a combination thereof. 65. The device of claim 64, further comprising an engageable platform;
wherein the engageable platform can be translocated from a retracted position to a deployed position; wherein in the retracted position the engageable platform is fluidly independent from the channel; and wherein in the deployed position the engageable platform is in fluid contact with the region of the channel. 66. The device of claim 65, wherein when the engageable platform is in the deployed position, the path for fluid flow from the fluid inlet to the fluid outlet is interrupted, such that fluid cannot flow from the fluid inlet to the fluid outlet. 67. The device of claim 65 or 66, wherein the engageable platform can be translocated from an incubation position to a retracted position to a deployed position,
wherein when the engageable platform is in the incubation position, the engageable platform is fluidly independent from the channel and the path for fluid flow from the fluid inlet to the fluid outlet is interrupted, such that fluid cannot flow from the fluid inlet to the fluid outlet. 68. The method of any of claims 65-67, wherein the engageable platform comprises an oxidant. 69. The device of claim 68, wherein the oxidant comprises potassium permanganate. 70. The device of any of claims 64-69, wherein the device is paper based. 71. The device of any of claims 64-70, wherein the channel comprises a hollow channel 72. The device of any of claims 64-71, further comprising a counter electrode, a reference electrode, or combinations thereof in electrochemical contact with the channel. | Methods and devices electrochemically detect analytes. The methods employ metal particles conjugated to the analytes. The metal particles can serve as an electrochemical label for the analyte to which they are conjugated. The metal particles can be oxidized to form metal ions that can subsequently be electrochemically detected and/or quantified. The metal ions can be electrodeposited as metal on a working electrode. The potential applied at the working electrode can then be varied to reoxidize the deposited metal to metal ions. The intensity of the resulting voltammetric peak reflects the amount of metal deposited on the working electrode, and therefore the amount of metal nanoparticle label and analyte. Sensitivity can tie improved by selectively localizing the analyte-metal particle conjugate in the vicinity of the working electrode. Analytes can be detected at concentrations as low as 767 fM via anodic stripping voltammetry, with no washing steps or electrode modifications.1. A method for detecting an analyte comprising:
(a) flowing fluid along a channel while applying a magnetic field to a region of the channel in electrochemical contact with a working electrode in order to accumulate the analyte conjugated to a metal particle and a magnetic particle in the region of the channel; (b) oxidizing the metal particle to form metal ions; and (c) electrochemically detecting the metal ions. 2. The method of claim 1, wherein step (a) comprises flowing fluid comprising the analyte conjugated to the metal particle and the magnetic particle along the channel, and applying the magnetic field to accumulate the analyte conjugated to the metal particle and the magnetic particle in the region of the channel. 3. The method of claim 1 or 2, further comprising interrupting fluid flow along the channel between steps (a) and (b). 4. The method of any of claims 1-3, wherein oxidizing the metal particle comprises contacting the metal particle with an oxidant. 5. The method of any of claims 1-4, wherein electrochemically detecting the metal ions comprises quantifying the concentration of the analyte. 6. The method of any of claims 1-5, wherein the analyte is selected from the group consisting of antibodies, peptides, proteins, polynucleotides, lipids, polysaccharides, small molecule organic compounds, pathogens, and combinations thereof. 7. The method of any of claims 1-6, wherein the analyte is bound to the metal particle by a recognition element. 8. The method of claim 7, wherein the recognition element comprises an antibody, polynucleotide, receptor, ligand, antigen, protein, small molecule organic compound, or combination thereof. 9. The method of any of claims 1-8, wherein the analyte is bound to the magnetic particle by a recognition element. 10. The method of claim 9, wherein the recognition element comprises an antibody, polynucleotide, receptor, ligand, antigen, protein, small molecule organic compound, or combination thereof. 11. The method of any of claims 1-10, wherein the analyte is bound to a first antibody and a second antibody, and wherein the metal particle is bound to the first antibody and the magnetic particle is bound to the second antibody. 12. The method of any of claims 1-10, wherein the analyte is bound to a first polynucleotide and a second polynucleotide, and wherein the metal particle is bound to the first polynucleotide and the magnetic particle is bound to the second polynucleotide. 13. The method of claim 12, wherein the analyte is a polynucleotide or a polynucleotide. 14. The method of any of claims 1-13, wherein the metal particle comprises a metal nanoparticle. 15. The method of any of claims 1-14, wherein the channel defines a path for fluid flow from a fluid inlet to a fluid outlet, and wherein the method further comprises injecting a sample comprising a molecule of interest into the fluid inlet. 16. The method of claim 15, wherein the molecule of interest is the analyte. 17. The method of claim 16, wherein the sample comprises the analyte conjugated to a metal particle and a magnetic particle. 18. The method of claim 15, wherein the analyte comprises a surrogate for the molecule of interest. 19. The method of claim 18, wherein the surrogate is conjugated to a fixed analyte support, the metal particle, the magnetic particle, or combinations thereof, and wherein the surrogate is displaced by the molecule of interest. 20. The method of any of claims 1-19, wherein the method further comprises flowing fluid along the channel while applying a magnetic field to the region of the channel in order to accumulate a second analyte conjugated to a second metal particle and a second magnetic particle in the region of the channel. 21. The method of claim 20, wherein the second metal particle comprises a different metal than the first metal particle. 22. The method of claim 20 or 21, wherein electrochemically detecting the metal ions comprises quantifying the concentration of the first analyte and the second analyte. 23. The method of any of claims 20-22, wherein electrochemically detecting the metal ions comprises quantifying the ratio of the first analyte to the second analyte. 24. A device comprising:
a channel defining a path for fluid flow from a fluid inlet to a fluid outlet; a working electrode positioned in electrochemical contact with a region of the channel; and a magnet configured to apply a magnetic field to the region of the channel. 25. The device of claim 24, further comprising an engageable platform;
wherein the engageable platform can be translocated from a retracted position to a deployed position; wherein in the retracted position the engageable platform is fluidly independent from the channel; and wherein in the deployed position the engageable platform is in fluid contact with the region of the channel. 26. The device of claim 25, wherein when the engageable platform is in the deployed position, the path for fluid flow from the fluid inlet to the fluid outlet is interrupted, such that fluid cannot flow from the fluid inlet to the fluid outlet. 27. The device of claim 25 or 26, wherein the engageable platform comprises an oxidant. 28. The device of claim 27, wherein the oxidant comprises potassium permanganate. 29. The device of any of claims 24-28, wherein the device is paper based. 30. The device of any of claims 24-29, wherein the channel comprises a hollow channel 31. The device of any of claims 24-30, further comprising a second working electrode in electrochemical contact with a second region of the channel, and a second magnet configured to apply a magnetic field to the second region of the channel. 32. The device of any of claims 24-31, further comprising a counter electrode, a reference electrode, or combinations thereof in electrochemical contact with the channel. 33. A device comprising:
a first layer comprising a top surface, a bottom surface, a fluid inlet defining a path for fluid flow from the top surface of the first layer to the bottom surface of the first layer, a fluid outlet defining a path for fluid flow from the bottom surface of the first layer to the top surface of the first layer, and a working electrode disposed on the bottom surface of the first layer; a second layer, comprising a top surface, a bottom surface, a hydrophobic boundary defining a channel for fluid flow within the second layer, and a port defining a path for fluid flow from the bottom surface of the second layer to the top surface of the second layer; a third layer, comprising a top surface, a bottom surface, a hydrophobic boundary defining a channel for fluid flow within the third layer, a port defining a path for fluid flow from the bottom surface of the third layer to the top surface of the third layer, and an engageable platform disposed within the third layer; a fourth layer, comprising a top surface, a bottom surface, a channel defining a path for fluid flow within the fourth layer formed from a porous hydrophilic material, and a sink fluidly connected to the channel and formed from a porous hydrophilic material; and a magnet; wherein the bottom surface of the first layer is in contact with the top surface of the second layer, the bottom surface of the second layer is in contact with the top surface of the third layer, and the bottom surface of the third layer is in contact with the top surface of the fourth layer; wherein the working electrode is in electrochemical contact with a region of the channel in the second layer; wherein the magnet is aligned with the working electrode so as to apply a magnetic field within the region of the channel in the second layer in electrochemical contact with the working electrode; wherein the first layer, the second layer, the third layer, and the fourth layer are aligned so as to form a path for fluid flow from the fluid inlet to the channel for fluid flow within the second layer, the channel for fluid flow within the third layer, and the channel within the fourth layer to the sink to the port in the third layer to the port in the second layer to the fluid outlet, and wherein the third layer can be translocated from a retracted position to a deployed position such that:
when the third layer is in the retracted position, the port of the third layer fluidly connects the port of the second layer and the sink and the engageable platform is fluidly independent from the channel for fluid flow within the second layer; and
when the third layer is in the deployed position, the engageable platform is in fluid contact with the region of the channel for fluid flow within the second layer and the port of the third layer is not aligned with the port of the second layer and the sink such that the path for fluid flow from the sink to the port of the second layer is interrupted. 34. The device of claim 33, wherein the engagable platform comprises an oxidant. 35. The device of claim 34, wherein the oxidant comprises potassium permanganate. 36. The device of any of claims 33-35, wherein the device is paper based. 37. The device of any of claims 33-36, wherein the first layer, the second layer, and the fourth layer are fabricated from a single piece of paper that is folded to form the device. 38. The device of any of the claims 33-37, further comprising a second working electrode disposed on the bottom surface of the first layer and a second magnet,
wherein the second working electrode is in electrochemical contact with a second region of channel in the second layer, and wherein the second magnet is aligned with the second working electrode so as to apply a magnetic field within the second region of the channel in the second layer in electrochemical contact with the second working electrode. 39. The device of any of claims 33-38, further comprising a counter electrode, a reference electrode, or combinations thereof disposed on the bottom surface of the first layer, wherein the counter electrode, the reference electrode, or the combinations thereof is in electrochemical with the channel in the second layer. 40. The device of any of claims 33-39, further comprising an indicator disposed on the sink, the port in the third layer, the port in the second layer, or combinations thereof. 41. The device of any of claims 33-40, wherein the fluid inlet comprises a reagent for the detection of a molecule of interest. 42. A method for detecting an analyte comprising:
(a) flowing fluid along a channel to accumulate the analyte conjugated to a metal particle in a region of the channel in electrochemical contact with a working electrode, wherein the analyte conjugated to the metal particle is accumulated in the region of the channel by a localization element; (b) oxidizing the metal particle to form metal ions; and (c) electrochemically detecting the metal ions, wherein the localization element is selected from the group consisting of a physical barrier disposed in the region of the channel, a localization electrode configured to apply an electric field to the region of the channel, a magnet configured to apply a magnetic field the region of the channel, or a combination thereof. 43. The method of claim 42, wherein the analyte comprises an analyte conjugated to a metal particle and a magnetic particle, and wherein the localization element comprises a magnet configured to apply a magnetic field to the region of the channel. 44. The method of claim 43, wherein step (a) comprises flowing fluid comprising the analyte conjugated to the metal particle and the magnetic particle along the channel, and applying the magnetic field to accumulate the analyte conjugated to the metal particle and the magnetic particle in the region of the channel. 45. The method of claim 42, wherein the analyte is charged, and wherein the localization element comprises a localization electrode configured to apply an electric field to the region of the channel. 46. The method of claim 45, wherein step (a) comprises flowing fluid comprising the charged analyte conjugated to the metal particle along the channel, and applying electric field to accumulate the charged analyte conjugated to the metal particle in the region of the channel. 47. The method of claim 42, the localization element comprises a physical barrier disposed in the region of the channel, and wherein step (a) comprises flowing fluid comprising the analyte conjugated to the metal particle along the channel to contact the physical barrier such that the analyte accumulates in the region of the channel. 48. The method of any of claims 42-47, further comprising interrupting fluid flow along the channel between steps (a) and (b). 49. The method of any of claims 42-48, wherein oxidizing the metal particle comprises contacting the metal particle with an oxidant. 50. The method of any of claims 42-49, wherein electrochemically detecting the metal ions comprises quantifying the concentration of the analyte. 51. The method of any of claims 42-50, wherein the analyte is selected from the group consisting of antibodies, peptides, proteins, polynucleotides, lipids, polysaccharides, small molecule organic compounds, pathogens, and combinations thereof. 52. The method of any of claims 42-51, wherein the analyte is bound to the metal particle by a recognition element. 53. The method of claim 52, wherein the recognition element comprises an antibody, polynucleotide, receptor, ligand, antigen, or combination thereof. 54. The method of any of claims 42-53, wherein the metal particle comprises a metal nanoparticle. 55. The method of any of claims 42-54, wherein the channel defines a path for fluid flow from a fluid inlet to a fluid outlet, and wherein the method further comprises injecting a sample comprising a molecule of interest into the fluid inlet. 56. The method of claim 55, wherein the molecule of interest is the analyte. 57. The method of claim 56, wherein the sample comprises the analyte conjugated to a metal particle. 58. The method of claim 55, wherein the analyte comprises a surrogate for the molecule of interest. 59. The method of claim 58, wherein the surrogate is conjugated to a fixed analyte support and wherein the analyte is displaced by the molecule of interest. 60. The method of any of claims 42-59, wherein the method further comprises flowing fluid along a channel to accumulate a second analyte conjugated to a second metal particle in the region of the channel in electrochemical contact with the working electrode, wherein the second analyte conjugated to the second metal particle is accumulated in the region of the channel by a localization element. 61. The method of claim 60, wherein the second metal particle comprises a different metal than the first metal particle. 62. The method of claim 60 or 61, wherein electrochemically detecting the metal ions comprises quantifying the concentration of the first analyte and the second analyte. 63. The method of any of claims 60-62, wherein electrochemically detecting the metal ions comprises quantifying the ratio of the first analyte to the second analyte. 64. A device for the detection of an analyte conjugated to a metal particle comprising:
a channel defining a path for fluid flow from a fluid inlet to a fluid outlet; a working electrode positioned in electrochemical contact with a region of the channel; and a localization element configured to accumulate the analyte conjugated to the metal particle in the region of the channel in electrochemical contact with the working electrode, wherein the localization element is selected from the group consisting of a physical barrier disposed in the region of the channel, a localization electrode configured to apply an electric field to the region of the channel, a magnet configured to apply a magnetic field the region of the channel, or a combination thereof. 65. The device of claim 64, further comprising an engageable platform;
wherein the engageable platform can be translocated from a retracted position to a deployed position; wherein in the retracted position the engageable platform is fluidly independent from the channel; and wherein in the deployed position the engageable platform is in fluid contact with the region of the channel. 66. The device of claim 65, wherein when the engageable platform is in the deployed position, the path for fluid flow from the fluid inlet to the fluid outlet is interrupted, such that fluid cannot flow from the fluid inlet to the fluid outlet. 67. The device of claim 65 or 66, wherein the engageable platform can be translocated from an incubation position to a retracted position to a deployed position,
wherein when the engageable platform is in the incubation position, the engageable platform is fluidly independent from the channel and the path for fluid flow from the fluid inlet to the fluid outlet is interrupted, such that fluid cannot flow from the fluid inlet to the fluid outlet. 68. The method of any of claims 65-67, wherein the engageable platform comprises an oxidant. 69. The device of claim 68, wherein the oxidant comprises potassium permanganate. 70. The device of any of claims 64-69, wherein the device is paper based. 71. The device of any of claims 64-70, wherein the channel comprises a hollow channel 72. The device of any of claims 64-71, further comprising a counter electrode, a reference electrode, or combinations thereof in electrochemical contact with the channel. | 1,600 |
886 | 13,697,578 | 1,628 | Theobromine for use in the treatment of increasing HDL-cholesterol and/or increasing the ratio HDL-cholesterol:LDL-cholesterol in humans and the use of theobromine for increasing HDL-cholesterol in humans, and/or for increasing the ratio HDL-C/LDL-C, and compositions comprising theobromine. | 1. Theobromine for use in the treatment of improving blood lipids. 2. Theobromine for use in the treatment of increasing HDL-cholesterol in humans. 3. Theobromine for use in the treatment of increasing the ratio HDL-cholesterol/LDL-cholesterol in humans. 4. Theobromine for use in the treatment of increasing the ratio HDL-cholesterol/non-HDL-cholesterol in humans. 5. Theobromine for use in the treatment according to any of claims 1 to 3, wherein the treatment comprises ingestion by a human of from 300 to 2000 mg theobromine per day. 6. Theobromine for use in the treatment according to claim 4, wherein the treatment comprises ingestion from 400 to 1800 mg theobromine per day, preferably from 500 to 1500 theobromine mg per day, more preferably from 600 to 1400 mg theobromine per day, even more preferably from 700 to 1300 mg theobromine per day, most preferably from 750 to 1250 mg theobromine per day. 7. Theobromine for use in the treatment according to any of claims 1 to 5, wherein the theobromine is ingested for at least 5 days per week for at least 3 weeks, preferably for at least 5 days per week for at least 4 weeks. 8. Theobromine for use in the treatment according to any of claims 1 to 6, wherein theobromine is ingested in the form of encapsulates. 9. Edible composition comprising theobromine and plant sterols, wherein the amount of theobromine is between 500 and 2000 mg per daily dosing and the amount of plant sterols is 1 to 3 g per daily dosing. 10. Edible composition comprising theobromine and plant sterols, wherein the amount of theobromine is between 300 and 2000 mg per daily dosing and the amount of plant sterols more than 1.8 g per daily dosing, preferably from 2 to 3 g per daily dosing. 11. Edible composition comprising theobromine and plant sterols, wherein the weight ratio theobromine:plant sterols is from 0.3:1 to 1:1, and wherein the amount of polyphenols in said composition is between 0% and 500% on the weight of theobromine in the composition. 12. Edible composition comprising theobromine and EPA and/or DHA, wherein the weight ratio of theobromine:EPA and DHA combined is from 1:4 to 1:0.3. 13. Edible composition comprising theobromine and a statin, in a weight ratio of from 200:1 to 5:1, more preferably from 100:1 to 10:1 (for theobromine:statin). 14. Edible emulsion comprising (by weight) 20 to 85% of oil, 15 to 80% water and 0.5 to 10% theobromine. 15. Emulsion according to claim 14, wherein said emulsion further comprises (by weight) 2-20% of plant sterols. 16. Emulsion according to claim 14 or 15, wherein the amount of polyphenols in said emulsion is between 0% and 500% on the weight of theobromine in the emulsion. 17. Edible emulsion according to any of claims 14 to 16, for use in the treatment of increasing HDL-cholesterol in humans and/or for use in the treatment of increasing the ratio HDL-cholesterol/LDL-cholesterol in humans. 18. Liquid composition comprising water in an amount of more than 70% by weight on the total composition, preferably more than 80% by weight on the total composition, and less than 99.8% by weight on the total composition, theobromine in an amount of from 0.3% by weight on the total composition to 2% by weight on the total composition, plant sterols in an amount such that theobromine and plant sterols are present in a weight ratio theobromine:plant sterols of from 1:1 to 1:10. 19. Edible composition according to claim 18, wherein the composition comprises from 85 to 99% by weight on the total composition of water. 20. Edible composition according to any of claims 18 or 19, wherein the composition comprises from 0.4 to 1.5% by weight on the total composition of theobromine. 21. Edible composition according to claims 18 to 20, for use in the treatment of increasing HDL-cholesterol in humans and/or for use in the treatment of increasing the ratio HDL-cholesterol/LDL-cholesterol in humans. 22. Fermented food composition comprising from 70 to 99 wt % water, from 0.1 to 10 wt % protein, at least 0.3 wt % lactic acid, and 0.2 to 2 wt % theobromine. 23. Fermented composition according to claim 22, which comprises at least 10 million bacteria per gram composition, from the group of: Streptococcus thermophilus, Lactobacillus delbrueckii, Lactobacillus species, Lactococcus species, Bifidobacterium species, and mixtures thereof. 24. Fermented composition according to claim 22 or 23, which composition further comprises plant sterols in an amount such that theobromine and plant sterols are present in a weight ratio theobromine:plant sterols of from 1:1 to 1:10. 25. Fermented composition according to claim 22 to 24, for use in the treatment of increasing HDL-cholesterol in humans and/or for use in the treatment of increasing the ratio HDL-cholesterol/LDL-cholesterol in humans. 26. Use of theobromine for increasing HDL-cholesterol in humans. 27. Use of theobromine for increasing the ratio HDL-cholesterol/LDL-cholesterol in humans. 28. A method for increasing HDL-cholesterol in a human, which method comprises administering to the human an HDL cholesterol raising effective amount of theobromine. 29. A method for increasing the ratio HDL-cholesterol/LDL-cholesterol in a human, which method comprises administering to the human an HDL-cholesterol/LDL-cholesterol ratio raising effective amount of theobromine. 30. A method for increasing the ratio HDL-cholesterol/non-HDL-cholesterol in a human, which method comprises administering to the human an HDL-cholesterol/non-HDL-cholesterol ratio raising effective amount of theobromine. 31. The method according to any of claims 28 to 30, wherein the effective amount is from 300 to 2000 mg theobromine per day. 32. The method according to any of claims 28 to 31, comprising ingestion of an amount of polyphenols of between 0% and 500% on the weight of theobromine ingested. 33. The method according to claim 28, 30, 31 or 32, wherein the increase in HDL-cholesterol in humans (in blood and/or serum) is at least 5%. 34. The method according to claim 29, 30, 31 or 32, wherein the increase in the ratio HDL-cholesterol/LDL-cholesterol in humans (in blood and/or serum) is at least 5%. | Theobromine for use in the treatment of increasing HDL-cholesterol and/or increasing the ratio HDL-cholesterol:LDL-cholesterol in humans and the use of theobromine for increasing HDL-cholesterol in humans, and/or for increasing the ratio HDL-C/LDL-C, and compositions comprising theobromine.1. Theobromine for use in the treatment of improving blood lipids. 2. Theobromine for use in the treatment of increasing HDL-cholesterol in humans. 3. Theobromine for use in the treatment of increasing the ratio HDL-cholesterol/LDL-cholesterol in humans. 4. Theobromine for use in the treatment of increasing the ratio HDL-cholesterol/non-HDL-cholesterol in humans. 5. Theobromine for use in the treatment according to any of claims 1 to 3, wherein the treatment comprises ingestion by a human of from 300 to 2000 mg theobromine per day. 6. Theobromine for use in the treatment according to claim 4, wherein the treatment comprises ingestion from 400 to 1800 mg theobromine per day, preferably from 500 to 1500 theobromine mg per day, more preferably from 600 to 1400 mg theobromine per day, even more preferably from 700 to 1300 mg theobromine per day, most preferably from 750 to 1250 mg theobromine per day. 7. Theobromine for use in the treatment according to any of claims 1 to 5, wherein the theobromine is ingested for at least 5 days per week for at least 3 weeks, preferably for at least 5 days per week for at least 4 weeks. 8. Theobromine for use in the treatment according to any of claims 1 to 6, wherein theobromine is ingested in the form of encapsulates. 9. Edible composition comprising theobromine and plant sterols, wherein the amount of theobromine is between 500 and 2000 mg per daily dosing and the amount of plant sterols is 1 to 3 g per daily dosing. 10. Edible composition comprising theobromine and plant sterols, wherein the amount of theobromine is between 300 and 2000 mg per daily dosing and the amount of plant sterols more than 1.8 g per daily dosing, preferably from 2 to 3 g per daily dosing. 11. Edible composition comprising theobromine and plant sterols, wherein the weight ratio theobromine:plant sterols is from 0.3:1 to 1:1, and wherein the amount of polyphenols in said composition is between 0% and 500% on the weight of theobromine in the composition. 12. Edible composition comprising theobromine and EPA and/or DHA, wherein the weight ratio of theobromine:EPA and DHA combined is from 1:4 to 1:0.3. 13. Edible composition comprising theobromine and a statin, in a weight ratio of from 200:1 to 5:1, more preferably from 100:1 to 10:1 (for theobromine:statin). 14. Edible emulsion comprising (by weight) 20 to 85% of oil, 15 to 80% water and 0.5 to 10% theobromine. 15. Emulsion according to claim 14, wherein said emulsion further comprises (by weight) 2-20% of plant sterols. 16. Emulsion according to claim 14 or 15, wherein the amount of polyphenols in said emulsion is between 0% and 500% on the weight of theobromine in the emulsion. 17. Edible emulsion according to any of claims 14 to 16, for use in the treatment of increasing HDL-cholesterol in humans and/or for use in the treatment of increasing the ratio HDL-cholesterol/LDL-cholesterol in humans. 18. Liquid composition comprising water in an amount of more than 70% by weight on the total composition, preferably more than 80% by weight on the total composition, and less than 99.8% by weight on the total composition, theobromine in an amount of from 0.3% by weight on the total composition to 2% by weight on the total composition, plant sterols in an amount such that theobromine and plant sterols are present in a weight ratio theobromine:plant sterols of from 1:1 to 1:10. 19. Edible composition according to claim 18, wherein the composition comprises from 85 to 99% by weight on the total composition of water. 20. Edible composition according to any of claims 18 or 19, wherein the composition comprises from 0.4 to 1.5% by weight on the total composition of theobromine. 21. Edible composition according to claims 18 to 20, for use in the treatment of increasing HDL-cholesterol in humans and/or for use in the treatment of increasing the ratio HDL-cholesterol/LDL-cholesterol in humans. 22. Fermented food composition comprising from 70 to 99 wt % water, from 0.1 to 10 wt % protein, at least 0.3 wt % lactic acid, and 0.2 to 2 wt % theobromine. 23. Fermented composition according to claim 22, which comprises at least 10 million bacteria per gram composition, from the group of: Streptococcus thermophilus, Lactobacillus delbrueckii, Lactobacillus species, Lactococcus species, Bifidobacterium species, and mixtures thereof. 24. Fermented composition according to claim 22 or 23, which composition further comprises plant sterols in an amount such that theobromine and plant sterols are present in a weight ratio theobromine:plant sterols of from 1:1 to 1:10. 25. Fermented composition according to claim 22 to 24, for use in the treatment of increasing HDL-cholesterol in humans and/or for use in the treatment of increasing the ratio HDL-cholesterol/LDL-cholesterol in humans. 26. Use of theobromine for increasing HDL-cholesterol in humans. 27. Use of theobromine for increasing the ratio HDL-cholesterol/LDL-cholesterol in humans. 28. A method for increasing HDL-cholesterol in a human, which method comprises administering to the human an HDL cholesterol raising effective amount of theobromine. 29. A method for increasing the ratio HDL-cholesterol/LDL-cholesterol in a human, which method comprises administering to the human an HDL-cholesterol/LDL-cholesterol ratio raising effective amount of theobromine. 30. A method for increasing the ratio HDL-cholesterol/non-HDL-cholesterol in a human, which method comprises administering to the human an HDL-cholesterol/non-HDL-cholesterol ratio raising effective amount of theobromine. 31. The method according to any of claims 28 to 30, wherein the effective amount is from 300 to 2000 mg theobromine per day. 32. The method according to any of claims 28 to 31, comprising ingestion of an amount of polyphenols of between 0% and 500% on the weight of theobromine ingested. 33. The method according to claim 28, 30, 31 or 32, wherein the increase in HDL-cholesterol in humans (in blood and/or serum) is at least 5%. 34. The method according to claim 29, 30, 31 or 32, wherein the increase in the ratio HDL-cholesterol/LDL-cholesterol in humans (in blood and/or serum) is at least 5%. | 1,600 |
887 | 15,396,207 | 1,619 | Novel hybrid coating compositions for mammalian nails, systems comprising the compositions, kits containing these compositions or systems, and methods of their use are disclosed. The novel compositions and/or kits are useful, inter alia, for providing durable, “soak-off” type nail coatings. | 1. A hybrid nail coating system comprising: a first layer comprising a solvent, a film former, and a photoinitiator, the photoinitiator comprising a self-initiating oligomer. 2. The hybrid nail coating system according to claim 1, wherein the self-initiating oligomer comprises a moiety selected from the group consisting of EBECRYL® LEO 10101, EBECRYL® LEO 10102, and EBECRYL® LEO 10103 radiation curing acrylate resins; DYNAX LS® light sensitive aliphatic and aromatic urethane acrylates; Michael adducts of beta-keto esters and (meth)acrylates and/or (meth)acrylated urethanes; and combinations thereof. 3. The hybrid nail coating system of claim 1, further comprising a second layer interposed between the first layer and a nail being coated, the second layer comprising a nail adhesion promoting monomer and a solvent. 4. The hybrid nail coating system according to claim 3, wherein the nail adhesion promoting monomer comprises an olefinically unsaturated carboxylic acid capable of free radically polymerizing. 5. The hybrid nail coating system according to claim 3, wherein the nail adhesion promoting monomer comprises acryloyloxyethyl phthalate, methacryloyloxyethyl maleate, or methacryloyloxyethyl succinate. 6. The hybrid nail coating system according to claim 3, further comprising a third layer interposed between the first layer and the second layer, the third layer comprising a solvent, a film former, a (meth)acrylated urethane, and a pigment or colorant. 7. The hybrid nail coating system according to claim 6, wherein the (meth)acrylated urethane comprises diurethane dimethacrylate or di-HEMA trimethylhexyl dicarbamate. 8. The hybrid nail coating system according to claim 1, wherein the coating is cured with UV or ambient light. 9. A hybrid nail coating composition comprising: a solvent, a film former, and a photoinitiator, the photoinitiator comprising a self-initiating oligomer. 10. A kit suitable for coating mammalian nails comprising a hybrid nail coating composition or hybrid nail coating system that contains the hybrid nail coating composition, the hybrid nail coating composition comprising:
solvent, a film former, and a photoinitiator, the photoinitiator comprising a self-initiating oligomer; wherein the kit comprises the nail coating composition or system containing such hybrid nail coating compositions; and a bottle for containing hybrid nail coating compositions, the bottle designed to substantially exclude the passage of UV and/or visible light. 11. A method for coating mammalian nails with a hybrid nail coating system, wherein the method comprises:
applying a second layer composition contiguously to a mammalian nail, the second layer composition comprising a nail adhesion promoting monomer and a solvent; thereafter, applying a first layer composition contiguously to a mammalian nail, the first layer composition comprising a solvent, a film former, and a photoinitiator, the photoinitiator comprising a self-initiating oligomer; and thereafter, curing the compositions on the nail or nail coating. 12. The method according to claim 11, wherein the method further comprises applying a third layer composition contiguously to a mammalian nail after the application of the second layer and prior to the application of the first layer, the third layer composition comprising a solvent, a film former, a (meth)acrylated urethane, and a pigment or colorant. 13. The method according to claim 11, wherein the system is cured with UV or ambient light. | Novel hybrid coating compositions for mammalian nails, systems comprising the compositions, kits containing these compositions or systems, and methods of their use are disclosed. The novel compositions and/or kits are useful, inter alia, for providing durable, “soak-off” type nail coatings.1. A hybrid nail coating system comprising: a first layer comprising a solvent, a film former, and a photoinitiator, the photoinitiator comprising a self-initiating oligomer. 2. The hybrid nail coating system according to claim 1, wherein the self-initiating oligomer comprises a moiety selected from the group consisting of EBECRYL® LEO 10101, EBECRYL® LEO 10102, and EBECRYL® LEO 10103 radiation curing acrylate resins; DYNAX LS® light sensitive aliphatic and aromatic urethane acrylates; Michael adducts of beta-keto esters and (meth)acrylates and/or (meth)acrylated urethanes; and combinations thereof. 3. The hybrid nail coating system of claim 1, further comprising a second layer interposed between the first layer and a nail being coated, the second layer comprising a nail adhesion promoting monomer and a solvent. 4. The hybrid nail coating system according to claim 3, wherein the nail adhesion promoting monomer comprises an olefinically unsaturated carboxylic acid capable of free radically polymerizing. 5. The hybrid nail coating system according to claim 3, wherein the nail adhesion promoting monomer comprises acryloyloxyethyl phthalate, methacryloyloxyethyl maleate, or methacryloyloxyethyl succinate. 6. The hybrid nail coating system according to claim 3, further comprising a third layer interposed between the first layer and the second layer, the third layer comprising a solvent, a film former, a (meth)acrylated urethane, and a pigment or colorant. 7. The hybrid nail coating system according to claim 6, wherein the (meth)acrylated urethane comprises diurethane dimethacrylate or di-HEMA trimethylhexyl dicarbamate. 8. The hybrid nail coating system according to claim 1, wherein the coating is cured with UV or ambient light. 9. A hybrid nail coating composition comprising: a solvent, a film former, and a photoinitiator, the photoinitiator comprising a self-initiating oligomer. 10. A kit suitable for coating mammalian nails comprising a hybrid nail coating composition or hybrid nail coating system that contains the hybrid nail coating composition, the hybrid nail coating composition comprising:
solvent, a film former, and a photoinitiator, the photoinitiator comprising a self-initiating oligomer; wherein the kit comprises the nail coating composition or system containing such hybrid nail coating compositions; and a bottle for containing hybrid nail coating compositions, the bottle designed to substantially exclude the passage of UV and/or visible light. 11. A method for coating mammalian nails with a hybrid nail coating system, wherein the method comprises:
applying a second layer composition contiguously to a mammalian nail, the second layer composition comprising a nail adhesion promoting monomer and a solvent; thereafter, applying a first layer composition contiguously to a mammalian nail, the first layer composition comprising a solvent, a film former, and a photoinitiator, the photoinitiator comprising a self-initiating oligomer; and thereafter, curing the compositions on the nail or nail coating. 12. The method according to claim 11, wherein the method further comprises applying a third layer composition contiguously to a mammalian nail after the application of the second layer and prior to the application of the first layer, the third layer composition comprising a solvent, a film former, a (meth)acrylated urethane, and a pigment or colorant. 13. The method according to claim 11, wherein the system is cured with UV or ambient light. | 1,600 |
888 | 14,980,374 | 1,611 | A method of treatment of a patient suffering from postoperative inflammatory stress and pain caused by mechanical impact exerted on portions of the body of the patient that causes damaged tissue wherein the inflammatory stress and pain of the operation outlast the healing of damaged tissue and which is not related to, or caused by, uncontrolled proteolysis. The treatment comprises administering a tetrahydropyrimidine selected from ectoine and/or hydroxyectoine to the patient. | 1. A method of treatment of a patient suffering from postoperative inflammatory stress and pain caused by mechanical impact exerted on portions of the body of the patient that causes damaged tissue wherein the inflammatory stress and pain of the operation outlast the healing of damaged tissue and which is not related to, or caused by, uncontrolled proteolysis, comprising administering a tetrahydropyrimidine selected from ectoine and/or hydroxyectoine to the patient. 2. The method of claim 1, wherein the postoperative inflammatory stress and pain is pain in the abdominal and intestinal region. 3. The method of claim 1, wherein the postoperative inflammatory stress and pain is pain caused by transplantation in the region of the abdomen. 4. The method of claim 1, wherein the postoperative inflammatory stress and pain is stress and pain after endoscopic or laparoscopic interventions caused by inflammation. 5. The method of claim 1, wherein the tetrahydropyrimidine is hydroxyectoine. 6. The method of claim 1 wherein the tetrahydropyrimidine is administered to a patient in an amount of 1 to 250 mg per kg of body weight and day. 7. The method of claim 1 wherein the tetrahydropyrimidine is in the form of a solution for topical application comprising the tetrahydropyrimidine in an amount ranging between 0.1 and 25% w/w. 8. The method of claim 6, wherein the tetrahydropyrimidine is administered to a patient in an amount of 5 to 150 mg per kg of body weight and day. 9. The method of claim 6, wherein the tetrahydropyrimidine is administered to a patient in an amount of 10 to 100 mg per kg of body weight and day. 10. The method of claim 7, wherein the solution comprises 9.5 to 5% w/w of the tetrahydropyrimidine. 11. The method of claim 1 wherein the mechanical impact is from an eye operation. | A method of treatment of a patient suffering from postoperative inflammatory stress and pain caused by mechanical impact exerted on portions of the body of the patient that causes damaged tissue wherein the inflammatory stress and pain of the operation outlast the healing of damaged tissue and which is not related to, or caused by, uncontrolled proteolysis. The treatment comprises administering a tetrahydropyrimidine selected from ectoine and/or hydroxyectoine to the patient.1. A method of treatment of a patient suffering from postoperative inflammatory stress and pain caused by mechanical impact exerted on portions of the body of the patient that causes damaged tissue wherein the inflammatory stress and pain of the operation outlast the healing of damaged tissue and which is not related to, or caused by, uncontrolled proteolysis, comprising administering a tetrahydropyrimidine selected from ectoine and/or hydroxyectoine to the patient. 2. The method of claim 1, wherein the postoperative inflammatory stress and pain is pain in the abdominal and intestinal region. 3. The method of claim 1, wherein the postoperative inflammatory stress and pain is pain caused by transplantation in the region of the abdomen. 4. The method of claim 1, wherein the postoperative inflammatory stress and pain is stress and pain after endoscopic or laparoscopic interventions caused by inflammation. 5. The method of claim 1, wherein the tetrahydropyrimidine is hydroxyectoine. 6. The method of claim 1 wherein the tetrahydropyrimidine is administered to a patient in an amount of 1 to 250 mg per kg of body weight and day. 7. The method of claim 1 wherein the tetrahydropyrimidine is in the form of a solution for topical application comprising the tetrahydropyrimidine in an amount ranging between 0.1 and 25% w/w. 8. The method of claim 6, wherein the tetrahydropyrimidine is administered to a patient in an amount of 5 to 150 mg per kg of body weight and day. 9. The method of claim 6, wherein the tetrahydropyrimidine is administered to a patient in an amount of 10 to 100 mg per kg of body weight and day. 10. The method of claim 7, wherein the solution comprises 9.5 to 5% w/w of the tetrahydropyrimidine. 11. The method of claim 1 wherein the mechanical impact is from an eye operation. | 1,600 |
889 | 15,198,306 | 1,612 | A consumer product including a personal care composition providing multiple blooms of fragrance, the multiple blooms being provided for by different populations of microcapsules. | 1. A consumer product comprising a composition, the composition comprising:
an adjunct material;
a first population of microcapsules, the first population having a first median volume weighted particle size and comprising microcapsules comprising a partitioning modifier and a first perfume oil at a first weight ratio; and
a second population of microcapsules, the second population having a second median volume weighted particle size and comprising microcapsules comprising the partitioning modifier and a second perfume oil at a second weight ratio;
wherein the first weight ratio and the second weight ratio are different, and/or the first median volume weighted particle size and the second median volume weighted particle size are different; and
wherein the composition is a personal care composition. 2. The consumer product of claim 1, wherein the first weight ratio is a weight ratio of from 2:3 to 3:2 of the partitioning modifier to the first perfume oil; and wherein the second weight ratio is a weight ratio of greater than 0 to less than 2:3 of the partitioning modifier to the second perfume oil. 3. The consumer product of claim 1, wherein a weight ratio of the first population of microcapsules to the second population of microcapsules is greater than 0 to less than 1:1. 4. The consumer product of claim 1, wherein a weight ratio of the first population of microcapsules to the second population of microcapsules exceeds 1:1. 5. The consumer product of claim 1, wherein the first and second median volume weighted particle size is from 2 microns to 80 microns. 6. The consumer product of claim 1, wherein the first median volume weighted particle size is different from the second median volume weighted particle size. 7. The consumer product of claim 1, wherein the first perfume oil and the second perfume oil are the same. 8. The consumer product of claim 1, wherein the adjunct material comprises a non-encapsulated perfume oil. 9. The consumer product of claim 8, wherein the non-encapsulated perfume oil is different from the first and second perfume oil. 10. The consumer product of claim 1, wherein the partitioning modifier is selected from the group consisting of isopropyl myristate, mono- , di- , and tri-esters of C4-C24 fatty acids, castor oil, mineral oil, soybean oil, hexadecanoic acid, methyl ester isododecane, isoparaffin oil, polydimethylsiloxane, brominated vegetable oil, and mixtures thereof. 11. The consumer product of claim 1, wherein the microcapsules further comprise a shell material selected from the group consisting of polyacrylates, polyethylenes, polyamides, polystyrenes, polyisoprenes, polycarbonates, polyesters, polyureas, polyurethanes, polyolefins, polysaccharides, epoxy resins, vinyl polymers, urea cross-linked with formaldehyde or gluteraldehyde, melamine cross-linked with formaldehyde; gelatin-polyphosphate coacervates optionally cross-linked with gluteraldehyde; gelatin-gum Arabic coacervates; cross-linked silicone fluids; polyamine reacted with polyisocyanates; acrylate monomers polymerized via free radical polymerization, silk, wool, gelatine, cellulose, proteins, and mixtures thereof. 12. The consumer product of claim 1, wherein the microcapsules further comprise a shell material comprising a reaction product of a first substance in the presence of a second substance comprising an emulsifier, the first substance comprising a reaction product of i) an oil soluble or dispersible amine with ii) a multifunctional acrylate or methacrylate monomer or oligomer, an oil soluble acid and an initiator, the emulsifier comprising a water soluble or water dispersible acrylic acid alkyl acid copolymer, an alkali or alkali salt, and optionally a water phase initiator. 13. The consumer product of claim 1, wherein the adjunct material comprises:
from about 2% to about 50%, by weight of the personal care composition, of one or more detersive surfactants; and from about 20% to about 95%, by weight of the personal care composition, of a first aqueous carrier. 14. The consumer product of claim 1, wherein the adjunct material comprises a gel matrix, the gel matrix comprising:
i. from about 0.1% to about 20%, by weight of the personal care composition, of one or more high melting point fatty compounds; ii. from about 0.1% to about 10%, by weight of the personal care composition, of a cationic surfactant system; and iii. at least about 20%, by weight of the personal care composition, of the carrier. 15. The consumer product of claim 1, wherein the adjunct material comprises:
i. from about 0.025% to about 0.25%, by weight of the personal care composition, of a compound selected from the group consisting of ethylenediamine-N,N′-disuccinic acid (EDDS), derivatives of ethylenediamine-N,N′-disuccinic acid (EDDS), salts of ethylenediamine-N,N′-disuccinic acid (EDDS), and mixtures thereof; ii. one or more rheology modifiers; and iii. at least 20%, by weight of the personal care composition, of an aqueous carrier. 16. The consumer product of claim 1, wherein the adjunct material comprises:
from about 0.1% to about 30%, by weight of the personal care composition, of one or more antiperspirant actives; from about 0.1% to about 35%, by weight of the personal care composition, of one or more structurants; and from about 10% to about 99%, by weight of the personal care composition, of an anhydrous carrier. 17. The consumer product of claim 1, wherein the adjunct material comprises from 0.1% to 20%, by weight of the personal care composition, of a primary surfactant. 18. The consumer product of claim 1, wherein the adjunct material comprises a cleansing phase and a benefit phase. 19. The consumer product of claim 1, wherein the adjunct material comprises from 10% to 99%, by weight of the personal care composition, of water. 20. The consumer product of claim 1, wherein the adjunct ingredient comprises a material selected from the group consisting of oil, water, silicone, and mixtures thereof; and the personal care composition is in the form of a water-in-oil emulsion, an oil-in-water emulsion, or a water-in-silicone emulsion. 21. The consumer product of claim 1, wherein the first perfume oil and the second perfume oil comprise at least one different material. 22. The consumer product of claim 1, wherein the first population and second population comprise different shell materials. | A consumer product including a personal care composition providing multiple blooms of fragrance, the multiple blooms being provided for by different populations of microcapsules.1. A consumer product comprising a composition, the composition comprising:
an adjunct material;
a first population of microcapsules, the first population having a first median volume weighted particle size and comprising microcapsules comprising a partitioning modifier and a first perfume oil at a first weight ratio; and
a second population of microcapsules, the second population having a second median volume weighted particle size and comprising microcapsules comprising the partitioning modifier and a second perfume oil at a second weight ratio;
wherein the first weight ratio and the second weight ratio are different, and/or the first median volume weighted particle size and the second median volume weighted particle size are different; and
wherein the composition is a personal care composition. 2. The consumer product of claim 1, wherein the first weight ratio is a weight ratio of from 2:3 to 3:2 of the partitioning modifier to the first perfume oil; and wherein the second weight ratio is a weight ratio of greater than 0 to less than 2:3 of the partitioning modifier to the second perfume oil. 3. The consumer product of claim 1, wherein a weight ratio of the first population of microcapsules to the second population of microcapsules is greater than 0 to less than 1:1. 4. The consumer product of claim 1, wherein a weight ratio of the first population of microcapsules to the second population of microcapsules exceeds 1:1. 5. The consumer product of claim 1, wherein the first and second median volume weighted particle size is from 2 microns to 80 microns. 6. The consumer product of claim 1, wherein the first median volume weighted particle size is different from the second median volume weighted particle size. 7. The consumer product of claim 1, wherein the first perfume oil and the second perfume oil are the same. 8. The consumer product of claim 1, wherein the adjunct material comprises a non-encapsulated perfume oil. 9. The consumer product of claim 8, wherein the non-encapsulated perfume oil is different from the first and second perfume oil. 10. The consumer product of claim 1, wherein the partitioning modifier is selected from the group consisting of isopropyl myristate, mono- , di- , and tri-esters of C4-C24 fatty acids, castor oil, mineral oil, soybean oil, hexadecanoic acid, methyl ester isododecane, isoparaffin oil, polydimethylsiloxane, brominated vegetable oil, and mixtures thereof. 11. The consumer product of claim 1, wherein the microcapsules further comprise a shell material selected from the group consisting of polyacrylates, polyethylenes, polyamides, polystyrenes, polyisoprenes, polycarbonates, polyesters, polyureas, polyurethanes, polyolefins, polysaccharides, epoxy resins, vinyl polymers, urea cross-linked with formaldehyde or gluteraldehyde, melamine cross-linked with formaldehyde; gelatin-polyphosphate coacervates optionally cross-linked with gluteraldehyde; gelatin-gum Arabic coacervates; cross-linked silicone fluids; polyamine reacted with polyisocyanates; acrylate monomers polymerized via free radical polymerization, silk, wool, gelatine, cellulose, proteins, and mixtures thereof. 12. The consumer product of claim 1, wherein the microcapsules further comprise a shell material comprising a reaction product of a first substance in the presence of a second substance comprising an emulsifier, the first substance comprising a reaction product of i) an oil soluble or dispersible amine with ii) a multifunctional acrylate or methacrylate monomer or oligomer, an oil soluble acid and an initiator, the emulsifier comprising a water soluble or water dispersible acrylic acid alkyl acid copolymer, an alkali or alkali salt, and optionally a water phase initiator. 13. The consumer product of claim 1, wherein the adjunct material comprises:
from about 2% to about 50%, by weight of the personal care composition, of one or more detersive surfactants; and from about 20% to about 95%, by weight of the personal care composition, of a first aqueous carrier. 14. The consumer product of claim 1, wherein the adjunct material comprises a gel matrix, the gel matrix comprising:
i. from about 0.1% to about 20%, by weight of the personal care composition, of one or more high melting point fatty compounds; ii. from about 0.1% to about 10%, by weight of the personal care composition, of a cationic surfactant system; and iii. at least about 20%, by weight of the personal care composition, of the carrier. 15. The consumer product of claim 1, wherein the adjunct material comprises:
i. from about 0.025% to about 0.25%, by weight of the personal care composition, of a compound selected from the group consisting of ethylenediamine-N,N′-disuccinic acid (EDDS), derivatives of ethylenediamine-N,N′-disuccinic acid (EDDS), salts of ethylenediamine-N,N′-disuccinic acid (EDDS), and mixtures thereof; ii. one or more rheology modifiers; and iii. at least 20%, by weight of the personal care composition, of an aqueous carrier. 16. The consumer product of claim 1, wherein the adjunct material comprises:
from about 0.1% to about 30%, by weight of the personal care composition, of one or more antiperspirant actives; from about 0.1% to about 35%, by weight of the personal care composition, of one or more structurants; and from about 10% to about 99%, by weight of the personal care composition, of an anhydrous carrier. 17. The consumer product of claim 1, wherein the adjunct material comprises from 0.1% to 20%, by weight of the personal care composition, of a primary surfactant. 18. The consumer product of claim 1, wherein the adjunct material comprises a cleansing phase and a benefit phase. 19. The consumer product of claim 1, wherein the adjunct material comprises from 10% to 99%, by weight of the personal care composition, of water. 20. The consumer product of claim 1, wherein the adjunct ingredient comprises a material selected from the group consisting of oil, water, silicone, and mixtures thereof; and the personal care composition is in the form of a water-in-oil emulsion, an oil-in-water emulsion, or a water-in-silicone emulsion. 21. The consumer product of claim 1, wherein the first perfume oil and the second perfume oil comprise at least one different material. 22. The consumer product of claim 1, wherein the first population and second population comprise different shell materials. | 1,600 |
890 | 15,626,021 | 1,636 | Gene expression can be identified by analyzing a DNA sequence. The DNA sequence can include a barcode sequence that corresponds to a particular gene. The barcode sequence can be produced during the expression of a gene by first adding a Homologous Directed Repair (HDR) template including the barcode sequence into the DNA sequence of the gene and then splicing the barcode sequence out of an RNA precursor during the expression of the gene. As the barcode sequence is made available from the RNA precursor, it can be added to the DNA strand using HDR. The resulting DNA strand can be sequenced and the sequence data can be analyzed to identify the barcode sequence within the DNA sequence, which provides an indicator of the expression of the gene in DNA rather than RNA. | 1. A method comprising:
producing a first homology directed repair (HDR) template including at least a first splicing region and a barcode region, the first splicing region including a first sequence of nucleotides that is recognized by an enzyme to produce a cut in the first splicing region and the barcode region including a sequence of nucleotides that corresponds to a gene; inserting the first HDR template into a target site of the gene using HDR; splicing, using the enzyme, the first HDR template in at least the first splicing region to produce a second HDR template, the second HDR template including a sequence of nucleotides that includes a portion of the first splicing region and the barcode region; inserting the second HDR template into a double stranded polynucleotide using HDR; sequencing the additional double stranded polynucleotide to produce sequencing data; and determining that the gene has been expressed based at least partly on identifying the sequence of nucleotides of the barcode region in the sequencing data. 2. The method of claim 1, wherein:
the first HDR template includes a second splicing region; the first splicing region is homologous to a first portion of a target site of the gene; and the second splicing region is homologous to a second portion of the target site of the gene. 3. The method of claim 1, wherein the first HDR template is inserted in the 3′ untranslated region of the gene. 4. The method of claim 1, wherein the double stranded polynucleotide is at least one of genomic DNA, artificial DNA, circular DNA, or linear DNA. 5. The method of claim 1, wherein the enzyme is a spliceosome, and the method further comprises designing the first HDR template such that the first splicing region includes the sequence of nucleotides recognized by the spliceosome and the second HDR template remains viable to perform HDR with the double stranded polynucleotide for a specified period of time. 6. The method of claim 1, further comprising:
before inserting the first HDR template into the target site, inserting a third HDR template into the gene using HDR, wherein the third HDR template includes the target site. 7. The method of claim 1, further comprising:
generating data indicating a plurality of barcode sequences, wherein the gene is one of a plurality of genes; and associating individual genes of the plurality of genes with a respective barcode sequence of the plurality of barcode sequences such that each barcode sequence of the plurality of barcode sequences corresponds to a particular gene. 8. The method of claim 1, further comprising producing a gene product as a result of the expression of the gene, wherein:
the gene product includes a single stranded polynucleotide sequence that includes a first section corresponding to the first splicing region and a second section corresponding to the barcode region. 9. A system comprising:
a gene including a double stranded polynucleotide having a target site; an enzyme configured to create a double strand break in the double stranded polynucleotide of the gene at a cut site in the target site; and a homology directed repair (HDR) template including at least a first splicing region and a barcode sequence corresponding to the gene; wherein the HDR template is inserted into the target site with HDR at the cut site after the enzyme creates a break at the cut site. 10. The system of claim 9, wherein the system comprises a single eukaryotic cell or a single prokaryotic cell. 11. The system of claim 9, further comprising an additional double stranded polynucleotide including an additional target site. 12. The system of claim 11, wherein:
at least a portion of the first HDR template is removed from the double stranded polynucleotide of the gene using at least one spliceosome to produce a second HDR template that includes at least the barcode sequence and a portion of the first splicing region. 13. The system of claim 9, wherein expression of the gene produces an RNA precursor that includes a single stranded polynucleotide including:
a first sequence that corresponds to the first splicing region; a second sequence that corresponds to the barcode sequence; a 3′ untranslated region (UTR) and a 5′ UTR; and a coding region that includes an intron and an exon. 14. The system of claim 13, wherein the intron included in the RNA precursor includes the HDR template. 15. The system of claim 13, wherein the 3′ UTR includes the first sequence and the second sequence. 16. A system comprising:
a gene; a double stranded polynucleotide including a target site; a homology directed repair (HDR) template including a barcode region having a sequence of nucleotides that corresponds to the gene; and an enzyme configured to create a double strand break in the double stranded polynucleotide at the target site; wherein the HDR template is inserted into the double stranded polynucleotide by HDR to produce a modified double stranded polynucleotide. 17. The system of claim 16, wherein:
the modified double stranded polynucleotide includes an additional target site; the system further comprises an additional HDR template; and the additional HDR template is inserted into the additional target site via HDR. 18. The system of claim 17, wherein:
the system further comprising a first gene encoding the HDR template and a second gene encoding the additional HDR template; expression of the first gene causes the HDR template to become available for insertion into the target site; and expression of the second gene causes the additional HDR template to become available for insertion into the additional target site. 19. The system of claim 18, wherein:
the second gene is expressed in response to a signal that occurs at a particular time; and analysis of a sequence of the modified double stranded polynucleotide indicates a period of time that the first gene was expressed based at least partly on the presence of the additional HDR template in the sequence of the modified double stranded polynucleotide. 20. The system of claim 16, further comprising:
an additional gene that includes an additional HDR template having a sequence that includes the sequence of nucleotides of the barcode region and at least one splicing region; and an additional enzyme to remove at least a portion of the additional HDR template to create the HDR template and make the HDR template available for insertion into the double stranded polynucleotide. | Gene expression can be identified by analyzing a DNA sequence. The DNA sequence can include a barcode sequence that corresponds to a particular gene. The barcode sequence can be produced during the expression of a gene by first adding a Homologous Directed Repair (HDR) template including the barcode sequence into the DNA sequence of the gene and then splicing the barcode sequence out of an RNA precursor during the expression of the gene. As the barcode sequence is made available from the RNA precursor, it can be added to the DNA strand using HDR. The resulting DNA strand can be sequenced and the sequence data can be analyzed to identify the barcode sequence within the DNA sequence, which provides an indicator of the expression of the gene in DNA rather than RNA.1. A method comprising:
producing a first homology directed repair (HDR) template including at least a first splicing region and a barcode region, the first splicing region including a first sequence of nucleotides that is recognized by an enzyme to produce a cut in the first splicing region and the barcode region including a sequence of nucleotides that corresponds to a gene; inserting the first HDR template into a target site of the gene using HDR; splicing, using the enzyme, the first HDR template in at least the first splicing region to produce a second HDR template, the second HDR template including a sequence of nucleotides that includes a portion of the first splicing region and the barcode region; inserting the second HDR template into a double stranded polynucleotide using HDR; sequencing the additional double stranded polynucleotide to produce sequencing data; and determining that the gene has been expressed based at least partly on identifying the sequence of nucleotides of the barcode region in the sequencing data. 2. The method of claim 1, wherein:
the first HDR template includes a second splicing region; the first splicing region is homologous to a first portion of a target site of the gene; and the second splicing region is homologous to a second portion of the target site of the gene. 3. The method of claim 1, wherein the first HDR template is inserted in the 3′ untranslated region of the gene. 4. The method of claim 1, wherein the double stranded polynucleotide is at least one of genomic DNA, artificial DNA, circular DNA, or linear DNA. 5. The method of claim 1, wherein the enzyme is a spliceosome, and the method further comprises designing the first HDR template such that the first splicing region includes the sequence of nucleotides recognized by the spliceosome and the second HDR template remains viable to perform HDR with the double stranded polynucleotide for a specified period of time. 6. The method of claim 1, further comprising:
before inserting the first HDR template into the target site, inserting a third HDR template into the gene using HDR, wherein the third HDR template includes the target site. 7. The method of claim 1, further comprising:
generating data indicating a plurality of barcode sequences, wherein the gene is one of a plurality of genes; and associating individual genes of the plurality of genes with a respective barcode sequence of the plurality of barcode sequences such that each barcode sequence of the plurality of barcode sequences corresponds to a particular gene. 8. The method of claim 1, further comprising producing a gene product as a result of the expression of the gene, wherein:
the gene product includes a single stranded polynucleotide sequence that includes a first section corresponding to the first splicing region and a second section corresponding to the barcode region. 9. A system comprising:
a gene including a double stranded polynucleotide having a target site; an enzyme configured to create a double strand break in the double stranded polynucleotide of the gene at a cut site in the target site; and a homology directed repair (HDR) template including at least a first splicing region and a barcode sequence corresponding to the gene; wherein the HDR template is inserted into the target site with HDR at the cut site after the enzyme creates a break at the cut site. 10. The system of claim 9, wherein the system comprises a single eukaryotic cell or a single prokaryotic cell. 11. The system of claim 9, further comprising an additional double stranded polynucleotide including an additional target site. 12. The system of claim 11, wherein:
at least a portion of the first HDR template is removed from the double stranded polynucleotide of the gene using at least one spliceosome to produce a second HDR template that includes at least the barcode sequence and a portion of the first splicing region. 13. The system of claim 9, wherein expression of the gene produces an RNA precursor that includes a single stranded polynucleotide including:
a first sequence that corresponds to the first splicing region; a second sequence that corresponds to the barcode sequence; a 3′ untranslated region (UTR) and a 5′ UTR; and a coding region that includes an intron and an exon. 14. The system of claim 13, wherein the intron included in the RNA precursor includes the HDR template. 15. The system of claim 13, wherein the 3′ UTR includes the first sequence and the second sequence. 16. A system comprising:
a gene; a double stranded polynucleotide including a target site; a homology directed repair (HDR) template including a barcode region having a sequence of nucleotides that corresponds to the gene; and an enzyme configured to create a double strand break in the double stranded polynucleotide at the target site; wherein the HDR template is inserted into the double stranded polynucleotide by HDR to produce a modified double stranded polynucleotide. 17. The system of claim 16, wherein:
the modified double stranded polynucleotide includes an additional target site; the system further comprises an additional HDR template; and the additional HDR template is inserted into the additional target site via HDR. 18. The system of claim 17, wherein:
the system further comprising a first gene encoding the HDR template and a second gene encoding the additional HDR template; expression of the first gene causes the HDR template to become available for insertion into the target site; and expression of the second gene causes the additional HDR template to become available for insertion into the additional target site. 19. The system of claim 18, wherein:
the second gene is expressed in response to a signal that occurs at a particular time; and analysis of a sequence of the modified double stranded polynucleotide indicates a period of time that the first gene was expressed based at least partly on the presence of the additional HDR template in the sequence of the modified double stranded polynucleotide. 20. The system of claim 16, further comprising:
an additional gene that includes an additional HDR template having a sequence that includes the sequence of nucleotides of the barcode region and at least one splicing region; and an additional enzyme to remove at least a portion of the additional HDR template to create the HDR template and make the HDR template available for insertion into the double stranded polynucleotide. | 1,600 |
891 | 15,570,118 | 1,628 | The present invention provides pharmaceutical compositions comprising cannabinoids and N-acylethanolamines, and methods for their use in preventing and treating a variety of cannabinoid-treatable conditions. | 1-48. (canceled) 49. A method for preventing or treating at least one symptom of Tourette syndrome in a human subject in need thereof, comprising administering to the subject a therapeutically-effective amount of a pharmaceutical composition comprising at least one cannabinoid or a salt thereof, and at least one N-acylethanolamine or a salt thereof, in a molar ratio of the cannabinoid and N-acylethanolamine between about 1:0.2 to about 1:2000, thereby preventing or treating the symptom. 50. The method of claim 49 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:0.2 to about 1:5. 51. The method of claim 49 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:0.5 to about 1:2. 52. The method of claim 49 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:15 to about 1:1800. 53. The method of claim 49 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:25 to about 1:450. 54. The method of claim 49 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:50 to about 1:100. 55. The method of claim 49, wherein the at least one cannabinoid is tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), a salt thereof, or any combination thereof. 56. The method of claim 55, wherein the at least one cannabinoid is THC or a salt thereof. 57. The method of claim 49, wherein the pharmaceutical composition comprises about 200-1800 mg of N-acylethanolamine or a salt thereof. 58. The method of claim 57, wherein the pharmaceutical composition comprises about 250 mg, about 500 mg, about 750 mg, about 1000 mg or about 1500 mg of N-acylethanolamine or a salt thereof. 59. The method of claim 49, wherein the at least one N-acylethanolamine is N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, palmitoylisopropylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), a salt thereof, or any combination thereof. 60. The pharmaceutical composition of claim 59, wherein the N-acylethanolamine is PEA or a salt thereof. 61. The method of claim 49 wherein the pharmaceutical composition comprises THC or a salt thereof, and PEA or a salt thereof. 62. The method of claim 49 wherein the pharmaceutical composition comprises about 0.5-10 mg of THC or a salt thereof, and about 200-1800 mg of PEA or a salt thereof. 63. The method of claim 49 wherein the pharmaceutical composition comprises about 2.5-10 mg of THC or a salt thereof and about 250-1000 mg of PEA or a salt thereof. 64. The method of claim 49 wherein the pharmaceutical composition comprises about 2.5 mg, about 5 mg, about 7.5 mg or about 10 mg of THC or a salt thereof, and about 250 mg, about 500 mg, about 750 mg or about 1000 mg of PEA or a salt thereof. 65. The method of claim 49 wherein the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalational, topical, rectal, vaginal, parenteral, intravenous, intramuscular, or subcutaneous administration. 66. The method of claim 65 wherein the pharmaceutical composition is formulated for oral, oral mucosal, nasal, or sublingual administration. 67. The method of claim 49, wherein the administration of the cannabinoid and the N-acylethanolamine is repeated. 68. The method of claim 67, wherein the administration of the cannabinoid and the N-acylethanolamine is repeated until a beneficial change in the condition of the subject according to the Yale Global Tic Severity Scale (YGTSS) is achieved compared to the condition of the subject prior to treatment. 69. The method of claim 67, wherein the administration of the cannabinoid and the N-acylethanolamine is repeated until a beneficial change in the condition of the subject according to at least one scale selected from the group consisting of (i) the Clinician Global Impression scale (CGIS), (ii) the Gilles de la Tourette Syndrome-Quality Of Life scale (GTS-QOL) (iii) the Tourette Syndrome Symptom List (TSSL) (iv) the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) (v) the ADHD Rating Scale-IV (ADHD-RS) and (vi) the Hamilton Anxiety Rating Scale (HAM-A), is achieved compared to the condition of the subject prior to treatment. 70. The method of claim 49, wherein the Tourette syndrome is classified as moderate to severe Tourette syndrome. 71. The method of claim 49, wherein the symptom is tics. 72. A dosage unit comprising a therapeutically-effective amount of a pharmaceutical composition comprising at least one cannabinoid or a salt thereof, and at least one N-acylethanolamine or a salt thereof in a molar ratio of the cannabinoid and N-acylethanolamine between about 1:0.2 to about 1:2000. 73. A dosage unit consisting essentially of a therapeutically-effective amount of at least one cannabinoid or a salt thereof, and at least one N-acylethanolamine or a salt thereof in a molar ratio of the cannabinoid and N-acylethanolamine between about 1:0.2 to about 1:2000. 74. A method for preventing or treating pain in a human subject in need thereof, comprising administering to the subject a therapeutically-effective amount of a pharmaceutical composition comprising at least one cannabinoid or a salt thereof, and at least one N-acylethanolamine or a salt thereof, in a molar ratio of the cannabinoid and N-acylethanolamine between about 1:0.2 to about 1:2000, thereby preventing or treating the pain. 75. The method of claim 74 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:0.2 to about 1:5. 76. The method of claim 74 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:0.5 to about 1:0.5 to about 1:2. 77. The method of claim 74 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:15 to about 1:1800. 78. The method of claim 74 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:25 to about 1:450. 79. The method of claim 74 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:50 to about 1:100. 80. The method of claim 74, wherein the at least one cannabinoid is tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), a salt thereof, or any combination thereof. 81. The method of claim 80, wherein the at least one cannabinoid is THC or a salt thereof. 82. The method of claim 74, wherein the pharmaceutical composition comprises about 200-1800 mg of N-acylethanolamine or a salt thereof. 83. The method of claim 82, wherein the pharmaceutical composition comprises about 250 mg, about 500 mg, about 750 mg, about 1000 mg or about 1500 mg of N-acylethanolamine or a salt thereof. 84. The method of claim 74, wherein the at least one N-acylethanolamine is N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, palmitoylisopropylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), a salt thereof, or any combination thereof. 85. The pharmaceutical composition of claim 84, wherein the N-acylethanolamine is PEA or a salt thereof. 86. The method of claim 74 wherein the pharmaceutical composition comprises THC or a salt thereof, and PEA or a salt thereof. 87. The method of claim 74 wherein the pharmaceutical composition comprises about 0.5-10 mg of THC or a salt thereof, and about 200-1800 mg of PEA or a salt thereof. 88. The method of claim 74 wherein the pharmaceutical composition comprises about 2.5-10 mg of THC or a salt thereof and about 250-1000 mg of PEA or a salt thereof. 89. The method of claim 74 wherein the pharmaceutical composition comprises about 2.5 mg, about 5 mg, about 7.5 mg or about 10 mg of THC or a salt thereof, and about 250 mg, about 500 mg, about 750 mg or about 1000 mg of PEA or a salt thereof. 90. The method of claim 74 wherein the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalational, topical, rectal, vaginal, parenteral, intravenous, intramuscular, or subcutaneous administration. 91. The method of claim 90 wherein the pharmaceutical composition is formulated for oral, oral mucosal, nasal, or sublingual administration. 92. The method of claim 74, wherein the administration of the cannabinoid and the N-acylethanolamine is repeated. 93. The method of claim 74, wherein the pain is an acute pain, chronic pain, or neuropathic pain. 94. A method for preventing or treating emesis in a human subject in need thereof, comprising administering to the subject a therapeutically-effective amount of a pharmaceutical composition comprising at least one cannabinoid or a salt thereof, and at least one N-acylethanolamine or a salt thereof, in a molar ratio of the cannabinoid and N-acylethanolamine between about 1:0.2 to about 1:2000, thereby preventing or treating the emesis. 95. The method of claim 94 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:0.2 to about 1:5. 96. The method of claim 94 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:0.5 to about 1:2. 97. The method of claim 94 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:15 to about 1:1800. 98. The method of claim 94 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:25 to about 1:450. 99. The method of claim 94 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:50 to about 1:100. 100. The method of claim 94, wherein the at least one cannabinoid is tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), a salt thereof, or any combination thereof. 101. The method of claim 100, wherein the at least one cannabinoid is THC or a salt thereof. 102. The method of claim 94, wherein the pharmaceutical composition comprises about 200-1800 mg of N-acylethanolamine or a salt thereof. 103. The method of claim 102, wherein the pharmaceutical composition comprises about 250 mg, about 500 mg, about 750 mg, about 1000 mg or about 1500 mg of N-acylethanolamine or a salt thereof. 104. The method of claim 94, wherein the at least one N-acylethanolamine is N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, palmitoylisopropylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), a salt thereof, or any combination thereof. 105. The pharmaceutical composition of claim 104, wherein the N-acylethanolamine is PEA or a salt thereof. 106. The method of claim 94 wherein the pharmaceutical composition comprises THC or a salt thereof, and PEA or a salt thereof. 107. The method of claim 94 wherein the pharmaceutical composition comprises about 0.5-10 mg of THC or a salt thereof, and about 200-1800 mg of PEA or a salt thereof. 108. The method of claim 94 wherein the pharmaceutical composition comprises about 2.5-10 mg of THC or a salt thereof and about 250-1000 mg of PEA or a salt thereof. 109. The method of claim 94 wherein the pharmaceutical composition comprises about 2.5 mg, about 5 mg, about 7.5 mg or about 10 mg of THC or a salt thereof, and about 250 mg, about 500 mg, about 750 mg or about 1000 mg of PEA or a salt thereof. 110. The method of claim 94 wherein the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalational, topical, rectal, vaginal, parenteral, intravenous, intramuscular, or subcutaneous administration. 111. The method of claim 110 wherein the pharmaceutical composition is formulated for oral, oral mucosal, nasal, or sublingual administration. 112. The method of claim 94, wherein the administration of the cannabinoid and the N-acylethanolamine is repeated. 113. A method for preventing or treating at least one side-effect associated with cannabinoid consumption in a human subject in need thereof, comprising administering to the subject a therapeutically-effective amount of a pharmaceutical composition comprising at least one cannabinoid or a salt thereof, and at least one N-acylethanolamine or a salt thereof, in a molar ratio of the cannabinoid and N-acylethanolamine between about 1:0.2 to about 1:2000, thereby preventing or treating the at least one side-effect. 114. The method of claim 113 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:0.2 to about 1:5. 115. The method of claim 113 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:0.5 to about 1:2. 116. The method of claim 113 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:15 to about 1:1800. 117. The method of claim 113 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:25 to about 1:450. 118. The method of claim 113 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:50 to about 1:100. 119. The method of claim 113, wherein the at least one cannabinoid is tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), a salt thereof, or any combination thereof. 120. The method of claim 119, wherein the at least one cannabinoid is THC or a salt thereof. 121. The method of claim 113, wherein the pharmaceutical composition comprises about 200-1800 mg of N-acylethanolamine or a salt thereof. 122. The method of claim 121, wherein the pharmaceutical composition comprises about 250 mg, about 500 mg, about 750 mg, about 1000 mg or about 1500 mg of N-acylethanolamine or a salt thereof. 123. The method of claim 113, wherein the at least one N-acylethanolamine is N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, palmitoylisopropylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), a salt thereof, or any combination thereof. 124. The pharmaceutical composition of claim 123, wherein the N-acylethanolamine is PEA or a salt thereof. 125. The method of claim 113 wherein the pharmaceutical composition comprises THC or a salt thereof, and PEA or a salt thereof. 126. The method of claim 113 wherein the pharmaceutical composition comprises about 0.5-10 mg of THC or a salt thereof, and about 200-1800 mg of PEA or a salt thereof. 127. The method of claim 113 wherein the pharmaceutical composition comprises about 2.5-10 mg of THC or a salt thereof and about 250-1000 mg of PEA or a salt thereof. 128. The method of claim 113 wherein the pharmaceutical composition comprises about 2.5 mg, about 5 mg, about 7.5 mg or about 10 mg of THC or a salt thereof, and about 250 mg, about 500 mg, about 750 mg or about 1000 mg of PEA or a salt thereof. 129. The method of claim 113 wherein the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalational, topical, rectal, vaginal, parenteral, intravenous, intramuscular, or subcutaneous administration. 130. The method of claim 129 wherein the pharmaceutical composition is formulated for oral, oral mucosal, nasal, or sublingual administration. 131. The method of claim 113, wherein the administration of the cannabinoid and the N-acylethanolamine is repeated. 132. The method of claim 113, wherein the side-effect associated with cannabinoid consumption is increased appetite or body-weight gain. 133. The method of claim 113, wherein the side-effect associated with cannabinoid consumption is confusion or disorientation. 134. The method of claim 1B, wherein the side-effect associated with cannabinoid consumption is anxiety. 135. A pharmaceutical composition comprising a therapeutically-effective amount of at least one cannabinoid or a salt thereof, and at least one N-acylethanolamine or a salt thereof, wherein the molar ratio between the cannabinoid and the N-acylethanolamine is between about 1:0.2 to about 1:2000. 136. The pharmaceutical composition of claim 135, wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:0.2 to about 1:5. 137. The pharmaceutical composition of claim 135, wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:0.5 to about 1:2. 138. The pharmaceutical composition of claim 135, wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:15 to about 1:1800. 139. The pharmaceutical composition of claim 135, wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the N-acylethanolamine or a salt thereof is between about 1:25 to about 1:450. 140. The pharmaceutical composition of claim 135, wherein the molar ratio between the cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:50 to about 1:100. 141. The pharmaceutical composition of claim 135, wherein the at least one cannabinoid is selected from tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), a salt thereof, or any combination thereof. 142. The pharmaceutical composition of claim 141, wherein the at least one cannabinoid is THC or a salt thereof. 143. The pharmaceutical composition of claim 135, comprising about 200-1800 mg of N-acylethanolamine or a salt thereof. 144. The pharmaceutical composition of claim 143, comprising about 250 mg, about 500 mg, about 750 mg, about 1000 mg or about 1500 mg of N-acylethanolamine or a salt thereof. 145. The pharmaceutical composition of claim 135, wherein the N-acylethanolamine is selected from the group consisting of N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, palmitoylisopropylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), a salt thereof, or any combination thereof. 146. The pharmaceutical composition of claim 145, wherein the N-acylethanolamine is PEA or a salt thereof. 147. The pharmaceutical composition of claim 135, comprising THC or a salt thereof, and PEA or a salt thereof. 148. The pharmaceutical composition of claim 147, wherein the pharmaceutical composition comprises about 0.5-10 mg of THC or a salt thereof, and about 200-1800 mg of PEA or a salt thereof. 149. The pharmaceutical composition of claim 148, wherein the pharmaceutical composition comprises about 2.5-10 mg of THC or a salt thereof, and about 250-1000 mg of PEA or a salt thereof. 150. The pharmaceutical composition of claim 149, wherein the pharmaceutical composition comprises about 2.5 mg, about 5 mg, about 7.5 mg or about 10 mg THC or a salt thereof, and about 250 mg, about 500 mg, about 750 mg or about 1000 mg PEA or a salt thereof. 151. The pharmaceutical composition of claim 135, wherein the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalational, topical, rectal, vaginal, parenteral, intravenous, intramuscular, or subcutaneous administration. 152. The pharmaceutical composition of claim 151, wherein the pharmaceutical composition is formulated for oral, oral mucosal, nasal, or sublingual administration. 153. The pharmaceutical composition of claim 135, wherein the therapeutic potency of the pharmaceutical composition is increased compared to the same pharmaceutical composition without the N-acylethanolamine. 154. The pharmaceutical composition of claim 135, wherein the required therapeutic dosage of the cannabinoid in the pharmaceutical composition is decreased compared to the same pharmaceutical composition without the N-acylethanolamine. 155. The pharmaceutical composition of claim 135, wherein at least one of the side-effects of the cannabinoid is reduced compared to the same pharmaceutical composition without the N-acylethanolamine. 156. The pharmaceutical composition of claim 135, wherein the therapeutic window of the cannabinoid is extended compared to the same pharmaceutical composition without the N-acylethanolamine. | The present invention provides pharmaceutical compositions comprising cannabinoids and N-acylethanolamines, and methods for their use in preventing and treating a variety of cannabinoid-treatable conditions.1-48. (canceled) 49. A method for preventing or treating at least one symptom of Tourette syndrome in a human subject in need thereof, comprising administering to the subject a therapeutically-effective amount of a pharmaceutical composition comprising at least one cannabinoid or a salt thereof, and at least one N-acylethanolamine or a salt thereof, in a molar ratio of the cannabinoid and N-acylethanolamine between about 1:0.2 to about 1:2000, thereby preventing or treating the symptom. 50. The method of claim 49 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:0.2 to about 1:5. 51. The method of claim 49 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:0.5 to about 1:2. 52. The method of claim 49 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:15 to about 1:1800. 53. The method of claim 49 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:25 to about 1:450. 54. The method of claim 49 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:50 to about 1:100. 55. The method of claim 49, wherein the at least one cannabinoid is tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), a salt thereof, or any combination thereof. 56. The method of claim 55, wherein the at least one cannabinoid is THC or a salt thereof. 57. The method of claim 49, wherein the pharmaceutical composition comprises about 200-1800 mg of N-acylethanolamine or a salt thereof. 58. The method of claim 57, wherein the pharmaceutical composition comprises about 250 mg, about 500 mg, about 750 mg, about 1000 mg or about 1500 mg of N-acylethanolamine or a salt thereof. 59. The method of claim 49, wherein the at least one N-acylethanolamine is N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, palmitoylisopropylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), a salt thereof, or any combination thereof. 60. The pharmaceutical composition of claim 59, wherein the N-acylethanolamine is PEA or a salt thereof. 61. The method of claim 49 wherein the pharmaceutical composition comprises THC or a salt thereof, and PEA or a salt thereof. 62. The method of claim 49 wherein the pharmaceutical composition comprises about 0.5-10 mg of THC or a salt thereof, and about 200-1800 mg of PEA or a salt thereof. 63. The method of claim 49 wherein the pharmaceutical composition comprises about 2.5-10 mg of THC or a salt thereof and about 250-1000 mg of PEA or a salt thereof. 64. The method of claim 49 wherein the pharmaceutical composition comprises about 2.5 mg, about 5 mg, about 7.5 mg or about 10 mg of THC or a salt thereof, and about 250 mg, about 500 mg, about 750 mg or about 1000 mg of PEA or a salt thereof. 65. The method of claim 49 wherein the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalational, topical, rectal, vaginal, parenteral, intravenous, intramuscular, or subcutaneous administration. 66. The method of claim 65 wherein the pharmaceutical composition is formulated for oral, oral mucosal, nasal, or sublingual administration. 67. The method of claim 49, wherein the administration of the cannabinoid and the N-acylethanolamine is repeated. 68. The method of claim 67, wherein the administration of the cannabinoid and the N-acylethanolamine is repeated until a beneficial change in the condition of the subject according to the Yale Global Tic Severity Scale (YGTSS) is achieved compared to the condition of the subject prior to treatment. 69. The method of claim 67, wherein the administration of the cannabinoid and the N-acylethanolamine is repeated until a beneficial change in the condition of the subject according to at least one scale selected from the group consisting of (i) the Clinician Global Impression scale (CGIS), (ii) the Gilles de la Tourette Syndrome-Quality Of Life scale (GTS-QOL) (iii) the Tourette Syndrome Symptom List (TSSL) (iv) the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) (v) the ADHD Rating Scale-IV (ADHD-RS) and (vi) the Hamilton Anxiety Rating Scale (HAM-A), is achieved compared to the condition of the subject prior to treatment. 70. The method of claim 49, wherein the Tourette syndrome is classified as moderate to severe Tourette syndrome. 71. The method of claim 49, wherein the symptom is tics. 72. A dosage unit comprising a therapeutically-effective amount of a pharmaceutical composition comprising at least one cannabinoid or a salt thereof, and at least one N-acylethanolamine or a salt thereof in a molar ratio of the cannabinoid and N-acylethanolamine between about 1:0.2 to about 1:2000. 73. A dosage unit consisting essentially of a therapeutically-effective amount of at least one cannabinoid or a salt thereof, and at least one N-acylethanolamine or a salt thereof in a molar ratio of the cannabinoid and N-acylethanolamine between about 1:0.2 to about 1:2000. 74. A method for preventing or treating pain in a human subject in need thereof, comprising administering to the subject a therapeutically-effective amount of a pharmaceutical composition comprising at least one cannabinoid or a salt thereof, and at least one N-acylethanolamine or a salt thereof, in a molar ratio of the cannabinoid and N-acylethanolamine between about 1:0.2 to about 1:2000, thereby preventing or treating the pain. 75. The method of claim 74 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:0.2 to about 1:5. 76. The method of claim 74 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:0.5 to about 1:0.5 to about 1:2. 77. The method of claim 74 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:15 to about 1:1800. 78. The method of claim 74 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:25 to about 1:450. 79. The method of claim 74 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:50 to about 1:100. 80. The method of claim 74, wherein the at least one cannabinoid is tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), a salt thereof, or any combination thereof. 81. The method of claim 80, wherein the at least one cannabinoid is THC or a salt thereof. 82. The method of claim 74, wherein the pharmaceutical composition comprises about 200-1800 mg of N-acylethanolamine or a salt thereof. 83. The method of claim 82, wherein the pharmaceutical composition comprises about 250 mg, about 500 mg, about 750 mg, about 1000 mg or about 1500 mg of N-acylethanolamine or a salt thereof. 84. The method of claim 74, wherein the at least one N-acylethanolamine is N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, palmitoylisopropylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), a salt thereof, or any combination thereof. 85. The pharmaceutical composition of claim 84, wherein the N-acylethanolamine is PEA or a salt thereof. 86. The method of claim 74 wherein the pharmaceutical composition comprises THC or a salt thereof, and PEA or a salt thereof. 87. The method of claim 74 wherein the pharmaceutical composition comprises about 0.5-10 mg of THC or a salt thereof, and about 200-1800 mg of PEA or a salt thereof. 88. The method of claim 74 wherein the pharmaceutical composition comprises about 2.5-10 mg of THC or a salt thereof and about 250-1000 mg of PEA or a salt thereof. 89. The method of claim 74 wherein the pharmaceutical composition comprises about 2.5 mg, about 5 mg, about 7.5 mg or about 10 mg of THC or a salt thereof, and about 250 mg, about 500 mg, about 750 mg or about 1000 mg of PEA or a salt thereof. 90. The method of claim 74 wherein the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalational, topical, rectal, vaginal, parenteral, intravenous, intramuscular, or subcutaneous administration. 91. The method of claim 90 wherein the pharmaceutical composition is formulated for oral, oral mucosal, nasal, or sublingual administration. 92. The method of claim 74, wherein the administration of the cannabinoid and the N-acylethanolamine is repeated. 93. The method of claim 74, wherein the pain is an acute pain, chronic pain, or neuropathic pain. 94. A method for preventing or treating emesis in a human subject in need thereof, comprising administering to the subject a therapeutically-effective amount of a pharmaceutical composition comprising at least one cannabinoid or a salt thereof, and at least one N-acylethanolamine or a salt thereof, in a molar ratio of the cannabinoid and N-acylethanolamine between about 1:0.2 to about 1:2000, thereby preventing or treating the emesis. 95. The method of claim 94 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:0.2 to about 1:5. 96. The method of claim 94 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:0.5 to about 1:2. 97. The method of claim 94 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:15 to about 1:1800. 98. The method of claim 94 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:25 to about 1:450. 99. The method of claim 94 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:50 to about 1:100. 100. The method of claim 94, wherein the at least one cannabinoid is tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), a salt thereof, or any combination thereof. 101. The method of claim 100, wherein the at least one cannabinoid is THC or a salt thereof. 102. The method of claim 94, wherein the pharmaceutical composition comprises about 200-1800 mg of N-acylethanolamine or a salt thereof. 103. The method of claim 102, wherein the pharmaceutical composition comprises about 250 mg, about 500 mg, about 750 mg, about 1000 mg or about 1500 mg of N-acylethanolamine or a salt thereof. 104. The method of claim 94, wherein the at least one N-acylethanolamine is N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, palmitoylisopropylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), a salt thereof, or any combination thereof. 105. The pharmaceutical composition of claim 104, wherein the N-acylethanolamine is PEA or a salt thereof. 106. The method of claim 94 wherein the pharmaceutical composition comprises THC or a salt thereof, and PEA or a salt thereof. 107. The method of claim 94 wherein the pharmaceutical composition comprises about 0.5-10 mg of THC or a salt thereof, and about 200-1800 mg of PEA or a salt thereof. 108. The method of claim 94 wherein the pharmaceutical composition comprises about 2.5-10 mg of THC or a salt thereof and about 250-1000 mg of PEA or a salt thereof. 109. The method of claim 94 wherein the pharmaceutical composition comprises about 2.5 mg, about 5 mg, about 7.5 mg or about 10 mg of THC or a salt thereof, and about 250 mg, about 500 mg, about 750 mg or about 1000 mg of PEA or a salt thereof. 110. The method of claim 94 wherein the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalational, topical, rectal, vaginal, parenteral, intravenous, intramuscular, or subcutaneous administration. 111. The method of claim 110 wherein the pharmaceutical composition is formulated for oral, oral mucosal, nasal, or sublingual administration. 112. The method of claim 94, wherein the administration of the cannabinoid and the N-acylethanolamine is repeated. 113. A method for preventing or treating at least one side-effect associated with cannabinoid consumption in a human subject in need thereof, comprising administering to the subject a therapeutically-effective amount of a pharmaceutical composition comprising at least one cannabinoid or a salt thereof, and at least one N-acylethanolamine or a salt thereof, in a molar ratio of the cannabinoid and N-acylethanolamine between about 1:0.2 to about 1:2000, thereby preventing or treating the at least one side-effect. 114. The method of claim 113 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:0.2 to about 1:5. 115. The method of claim 113 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:0.5 to about 1:2. 116. The method of claim 113 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:15 to about 1:1800. 117. The method of claim 113 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:25 to about 1:450. 118. The method of claim 113 wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:50 to about 1:100. 119. The method of claim 113, wherein the at least one cannabinoid is tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), a salt thereof, or any combination thereof. 120. The method of claim 119, wherein the at least one cannabinoid is THC or a salt thereof. 121. The method of claim 113, wherein the pharmaceutical composition comprises about 200-1800 mg of N-acylethanolamine or a salt thereof. 122. The method of claim 121, wherein the pharmaceutical composition comprises about 250 mg, about 500 mg, about 750 mg, about 1000 mg or about 1500 mg of N-acylethanolamine or a salt thereof. 123. The method of claim 113, wherein the at least one N-acylethanolamine is N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, palmitoylisopropylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), a salt thereof, or any combination thereof. 124. The pharmaceutical composition of claim 123, wherein the N-acylethanolamine is PEA or a salt thereof. 125. The method of claim 113 wherein the pharmaceutical composition comprises THC or a salt thereof, and PEA or a salt thereof. 126. The method of claim 113 wherein the pharmaceutical composition comprises about 0.5-10 mg of THC or a salt thereof, and about 200-1800 mg of PEA or a salt thereof. 127. The method of claim 113 wherein the pharmaceutical composition comprises about 2.5-10 mg of THC or a salt thereof and about 250-1000 mg of PEA or a salt thereof. 128. The method of claim 113 wherein the pharmaceutical composition comprises about 2.5 mg, about 5 mg, about 7.5 mg or about 10 mg of THC or a salt thereof, and about 250 mg, about 500 mg, about 750 mg or about 1000 mg of PEA or a salt thereof. 129. The method of claim 113 wherein the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalational, topical, rectal, vaginal, parenteral, intravenous, intramuscular, or subcutaneous administration. 130. The method of claim 129 wherein the pharmaceutical composition is formulated for oral, oral mucosal, nasal, or sublingual administration. 131. The method of claim 113, wherein the administration of the cannabinoid and the N-acylethanolamine is repeated. 132. The method of claim 113, wherein the side-effect associated with cannabinoid consumption is increased appetite or body-weight gain. 133. The method of claim 113, wherein the side-effect associated with cannabinoid consumption is confusion or disorientation. 134. The method of claim 1B, wherein the side-effect associated with cannabinoid consumption is anxiety. 135. A pharmaceutical composition comprising a therapeutically-effective amount of at least one cannabinoid or a salt thereof, and at least one N-acylethanolamine or a salt thereof, wherein the molar ratio between the cannabinoid and the N-acylethanolamine is between about 1:0.2 to about 1:2000. 136. The pharmaceutical composition of claim 135, wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:0.2 to about 1:5. 137. The pharmaceutical composition of claim 135, wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:0.5 to about 1:2. 138. The pharmaceutical composition of claim 135, wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:15 to about 1:1800. 139. The pharmaceutical composition of claim 135, wherein the molar ratio between the at least one cannabinoid or a salt thereof, and the N-acylethanolamine or a salt thereof is between about 1:25 to about 1:450. 140. The pharmaceutical composition of claim 135, wherein the molar ratio between the cannabinoid or a salt thereof, and the at least one N-acylethanolamine or a salt thereof is between about 1:50 to about 1:100. 141. The pharmaceutical composition of claim 135, wherein the at least one cannabinoid is selected from tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), a salt thereof, or any combination thereof. 142. The pharmaceutical composition of claim 141, wherein the at least one cannabinoid is THC or a salt thereof. 143. The pharmaceutical composition of claim 135, comprising about 200-1800 mg of N-acylethanolamine or a salt thereof. 144. The pharmaceutical composition of claim 143, comprising about 250 mg, about 500 mg, about 750 mg, about 1000 mg or about 1500 mg of N-acylethanolamine or a salt thereof. 145. The pharmaceutical composition of claim 135, wherein the N-acylethanolamine is selected from the group consisting of N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, palmitoylisopropylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), a salt thereof, or any combination thereof. 146. The pharmaceutical composition of claim 145, wherein the N-acylethanolamine is PEA or a salt thereof. 147. The pharmaceutical composition of claim 135, comprising THC or a salt thereof, and PEA or a salt thereof. 148. The pharmaceutical composition of claim 147, wherein the pharmaceutical composition comprises about 0.5-10 mg of THC or a salt thereof, and about 200-1800 mg of PEA or a salt thereof. 149. The pharmaceutical composition of claim 148, wherein the pharmaceutical composition comprises about 2.5-10 mg of THC or a salt thereof, and about 250-1000 mg of PEA or a salt thereof. 150. The pharmaceutical composition of claim 149, wherein the pharmaceutical composition comprises about 2.5 mg, about 5 mg, about 7.5 mg or about 10 mg THC or a salt thereof, and about 250 mg, about 500 mg, about 750 mg or about 1000 mg PEA or a salt thereof. 151. The pharmaceutical composition of claim 135, wherein the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalational, topical, rectal, vaginal, parenteral, intravenous, intramuscular, or subcutaneous administration. 152. The pharmaceutical composition of claim 151, wherein the pharmaceutical composition is formulated for oral, oral mucosal, nasal, or sublingual administration. 153. The pharmaceutical composition of claim 135, wherein the therapeutic potency of the pharmaceutical composition is increased compared to the same pharmaceutical composition without the N-acylethanolamine. 154. The pharmaceutical composition of claim 135, wherein the required therapeutic dosage of the cannabinoid in the pharmaceutical composition is decreased compared to the same pharmaceutical composition without the N-acylethanolamine. 155. The pharmaceutical composition of claim 135, wherein at least one of the side-effects of the cannabinoid is reduced compared to the same pharmaceutical composition without the N-acylethanolamine. 156. The pharmaceutical composition of claim 135, wherein the therapeutic window of the cannabinoid is extended compared to the same pharmaceutical composition without the N-acylethanolamine. | 1,600 |
892 | 12,688,193 | 1,639 | A method of determining a number of a solution constituent includes introducing a first number of solution constituents to a first test location, establishing a first binding environment for the introduced first number of solution constituents, creating a first residual number of solution constituents by binding a first plurality of solution constituents, establishing a second binding environment for the first residual number of solution constituents, creating a second residual number of solution constituents by binding a second plurality of solution constituents from the first residual number of solution constituents, obtaining a first signal associated with the bound first plurality of solution constituents, obtaining a second signal associated with the bound second plurality of solution constituents, and determining a second number of a constituent of interest based upon the obtained first signal and the obtained second signal. | 1. A method of determining a number of a solution constituent comprising:
introducing a first number of solution constituents to a first test location; creating a first residual number of solution constituents by binding a first plurality of solution constituents at the first test location; creating a second residual number of solution constituents by binding a second plurality of solution constituents from the first residual number of solution constituents; obtaining a first signal associated with the bound first plurality of solution constituents; obtaining a second signal associated with the bound second plurality of solution constituents; and determining a second number of a first solution constituent of interest based upon the obtained first signal and the obtained second signal. 2. The method of claim 1, further comprising:
transporting the first residual number of solution constituents from the first test site to a second test site. 3. The method of claim 2, wherein transporting the first residual number of solution constituents comprises:
transporting a plurality of analytes bound to a respective plurality of capture probes from the first test site to a second test site. 4. The method of claim 3, further comprising:
releasing the transported plurality of bound analytes from the respective plurality of capture probes. 5. The method of claim 4, wherein releasing the transported plurality of bound analytes comprises:
releasing the transported plurality of bound analytes by modifying the temperature of the transported plurality of bound analytes. 6. The method of claim 4, wherein releasing the transported plurality of bound analytes comprises:
releasing the transported plurality of bound analytes by exposing the transported plurality of bound analytes to a dehybridation solution. 7. The method of claim 2, wherein transporting the first residual number of solution constituents comprises:
transporting the first residual number of solution constituents using a microfluidics technology. 8. The method of claim 2, wherein transporting the first residual number of solution constituents comprises:
transporting the first residual number of solution constituents using a capillary flow. 9. The method of claim 2, wherein transporting the first residual number of solution constituents comprises:
transporting the first residual number of solution constituents using magnetic beads. 10. The method of claim 2, wherein transporting the first residual number of solution constituents comprises:
transporting the first residual number of solution constituents by modifying an electrical charge acting upon the first residual number of solution constituents. 11. The method of claim 1, further comprising:
creating a third residual number of solution constituents by binding a third plurality of solution constituents from the second residual number of solution constituents; obtaining a third signal associated with the bound third plurality of solution constituents; and determining a third number of a second solution constituent of interest based upon the obtained first signal, the obtained second signal, and the obtained third signal. 12. A method of determining the number of molecules involved in an analyte capture system comprising:
introducing a first number of solution constituents to a first test location; creating a first residual number of solution constituents by binding a first plurality of solution constituents to a first percentage of a plurality of capture probes at the first test location; creating a second residual number of solution constituents by binding a second plurality of solution constituents from the first residual number of solution constituents to a second percentage of a plurality of capture probes at a second test location; obtaining a first signal associated with the bound first plurality of solution constituents; obtaining a second signal associated with the bound second plurality of solution constituents; and determining a second number of a molecule of interest based upon the obtained first signal and the obtained second signal. 13. The method of claim 12, wherein the first plurality of solution constituents consist of the molecule of interest. 14. The method of claim 12, wherein the plurality of capture probes consist of the molecule of interest. 15. A successive sampling system comprising:
a plurality of first capture probes; a plurality of second capture probes; a transport system for moving a first number of analytes in a solution from a location proximate the plurality of first capture probes to a location proximate the plurality of second capture probes; a memory in which command instructions are stored; and a processor configured to execute the command instructions to
obtain a first signal associated with a first plurality of bound first capture probes,
obtain a second signal associated with a second plurality of bound second capture probes, and
determine a first number of a first constituent of interest based upon the obtained first signal and the obtained second signal. 16. The system of claim 15, further comprising:
a plurality of third capture probes, wherein the processor is further configured to execute the command instructions to
obtain a third signal associated with a third plurality of bound third capture probes, and
determine a second number of a second constituent of interest based upon the obtained first signal, the obtained second signal, and the obtained third signal. 17. The system of claim 15, wherein the first constituent of interest is a capture probe. 18. The system of claim 15, wherein the first constituent of interest is an analyte within the solution. | A method of determining a number of a solution constituent includes introducing a first number of solution constituents to a first test location, establishing a first binding environment for the introduced first number of solution constituents, creating a first residual number of solution constituents by binding a first plurality of solution constituents, establishing a second binding environment for the first residual number of solution constituents, creating a second residual number of solution constituents by binding a second plurality of solution constituents from the first residual number of solution constituents, obtaining a first signal associated with the bound first plurality of solution constituents, obtaining a second signal associated with the bound second plurality of solution constituents, and determining a second number of a constituent of interest based upon the obtained first signal and the obtained second signal.1. A method of determining a number of a solution constituent comprising:
introducing a first number of solution constituents to a first test location; creating a first residual number of solution constituents by binding a first plurality of solution constituents at the first test location; creating a second residual number of solution constituents by binding a second plurality of solution constituents from the first residual number of solution constituents; obtaining a first signal associated with the bound first plurality of solution constituents; obtaining a second signal associated with the bound second plurality of solution constituents; and determining a second number of a first solution constituent of interest based upon the obtained first signal and the obtained second signal. 2. The method of claim 1, further comprising:
transporting the first residual number of solution constituents from the first test site to a second test site. 3. The method of claim 2, wherein transporting the first residual number of solution constituents comprises:
transporting a plurality of analytes bound to a respective plurality of capture probes from the first test site to a second test site. 4. The method of claim 3, further comprising:
releasing the transported plurality of bound analytes from the respective plurality of capture probes. 5. The method of claim 4, wherein releasing the transported plurality of bound analytes comprises:
releasing the transported plurality of bound analytes by modifying the temperature of the transported plurality of bound analytes. 6. The method of claim 4, wherein releasing the transported plurality of bound analytes comprises:
releasing the transported plurality of bound analytes by exposing the transported plurality of bound analytes to a dehybridation solution. 7. The method of claim 2, wherein transporting the first residual number of solution constituents comprises:
transporting the first residual number of solution constituents using a microfluidics technology. 8. The method of claim 2, wherein transporting the first residual number of solution constituents comprises:
transporting the first residual number of solution constituents using a capillary flow. 9. The method of claim 2, wherein transporting the first residual number of solution constituents comprises:
transporting the first residual number of solution constituents using magnetic beads. 10. The method of claim 2, wherein transporting the first residual number of solution constituents comprises:
transporting the first residual number of solution constituents by modifying an electrical charge acting upon the first residual number of solution constituents. 11. The method of claim 1, further comprising:
creating a third residual number of solution constituents by binding a third plurality of solution constituents from the second residual number of solution constituents; obtaining a third signal associated with the bound third plurality of solution constituents; and determining a third number of a second solution constituent of interest based upon the obtained first signal, the obtained second signal, and the obtained third signal. 12. A method of determining the number of molecules involved in an analyte capture system comprising:
introducing a first number of solution constituents to a first test location; creating a first residual number of solution constituents by binding a first plurality of solution constituents to a first percentage of a plurality of capture probes at the first test location; creating a second residual number of solution constituents by binding a second plurality of solution constituents from the first residual number of solution constituents to a second percentage of a plurality of capture probes at a second test location; obtaining a first signal associated with the bound first plurality of solution constituents; obtaining a second signal associated with the bound second plurality of solution constituents; and determining a second number of a molecule of interest based upon the obtained first signal and the obtained second signal. 13. The method of claim 12, wherein the first plurality of solution constituents consist of the molecule of interest. 14. The method of claim 12, wherein the plurality of capture probes consist of the molecule of interest. 15. A successive sampling system comprising:
a plurality of first capture probes; a plurality of second capture probes; a transport system for moving a first number of analytes in a solution from a location proximate the plurality of first capture probes to a location proximate the plurality of second capture probes; a memory in which command instructions are stored; and a processor configured to execute the command instructions to
obtain a first signal associated with a first plurality of bound first capture probes,
obtain a second signal associated with a second plurality of bound second capture probes, and
determine a first number of a first constituent of interest based upon the obtained first signal and the obtained second signal. 16. The system of claim 15, further comprising:
a plurality of third capture probes, wherein the processor is further configured to execute the command instructions to
obtain a third signal associated with a third plurality of bound third capture probes, and
determine a second number of a second constituent of interest based upon the obtained first signal, the obtained second signal, and the obtained third signal. 17. The system of claim 15, wherein the first constituent of interest is a capture probe. 18. The system of claim 15, wherein the first constituent of interest is an analyte within the solution. | 1,600 |
893 | 13,945,438 | 1,619 | The invention relates to an aqueous transparent oil-in-water emulsion comprising a carotenoid and a process for producing said emulsion. | 1. An aqueous transparent oil-in-water emulsion comprising an emulsified carotenoid in a concentration of 0.025-2000 ppm. 2. The emulsion according to claim 1 whereby the carotenoid is selected from the group consisting of: cantaxanthin, astaxanthin, lutein, zeaxanthin, beta-zeacaroten, lycopene, apocarotenal, bixin, paprika olioresin, capsanthin and capsorubin, preferably apocarotenal, more preferably beta-apo-8-carotenal. 3. The emulsion according to claim 1 with a NTU (Turbidity) value at a concentration of 5 ppm of carotenoid of 1-35 NTU. 4. The emulsion according to claim 1 with a colour intensity value (E 1/1) of 140-280, whereby the colour intensity value (E 1/1) is defined as the absorbance of light at maximum absorbance going through 1 cm cuvette containing 1% carotene dissolved in organic solvent. 5. The emulsion according to claim 1 with an oil droplets size measured with dynamic light scattering of 50-400 nm. 6. The emulsion according to claim 1 comprising a triacylglycerol oil, selected from the group consisting of: medium-chain triacylglycerol (MCT) oil, olive oil, sunflower oil, peanut oil, soy oil and vegetable oil, preferably MCT oil, in a concentration of 0.1-150 ppm. 7. The emulsion according to claim 1 comprising modified starch and/or at least one surface active protein, in a concentration of 0.5-600 ppm with a molecular weight MW-distribution of 10,000-2,000,000 g/mol. 8. The emulsion according to claim 1 comprising at least one carbohydrate selected from the group consisting of: mono-, di- and oligosaccharides, glucose-syrup, maltose and trehalose, said at least one carbohydrate having a DE between 20 and 50 in a concentration of 0.5-10000 ppm. 9. The emulsion according to claim 1 comprising at least one water soluble antioxidant selected from the group consisting of:
natural compounds that are active as antioxidants by comprising a phenolic OH-group in their chemical structure;
caffeic acid, ferulic acid, tyrosol, hydroxytyrosol, cinnamic acid, chlorogenic acid, coumarin, coumarinic acid, sinapic acid, cinnamic acid, chicoric acid, and esters of any of these compounds with C1-C20;
extracts of plants rich in at least one of the above compounds;
rosmarinic acid, hydroxytyrosol;
extracts from common spices;
flavons, preferably extracted from plants such as tea or any other plant that comprising catechin or epicatechin or derivatives;
extracts from plants such as tea, olives, pears, apples comprising one or more of the above mentioned compounds;
sodium ascorbate, polyphenole, Teanova 80, glutathione, lipoic acid, catechin, punicalagin, xanthone, benzotropolones, preferably sodium ascorbate, whereby the water soluble antioxidant is in a concentration of 0.001-60 ppm. 10. The emulsion according to claim 1 comprising an oil soluble antioxidant, selected from the group consisting of:
ethoxyquin,
hindered phenolic antioxidants, such as t-butylhydroxytoluol, t-butylhydroxyanisol, t-butylhydroxyquinone;
Vitamin A, retinoic acid and its esters with C1-C20;
Vitamin D2 and D3;
alpha, beta, gamma, and delta Tocopherol or mixtures comprising at least two of the tocopherols;
alpha, beta, gamma, and delta Tocotrienols or mixtures comprising at least two of the tocotrienols;
natural extracts comprising at least one of the above compounds,
phenolic diterpenes such as Carnosol, Carnosic acid;
derivatives of cinnamic acid like 2-ethoxyethyl p-methoxycinnamate, ethylhexyl p-methoxycinnamate, 2-ethylhexyl 4-methoxycinnamate, methyl diisopropylcinnamate, isoamyl 4-methoxycinnamate, diethanolamin 4-methoxycinnamate and
LC-gallates, Eugenol, Thymol,
whereby the oil soluble antioxidant is in a concentration of 0.001-60 ppm. 11. The emulsion according to claim 1 whereby the carotenoid has an isomerized, trans-isomer content between 30 and 100%. 12. A process for manufacturing the emulsion according to claim 1 comprising the following steps:
a) manufacturing a solution comprising modified starch and/or at least one surface active protein in a concentration of 0.7-70%, at least one sugar in a concentration of 0.001-80%, and water, and mixing the components,
b) manufacturing a solution by mixing at least one carotenoid in a concentration of 0.1-15%, in triacylglycerol oil in a concentration of 1-30% and melting the dispersed carotenoid at a temperature of 100-200° C.,
c) introducing the solution of step b) into the solution of step a),
d) performing at least one step of pre-emulsification by passing the mixture of step c) through a rotator/stator mixer,
e) performing at least one step of high pressure homogenization,
f) spray drying the emulsion of step e) to obtain a powder,
g-1) manufacturing an emulsion by introducing the powder of step f) in water;
whereby the percent are weight percent referring to the emulsion of step c) to e). 13. A process for manufacturing an oil-in-water emulsion comprising an emulsified carotenoid comprising the following steps:
a) manufacturing a solution comprising modified starch and/or at least one surface active protein in a concentration of 0.7-70%, at least one carbohydrate in a concentration of 0.001-80%, and water, and mixing the components, b) manufacturing a solution by mixing at least one carotenoid in a concentration of 0.1-15% in triacylglycerol oil in a concentration of 1-30% and melting the dispersed carotenoid at a temperature of 100-200° C., c) introducing the solution of step b) into the solution of step a), d) performing at least one step of pre-emulsification by passing the mixture of step c) through a rotator/stator mixer, e) performing at least one step, preferably two steps of high pressure homogenization, whereby the percent are weight percent referring to the emulsion of step c) to e); f) spray drying the emulsion of step e) to obtain a powder, and g-2) manufacturing an emulsion by introducing the powder of step f) in water in a concentration of 5%-70%, whereby the percent are weight percent referring to the concentration of the powder according to step f) in water. 14. The process of claim 12 comprising one or more of the alternatives comprising:
mixing the carbohydrate into the emulsion in step c) or d)
adding the water soluble antioxidant after step c), d) or e),
adding the oil soluble antioxidant in step a), c) or d). 15. A powder comprising a carotenoid made by the process according to step a) to f) of claim 12. 16. An oil-in-water emulsion comprising a carotenoid made by the process according to step a) to g-2) of claim 13. 17. A colorant, preferably a natural or nature identical colorant in food, feed, pharmaceutical preparations, cosmetic products, and/or dermal products comprising the powder of claim 15. 18. A method for replacing azo dyes comprising utilizing the powder of claim 15 as a colorant in food, feed, pharmaceutical preparations, cosmetic products and/or dermal products. 19. A colorant in food, feed, pharmaceutical preparations, cosmetic products, and/or dermal products, comprising the oil-in-water emulsion of claim 16. 20. A method for replacing azo dyes comprising utilizing the oil-in-water emulsion of claim 16 as a colorant in food, feed, pharmaceutical preparations, cosmetic products, and/or dermal products. | The invention relates to an aqueous transparent oil-in-water emulsion comprising a carotenoid and a process for producing said emulsion.1. An aqueous transparent oil-in-water emulsion comprising an emulsified carotenoid in a concentration of 0.025-2000 ppm. 2. The emulsion according to claim 1 whereby the carotenoid is selected from the group consisting of: cantaxanthin, astaxanthin, lutein, zeaxanthin, beta-zeacaroten, lycopene, apocarotenal, bixin, paprika olioresin, capsanthin and capsorubin, preferably apocarotenal, more preferably beta-apo-8-carotenal. 3. The emulsion according to claim 1 with a NTU (Turbidity) value at a concentration of 5 ppm of carotenoid of 1-35 NTU. 4. The emulsion according to claim 1 with a colour intensity value (E 1/1) of 140-280, whereby the colour intensity value (E 1/1) is defined as the absorbance of light at maximum absorbance going through 1 cm cuvette containing 1% carotene dissolved in organic solvent. 5. The emulsion according to claim 1 with an oil droplets size measured with dynamic light scattering of 50-400 nm. 6. The emulsion according to claim 1 comprising a triacylglycerol oil, selected from the group consisting of: medium-chain triacylglycerol (MCT) oil, olive oil, sunflower oil, peanut oil, soy oil and vegetable oil, preferably MCT oil, in a concentration of 0.1-150 ppm. 7. The emulsion according to claim 1 comprising modified starch and/or at least one surface active protein, in a concentration of 0.5-600 ppm with a molecular weight MW-distribution of 10,000-2,000,000 g/mol. 8. The emulsion according to claim 1 comprising at least one carbohydrate selected from the group consisting of: mono-, di- and oligosaccharides, glucose-syrup, maltose and trehalose, said at least one carbohydrate having a DE between 20 and 50 in a concentration of 0.5-10000 ppm. 9. The emulsion according to claim 1 comprising at least one water soluble antioxidant selected from the group consisting of:
natural compounds that are active as antioxidants by comprising a phenolic OH-group in their chemical structure;
caffeic acid, ferulic acid, tyrosol, hydroxytyrosol, cinnamic acid, chlorogenic acid, coumarin, coumarinic acid, sinapic acid, cinnamic acid, chicoric acid, and esters of any of these compounds with C1-C20;
extracts of plants rich in at least one of the above compounds;
rosmarinic acid, hydroxytyrosol;
extracts from common spices;
flavons, preferably extracted from plants such as tea or any other plant that comprising catechin or epicatechin or derivatives;
extracts from plants such as tea, olives, pears, apples comprising one or more of the above mentioned compounds;
sodium ascorbate, polyphenole, Teanova 80, glutathione, lipoic acid, catechin, punicalagin, xanthone, benzotropolones, preferably sodium ascorbate, whereby the water soluble antioxidant is in a concentration of 0.001-60 ppm. 10. The emulsion according to claim 1 comprising an oil soluble antioxidant, selected from the group consisting of:
ethoxyquin,
hindered phenolic antioxidants, such as t-butylhydroxytoluol, t-butylhydroxyanisol, t-butylhydroxyquinone;
Vitamin A, retinoic acid and its esters with C1-C20;
Vitamin D2 and D3;
alpha, beta, gamma, and delta Tocopherol or mixtures comprising at least two of the tocopherols;
alpha, beta, gamma, and delta Tocotrienols or mixtures comprising at least two of the tocotrienols;
natural extracts comprising at least one of the above compounds,
phenolic diterpenes such as Carnosol, Carnosic acid;
derivatives of cinnamic acid like 2-ethoxyethyl p-methoxycinnamate, ethylhexyl p-methoxycinnamate, 2-ethylhexyl 4-methoxycinnamate, methyl diisopropylcinnamate, isoamyl 4-methoxycinnamate, diethanolamin 4-methoxycinnamate and
LC-gallates, Eugenol, Thymol,
whereby the oil soluble antioxidant is in a concentration of 0.001-60 ppm. 11. The emulsion according to claim 1 whereby the carotenoid has an isomerized, trans-isomer content between 30 and 100%. 12. A process for manufacturing the emulsion according to claim 1 comprising the following steps:
a) manufacturing a solution comprising modified starch and/or at least one surface active protein in a concentration of 0.7-70%, at least one sugar in a concentration of 0.001-80%, and water, and mixing the components,
b) manufacturing a solution by mixing at least one carotenoid in a concentration of 0.1-15%, in triacylglycerol oil in a concentration of 1-30% and melting the dispersed carotenoid at a temperature of 100-200° C.,
c) introducing the solution of step b) into the solution of step a),
d) performing at least one step of pre-emulsification by passing the mixture of step c) through a rotator/stator mixer,
e) performing at least one step of high pressure homogenization,
f) spray drying the emulsion of step e) to obtain a powder,
g-1) manufacturing an emulsion by introducing the powder of step f) in water;
whereby the percent are weight percent referring to the emulsion of step c) to e). 13. A process for manufacturing an oil-in-water emulsion comprising an emulsified carotenoid comprising the following steps:
a) manufacturing a solution comprising modified starch and/or at least one surface active protein in a concentration of 0.7-70%, at least one carbohydrate in a concentration of 0.001-80%, and water, and mixing the components, b) manufacturing a solution by mixing at least one carotenoid in a concentration of 0.1-15% in triacylglycerol oil in a concentration of 1-30% and melting the dispersed carotenoid at a temperature of 100-200° C., c) introducing the solution of step b) into the solution of step a), d) performing at least one step of pre-emulsification by passing the mixture of step c) through a rotator/stator mixer, e) performing at least one step, preferably two steps of high pressure homogenization, whereby the percent are weight percent referring to the emulsion of step c) to e); f) spray drying the emulsion of step e) to obtain a powder, and g-2) manufacturing an emulsion by introducing the powder of step f) in water in a concentration of 5%-70%, whereby the percent are weight percent referring to the concentration of the powder according to step f) in water. 14. The process of claim 12 comprising one or more of the alternatives comprising:
mixing the carbohydrate into the emulsion in step c) or d)
adding the water soluble antioxidant after step c), d) or e),
adding the oil soluble antioxidant in step a), c) or d). 15. A powder comprising a carotenoid made by the process according to step a) to f) of claim 12. 16. An oil-in-water emulsion comprising a carotenoid made by the process according to step a) to g-2) of claim 13. 17. A colorant, preferably a natural or nature identical colorant in food, feed, pharmaceutical preparations, cosmetic products, and/or dermal products comprising the powder of claim 15. 18. A method for replacing azo dyes comprising utilizing the powder of claim 15 as a colorant in food, feed, pharmaceutical preparations, cosmetic products and/or dermal products. 19. A colorant in food, feed, pharmaceutical preparations, cosmetic products, and/or dermal products, comprising the oil-in-water emulsion of claim 16. 20. A method for replacing azo dyes comprising utilizing the oil-in-water emulsion of claim 16 as a colorant in food, feed, pharmaceutical preparations, cosmetic products, and/or dermal products. | 1,600 |
894 | 14,388,575 | 1,646 | The invention provides methods of treating neoplasia, for example bladder cancer, by administering an IL-2 fusion protein and one or more therapeutic agents, where the IL-2 fusion protein does not necessarily have to target the neoplasia. | 1. A method of ameliorating cancer in a subject comprising:
administering an effective amount of an IL-2 fusion protein and one or more therapeutic agents to the subject in need thereof, thereby ameliorate the cancer. 2. The method of claim 1, wherein the IL-2 fusion protein does not specifically target or bind to the cancer. 3. The method of claim 1, wherein the IL-2 fusion protein comprises a T cell receptor (TCR) domain. 4. The method of claim 3, wherein the T cell receptor domain is a single chain T cell receptor. 5. The method of claim 1, wherein the one or more therapeutic agents are selected from the group consisting of abiraterone acetate, altretamine, anhydrovinblastine, auristatin, azacitidin, AZD 8477, bendamustin, bevacizumab, bexarotene, bicalutamide, BMS184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, bleomycin, bortezomib, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly-1-Lproline-t-butylamide (SEQ ID NO: 11), cachectin, capecitabin, cemadotin, cetuximab, chlorambucil, cyclophosphamide, 3′,4′-didehydro-4′-deoxy-8′-norvin-caleukoblastine, docetaxol, doxetaxel, cyclophosphamide, carboplatin, carmustine (BCNU), cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, dasatinib, daunorubicin, dolastatin, dovitinib, doxorubicin (adriamycin), epirubicin, epothilone B, erlotinib, eribulin, etoposide, everolimus, 5-fluorouracil, finasteride, flutamide, gefitinib, gemcitabine, hydroxyurea and hydroxyureataxanes, ifosfamide, interferon alfa, imatinib, ipilimumab, irinotecan, largotaxel, lapatinib, lenalidomid, liarozole, lonafarnib, lonidamine, lomustine (CCNU), mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, 5-fluorouracil, nilutamide, onapristone, oxaliplatin, paclitaxel, panitumumab, pazopanib, pralatrexate, prednimustine, piritrexim, procarbazine, pyrazoloacridine, rituximab, RPR109881, romidepsin, sorafinib, stramustine phosphate, sunitinib, tamoxifen, tasonermin, taxol, temozolomide, topotecan, transtuzumab, tretinoin, trimetrexate, vemurafenib, vinblastine, vincristine, vindesine sulfate, vinflunine, and vorinostat. 6. The method of claim 1, wherein the one or more therapeutic agents are selected from the group consisting of gemcitabine and platinum-based compounds including cisplatin. 7. The method of claim 1, wherein the cancer is selected from the group consisting of bladder cancer, urothelial cancer of the urethra, ureter and renal pelvis, multiple myeloma, kidney cancer, breast cancer, colon cancer, head and neck cancer, lung cancer, prostate cancer, glioblastoma, osteosarcoma, liposarcoma, soft-tissue sarcoma, ovarian cancer, melanoma, liver cancer, esophageal cancer, pancreatic cancer and stomach cancer. 8. The method of claim 1, wherein the cancer is bladder or urothelial cancer. 9. The method of claim 1, wherein the cancer is chemo-resistant. 10. The method of claim 1, wherein the IL-2 fusion protein and the one or more therapeutic agents are administered within about 7-14 days. 11. The method of claim 1, wherein the IL-2 fusion protein and the one or more therapeutic agents are administered within about 3-5 days or are administered concurrently. 12. The method of claim 1, wherein the IL-2 fusion protein is ALT-801 and the one or more therapeutic agents is cisplatin. 13. The method of claim 12, wherein the one or more therapeutic agents is gemcitabine. 14. The method of claim 1, wherein the IL-2 fusion protein specifically targets the cancer cells. 15. The method of claim 14, wherein the IL-2 fusion protein specifically targets p53 peptide/HLA complexes on the surface of the cancer cells. 16. A method of reducing tumor burden in a subject comprising:
administering an effective amount of an IL-2 fusion protein and a therapeutic agent to the subject in need thereof, thereby reducing the tumor volume. 17. The method of claim 16, wherein the IL-2 fusion protein does not specifically target or bind to the cancer. 18. The method of claim 16, wherein the IL-2 fusion protein comprises a T cell receptor (TCR) domain. 19. The method of claim 18, wherein the T cell receptor domain is a single chain T cell receptor. 20. The method of claim 16, wherein the one or more therapeutic agents are selected from the group consisting of abiraterone acetate, altretamine, anhydrovinblastine, auristatin, azacitidin, AZD 8477, bendamustin, bevacizumab, bexarotene, bicalutamide, BMS184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, bleomycin, bortezomib, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly-1-Lproline-t-butylamide (SEQ ID NO: 11), cachectin, capecitabin, cemadotin, cetuximab, chlorambucil, cyclophosphamide, 3′,4′-didehydro-4′-deoxy-8′-norvin-caleukoblastine, docetaxol, doxetaxel, cyclophosphamide, carboplatin, carmustine (BCNU), cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, dasatinib, daunorubicin, dolastatin, dovitinib, doxorubicin (adriamycin), epirubicin, epothilone B, erlotinib, eribulin, etoposide, everolimus, 5-fluorouracil, finasteride, flutamide, gefitinib, gemcitabine, hydroxyurea and hydroxyureataxanes, ifosfamide, interferon alfa, imatinib, ipilimumab, irinotecan, largotaxel, lapatinib, lenalidomid, liarozole, lonafarnib, lonidamine, lomustine (CCNU), mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, 5-fluorouracil, nilutamide, onapristone, oxaliplatin, paclitaxel, panitumumab, pazopanib, pralatrexate, prednimustine, piritrexim, procarbazine, pyrazoloacridine, rituximab, RPR109881, romidepsin, sorafinib, stramustine phosphate, sunitinib, tamoxifen, tasonermin, taxol, temozolomide, topotecan, transtuzumab, tretinoin, trimetrexate, vemurafenib, vinblastine, vincristine, vindesine sulfate, vinflunine, and vorinostat. 21. The method of claim 16, wherein the one or more therapeutic agents are selected from the group consisting of gemcitabine and platinum-based compounds including cisplatin. 22. The method of claim 16, wherein the tumor burden is selected from the group consisting of bladder cancer, urothelial cancer of the urethra, ureter and renal pelvis, multiple myeloma, kidney cancer, breast cancer, colon cancer, head and neck cancer, lung cancer, prostate cancer, glioblastoma, osteosarcoma, liposarcoma, soft-tissue sarcoma, ovarian cancer, melanoma, liver cancer, esophageal cancer, pancreatic cancer and stomach cancer. 23. The method of claim 16, wherein the tumor burden is bladder or urothelial cancer. 24. The method of claim 16, wherein the tumor burden is chemo-resistant. 25. The method of claim 16, wherein the IL-2 fusion protein and the one or more therapeutic agents are administered within about 7-14 days. 26. The method of claim 16, wherein the IL-2 fusion protein and the one or more therapeutic agents are administered within about 3-5 days or are administered concurrently. 27. The method of claim 16, wherein the IL-2 fusion protein is ALT-801 and the one or more therapeutic agents are gemcitabine and cisplatin. 28. The method of claim 27, wherein the one or more therapeutic agents is gemcitabine. 29. The method of claim 16, wherein the IL-2 fusion protein specifically targets the cancer cells. 30. The method of claim 29, wherein the IL-2 fusion protein specifically targets p53 peptide/HLA complexes on the surface of the cancer cells. 31. A method of treating chemo-resistant cancer in a subject comprising:
administering an effective amount of an IL-2 fusion protein and a therapeutic agent to the subject in need thereof, thereby treating the chemo-resistant cancer. 32. The method of claim 31, wherein the IL-2 fusion protein does not specifically target or bind to the cancer. 33. The method of claim 31, wherein the IL-2 fusion protein comprises a T cell receptor (TCR) domain. 34. The method of claim 33, wherein the T cell receptor domain is a single chain T cell receptor. 35. The method of claim 31, wherein the one or more therapeutic agents are selected from the group consisting of abiraterone acetate, altretamine, anhydrovinblastine, auristatin, azacitidin, AZD 8477, bendamustin, bevacizumab, bexarotene, bicalutamide, BMS184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, bleomycin, bortezomib, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly-1-Lproline-t-butylamide (SEQ ID NO: 11), cachectin, capecitabin, cemadotin, cetuximab, chlorambucil, cyclophosphamide, 3′,4′-didehydro-4′-deoxy-8′-norvin-caleukoblastine, docetaxol, doxetaxel, cyclophosphamide, carboplatin, carmustine (BCNU), cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, dasatinib, daunorubicin, dolastatin, dovitinib, doxorubicin (adriamycin), epirubicin, epothilone B, erlotinib, eribulin, etoposide, everolimus, 5-fluorouracil, finasteride, flutamide, gefitinib, gemcitabine, hydroxyurea and hydroxyureataxanes, ifosfamide, interferon alfa, imatinib, ipilimumab, irinotecan, largotaxel, lapatinib, lenalidomid, liarozole, lonafarnib, lonidamine, lomustine (CCNU), mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, 5-fluorouracil, nilutamide, onapristone, oxaliplatin, paclitaxel, panitumumab, pazopanib, pralatrexate, prednimustine, piritrexim, procarbazine, pyrazoloacridine, rituximab, RPR109881, romidepsin, sorafinib, stramustine phosphate, sunitinib, tamoxifen, tasonermin, taxol, temozolomide, topotecan, transtuzumab, tretinoin, trimetrexate, vemurafenib, vinblastine, vincristine, vindesine sulfate, vinflunine, and vorinostat. 36. The method of claim 31, wherein the one or more therapeutic agents are selected from the group consisting of gemcitabine and platinum-based compounds including cisplatin. 37. The method of claim 31, wherein the cancer is selected from the group consisting of bladder cancer, urothelial cancer of the urethra, ureter and renal pelvis, multiple myeloma, kidney cancer, breast cancer, colon cancer, head and neck cancer, lung cancer, prostate cancer, glioblastoma, osteosarcoma, liposarcoma, soft-tissue sarcoma, ovarian cancer, melanoma, liver cancer, esophageal cancer, pancreatic cancer and stomach cancer. 38. The method of claim 31, wherein the cancer is bladder or urothelial cancer. 39. The method of claim 31, wherein the cancer is chemo-resistant. 40. The method of claim 31, wherein the IL-2 fusion protein and the one or more therapeutic agents are administered within about 7-14 days. 41. The method of claim 31, wherein the IL-2 fusion protein and the one or more therapeutic agents are administered within about 3-5 days or are administered concurrently. 42. The method of claim 31, wherein the IL-2 fusion protein is ALT-801 and the one or more therapeutic agents is cisplatin. 43. The method of claim 42, wherein the one or more therapeutic agents is gemcitabine. 44. The method of claim 31, wherein the IL-2 fusion protein specifically targets the cancer cells. 45. The method of claim 44, wherein the IL-2 fusion protein specifically targets p53 peptide/HLA complexes on the surface of the cancer cells. 46. A method of inducing a durable immunological memory response against cancer in a subject comprising:
administering an effective amount of an IL-2 fusion protein and a therapeutic agent to the subject in need thereof, thereby inducing a durable immunological memory response against cancer. 47. The method of claim 46, wherein the IL-2 fusion protein does not specifically target or bind to the cancer. 48. The method of claim 46, wherein the IL-2 fusion protein comprises a T cell receptor (TCR) domain. 49. The method of claim 48, wherein the T cell receptor domain is a single chain T cell receptor. 50. The method of claim 46, wherein the one or more therapeutic agents are selected from the group consisting of abiraterone acetate, altretamine, anhydrovinblastine, auristatin, azacitidin, AZD 8477, bendamustin, bevacizumab, bexarotene, bicalutamide, BMS184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, bleomycin, bortezomib, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly-1-Lproline-t-butylamide (SEQ ID NO: 11), cachectin, capecitabin, cemadotin, cetuximab, chlorambucil, cyclophosphamide, 3′,4′-didehydro-4′-deoxy-8′-norvin-caleukoblastine, docetaxol, doxetaxel, cyclophosphamide, carboplatin, carmustine (BCNU), cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, dasatinib, daunorubicin, dolastatin, dovitinib, doxorubicin (adriamycin), epirubicin, epothilone B, erlotinib, eribulin, etoposide, everolimus, 5-fluorouracil, finasteride, flutamide, gefitinib, gemcitabine, hydroxyurea and hydroxyureataxanes, ifosfamide, interferon alfa, imatinib, ipilimumab, irinotecan, largotaxel, lapatinib, lenalidomid, liarozole, lonafarnib, lonidamine, lomustine (CCNU), mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, 5-fluorouracil, nilutamide, onapristone, oxaliplatin, paclitaxel, panitumumab, pazopanib, pralatrexate, prednimustine, piritrexim, procarbazine, pyrazoloacridine, rituximab, RPR109881, romidepsin, sorafinib, stramustine phosphate, sunitinib, tamoxifen, tasonermin, taxol, temozolomide, topotecan, transtuzumab, tretinoin, trimetrexate, vemurafenib, vinblastine, vincristine, vindesine sulfate, vinflunine, and vorinostat. 51. The method of claim 46, wherein the one or more therapeutic agents are selected from the group consisting of gemcitabine and platinum-based compounds including cisplatin. 52. The method of claim 46, wherein the cancer is selected from the group consisting of bladder cancer, urothelial cancer of the urethra, ureter and renal pelvis, multiple myeloma, kidney cancer, breast cancer, colon cancer, head and neck cancer, lung cancer, prostate cancer, glioblastoma, osteosarcoma, liposarcoma, soft-tissue sarcoma, ovarian cancer, melanoma, liver cancer, esophageal cancer, pancreatic cancer and stomach cancer. 53. The method of claim 46, wherein the cancer is bladder or urothelial cancer. 54. The method of claim 46, wherein the cancer is chemo-resistant. 55. The method of claim 46, wherein the IL-2 fusion protein and the one or more therapeutic agents are administered within about 7-14 days. 56. The method of claim 46, wherein the IL-2 fusion protein and the one or more therapeutic agents are administered within about 3-5 days or are administered concurrently. 57. The method of claim 46, wherein the IL-2 fusion protein is ALT-801 and the one or more therapeutic agents is cisplatin. 58. The method of claim 57, wherein the one or more therapeutic agents is gemcitabine. 59. The method of claim 46, wherein the IL-2 fusion protein specifically targets the cancer cells. 60. The method of claim 59, wherein the IL-2 fusion protein specifically targets p53 peptide/HLA complexes on the surface of the cancer cells. 61. A method of increasing the survival of a subject having cancer comprising:
administering an effective amount of an IL-2 fusion protein and a therapeutic agent to the subject in need thereof, thereby increasing the survival of the subject. 62. The method of claim 61, wherein the IL-2 fusion protein does not specifically target or bind to the cancer. 63. The method of claim 61, wherein the IL-2 fusion protein comprises a T cell receptor (TCR) domain. 64. The method of claim 63, wherein the T cell receptor domain is a single chain T cell receptor. 65. The method of claim 61, wherein the one or more therapeutic agents are selected from the group consisting of abiraterone acetate, altretamine, anhydrovinblastine, auristatin, azacitidin, AZD 8477, bendamustin, bevacizumab, bexarotene, bicalutamide, BMS184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, bleomycin, bortezomib, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly-1-Lproline-t-butylamide (SEQ ID NO: 11), cachectin, capecitabin, cemadotin, cetuximab, chlorambucil, cyclophosphamide, 3′,4′-didehydro-4′-deoxy-8′-norvin-caleukoblastine, docetaxol, doxetaxel, cyclophosphamide, carboplatin, carmustine (BCNU), cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, dasatinib, daunorubicin, dolastatin, dovitinib, doxorubicin (adriamycin), epirubicin, epothilone B, erlotinib, eribulin, etoposide, everolimus, 5-fluorouracil, finasteride, flutamide, gefitinib, gemcitabine, hydroxyurea and hydroxyureataxanes, ifosfamide, interferon alfa, imatinib, ipilimumab, irinotecan, largotaxel, lapatinib, lenalidomid, liarozole, lonafarnib, lonidamine, lomustine (CCNU), mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, 5-fluorouracil, nilutamide, onapristone, oxaliplatin, paclitaxel, panitumumab, pazopanib, pralatrexate, prednimustine, piritrexim, procarbazine, pyrazoloacridine, rituximab, RPR109881, romidepsin, sorafinib, stramustine phosphate, sunitinib, tamoxifen, tasonermin, taxol, temozolomide, topotecan, transtuzumab, tretinoin, trimetrexate, vemurafenib, vinblastine, vincristine, vindesine sulfate, vinflunine, and vorinostat. 66. The method of claim 61, wherein the one or more therapeutic agents are selected from the group consisting of gemcitabine and platinum-based compounds including cisplatin. 67. The method of claim 61, wherein the cancer is selected from the group consisting of bladder cancer, urothelial cancer of the urethra, ureter and renal pelvis, multiple myeloma, kidney cancer, breast cancer, colon cancer, head and neck cancer, lung cancer, prostate cancer, glioblastoma, osteosarcoma, liposarcoma, soft-tissue sarcoma, ovarian cancer, melanoma, liver cancer, esophageal cancer, pancreatic cancer and stomach cancer. 68. The method of claim 61, wherein the cancer is bladder or urothelial cancer. 69. The method of claim 61, wherein the cancer is chemo-resistant. 70. The method of claim 61, wherein the IL-2 fusion protein and the one or more therapeutic agents are administered within about 7-14 days. 71. The method of claim 61, wherein the IL-2 fusion protein and the one or more therapeutic agents are administered within about 3-5 days or are administered concurrently. 72. The method of claim 61, wherein the IL-2 fusion protein is ALT-801 and the one or more therapeutic agents is cisplatin. 73. The method of claim 72, wherein the one or more therapeutic agents is gemcitabine. 74. The method of claim 61, wherein the IL-2 fusion protein specifically targets the cancer cells. 75. The method of claim 74, wherein the IL-2 fusion protein specifically targets p53 peptide/HLA complexes on the surface of the cancer cells. 76. A kit for the treatment of bladder cancer comprising an IL-2 fusion protein and one or more therapeutic agents. 77. The kit of claim 76, wherein the IL-2 fusion protein is ALT-801 and the one or more therapeutic agents is cisplatin. 78. The kit of claim 77, wherein the one or more therapeutic agents is gemcitabine. | The invention provides methods of treating neoplasia, for example bladder cancer, by administering an IL-2 fusion protein and one or more therapeutic agents, where the IL-2 fusion protein does not necessarily have to target the neoplasia.1. A method of ameliorating cancer in a subject comprising:
administering an effective amount of an IL-2 fusion protein and one or more therapeutic agents to the subject in need thereof, thereby ameliorate the cancer. 2. The method of claim 1, wherein the IL-2 fusion protein does not specifically target or bind to the cancer. 3. The method of claim 1, wherein the IL-2 fusion protein comprises a T cell receptor (TCR) domain. 4. The method of claim 3, wherein the T cell receptor domain is a single chain T cell receptor. 5. The method of claim 1, wherein the one or more therapeutic agents are selected from the group consisting of abiraterone acetate, altretamine, anhydrovinblastine, auristatin, azacitidin, AZD 8477, bendamustin, bevacizumab, bexarotene, bicalutamide, BMS184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, bleomycin, bortezomib, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly-1-Lproline-t-butylamide (SEQ ID NO: 11), cachectin, capecitabin, cemadotin, cetuximab, chlorambucil, cyclophosphamide, 3′,4′-didehydro-4′-deoxy-8′-norvin-caleukoblastine, docetaxol, doxetaxel, cyclophosphamide, carboplatin, carmustine (BCNU), cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, dasatinib, daunorubicin, dolastatin, dovitinib, doxorubicin (adriamycin), epirubicin, epothilone B, erlotinib, eribulin, etoposide, everolimus, 5-fluorouracil, finasteride, flutamide, gefitinib, gemcitabine, hydroxyurea and hydroxyureataxanes, ifosfamide, interferon alfa, imatinib, ipilimumab, irinotecan, largotaxel, lapatinib, lenalidomid, liarozole, lonafarnib, lonidamine, lomustine (CCNU), mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, 5-fluorouracil, nilutamide, onapristone, oxaliplatin, paclitaxel, panitumumab, pazopanib, pralatrexate, prednimustine, piritrexim, procarbazine, pyrazoloacridine, rituximab, RPR109881, romidepsin, sorafinib, stramustine phosphate, sunitinib, tamoxifen, tasonermin, taxol, temozolomide, topotecan, transtuzumab, tretinoin, trimetrexate, vemurafenib, vinblastine, vincristine, vindesine sulfate, vinflunine, and vorinostat. 6. The method of claim 1, wherein the one or more therapeutic agents are selected from the group consisting of gemcitabine and platinum-based compounds including cisplatin. 7. The method of claim 1, wherein the cancer is selected from the group consisting of bladder cancer, urothelial cancer of the urethra, ureter and renal pelvis, multiple myeloma, kidney cancer, breast cancer, colon cancer, head and neck cancer, lung cancer, prostate cancer, glioblastoma, osteosarcoma, liposarcoma, soft-tissue sarcoma, ovarian cancer, melanoma, liver cancer, esophageal cancer, pancreatic cancer and stomach cancer. 8. The method of claim 1, wherein the cancer is bladder or urothelial cancer. 9. The method of claim 1, wherein the cancer is chemo-resistant. 10. The method of claim 1, wherein the IL-2 fusion protein and the one or more therapeutic agents are administered within about 7-14 days. 11. The method of claim 1, wherein the IL-2 fusion protein and the one or more therapeutic agents are administered within about 3-5 days or are administered concurrently. 12. The method of claim 1, wherein the IL-2 fusion protein is ALT-801 and the one or more therapeutic agents is cisplatin. 13. The method of claim 12, wherein the one or more therapeutic agents is gemcitabine. 14. The method of claim 1, wherein the IL-2 fusion protein specifically targets the cancer cells. 15. The method of claim 14, wherein the IL-2 fusion protein specifically targets p53 peptide/HLA complexes on the surface of the cancer cells. 16. A method of reducing tumor burden in a subject comprising:
administering an effective amount of an IL-2 fusion protein and a therapeutic agent to the subject in need thereof, thereby reducing the tumor volume. 17. The method of claim 16, wherein the IL-2 fusion protein does not specifically target or bind to the cancer. 18. The method of claim 16, wherein the IL-2 fusion protein comprises a T cell receptor (TCR) domain. 19. The method of claim 18, wherein the T cell receptor domain is a single chain T cell receptor. 20. The method of claim 16, wherein the one or more therapeutic agents are selected from the group consisting of abiraterone acetate, altretamine, anhydrovinblastine, auristatin, azacitidin, AZD 8477, bendamustin, bevacizumab, bexarotene, bicalutamide, BMS184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, bleomycin, bortezomib, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly-1-Lproline-t-butylamide (SEQ ID NO: 11), cachectin, capecitabin, cemadotin, cetuximab, chlorambucil, cyclophosphamide, 3′,4′-didehydro-4′-deoxy-8′-norvin-caleukoblastine, docetaxol, doxetaxel, cyclophosphamide, carboplatin, carmustine (BCNU), cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, dasatinib, daunorubicin, dolastatin, dovitinib, doxorubicin (adriamycin), epirubicin, epothilone B, erlotinib, eribulin, etoposide, everolimus, 5-fluorouracil, finasteride, flutamide, gefitinib, gemcitabine, hydroxyurea and hydroxyureataxanes, ifosfamide, interferon alfa, imatinib, ipilimumab, irinotecan, largotaxel, lapatinib, lenalidomid, liarozole, lonafarnib, lonidamine, lomustine (CCNU), mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, 5-fluorouracil, nilutamide, onapristone, oxaliplatin, paclitaxel, panitumumab, pazopanib, pralatrexate, prednimustine, piritrexim, procarbazine, pyrazoloacridine, rituximab, RPR109881, romidepsin, sorafinib, stramustine phosphate, sunitinib, tamoxifen, tasonermin, taxol, temozolomide, topotecan, transtuzumab, tretinoin, trimetrexate, vemurafenib, vinblastine, vincristine, vindesine sulfate, vinflunine, and vorinostat. 21. The method of claim 16, wherein the one or more therapeutic agents are selected from the group consisting of gemcitabine and platinum-based compounds including cisplatin. 22. The method of claim 16, wherein the tumor burden is selected from the group consisting of bladder cancer, urothelial cancer of the urethra, ureter and renal pelvis, multiple myeloma, kidney cancer, breast cancer, colon cancer, head and neck cancer, lung cancer, prostate cancer, glioblastoma, osteosarcoma, liposarcoma, soft-tissue sarcoma, ovarian cancer, melanoma, liver cancer, esophageal cancer, pancreatic cancer and stomach cancer. 23. The method of claim 16, wherein the tumor burden is bladder or urothelial cancer. 24. The method of claim 16, wherein the tumor burden is chemo-resistant. 25. The method of claim 16, wherein the IL-2 fusion protein and the one or more therapeutic agents are administered within about 7-14 days. 26. The method of claim 16, wherein the IL-2 fusion protein and the one or more therapeutic agents are administered within about 3-5 days or are administered concurrently. 27. The method of claim 16, wherein the IL-2 fusion protein is ALT-801 and the one or more therapeutic agents are gemcitabine and cisplatin. 28. The method of claim 27, wherein the one or more therapeutic agents is gemcitabine. 29. The method of claim 16, wherein the IL-2 fusion protein specifically targets the cancer cells. 30. The method of claim 29, wherein the IL-2 fusion protein specifically targets p53 peptide/HLA complexes on the surface of the cancer cells. 31. A method of treating chemo-resistant cancer in a subject comprising:
administering an effective amount of an IL-2 fusion protein and a therapeutic agent to the subject in need thereof, thereby treating the chemo-resistant cancer. 32. The method of claim 31, wherein the IL-2 fusion protein does not specifically target or bind to the cancer. 33. The method of claim 31, wherein the IL-2 fusion protein comprises a T cell receptor (TCR) domain. 34. The method of claim 33, wherein the T cell receptor domain is a single chain T cell receptor. 35. The method of claim 31, wherein the one or more therapeutic agents are selected from the group consisting of abiraterone acetate, altretamine, anhydrovinblastine, auristatin, azacitidin, AZD 8477, bendamustin, bevacizumab, bexarotene, bicalutamide, BMS184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, bleomycin, bortezomib, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly-1-Lproline-t-butylamide (SEQ ID NO: 11), cachectin, capecitabin, cemadotin, cetuximab, chlorambucil, cyclophosphamide, 3′,4′-didehydro-4′-deoxy-8′-norvin-caleukoblastine, docetaxol, doxetaxel, cyclophosphamide, carboplatin, carmustine (BCNU), cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, dasatinib, daunorubicin, dolastatin, dovitinib, doxorubicin (adriamycin), epirubicin, epothilone B, erlotinib, eribulin, etoposide, everolimus, 5-fluorouracil, finasteride, flutamide, gefitinib, gemcitabine, hydroxyurea and hydroxyureataxanes, ifosfamide, interferon alfa, imatinib, ipilimumab, irinotecan, largotaxel, lapatinib, lenalidomid, liarozole, lonafarnib, lonidamine, lomustine (CCNU), mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, 5-fluorouracil, nilutamide, onapristone, oxaliplatin, paclitaxel, panitumumab, pazopanib, pralatrexate, prednimustine, piritrexim, procarbazine, pyrazoloacridine, rituximab, RPR109881, romidepsin, sorafinib, stramustine phosphate, sunitinib, tamoxifen, tasonermin, taxol, temozolomide, topotecan, transtuzumab, tretinoin, trimetrexate, vemurafenib, vinblastine, vincristine, vindesine sulfate, vinflunine, and vorinostat. 36. The method of claim 31, wherein the one or more therapeutic agents are selected from the group consisting of gemcitabine and platinum-based compounds including cisplatin. 37. The method of claim 31, wherein the cancer is selected from the group consisting of bladder cancer, urothelial cancer of the urethra, ureter and renal pelvis, multiple myeloma, kidney cancer, breast cancer, colon cancer, head and neck cancer, lung cancer, prostate cancer, glioblastoma, osteosarcoma, liposarcoma, soft-tissue sarcoma, ovarian cancer, melanoma, liver cancer, esophageal cancer, pancreatic cancer and stomach cancer. 38. The method of claim 31, wherein the cancer is bladder or urothelial cancer. 39. The method of claim 31, wherein the cancer is chemo-resistant. 40. The method of claim 31, wherein the IL-2 fusion protein and the one or more therapeutic agents are administered within about 7-14 days. 41. The method of claim 31, wherein the IL-2 fusion protein and the one or more therapeutic agents are administered within about 3-5 days or are administered concurrently. 42. The method of claim 31, wherein the IL-2 fusion protein is ALT-801 and the one or more therapeutic agents is cisplatin. 43. The method of claim 42, wherein the one or more therapeutic agents is gemcitabine. 44. The method of claim 31, wherein the IL-2 fusion protein specifically targets the cancer cells. 45. The method of claim 44, wherein the IL-2 fusion protein specifically targets p53 peptide/HLA complexes on the surface of the cancer cells. 46. A method of inducing a durable immunological memory response against cancer in a subject comprising:
administering an effective amount of an IL-2 fusion protein and a therapeutic agent to the subject in need thereof, thereby inducing a durable immunological memory response against cancer. 47. The method of claim 46, wherein the IL-2 fusion protein does not specifically target or bind to the cancer. 48. The method of claim 46, wherein the IL-2 fusion protein comprises a T cell receptor (TCR) domain. 49. The method of claim 48, wherein the T cell receptor domain is a single chain T cell receptor. 50. The method of claim 46, wherein the one or more therapeutic agents are selected from the group consisting of abiraterone acetate, altretamine, anhydrovinblastine, auristatin, azacitidin, AZD 8477, bendamustin, bevacizumab, bexarotene, bicalutamide, BMS184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, bleomycin, bortezomib, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly-1-Lproline-t-butylamide (SEQ ID NO: 11), cachectin, capecitabin, cemadotin, cetuximab, chlorambucil, cyclophosphamide, 3′,4′-didehydro-4′-deoxy-8′-norvin-caleukoblastine, docetaxol, doxetaxel, cyclophosphamide, carboplatin, carmustine (BCNU), cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, dasatinib, daunorubicin, dolastatin, dovitinib, doxorubicin (adriamycin), epirubicin, epothilone B, erlotinib, eribulin, etoposide, everolimus, 5-fluorouracil, finasteride, flutamide, gefitinib, gemcitabine, hydroxyurea and hydroxyureataxanes, ifosfamide, interferon alfa, imatinib, ipilimumab, irinotecan, largotaxel, lapatinib, lenalidomid, liarozole, lonafarnib, lonidamine, lomustine (CCNU), mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, 5-fluorouracil, nilutamide, onapristone, oxaliplatin, paclitaxel, panitumumab, pazopanib, pralatrexate, prednimustine, piritrexim, procarbazine, pyrazoloacridine, rituximab, RPR109881, romidepsin, sorafinib, stramustine phosphate, sunitinib, tamoxifen, tasonermin, taxol, temozolomide, topotecan, transtuzumab, tretinoin, trimetrexate, vemurafenib, vinblastine, vincristine, vindesine sulfate, vinflunine, and vorinostat. 51. The method of claim 46, wherein the one or more therapeutic agents are selected from the group consisting of gemcitabine and platinum-based compounds including cisplatin. 52. The method of claim 46, wherein the cancer is selected from the group consisting of bladder cancer, urothelial cancer of the urethra, ureter and renal pelvis, multiple myeloma, kidney cancer, breast cancer, colon cancer, head and neck cancer, lung cancer, prostate cancer, glioblastoma, osteosarcoma, liposarcoma, soft-tissue sarcoma, ovarian cancer, melanoma, liver cancer, esophageal cancer, pancreatic cancer and stomach cancer. 53. The method of claim 46, wherein the cancer is bladder or urothelial cancer. 54. The method of claim 46, wherein the cancer is chemo-resistant. 55. The method of claim 46, wherein the IL-2 fusion protein and the one or more therapeutic agents are administered within about 7-14 days. 56. The method of claim 46, wherein the IL-2 fusion protein and the one or more therapeutic agents are administered within about 3-5 days or are administered concurrently. 57. The method of claim 46, wherein the IL-2 fusion protein is ALT-801 and the one or more therapeutic agents is cisplatin. 58. The method of claim 57, wherein the one or more therapeutic agents is gemcitabine. 59. The method of claim 46, wherein the IL-2 fusion protein specifically targets the cancer cells. 60. The method of claim 59, wherein the IL-2 fusion protein specifically targets p53 peptide/HLA complexes on the surface of the cancer cells. 61. A method of increasing the survival of a subject having cancer comprising:
administering an effective amount of an IL-2 fusion protein and a therapeutic agent to the subject in need thereof, thereby increasing the survival of the subject. 62. The method of claim 61, wherein the IL-2 fusion protein does not specifically target or bind to the cancer. 63. The method of claim 61, wherein the IL-2 fusion protein comprises a T cell receptor (TCR) domain. 64. The method of claim 63, wherein the T cell receptor domain is a single chain T cell receptor. 65. The method of claim 61, wherein the one or more therapeutic agents are selected from the group consisting of abiraterone acetate, altretamine, anhydrovinblastine, auristatin, azacitidin, AZD 8477, bendamustin, bevacizumab, bexarotene, bicalutamide, BMS184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, bleomycin, bortezomib, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly-1-Lproline-t-butylamide (SEQ ID NO: 11), cachectin, capecitabin, cemadotin, cetuximab, chlorambucil, cyclophosphamide, 3′,4′-didehydro-4′-deoxy-8′-norvin-caleukoblastine, docetaxol, doxetaxel, cyclophosphamide, carboplatin, carmustine (BCNU), cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, dasatinib, daunorubicin, dolastatin, dovitinib, doxorubicin (adriamycin), epirubicin, epothilone B, erlotinib, eribulin, etoposide, everolimus, 5-fluorouracil, finasteride, flutamide, gefitinib, gemcitabine, hydroxyurea and hydroxyureataxanes, ifosfamide, interferon alfa, imatinib, ipilimumab, irinotecan, largotaxel, lapatinib, lenalidomid, liarozole, lonafarnib, lonidamine, lomustine (CCNU), mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, 5-fluorouracil, nilutamide, onapristone, oxaliplatin, paclitaxel, panitumumab, pazopanib, pralatrexate, prednimustine, piritrexim, procarbazine, pyrazoloacridine, rituximab, RPR109881, romidepsin, sorafinib, stramustine phosphate, sunitinib, tamoxifen, tasonermin, taxol, temozolomide, topotecan, transtuzumab, tretinoin, trimetrexate, vemurafenib, vinblastine, vincristine, vindesine sulfate, vinflunine, and vorinostat. 66. The method of claim 61, wherein the one or more therapeutic agents are selected from the group consisting of gemcitabine and platinum-based compounds including cisplatin. 67. The method of claim 61, wherein the cancer is selected from the group consisting of bladder cancer, urothelial cancer of the urethra, ureter and renal pelvis, multiple myeloma, kidney cancer, breast cancer, colon cancer, head and neck cancer, lung cancer, prostate cancer, glioblastoma, osteosarcoma, liposarcoma, soft-tissue sarcoma, ovarian cancer, melanoma, liver cancer, esophageal cancer, pancreatic cancer and stomach cancer. 68. The method of claim 61, wherein the cancer is bladder or urothelial cancer. 69. The method of claim 61, wherein the cancer is chemo-resistant. 70. The method of claim 61, wherein the IL-2 fusion protein and the one or more therapeutic agents are administered within about 7-14 days. 71. The method of claim 61, wherein the IL-2 fusion protein and the one or more therapeutic agents are administered within about 3-5 days or are administered concurrently. 72. The method of claim 61, wherein the IL-2 fusion protein is ALT-801 and the one or more therapeutic agents is cisplatin. 73. The method of claim 72, wherein the one or more therapeutic agents is gemcitabine. 74. The method of claim 61, wherein the IL-2 fusion protein specifically targets the cancer cells. 75. The method of claim 74, wherein the IL-2 fusion protein specifically targets p53 peptide/HLA complexes on the surface of the cancer cells. 76. A kit for the treatment of bladder cancer comprising an IL-2 fusion protein and one or more therapeutic agents. 77. The kit of claim 76, wherein the IL-2 fusion protein is ALT-801 and the one or more therapeutic agents is cisplatin. 78. The kit of claim 77, wherein the one or more therapeutic agents is gemcitabine. | 1,600 |
895 | 12,387,977 | 1,619 | A tablet with an enhanced dissolution profile for a medicinally active ingredient such as aspirin and methods for making the tablet. The tablet comprises a blend of crystals of the medicinally active ingredient and a dissolution aid such as sodium or calcium carbonate or bicarbonate that coats the crystals upon co-milling. The blend is then compressed to form tablets that have an enhanced dissolution profile for the medicinally active ingredient. | 1. A blend for forming into a pharmaceutical tablet comprising crystals of a medicinally active ingredient having a particle size less than about 40 μm and a dissolution aid, wherein said blend has been sufficiently milled to substantially coat said crystals with said dissolution aid, whereby the dissolution rate of said medicinally active ingredient when formed into a tablet is enhanced compared to the dissolution rate of said active ingredient in a tablet without such milling. 2. The blend of claim 1, wherein said medicinally active ingredient is selected from the group consisting of analgesics, sympathomimetic amine drugs, beta blockers, anti-histamines; calcium channel blockers, nutritional supplements, Cox-II inhibitors, selective serotonin re-uptake inhibitors, benzodiazepines, codeine and synthetic derivatives, muscle relaxants, and salts and combinations thereof. 3. The blend of claim 1, wherein said medicinally active ingredient is selected from the group consisting of acetaminophen, aspirin, ibuprofen, ketoprofen, naproxen, pseudoephedrine, phenylephrine, and phenylpropanolamine, ranitidine, famotidine, cimetidine and nizatidine; anti-diphenhydramine hydrochloride, brompheniramine, chlorpheniramine, dimenhydrinate, diphenhydramine, doxylamine, ceterazine hydrochloride, meclizine, loratadine, cartelol, propafenose hydrochloride, pindolol, rimipril, atenolol, bepridil, diltiazem, and verapamil, co-Q10, ginseng, lycopene, glucosamine/chondroitin, S-adenosylmethione, curcumin, holy basil, zinc, omega 3 fatty acids DHA and EPA, Vitamin C, Vitamin E, Saint John's Wort, celecoxib, valdecoxib, carisoprodol and aspirin, methocarbamol and aspirin, cyclobenzaprine HCl, clonazepam, diazepam, alprazolam, hydrocodone, oxyocodone and acetaminophen, Hydrocodone Bitartrate and Acetaminophen, Oxycodone Hydrochloride, Acetaminophen and Codeine; selective serotonin re-uptake inhibitors (SSRIs) salts and combinations thereof. 4. The blend of claim 2, wherein said medicinally active ingredient is selected from the group consisting of acetaminophen, aspirin, ibuprofen, ketoprofen, naproxen and salts and combinations thereof. 5. The blend of claim 1, wherein said dissolution aid is selected from the group consisting of carbonates and bicarbonates. 6. The blend of claim 5, wherein said dissolution aid is selected from the group consisting of sodium, calcium, magnesium and potassium salts of carbonates and bicarbonates. 7. The blend of claim 1, wherein said medicinally active ingredient comprises aspirin and said dissolution aid is selected from the group consisting of sodium and calcium salts of carbonates and bicarbonates. 8. The blend of claim 7, wherein said blend comprises from about 37 mg to about 500 mg aspirin, and said dissolution aid comprises from about 5% to about 40% by weight of aspirin present in said blend. 9. The blend of claim 7, wherein said blend is milled for a period of not less than three minutes, thereby substantially coating said crystals with said dissolution aid. 10. A method for manufacturing a delivery vehicle for a medicinally active ingredient comprising the steps of:
a. Preparing a pre-blend of crystals of said medicinally active ingredient and a dissolution aid; b. Milling said pre-blend for a time sufficient to establish a particle size of said crystals of not more than about 40 μm and to substantially coat said crystals with said dissolution aid to form a blend; and c. Compressing said blend to form said delivery vehicle. 11. The method of claim 10, further comprising the step of roller compacting said blend before compressing said blend. 12. The method claim 10, wherein said medicinally active ingredient is selected from the group consisting of acetaminophen, aspirin, ibuprofen, ketoprofen, naproxen and salts and combinations thereof. 13. The method of claim 10, wherein said dissolution aid is selected from the group consisting of carbonates and bicarbonates. 14. The method of claim 13, wherein said dissolution aid is selected from the group consisting of sodium and calcium salts of carbonates and bicarbonates. 15. The method of claim 10, wherein said medicinally active ingredient comprises aspirin and said dissolution aid is selected from the group consisting of sodium and calcium salts of carbonates and bicarbonates. 16. The method of claim 15, wherein said blend comprises from about 37 mg. to about 500 mg aspirin, and said dissolution aid, comprises from about 5% to about 40% by weight of the amount of aspirin present in said blend. 17. The method of claim 15, wherein said blend is milled for a period of not less than three minutes. | A tablet with an enhanced dissolution profile for a medicinally active ingredient such as aspirin and methods for making the tablet. The tablet comprises a blend of crystals of the medicinally active ingredient and a dissolution aid such as sodium or calcium carbonate or bicarbonate that coats the crystals upon co-milling. The blend is then compressed to form tablets that have an enhanced dissolution profile for the medicinally active ingredient.1. A blend for forming into a pharmaceutical tablet comprising crystals of a medicinally active ingredient having a particle size less than about 40 μm and a dissolution aid, wherein said blend has been sufficiently milled to substantially coat said crystals with said dissolution aid, whereby the dissolution rate of said medicinally active ingredient when formed into a tablet is enhanced compared to the dissolution rate of said active ingredient in a tablet without such milling. 2. The blend of claim 1, wherein said medicinally active ingredient is selected from the group consisting of analgesics, sympathomimetic amine drugs, beta blockers, anti-histamines; calcium channel blockers, nutritional supplements, Cox-II inhibitors, selective serotonin re-uptake inhibitors, benzodiazepines, codeine and synthetic derivatives, muscle relaxants, and salts and combinations thereof. 3. The blend of claim 1, wherein said medicinally active ingredient is selected from the group consisting of acetaminophen, aspirin, ibuprofen, ketoprofen, naproxen, pseudoephedrine, phenylephrine, and phenylpropanolamine, ranitidine, famotidine, cimetidine and nizatidine; anti-diphenhydramine hydrochloride, brompheniramine, chlorpheniramine, dimenhydrinate, diphenhydramine, doxylamine, ceterazine hydrochloride, meclizine, loratadine, cartelol, propafenose hydrochloride, pindolol, rimipril, atenolol, bepridil, diltiazem, and verapamil, co-Q10, ginseng, lycopene, glucosamine/chondroitin, S-adenosylmethione, curcumin, holy basil, zinc, omega 3 fatty acids DHA and EPA, Vitamin C, Vitamin E, Saint John's Wort, celecoxib, valdecoxib, carisoprodol and aspirin, methocarbamol and aspirin, cyclobenzaprine HCl, clonazepam, diazepam, alprazolam, hydrocodone, oxyocodone and acetaminophen, Hydrocodone Bitartrate and Acetaminophen, Oxycodone Hydrochloride, Acetaminophen and Codeine; selective serotonin re-uptake inhibitors (SSRIs) salts and combinations thereof. 4. The blend of claim 2, wherein said medicinally active ingredient is selected from the group consisting of acetaminophen, aspirin, ibuprofen, ketoprofen, naproxen and salts and combinations thereof. 5. The blend of claim 1, wherein said dissolution aid is selected from the group consisting of carbonates and bicarbonates. 6. The blend of claim 5, wherein said dissolution aid is selected from the group consisting of sodium, calcium, magnesium and potassium salts of carbonates and bicarbonates. 7. The blend of claim 1, wherein said medicinally active ingredient comprises aspirin and said dissolution aid is selected from the group consisting of sodium and calcium salts of carbonates and bicarbonates. 8. The blend of claim 7, wherein said blend comprises from about 37 mg to about 500 mg aspirin, and said dissolution aid comprises from about 5% to about 40% by weight of aspirin present in said blend. 9. The blend of claim 7, wherein said blend is milled for a period of not less than three minutes, thereby substantially coating said crystals with said dissolution aid. 10. A method for manufacturing a delivery vehicle for a medicinally active ingredient comprising the steps of:
a. Preparing a pre-blend of crystals of said medicinally active ingredient and a dissolution aid; b. Milling said pre-blend for a time sufficient to establish a particle size of said crystals of not more than about 40 μm and to substantially coat said crystals with said dissolution aid to form a blend; and c. Compressing said blend to form said delivery vehicle. 11. The method of claim 10, further comprising the step of roller compacting said blend before compressing said blend. 12. The method claim 10, wherein said medicinally active ingredient is selected from the group consisting of acetaminophen, aspirin, ibuprofen, ketoprofen, naproxen and salts and combinations thereof. 13. The method of claim 10, wherein said dissolution aid is selected from the group consisting of carbonates and bicarbonates. 14. The method of claim 13, wherein said dissolution aid is selected from the group consisting of sodium and calcium salts of carbonates and bicarbonates. 15. The method of claim 10, wherein said medicinally active ingredient comprises aspirin and said dissolution aid is selected from the group consisting of sodium and calcium salts of carbonates and bicarbonates. 16. The method of claim 15, wherein said blend comprises from about 37 mg. to about 500 mg aspirin, and said dissolution aid, comprises from about 5% to about 40% by weight of the amount of aspirin present in said blend. 17. The method of claim 15, wherein said blend is milled for a period of not less than three minutes. | 1,600 |
896 | 15,206,639 | 1,619 | An oil-in-water type emulsified cosmetic and a method of making can be prepared in a system not containing a silicone and is surprising produced without a wet-type dispersion apparatus by using a specific combination of the oil component constituting the oily phase and a hydrophobizing agent for a hydrophobized powder. The composition includes an aqueous phase; an oily phase dispersed in the aqueous phase; and a powder dispersed in the oily phase. The oily phase comprises (a) volatile hydrocarbon oil and (b) non-volatile hydrocarbon oil in a combined amount of 40% by mass or more with respect to the total oil content, wherein the blending ratio of (b) non-volatile hydrocarbon oil to (a) volatile hydrocarbon oil, [(b)/(a)], is within a range of 0 to 2.5, and the powder comprises a powder having a surface hydrophobized by a treatment with a metallic soap consisting of a higher fatty acid and a divalent metal or a composite treatment with a higher fatty acid and a divalent metal hydroxide. | 1. An oil-in-water type emulsified cosmetic composition, comprising:
an aqueous phase; an oily phase dispersed in the aqueous phase; and a powder dispersed in the oily phase; wherein the oily phase further comprises: (a) volatile hydrocarbon oil and (b) non-volatile hydrocarbon oil in a combined amount of 40% by mass or more with respect to the total oil content; wherein a blending ratio of said (b) non-volatile hydrocarbon oil to said (a) volatile hydrocarbon oil, [(b)/(a)], is within a range of 0 to 2.5; and wherein the powder further comprises:
a powder having a surface hydrophobized by a treatment with a metallic soap consisting of a higher fatty acid and a divalent metal or a composite treatment with a higher fatty acid and a divalent metal hydroxide. 2. The cosmetic composition according to claim 1, further comprising:
a thickener in the aqueous phase. 3. The cosmetic composition according to claim 2, wherein:
the thickener is one or more selected from the group consisting of succinoglycan, xanthan gum, carrageenan, gellan gum, starch, hydroxyalkylcellulose, pullulan, carbomer, (Na/Mg) silicate, bentonite, acrylamide copolymer, sodium acryloyl dimethyl taurine/hydroxyethyl acrylate copolymer, agar, polyurethane, and hydrophobic polyether polyurethane. 4. The cosmetic composition according to claim 1, wherein:
the powder having a hydrophobized surface is one or more selected from the group consisting of: titanium dioxide, iron oxide and zinc oxide. 5. The cosmetic composition according to claim 1, wherein:
the powder having a hydrophobized surface is one or more selected from the group consisting of: titanium dioxide, iron oxide and zinc oxide each having a pigment grade. 6. The cosmetic composition according to claim 1, wherein:
the higher fatty acid is a C8 to C24, and the divalent metal is magnesium. 7. The cosmetic composition according to claim 6, wherein:
the higher fatty acid is a 12 to C22 linear or branched carboxylic acid. 8. The cosmetic composition, according to claim 1, wherein:
said composition is absent a silicone oil. 9. The cosmetic composition, according to claim 1, wherein:
the powder having a hydrophobized surface further comprises:
a pigment-grade powder selected from the group consisting of titanium dioxide, iron oxide and zinc oxide of pigment grade, and a microparticle powder selected from the group consisting of titanium dioxide microparticles, iron oxide microparticles and zinc oxide microparticles. 10. An oil-in-water type emulsified cosmetic composition, comprising:
an aqueous phase; an oily phase dispersed in the aqueous phase; and a powder dispersed in the oily phase; wherein the oily phase does not include a silicone oil and further comprises: (a) volatile hydrocarbon oil and (b) non-volatile hydrocarbon oil in a combined amount of 40% by mass or more with respect to the total oil content; wherein a blending ratio of said (b) non-volatile hydrocarbon oil to said (a) volatile hydrocarbon oil, [(b)/(a)], is within a range of 0 to 2.5; and wherein the powder further comprises:
a powder having a surface hydrophobized by a treatment with a metallic soap consisting of a higher fatty acid and a divalent metal or a composite treatment with a higher fatty acid and a divalent metal hydroxide. 11. The cosmetic composition, according to claim 10, wherein:
the powder having a hydrophobized surface further comprises:
a pigment-grade powder selected from the group consisting of titanium dioxide, iron oxide and zinc oxide of pigment grade, and a microparticle powder selected from the group consisting of titanium dioxide microparticles, iron oxide microparticles and zinc oxide microparticles. 12. An oil-in-water type emulsified cosmetic composition, comprising:
an aqueous phase; an oily phase dispersed in the aqueous phase; and a powder dispersed in the oily phase; wherein the oily phase further comprises: (a) volatile hydrocarbon oil and (b) non-volatile hydrocarbon oil in a combined amount of 40% by mass or more with respect to the total oil content, and does not include a silicone oil; wherein a blending ratio of said (b) non-volatile hydrocarbon oil to said (a) volatile hydrocarbon oil, [(b)/(a)], is within a range of 0 to 2.5; wherein the powder further comprises:
a powder having a surface hydrophobized by a treatment with a metallic soap consisting of a higher fatty acid and a divalent metal or a composite treatment with a higher fatty acid and a divalent metal hydroxide; and
wherein the powder having a hydrophobized surface further comprises a pigment-grade powder selected from the group consisting of titanium dioxide, iron oxide and zinc oxide of pigment grade, and a microparticle powder selected from the group consisting of titanium dioxide microparticles, iron oxide microparticles and zinc oxide microparticles. | An oil-in-water type emulsified cosmetic and a method of making can be prepared in a system not containing a silicone and is surprising produced without a wet-type dispersion apparatus by using a specific combination of the oil component constituting the oily phase and a hydrophobizing agent for a hydrophobized powder. The composition includes an aqueous phase; an oily phase dispersed in the aqueous phase; and a powder dispersed in the oily phase. The oily phase comprises (a) volatile hydrocarbon oil and (b) non-volatile hydrocarbon oil in a combined amount of 40% by mass or more with respect to the total oil content, wherein the blending ratio of (b) non-volatile hydrocarbon oil to (a) volatile hydrocarbon oil, [(b)/(a)], is within a range of 0 to 2.5, and the powder comprises a powder having a surface hydrophobized by a treatment with a metallic soap consisting of a higher fatty acid and a divalent metal or a composite treatment with a higher fatty acid and a divalent metal hydroxide.1. An oil-in-water type emulsified cosmetic composition, comprising:
an aqueous phase; an oily phase dispersed in the aqueous phase; and a powder dispersed in the oily phase; wherein the oily phase further comprises: (a) volatile hydrocarbon oil and (b) non-volatile hydrocarbon oil in a combined amount of 40% by mass or more with respect to the total oil content; wherein a blending ratio of said (b) non-volatile hydrocarbon oil to said (a) volatile hydrocarbon oil, [(b)/(a)], is within a range of 0 to 2.5; and wherein the powder further comprises:
a powder having a surface hydrophobized by a treatment with a metallic soap consisting of a higher fatty acid and a divalent metal or a composite treatment with a higher fatty acid and a divalent metal hydroxide. 2. The cosmetic composition according to claim 1, further comprising:
a thickener in the aqueous phase. 3. The cosmetic composition according to claim 2, wherein:
the thickener is one or more selected from the group consisting of succinoglycan, xanthan gum, carrageenan, gellan gum, starch, hydroxyalkylcellulose, pullulan, carbomer, (Na/Mg) silicate, bentonite, acrylamide copolymer, sodium acryloyl dimethyl taurine/hydroxyethyl acrylate copolymer, agar, polyurethane, and hydrophobic polyether polyurethane. 4. The cosmetic composition according to claim 1, wherein:
the powder having a hydrophobized surface is one or more selected from the group consisting of: titanium dioxide, iron oxide and zinc oxide. 5. The cosmetic composition according to claim 1, wherein:
the powder having a hydrophobized surface is one or more selected from the group consisting of: titanium dioxide, iron oxide and zinc oxide each having a pigment grade. 6. The cosmetic composition according to claim 1, wherein:
the higher fatty acid is a C8 to C24, and the divalent metal is magnesium. 7. The cosmetic composition according to claim 6, wherein:
the higher fatty acid is a 12 to C22 linear or branched carboxylic acid. 8. The cosmetic composition, according to claim 1, wherein:
said composition is absent a silicone oil. 9. The cosmetic composition, according to claim 1, wherein:
the powder having a hydrophobized surface further comprises:
a pigment-grade powder selected from the group consisting of titanium dioxide, iron oxide and zinc oxide of pigment grade, and a microparticle powder selected from the group consisting of titanium dioxide microparticles, iron oxide microparticles and zinc oxide microparticles. 10. An oil-in-water type emulsified cosmetic composition, comprising:
an aqueous phase; an oily phase dispersed in the aqueous phase; and a powder dispersed in the oily phase; wherein the oily phase does not include a silicone oil and further comprises: (a) volatile hydrocarbon oil and (b) non-volatile hydrocarbon oil in a combined amount of 40% by mass or more with respect to the total oil content; wherein a blending ratio of said (b) non-volatile hydrocarbon oil to said (a) volatile hydrocarbon oil, [(b)/(a)], is within a range of 0 to 2.5; and wherein the powder further comprises:
a powder having a surface hydrophobized by a treatment with a metallic soap consisting of a higher fatty acid and a divalent metal or a composite treatment with a higher fatty acid and a divalent metal hydroxide. 11. The cosmetic composition, according to claim 10, wherein:
the powder having a hydrophobized surface further comprises:
a pigment-grade powder selected from the group consisting of titanium dioxide, iron oxide and zinc oxide of pigment grade, and a microparticle powder selected from the group consisting of titanium dioxide microparticles, iron oxide microparticles and zinc oxide microparticles. 12. An oil-in-water type emulsified cosmetic composition, comprising:
an aqueous phase; an oily phase dispersed in the aqueous phase; and a powder dispersed in the oily phase; wherein the oily phase further comprises: (a) volatile hydrocarbon oil and (b) non-volatile hydrocarbon oil in a combined amount of 40% by mass or more with respect to the total oil content, and does not include a silicone oil; wherein a blending ratio of said (b) non-volatile hydrocarbon oil to said (a) volatile hydrocarbon oil, [(b)/(a)], is within a range of 0 to 2.5; wherein the powder further comprises:
a powder having a surface hydrophobized by a treatment with a metallic soap consisting of a higher fatty acid and a divalent metal or a composite treatment with a higher fatty acid and a divalent metal hydroxide; and
wherein the powder having a hydrophobized surface further comprises a pigment-grade powder selected from the group consisting of titanium dioxide, iron oxide and zinc oxide of pigment grade, and a microparticle powder selected from the group consisting of titanium dioxide microparticles, iron oxide microparticles and zinc oxide microparticles. | 1,600 |
897 | 15,100,407 | 1,613 | The present invention relates to the use of a nutritional composition having a low amount of protein, such as less than 1.8 g/100 kcal for administration to infants of non-obese and non-overweight mothers so as to reduce the risk of developing metabolic syndrome, increased weight gain, increased fat deposition, overweight, obesity, insulin resistance, glucose intolerance or diabetes mellitus later in said infant's life. | 1. A method for reducing the risk of developing a disorder selected from the group consisting of metabolic syndrome, increased weight gain, increased fat deposition, overweight, obesity, insulin resistance, glucose intolerance and diabetes mellitus later in an infant's life comprising administering a nutritional composition comprising a protein source, a lipid source and a carbohydrate source, wherein the protein content is less than 1.8 g/100 kcal for use in administration to an infant born to a non-obese and non-overweight mother, in the first year of the life of the infant. 2. A method for obtaining a hormonal profile closer to that of breast fed infants in an infant fed formula comprising administering a nutritional composition comprising a protein source, a lipid source and a carbohydrate source, wherein the protein content is less than 1.8g/100 kcal and is administered to an infant born to a non-obese and non-overweight mother, in the first year of the life of the infant. 3. A method for reducing the protein burden on non-mature organs in an infant comprising administering a nutritional composition comprising a protein source, a lipid source and a carbohydrate source, wherein the protein content is less than 1.8g/100 kcal and is administered to an infant born to a non-obese and non-overweight mother, in the first year of the life of the infant. 4. A method for promoting a rate of growth in a non-breast fed infant which approximates to the rate of growth of a breast fed infant of the same age comprising administering a nutritional composition comprising a protein source, a lipid source and a carbohydrate source, wherein the protein content is less than 1.8 g/100 kcal for use in for administration to the infant born to a non-obese and non-overweight mother, in the first year of the life of the infant. 5. The method according to claim 1, wherein the energy density of the composition is from 600 to 680 kcal/litre. 6. The method according to claim 1, wherein the energy density of the composition is from 620 to 650 kcal/litre. 7. The method according to claim 1, wherein the energy density of the composition is from 650 to 680 kcal/litre. 8. The method according to claims 1, wherein the protein content of the composition is from 1.4 to 1.7 g/100 kcal. 9. The method according to claim 1, wherein the protein source includes casein and/or whey protein. 10. The method according to claim 1, wherein the protein source includes casein. 11. The method according to claim 1, wherein protein source has a casein to whey ratio from 30:70 to 70:30. 12. The method according to claim 1, wherein the whey protein is sweet whey from which the caseino-glycomacropeptide has been removed and the nutritional composition additionally includes free phenylalanine in an amount of up to 2.2%, free isoleucine in an amount of up to 0.92%, free tryptophan in an amount of up to 0.34% and free histidine in an amount of up to 0.19%, in each case as a percentage by weight of total protein content. 13. The method according to claim 1, wherein the protein(s) of the composition are fully or partially hydrolysed. 14. The method according to claim 1, wherein the protein(s) of the composition are intact. 15. The method according to claim 1, wherein the composition includes a probiotic strain in an amount of from 106 to 1011 cfu/g of composition (dry weight). 16. The method according to claim 2, wherein the energy density of the composition is from 600 to 680 kcal/litre. 17. The method according to claim 2, wherein the energy density of the composition is from 620 to 650 kcal/litre. 18. The method according to claim 2, wherein the energy density of the composition is from 650 to 680 kcal/litre. 19. The method according to claim 2, wherein the protein content of the composition is from 1.4 to 1.7 g/100 kcal. 20. The method according to claim 2, wherein the protein source includes casein and/or whey protein. 21. The method according to claim 2, wherein the protein source includes casein. 22. The method according to claim 2, wherein protein source has a casein to whey ratio from 30:70 to 70:30. 23. The method according to claim 2, wherein the protein comprises sweet whey from which the caseino-glycomacropeptide has been removed and the nutritional composition additionally includes free phenylalanine in an amount of up to 2.2%, free isoleucine in an amount of up to 0.92%, free tryptophan in an amount of up to 0.34% and free histidine in an amount of up to 0.19%, in each case as a percentage by weight of total protein content. 24. The method according to claim 2, wherein the protein(s) of the composition are fully or partially hydrolysed. 25. The method according to claim 2, wherein the protein(s) of the composition are intact. 26. The method according to claim 2, wherein the composition includes a probiotic strain in an amount of from 106 to 1011 cfu/g of composition (dry weight). 27. The method according to claim 3, wherein the energy density of the composition is from 600 to 680 kcal/litre. 28. The method according to claim 3, wherein the energy density of the composition is from 620 to 650 kcal/litre. 29. The method according to claim 3, wherein the energy density of the composition is from 650 to 680 kcal/litre. 30. The method according to claim 3, wherein the protein content of the composition is from 1.4 to 1.7 g/100 kcal. 31. The method according to claim 3, wherein the protein source includes casein and/or whey protein. 32. The method according to claim 3, wherein the protein source includes casein. 33. The method according to claim 3, wherein protein source has a casein to whey ratio from 30:70 to 70:30. 34. The method according to claim 3, wherein the protein comprises sweet whey from which the caseino-glycomacropeptide has been removed and the nutritional composition additionally includes free phenylalanine in an amount of up to 2.2%, free isoleucine in an amount of up to 0.92%, free tryptophan in an amount of up to 0.34% and free histidine in an amount of up to 0.19%, in each case as a percentage by weight of total protein content. 35. The method according to claim 3, wherein the protein(s) of the composition are fully or partially hydrolysed. 36. The method according to claim 3, wherein the protein(s) of the composition are intact. 37. The method according to claim 3, wherein the composition includes a probiotic strain in an amount of from 106 to 1011 cfu/g of composition (dry weight). 38. The method according to claim 4, wherein the energy density of the composition is from 600 to 680 kcal/litre. 39. The method according to claim 4, wherein the energy density of the composition is from 620 to 650 kcal/litre. 40. The method according to claim 4, wherein the energy density of the composition is from 650 to 680 kcal/litre. 41. The method according to claim 4, wherein the protein content of the composition is from 1.4 to 1.7 g/100 kcal. 42. The method according to claim 4, wherein the protein source includes casein and/or whey protein. 43. The method according to claim 4, wherein the protein source includes casein. 44. The method according to claim 4, wherein protein source has a casein to whey ratio from 30:70 to 70:30. 45. The method according to claim 4, wherein the protein comprises sweet whey from which the caseino-glycomacropeptide has been removed and the nutritional composition additionally includes free phenylalanine in an amount of up to 2.2%, free isoleucine in an amount of up to 0.92%, free tryptophan in an amount of up to 0.34% and free histidine in an amount of up to 0.19%, in each case as a percentage by weight of total protein content. 46. The method according to claim 4, wherein the protein(s) of the composition are fully or partially hydrolysed. 47. The method according to claim 4, wherein the protein(s) of the composition are intact. 48. The method according to claim 4, wherein the composition includes a probiotic strain in an amount of from 106 to 1011 cfu/g of composition (dry weight). | The present invention relates to the use of a nutritional composition having a low amount of protein, such as less than 1.8 g/100 kcal for administration to infants of non-obese and non-overweight mothers so as to reduce the risk of developing metabolic syndrome, increased weight gain, increased fat deposition, overweight, obesity, insulin resistance, glucose intolerance or diabetes mellitus later in said infant's life.1. A method for reducing the risk of developing a disorder selected from the group consisting of metabolic syndrome, increased weight gain, increased fat deposition, overweight, obesity, insulin resistance, glucose intolerance and diabetes mellitus later in an infant's life comprising administering a nutritional composition comprising a protein source, a lipid source and a carbohydrate source, wherein the protein content is less than 1.8 g/100 kcal for use in administration to an infant born to a non-obese and non-overweight mother, in the first year of the life of the infant. 2. A method for obtaining a hormonal profile closer to that of breast fed infants in an infant fed formula comprising administering a nutritional composition comprising a protein source, a lipid source and a carbohydrate source, wherein the protein content is less than 1.8g/100 kcal and is administered to an infant born to a non-obese and non-overweight mother, in the first year of the life of the infant. 3. A method for reducing the protein burden on non-mature organs in an infant comprising administering a nutritional composition comprising a protein source, a lipid source and a carbohydrate source, wherein the protein content is less than 1.8g/100 kcal and is administered to an infant born to a non-obese and non-overweight mother, in the first year of the life of the infant. 4. A method for promoting a rate of growth in a non-breast fed infant which approximates to the rate of growth of a breast fed infant of the same age comprising administering a nutritional composition comprising a protein source, a lipid source and a carbohydrate source, wherein the protein content is less than 1.8 g/100 kcal for use in for administration to the infant born to a non-obese and non-overweight mother, in the first year of the life of the infant. 5. The method according to claim 1, wherein the energy density of the composition is from 600 to 680 kcal/litre. 6. The method according to claim 1, wherein the energy density of the composition is from 620 to 650 kcal/litre. 7. The method according to claim 1, wherein the energy density of the composition is from 650 to 680 kcal/litre. 8. The method according to claims 1, wherein the protein content of the composition is from 1.4 to 1.7 g/100 kcal. 9. The method according to claim 1, wherein the protein source includes casein and/or whey protein. 10. The method according to claim 1, wherein the protein source includes casein. 11. The method according to claim 1, wherein protein source has a casein to whey ratio from 30:70 to 70:30. 12. The method according to claim 1, wherein the whey protein is sweet whey from which the caseino-glycomacropeptide has been removed and the nutritional composition additionally includes free phenylalanine in an amount of up to 2.2%, free isoleucine in an amount of up to 0.92%, free tryptophan in an amount of up to 0.34% and free histidine in an amount of up to 0.19%, in each case as a percentage by weight of total protein content. 13. The method according to claim 1, wherein the protein(s) of the composition are fully or partially hydrolysed. 14. The method according to claim 1, wherein the protein(s) of the composition are intact. 15. The method according to claim 1, wherein the composition includes a probiotic strain in an amount of from 106 to 1011 cfu/g of composition (dry weight). 16. The method according to claim 2, wherein the energy density of the composition is from 600 to 680 kcal/litre. 17. The method according to claim 2, wherein the energy density of the composition is from 620 to 650 kcal/litre. 18. The method according to claim 2, wherein the energy density of the composition is from 650 to 680 kcal/litre. 19. The method according to claim 2, wherein the protein content of the composition is from 1.4 to 1.7 g/100 kcal. 20. The method according to claim 2, wherein the protein source includes casein and/or whey protein. 21. The method according to claim 2, wherein the protein source includes casein. 22. The method according to claim 2, wherein protein source has a casein to whey ratio from 30:70 to 70:30. 23. The method according to claim 2, wherein the protein comprises sweet whey from which the caseino-glycomacropeptide has been removed and the nutritional composition additionally includes free phenylalanine in an amount of up to 2.2%, free isoleucine in an amount of up to 0.92%, free tryptophan in an amount of up to 0.34% and free histidine in an amount of up to 0.19%, in each case as a percentage by weight of total protein content. 24. The method according to claim 2, wherein the protein(s) of the composition are fully or partially hydrolysed. 25. The method according to claim 2, wherein the protein(s) of the composition are intact. 26. The method according to claim 2, wherein the composition includes a probiotic strain in an amount of from 106 to 1011 cfu/g of composition (dry weight). 27. The method according to claim 3, wherein the energy density of the composition is from 600 to 680 kcal/litre. 28. The method according to claim 3, wherein the energy density of the composition is from 620 to 650 kcal/litre. 29. The method according to claim 3, wherein the energy density of the composition is from 650 to 680 kcal/litre. 30. The method according to claim 3, wherein the protein content of the composition is from 1.4 to 1.7 g/100 kcal. 31. The method according to claim 3, wherein the protein source includes casein and/or whey protein. 32. The method according to claim 3, wherein the protein source includes casein. 33. The method according to claim 3, wherein protein source has a casein to whey ratio from 30:70 to 70:30. 34. The method according to claim 3, wherein the protein comprises sweet whey from which the caseino-glycomacropeptide has been removed and the nutritional composition additionally includes free phenylalanine in an amount of up to 2.2%, free isoleucine in an amount of up to 0.92%, free tryptophan in an amount of up to 0.34% and free histidine in an amount of up to 0.19%, in each case as a percentage by weight of total protein content. 35. The method according to claim 3, wherein the protein(s) of the composition are fully or partially hydrolysed. 36. The method according to claim 3, wherein the protein(s) of the composition are intact. 37. The method according to claim 3, wherein the composition includes a probiotic strain in an amount of from 106 to 1011 cfu/g of composition (dry weight). 38. The method according to claim 4, wherein the energy density of the composition is from 600 to 680 kcal/litre. 39. The method according to claim 4, wherein the energy density of the composition is from 620 to 650 kcal/litre. 40. The method according to claim 4, wherein the energy density of the composition is from 650 to 680 kcal/litre. 41. The method according to claim 4, wherein the protein content of the composition is from 1.4 to 1.7 g/100 kcal. 42. The method according to claim 4, wherein the protein source includes casein and/or whey protein. 43. The method according to claim 4, wherein the protein source includes casein. 44. The method according to claim 4, wherein protein source has a casein to whey ratio from 30:70 to 70:30. 45. The method according to claim 4, wherein the protein comprises sweet whey from which the caseino-glycomacropeptide has been removed and the nutritional composition additionally includes free phenylalanine in an amount of up to 2.2%, free isoleucine in an amount of up to 0.92%, free tryptophan in an amount of up to 0.34% and free histidine in an amount of up to 0.19%, in each case as a percentage by weight of total protein content. 46. The method according to claim 4, wherein the protein(s) of the composition are fully or partially hydrolysed. 47. The method according to claim 4, wherein the protein(s) of the composition are intact. 48. The method according to claim 4, wherein the composition includes a probiotic strain in an amount of from 106 to 1011 cfu/g of composition (dry weight). | 1,600 |
898 | 15,500,493 | 1,613 | Technical Problem
A problem of the present invention is, in one aspect, to provide a capsule formulation including an active ingredient and the like that may deteriorate upon contacting an acid, wherein the capsule formulation makes it possible not to deteriorate the active ingredient and the like by a gastric acid which enters into a capsule film.
Technical Solution
A capsule formulation comprising an active ingredient and oil, wherein said capsule of said formulation is an enteric capsule comprising a water soluble film forming polymer and gellan gum; said oil is an oil acceptable for pharmaceuticals or foods; and said active ingredient is encapsulated in said capsule together with said oil, and the production method thereof, are provided. | 1. A capsule formulation, comprising:
an enteric capsule comprising a water soluble film forming polymer and gellan gum; an active ingredient; and an oil acceptable for pharmaceuticals or foods; wherein the active ingredient and the oil are encapsulated by the enteric capsule. 2. The capsule formulation according to claim 1, wherein the enteric capsule does not have an enteric coating. 3. The capsule formulation according to claim 1, wherein the water soluble film forming polymer and the gellan gum are present in the enteric capsule at a weight ratio of 4 to 15 parts by weight of gellan gum relative to 100 parts by weight of the water soluble film forming polymer. 4. The capsule formulation according to claim 1, wherein the enteric capsule is a hard enteric capsule having a body portion and a cap portion, and a fitted part of the body portion and the cap portion is sealed by band-sealing. 5. The capsule formulation according to claim 1, wherein the oil is a plant oil, an animal oil, a fish oil or a mineral oil. 6. The capsule formulation according to claim 1, wherein the oil is an edible oil, and the edible oil is selected from medium-chain triglyceride, safflower oil, olive oil, soybean oil, linseed oil, rice germ oil, wheat germ oil, coconut oil, corn oil, cottonseed oil, palm oil, palm nucleus oil, peanut oil, rapeseed oil, sesame oil, sunflower oil, almond oil, cashew oil, hazelnut oil, macadamia nut oil, mongongo oil, pecan oil, pine nut oil, pistachio oil, walnut oil, calabash seed oil, buffalo gourd oil, pumpkin seed oil, watermelon seed oil, acai berry extract, blackcurrant seed oil, borage seed oil, evening primrose oil, amaranth oil, apricot oil, apple seed oil, argan oil, artichoke oil, avocado oil, babassu oil, ben oil, cape chestnut oil, carob oil, cohune palm oil, coriander oil, dica oil, false flax oil, grape seed oil, hemp oil, kapok seed oil, lallemantia oil, marula oil, meadowfoam seed oil, mustard oil, okra seed oil (hibiscus oil), papaya oil, perilla oil, poppyseed oil, prune kernel oil, quinoa oil, ramtil oil, camellia oil, thistle oil, tomato oil, saw palmetto oil, krill oil, borage oil, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), vitamin A oil, vitamin D oil, vitamin E oil, vitamin K oil, lecithin, and any combination thereof. 7. The capsule formulation according to claim 1, wherein an amount of the oil in the whole content encapsulated in the enteric capsule is not less than 40% by weight. 8. The capsule formulation according to claim 1, wherein the active ingredient is dispersed or dissolved in the oil. 9. The capsule formulation according to claim 1, wherein a surfactant acceptable for pharmaceuticals or foods is further encapsulated in the enteric capsule. 10. The capsule formulation according to claim 9, wherein the active ingredient is emulsified in the oil by the surfactant. 11. The capsule formulation according to claim 1, wherein the active ingredient is a pharmaceutical, a dietary supplement, peptides, amino acids, proteins, glycoproteins, enzyme fermented foods, enzymes, coenzymes, vitamins, minerals, living microbes, plant extracts, natural organic matters, or any combination thereof. 12. A method for producing a capsule formulation, comprising:
dispersing or dissolving an active ingredient in an oil acceptable for pharmaceuticals or foods; and encapsulating the oil having the dispersed active ingredient into an enteric capsule comprising a water soluble film forming polymer and gellan gum. 13. The method for producing a capsule formulation according to claim 12,
wherein the enteric capsule is a hard enteric capsule having a body portion and a cap portion; and the method comprises sealing the fitted part of the body portion and the cap portion by band-sealing after encapsulation into the enteric capsule. 14. A capsule formulation produced according to the method of claim 12. | Technical Problem
A problem of the present invention is, in one aspect, to provide a capsule formulation including an active ingredient and the like that may deteriorate upon contacting an acid, wherein the capsule formulation makes it possible not to deteriorate the active ingredient and the like by a gastric acid which enters into a capsule film.
Technical Solution
A capsule formulation comprising an active ingredient and oil, wherein said capsule of said formulation is an enteric capsule comprising a water soluble film forming polymer and gellan gum; said oil is an oil acceptable for pharmaceuticals or foods; and said active ingredient is encapsulated in said capsule together with said oil, and the production method thereof, are provided.1. A capsule formulation, comprising:
an enteric capsule comprising a water soluble film forming polymer and gellan gum; an active ingredient; and an oil acceptable for pharmaceuticals or foods; wherein the active ingredient and the oil are encapsulated by the enteric capsule. 2. The capsule formulation according to claim 1, wherein the enteric capsule does not have an enteric coating. 3. The capsule formulation according to claim 1, wherein the water soluble film forming polymer and the gellan gum are present in the enteric capsule at a weight ratio of 4 to 15 parts by weight of gellan gum relative to 100 parts by weight of the water soluble film forming polymer. 4. The capsule formulation according to claim 1, wherein the enteric capsule is a hard enteric capsule having a body portion and a cap portion, and a fitted part of the body portion and the cap portion is sealed by band-sealing. 5. The capsule formulation according to claim 1, wherein the oil is a plant oil, an animal oil, a fish oil or a mineral oil. 6. The capsule formulation according to claim 1, wherein the oil is an edible oil, and the edible oil is selected from medium-chain triglyceride, safflower oil, olive oil, soybean oil, linseed oil, rice germ oil, wheat germ oil, coconut oil, corn oil, cottonseed oil, palm oil, palm nucleus oil, peanut oil, rapeseed oil, sesame oil, sunflower oil, almond oil, cashew oil, hazelnut oil, macadamia nut oil, mongongo oil, pecan oil, pine nut oil, pistachio oil, walnut oil, calabash seed oil, buffalo gourd oil, pumpkin seed oil, watermelon seed oil, acai berry extract, blackcurrant seed oil, borage seed oil, evening primrose oil, amaranth oil, apricot oil, apple seed oil, argan oil, artichoke oil, avocado oil, babassu oil, ben oil, cape chestnut oil, carob oil, cohune palm oil, coriander oil, dica oil, false flax oil, grape seed oil, hemp oil, kapok seed oil, lallemantia oil, marula oil, meadowfoam seed oil, mustard oil, okra seed oil (hibiscus oil), papaya oil, perilla oil, poppyseed oil, prune kernel oil, quinoa oil, ramtil oil, camellia oil, thistle oil, tomato oil, saw palmetto oil, krill oil, borage oil, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), vitamin A oil, vitamin D oil, vitamin E oil, vitamin K oil, lecithin, and any combination thereof. 7. The capsule formulation according to claim 1, wherein an amount of the oil in the whole content encapsulated in the enteric capsule is not less than 40% by weight. 8. The capsule formulation according to claim 1, wherein the active ingredient is dispersed or dissolved in the oil. 9. The capsule formulation according to claim 1, wherein a surfactant acceptable for pharmaceuticals or foods is further encapsulated in the enteric capsule. 10. The capsule formulation according to claim 9, wherein the active ingredient is emulsified in the oil by the surfactant. 11. The capsule formulation according to claim 1, wherein the active ingredient is a pharmaceutical, a dietary supplement, peptides, amino acids, proteins, glycoproteins, enzyme fermented foods, enzymes, coenzymes, vitamins, minerals, living microbes, plant extracts, natural organic matters, or any combination thereof. 12. A method for producing a capsule formulation, comprising:
dispersing or dissolving an active ingredient in an oil acceptable for pharmaceuticals or foods; and encapsulating the oil having the dispersed active ingredient into an enteric capsule comprising a water soluble film forming polymer and gellan gum. 13. The method for producing a capsule formulation according to claim 12,
wherein the enteric capsule is a hard enteric capsule having a body portion and a cap portion; and the method comprises sealing the fitted part of the body portion and the cap portion by band-sealing after encapsulation into the enteric capsule. 14. A capsule formulation produced according to the method of claim 12. | 1,600 |
899 | 14,855,814 | 1,631 | A method for predicting characteristics of a compound includes collecting a first experimental information database for characteristics of reference compounds according to a quantum phenomenon, collecting a simulation database for characteristics of the reference compounds according to the quantum phenomenon by applying density functional theory methods, comparing the simulation database to the first experimental information database for each reference compound to calculate accuracy of the simulation database, clustering the reference compounds into clusters based on the accuracy of the simulation database and designating a proper density functional theory method for each cluster, comparing a similarity between a test compound to predict a characteristic according to the quantum phenomenon and the reference compounds included in each cluster, determining a proper density functional theory method for the test compound according to the similarity, and conducting a simulation with the test compound according to the determined density functional theory method. | 1. A method for predicting a characteristic of a compound, the method comprising:
collecting a first experimental information database for characteristics of a plurality of reference compounds according to a quantum phenomenon; collecting a simulation database for characteristics of the plurality of reference compounds according to the quantum phenomenon by applying a plurality of density functional theory methods; comparing the simulation database to the first experimental information database for each reference compound of the plurality of reference compounds to calculate accuracy of the simulation database; clustering the plurality of reference compounds into a plurality of clusters based on the accuracy of the simulation database and designating a proper density functional theory method for each cluster of the plurality of clusters; comparing a similarity between a test compound to predict a characteristic according to the quantum phenomenon and the reference compounds included in each cluster of the plurality of clusters; determining a proper density functional theory method for the test compound according to the similarity; and conducting a simulation with the test compound according to the determined density functional theory method. 2. The method of claim 1, wherein the collecting a first experimental information database for characteristics of a plurality of reference compounds according to a quantum phenomenon collects the first experimental information database for absorbance according to a wavelength of the plurality of reference compounds. 3. The method of claim 2, wherein the collecting the first experimental information database for absorbance according to a wavelength of the plurality of reference compounds collects the first experimental information database for a full width at half maximum (FWHM) of a light absorption spectrum in a visible ray region. 4. The method of claim 3, wherein the collecting the first experimental information database for a full width at half maximum (FWHM) of a light absorption spectrum in a visible ray region collects the first experimental information database for the full width at half maximum (FWHM) of the light absorption spectrum in the visible ray region by UV-Vis spectroscopy. 5. The method of claim 4, wherein the collecting the first experimental information database for a full width at half maximum (FWHM) of a light absorption spectrum in a visible ray region collects the experimental information for the full width at half maximum (FWHM) of the light absorption spectrum in the visible ray region by preparing the plurality of reference compounds as a solution, the plurality of reference compounds having the full width at half maximum (FWHM) of about 40 nm to about 110 nm. 6. The method of claim 5, wherein
the collecting a simulation database for characteristics of the plurality of reference compounds according to the quantum phenomenon by applying a plurality of density functional theory methods collects the simulation database for characteristics of the plurality of reference compounds according to the quantum phenomenon by applying a first density functional theory method and a second density functional theory method, the clustering clusters the plurality of reference compounds into a first group of clusters having higher accuracy of the simulation database of the first density functional theory method and a second group of clusters having a higher accuracy of the simulation database of the second density functional theory method, the clustering clusters the plurality of reference compounds included in the first group of clusters having a full width at half maximum (FWHM) of about 40 nm to about 110 nm when applying the first density functional theory method, and the clustering clusters the plurality of reference compounds included in the second group of clusters having a full width at half maximum (FWHM) of about 40 nm to about 110 nm when applying the second density functional theory method. 7. The method of claim 6, wherein the clustering predicts characteristics of a compound of the plurality of reference compounds included in the first group of clusters, the compound having an arylamine moiety substituted with at least two aryl groups. 8. The method of claim 1, wherein the comparing the simulation database to the first experimental information database for each reference compound of the plurality of reference compounds calculates the accuracy of the simulation database to be greater than or equal to about 80%. 9. The method of claim 1, wherein the comparing a similarity between a test compound to predict a characteristic according to the quantum phenomenon and the plurality of reference compounds included in each cluster of the plurality of clusters compares a structural similarity of the test compound and the plurality of reference compounds. 10. The method of claim 1, wherein prior to the clustering, further comprising:
clustering the plurality of reference compounds according to a structural similarity after the comparing the simulation database to the first experimental information database for each reference compound of the plurality of reference compounds. 11. The method of claim 1, further comprising:
separating a reference compound that does not cluster from the plurality of reference compounds after the comparing the simulation database to the first experimental information database for each reference compound of the plurality of reference compounds. 12. The method of claim 1, further comprising:
conducting an experiment with the test compound to collect a second experimental information database; and updating the test compound to the plurality of reference compounds using the second experimental information database. 13. The method of claim 1, wherein the plurality of reference compounds and the test compound are one of p-type and n-type light-absorbing materials. 14. A system of predicting a characteristic of a compound according to the method of claim 1. 15. A system for predicting a characteristic of a compound, the system comprising:
a non-transitory computer readable medium having a computer program logic embodied thereon, the computer program logic configured to,
collect a simulation database for characteristics of a plurality of reference compounds according to a quantum phenomenon by applying an experimental information database for characteristics of the plurality of reference compounds according to the quantum phenomenon and a plurality of density functional theory methods;
calculate accuracy of the simulation database by comparing the experimental information database to the simulation database;
cluster the plurality of reference compounds based on the accuracy of the simulation database and designating a proper density functional theory method for each cluster;
compare a similarity between the test compound and the reference compounds included in each cluster to predict the characteristics according to the quantum phenomenon;
determine a proper density functional theory method for the test compound according to the similarity; and
conduct a simulation of the test compound according to the determined density functional theory method. 16. The system of claim 15, wherein the characteristics according to the quantum phenomenon include a full width at half maximum (FWHM) of a light absorption spectrum in a visible ray region. 17. The system of claim 16, wherein
the plurality of density functional theory methods include a first density functional theory method and a second density functional theory method, the cluster includes a first group of clusters having higher accuracy of the simulation database of the first density functional theory method and a second group of clusters having higher accuracy of the simulation database of the second density functional theory method, the plurality of reference compounds included in the first group of clusters have a full width at half maximum (FWHM) of about 40 nm to about 110 nm when applying the first density functional theory method, and the plurality of reference compounds included in the second group of clusters have a full width at half maximum (FWHM) of about 40 nm to about 110 nm when applying the second density functional theory method. | A method for predicting characteristics of a compound includes collecting a first experimental information database for characteristics of reference compounds according to a quantum phenomenon, collecting a simulation database for characteristics of the reference compounds according to the quantum phenomenon by applying density functional theory methods, comparing the simulation database to the first experimental information database for each reference compound to calculate accuracy of the simulation database, clustering the reference compounds into clusters based on the accuracy of the simulation database and designating a proper density functional theory method for each cluster, comparing a similarity between a test compound to predict a characteristic according to the quantum phenomenon and the reference compounds included in each cluster, determining a proper density functional theory method for the test compound according to the similarity, and conducting a simulation with the test compound according to the determined density functional theory method.1. A method for predicting a characteristic of a compound, the method comprising:
collecting a first experimental information database for characteristics of a plurality of reference compounds according to a quantum phenomenon; collecting a simulation database for characteristics of the plurality of reference compounds according to the quantum phenomenon by applying a plurality of density functional theory methods; comparing the simulation database to the first experimental information database for each reference compound of the plurality of reference compounds to calculate accuracy of the simulation database; clustering the plurality of reference compounds into a plurality of clusters based on the accuracy of the simulation database and designating a proper density functional theory method for each cluster of the plurality of clusters; comparing a similarity between a test compound to predict a characteristic according to the quantum phenomenon and the reference compounds included in each cluster of the plurality of clusters; determining a proper density functional theory method for the test compound according to the similarity; and conducting a simulation with the test compound according to the determined density functional theory method. 2. The method of claim 1, wherein the collecting a first experimental information database for characteristics of a plurality of reference compounds according to a quantum phenomenon collects the first experimental information database for absorbance according to a wavelength of the plurality of reference compounds. 3. The method of claim 2, wherein the collecting the first experimental information database for absorbance according to a wavelength of the plurality of reference compounds collects the first experimental information database for a full width at half maximum (FWHM) of a light absorption spectrum in a visible ray region. 4. The method of claim 3, wherein the collecting the first experimental information database for a full width at half maximum (FWHM) of a light absorption spectrum in a visible ray region collects the first experimental information database for the full width at half maximum (FWHM) of the light absorption spectrum in the visible ray region by UV-Vis spectroscopy. 5. The method of claim 4, wherein the collecting the first experimental information database for a full width at half maximum (FWHM) of a light absorption spectrum in a visible ray region collects the experimental information for the full width at half maximum (FWHM) of the light absorption spectrum in the visible ray region by preparing the plurality of reference compounds as a solution, the plurality of reference compounds having the full width at half maximum (FWHM) of about 40 nm to about 110 nm. 6. The method of claim 5, wherein
the collecting a simulation database for characteristics of the plurality of reference compounds according to the quantum phenomenon by applying a plurality of density functional theory methods collects the simulation database for characteristics of the plurality of reference compounds according to the quantum phenomenon by applying a first density functional theory method and a second density functional theory method, the clustering clusters the plurality of reference compounds into a first group of clusters having higher accuracy of the simulation database of the first density functional theory method and a second group of clusters having a higher accuracy of the simulation database of the second density functional theory method, the clustering clusters the plurality of reference compounds included in the first group of clusters having a full width at half maximum (FWHM) of about 40 nm to about 110 nm when applying the first density functional theory method, and the clustering clusters the plurality of reference compounds included in the second group of clusters having a full width at half maximum (FWHM) of about 40 nm to about 110 nm when applying the second density functional theory method. 7. The method of claim 6, wherein the clustering predicts characteristics of a compound of the plurality of reference compounds included in the first group of clusters, the compound having an arylamine moiety substituted with at least two aryl groups. 8. The method of claim 1, wherein the comparing the simulation database to the first experimental information database for each reference compound of the plurality of reference compounds calculates the accuracy of the simulation database to be greater than or equal to about 80%. 9. The method of claim 1, wherein the comparing a similarity between a test compound to predict a characteristic according to the quantum phenomenon and the plurality of reference compounds included in each cluster of the plurality of clusters compares a structural similarity of the test compound and the plurality of reference compounds. 10. The method of claim 1, wherein prior to the clustering, further comprising:
clustering the plurality of reference compounds according to a structural similarity after the comparing the simulation database to the first experimental information database for each reference compound of the plurality of reference compounds. 11. The method of claim 1, further comprising:
separating a reference compound that does not cluster from the plurality of reference compounds after the comparing the simulation database to the first experimental information database for each reference compound of the plurality of reference compounds. 12. The method of claim 1, further comprising:
conducting an experiment with the test compound to collect a second experimental information database; and updating the test compound to the plurality of reference compounds using the second experimental information database. 13. The method of claim 1, wherein the plurality of reference compounds and the test compound are one of p-type and n-type light-absorbing materials. 14. A system of predicting a characteristic of a compound according to the method of claim 1. 15. A system for predicting a characteristic of a compound, the system comprising:
a non-transitory computer readable medium having a computer program logic embodied thereon, the computer program logic configured to,
collect a simulation database for characteristics of a plurality of reference compounds according to a quantum phenomenon by applying an experimental information database for characteristics of the plurality of reference compounds according to the quantum phenomenon and a plurality of density functional theory methods;
calculate accuracy of the simulation database by comparing the experimental information database to the simulation database;
cluster the plurality of reference compounds based on the accuracy of the simulation database and designating a proper density functional theory method for each cluster;
compare a similarity between the test compound and the reference compounds included in each cluster to predict the characteristics according to the quantum phenomenon;
determine a proper density functional theory method for the test compound according to the similarity; and
conduct a simulation of the test compound according to the determined density functional theory method. 16. The system of claim 15, wherein the characteristics according to the quantum phenomenon include a full width at half maximum (FWHM) of a light absorption spectrum in a visible ray region. 17. The system of claim 16, wherein
the plurality of density functional theory methods include a first density functional theory method and a second density functional theory method, the cluster includes a first group of clusters having higher accuracy of the simulation database of the first density functional theory method and a second group of clusters having higher accuracy of the simulation database of the second density functional theory method, the plurality of reference compounds included in the first group of clusters have a full width at half maximum (FWHM) of about 40 nm to about 110 nm when applying the first density functional theory method, and the plurality of reference compounds included in the second group of clusters have a full width at half maximum (FWHM) of about 40 nm to about 110 nm when applying the second density functional theory method. | 1,600 |
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