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1,200 | 15,141,542 | 1,611 |
Compositions and methods of using them for protecting skin, hair and nails against exposure to high energy visible light are described. The compositions can include one or more natural oils or extracts which are effective to absorb the high energy visible light at least to some degree.
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1. A method of protecting cellular damage of an animal cell from exposure to incident high energy light comprising a wavelength of about 380 nm to about 500 nm, the method comprising topically administering a composition to the animal cell comprising at least one natural oil or extract present in an effective amount to provide a HEV/VIS ratio of greater than or equal to 1.5 at an area of the animal cell where the composition has been topically administered. 2. The method of claim 1, further comprising selecting the natural oil or extract from the group consisting of extra virgin olive oil, wheat germ oil, sunflower oil, flax seed oil, rosehip oil, carrot seed oil, apricot seed oil, pumpkin seed oil, hemp oil, jojoba oil, argan oil, cranberry oil, broccoli seed oil, pomegranate oil, evening primrose oil, red raspberry oil, black raspberry oil, sea buckthorn berry oil, sea buckthorn seed oil, sesame oil, turmeric oil, cumin oil, marula oil, chia seed oil, shea butter, chaga extract and bees wax. 3. The method of claim 1, further comprising configuring the composition to comprise at least two natural oils or extracts or their combination. 4. The method of claim 3, further comprising selecting each of the two natural oils or extract to independently be one of extra virgin olive oil, wheat germ oil, sunflower oil, flax seed oil, rosehip oil, carrot seed oil, apricot seed oil, pumpkin seed oil, hemp oil, jojoba oil, argan oil, cranberry oil, broccoli seed oil, pomegranate oil, evening primrose oil, red raspberry oil, black raspberry oil, sea buckthorn oil, sesame oil, turmeric oil, cumin oil, marula oil, chia seed oil, shea butter, chaga extract and bees wax, wherein the two natural oils are different oils and wherein the amount of each of the two natural oils is selected so the composition absorbs about 30% of the incident high energy light. 5. The method of claim 1, further comprising configuring the composition to comprise at least three natural oils or extracts or their combination. 6. The method of claim 5, further comprising selecting each of the three natural oils or extracts to independently be one of extra virgin olive oil, wheat germ oil, sunflower oil, flax seed oil, rosehip oil, carrot seed oil, apricot seed oil, pumpkin seed oil, hemp oil, jojoba oil, argan oil, cranberry oil, broccoli seed oil, pomegranate oil, evening primrose oil, red raspberry oil, black raspberry oil, sea buckthorn oil, sesame oil, turmeric oil, cumin oil, marula oil, chia seed oil, shea butter, chaga extract and bees wax, wherein the three natural oils are different oils and wherein the amount of each of the three natural oils is selected to provide a HEV/VIS ratio for the total composition of greater than or equal to 1.5 at an area of the animal cell where the composition has been topically administered. 7. The method of claim 1, further comprising configuring the composition to comprise at least four natural oils or extracts or their combination. 8. The method of claim 7, further comprising selecting each of the four natural oils or extracts to independently be one of extra virgin olive oil, wheat germ oil, sunflower oil, flax seed oil, rosehip oil, carrot seed oil, apricot seed oil, pumpkin seed oil, hemp oil, jojoba oil, argan oil, cranberry oil, broccoli seed oil, pomegranate oil, evening primrose oil, red raspberry oil, black raspberry oil, sea buckthorn oil, sesame oil, turmeric oil, cumin oil, marula oil, chia seed oil, shea butter, chaga extract and bees wax, wherein the four natural oils are different oils and wherein the amount of each of the four natural oils is selected to provide a HEV/VIS ratio for the total composition of greater than or equal to 1.5 at an area of the animal cell where the composition has been topically administered. 9. The method of claim 1, further comprising configuring the composition to comprise at least one Group A natural oil and at least one Group B natural oil. 10. The method of claim 1, further comprising selecting the at least one natural oil from Type I oils. 11. The method of claim 10, further comprising further configuring the composition with at least one Type II oil. 12. The method of claim 11, further comprising further configuring the composition with at least one Type III oil. 13. The method of claim 11, further comprising configuring the composition with at least one booster. 14. The method of claim 13, in which the booster is selected from the group consisting of chaga extract, cumin oil, seabuckthorn oil/extract, pomegranate seed oil, turmeric oil, green tea extracts, berry extracts/oils, rosehip oil, cranberry oil, broccoli seed oil, grape seed extract/oil, extra virgin olive oil, clove oil and cinnamon bark oil. 15. The method of claim 1, further comprising configuring the composition with at least one carrier effective to permit topical administration of the composition. 16. The method of claim 1, further comprising configuring the carrier to enhance transport of the composition into cells. 17. The method of claim 1, further comprising configuring the composition with a first natural oil that absorbs at least 30% of the incident high energy light having a wavelength of about 380-400 nm that is incident on the area of the animal cell where the composition has been topically administered. 18. The method of claim 17, further comprising configuring the composition with a second natural oil that absorbs at least 30% of the incident high energy light having a wavelength of about 400-440 nm that is incident on the area of the animal cell where the composition has been topically administered. 19. The method of claim 18, further comprising configuring the composition with a third natural oil that absorbs at least 30% of the incident high energy light having a wavelength of about 440-500 nm that is incident on the area of the animal cell where the composition has been topically administered. 20. The method of claim 1, further comprising configuring the composition with at least one of (i) an additional component effective to absorb incident light having a wavelength below 380 nm, (ii) a booster effective to reduce reactive oxygen species or (iii) particles effective to scatter light comprising a wavelength of about 380 nm to about 500 nm. 21-131. (canceled)
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Compositions and methods of using them for protecting skin, hair and nails against exposure to high energy visible light are described. The compositions can include one or more natural oils or extracts which are effective to absorb the high energy visible light at least to some degree.1. A method of protecting cellular damage of an animal cell from exposure to incident high energy light comprising a wavelength of about 380 nm to about 500 nm, the method comprising topically administering a composition to the animal cell comprising at least one natural oil or extract present in an effective amount to provide a HEV/VIS ratio of greater than or equal to 1.5 at an area of the animal cell where the composition has been topically administered. 2. The method of claim 1, further comprising selecting the natural oil or extract from the group consisting of extra virgin olive oil, wheat germ oil, sunflower oil, flax seed oil, rosehip oil, carrot seed oil, apricot seed oil, pumpkin seed oil, hemp oil, jojoba oil, argan oil, cranberry oil, broccoli seed oil, pomegranate oil, evening primrose oil, red raspberry oil, black raspberry oil, sea buckthorn berry oil, sea buckthorn seed oil, sesame oil, turmeric oil, cumin oil, marula oil, chia seed oil, shea butter, chaga extract and bees wax. 3. The method of claim 1, further comprising configuring the composition to comprise at least two natural oils or extracts or their combination. 4. The method of claim 3, further comprising selecting each of the two natural oils or extract to independently be one of extra virgin olive oil, wheat germ oil, sunflower oil, flax seed oil, rosehip oil, carrot seed oil, apricot seed oil, pumpkin seed oil, hemp oil, jojoba oil, argan oil, cranberry oil, broccoli seed oil, pomegranate oil, evening primrose oil, red raspberry oil, black raspberry oil, sea buckthorn oil, sesame oil, turmeric oil, cumin oil, marula oil, chia seed oil, shea butter, chaga extract and bees wax, wherein the two natural oils are different oils and wherein the amount of each of the two natural oils is selected so the composition absorbs about 30% of the incident high energy light. 5. The method of claim 1, further comprising configuring the composition to comprise at least three natural oils or extracts or their combination. 6. The method of claim 5, further comprising selecting each of the three natural oils or extracts to independently be one of extra virgin olive oil, wheat germ oil, sunflower oil, flax seed oil, rosehip oil, carrot seed oil, apricot seed oil, pumpkin seed oil, hemp oil, jojoba oil, argan oil, cranberry oil, broccoli seed oil, pomegranate oil, evening primrose oil, red raspberry oil, black raspberry oil, sea buckthorn oil, sesame oil, turmeric oil, cumin oil, marula oil, chia seed oil, shea butter, chaga extract and bees wax, wherein the three natural oils are different oils and wherein the amount of each of the three natural oils is selected to provide a HEV/VIS ratio for the total composition of greater than or equal to 1.5 at an area of the animal cell where the composition has been topically administered. 7. The method of claim 1, further comprising configuring the composition to comprise at least four natural oils or extracts or their combination. 8. The method of claim 7, further comprising selecting each of the four natural oils or extracts to independently be one of extra virgin olive oil, wheat germ oil, sunflower oil, flax seed oil, rosehip oil, carrot seed oil, apricot seed oil, pumpkin seed oil, hemp oil, jojoba oil, argan oil, cranberry oil, broccoli seed oil, pomegranate oil, evening primrose oil, red raspberry oil, black raspberry oil, sea buckthorn oil, sesame oil, turmeric oil, cumin oil, marula oil, chia seed oil, shea butter, chaga extract and bees wax, wherein the four natural oils are different oils and wherein the amount of each of the four natural oils is selected to provide a HEV/VIS ratio for the total composition of greater than or equal to 1.5 at an area of the animal cell where the composition has been topically administered. 9. The method of claim 1, further comprising configuring the composition to comprise at least one Group A natural oil and at least one Group B natural oil. 10. The method of claim 1, further comprising selecting the at least one natural oil from Type I oils. 11. The method of claim 10, further comprising further configuring the composition with at least one Type II oil. 12. The method of claim 11, further comprising further configuring the composition with at least one Type III oil. 13. The method of claim 11, further comprising configuring the composition with at least one booster. 14. The method of claim 13, in which the booster is selected from the group consisting of chaga extract, cumin oil, seabuckthorn oil/extract, pomegranate seed oil, turmeric oil, green tea extracts, berry extracts/oils, rosehip oil, cranberry oil, broccoli seed oil, grape seed extract/oil, extra virgin olive oil, clove oil and cinnamon bark oil. 15. The method of claim 1, further comprising configuring the composition with at least one carrier effective to permit topical administration of the composition. 16. The method of claim 1, further comprising configuring the carrier to enhance transport of the composition into cells. 17. The method of claim 1, further comprising configuring the composition with a first natural oil that absorbs at least 30% of the incident high energy light having a wavelength of about 380-400 nm that is incident on the area of the animal cell where the composition has been topically administered. 18. The method of claim 17, further comprising configuring the composition with a second natural oil that absorbs at least 30% of the incident high energy light having a wavelength of about 400-440 nm that is incident on the area of the animal cell where the composition has been topically administered. 19. The method of claim 18, further comprising configuring the composition with a third natural oil that absorbs at least 30% of the incident high energy light having a wavelength of about 440-500 nm that is incident on the area of the animal cell where the composition has been topically administered. 20. The method of claim 1, further comprising configuring the composition with at least one of (i) an additional component effective to absorb incident light having a wavelength below 380 nm, (ii) a booster effective to reduce reactive oxygen species or (iii) particles effective to scatter light comprising a wavelength of about 380 nm to about 500 nm. 21-131. (canceled)
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1,201 | 15,673,167 | 1,649 |
The present invention relates to methods and medicaments used for treating conditions that require axonal regeneration, e.g. in mammals affected by injury or disease of the central or peripheral nervous system. The medicaments used in these methods facilitate axonal regeneration by inhibition of the complement system. Conditions requiring axonal regeneration that may be treated in accordance with the invention include physical injuries as well as neurodegenerative disorders of the peripheral or central nervous system.
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1-14. (canceled) 15. A method of inhibiting the formation of membrane attack complex (MAC) in a subject diagnosed with a neurodegenerative disorder or physical injury of a nerve, comprising administering to the subject a therapeutically effective amount of an inhibitor of a mammalian complement system, wherein the inhibitor is an antisense oligonucleotide that binds to the mRNA sequence of human C5 or C6 of the complement system. 16. The method according to claim 15, wherein the physical injury is of the peripheral or central nervous system. 17. The method according to claim 15, wherein the neurodegenerative disorder is of the peripheral or central nervous system. 18. The method according to claim 15, wherein the neurodegenerative disorder is Amyotrophic Lateral Sclerosis (ALS). 19. The method of claim 15, wherein the antisense oligonucleotide is administered by an intradermal, intramuscular, intraperitoneal, intravenous, or subcutaneous route. 20. The method according to claim 15, wherein the neurodegenerative disorder is Multiple Sclerosis (MS). 21. (canceled) 22. A method of promoting functional recovery of damaged or degenerating nerves in a subject by inhibiting the formation of membrane attack complex, comprising administering to the subject a therapeutically effective amount of an inhibitor of a mammalian complement system, wherein the inhibitor is an antisense oligonucleotide that binds to the mRNA sequence of human C5 or C6 of the complement system. 23. The method of claim 15 or 22, wherein the antisense oligonucleotide is administered by an intradermal, intramuscular, intraperitoneal, intravenous, or subcutaneous route. 24. The method of claim 15 or 22 wherein the damaged or degenerating nerves are of the PNS or CNS. 25. The method of claim 15 or 22, wherein the antisense oligonucleotide comprises one or more locked nucleic acids (LNA). 26. (canceled) 27. The method of claim 15 or 22, wherein the antisense oligonucleotide comprises one or more peptide nucleic acids (PNA) or ethylene-bridged nucleotides (ENA). 28. A method of inhibiting the formation of membrane attack complex (MAC) in a subject diagnosed with a neurodegenerative disorder or physical injury of a nerve, comprising administering to the subject a therapeutically effective amount of an inhibitor of a mammalian complement system, wherein the inhibitor is a complement receptor.
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The present invention relates to methods and medicaments used for treating conditions that require axonal regeneration, e.g. in mammals affected by injury or disease of the central or peripheral nervous system. The medicaments used in these methods facilitate axonal regeneration by inhibition of the complement system. Conditions requiring axonal regeneration that may be treated in accordance with the invention include physical injuries as well as neurodegenerative disorders of the peripheral or central nervous system.1-14. (canceled) 15. A method of inhibiting the formation of membrane attack complex (MAC) in a subject diagnosed with a neurodegenerative disorder or physical injury of a nerve, comprising administering to the subject a therapeutically effective amount of an inhibitor of a mammalian complement system, wherein the inhibitor is an antisense oligonucleotide that binds to the mRNA sequence of human C5 or C6 of the complement system. 16. The method according to claim 15, wherein the physical injury is of the peripheral or central nervous system. 17. The method according to claim 15, wherein the neurodegenerative disorder is of the peripheral or central nervous system. 18. The method according to claim 15, wherein the neurodegenerative disorder is Amyotrophic Lateral Sclerosis (ALS). 19. The method of claim 15, wherein the antisense oligonucleotide is administered by an intradermal, intramuscular, intraperitoneal, intravenous, or subcutaneous route. 20. The method according to claim 15, wherein the neurodegenerative disorder is Multiple Sclerosis (MS). 21. (canceled) 22. A method of promoting functional recovery of damaged or degenerating nerves in a subject by inhibiting the formation of membrane attack complex, comprising administering to the subject a therapeutically effective amount of an inhibitor of a mammalian complement system, wherein the inhibitor is an antisense oligonucleotide that binds to the mRNA sequence of human C5 or C6 of the complement system. 23. The method of claim 15 or 22, wherein the antisense oligonucleotide is administered by an intradermal, intramuscular, intraperitoneal, intravenous, or subcutaneous route. 24. The method of claim 15 or 22 wherein the damaged or degenerating nerves are of the PNS or CNS. 25. The method of claim 15 or 22, wherein the antisense oligonucleotide comprises one or more locked nucleic acids (LNA). 26. (canceled) 27. The method of claim 15 or 22, wherein the antisense oligonucleotide comprises one or more peptide nucleic acids (PNA) or ethylene-bridged nucleotides (ENA). 28. A method of inhibiting the formation of membrane attack complex (MAC) in a subject diagnosed with a neurodegenerative disorder or physical injury of a nerve, comprising administering to the subject a therapeutically effective amount of an inhibitor of a mammalian complement system, wherein the inhibitor is a complement receptor.
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1,202 | 16,047,929 | 1,643 |
An anti-C3d antibody or antibody fragment; method for use thereof to kill cancer cells; and related methods and compositions.
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1.-14. (canceled) 15. A method of killing a cancer cell having C3d complement protein on the surface thereof in a subject, the method comprising administering to the subject (1) an anti-C3d antibody or antibody fragment comprising a heavy chain variable region comprising
SEQ ID NO: 1 as heavy chain complementary determining region-1 (CDRH1); SEQ ID NO: 2 as heavy chain complementary determining region-2 (CDRH2); and SEQ ID NO: 3 or 4 as heavy chain complementary determining region-3 (CDRH3); and
a light chain variable region comprising
SEQ ID NO: 5 as light chain complementary determining region-1 (CDRL1);
SEQ ID NO: 6 as light chain complementary determining region-2 (CDRL2); and
SEQ ID NO: 7 as light chain complementary determining region-3 (CDRL3), and
(2) an antibody or antibody fragment to a cell surface protein other than C3d selected from the group consisting of an anti-CD33 antibody or antibody fragment, an anti-CD38 antibody or antibody fragment, an anti-EGFR antibody or antibody fragment, and an anti-ERBB2 antibody or antibody fragment,
wherein administration of the antibody or antibody fragment to a cell surface protein other than C3d induces formation of C3d complement protein the surface of the cancer cell. 16.-38. (canceled) 39. The method of claim 15, wherein the heavy chain variable region of the anti-C3d antibody or antibody fragment comprises SEQ ID NO: 3 as heavy chain complementary determining region-3 (CDRH3). 40. The method of claim 15, wherein the heavy chain variable region of the anti-C3d antibody or antibody fragment comprises SEQ ID NO: 4 as heavy chain complementary determining region-3 (CDRH3). 41. The method of claim 15, wherein the anti-C3d antibody or antibody fragment comprises a heavy chain comprising SEQ ID NO: 8 and a light chain comprising SEQ ID NO: 9. 42. The method of claim 15, wherein the anti-C3d antibody or antibody fragment comprises a heavy chain comprising SEQ ID NO: 10 and a light chain comprising SEQ ID NO: 11. 43. The method of claim 15, wherein the anti-C3d antibody or antibody fragment is selected from the group consisting of IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, IgM, scFv, IgGACH2, F(ab′)2, scFv2CH3, F(ab), scFv4, scFv3, scFv2, dsFv, Fv, scFv-Fc, (scFv)2, a diabody, a T-body, a multispecific antibody, and a multivalent antibody. 44. The method of claim 15, wherein the anti-CD33 antibody or antibody fragment is administered simultaneously with the administration of the antibody or antibody fragment to a cell surface protein other than C3d. 45. The method of claim 15, wherein the anti-CD33 antibody or antibody fragment is administered sequentially in any order with the administration of the antibody or antibody fragment to a cell surface protein other than C3d. 46. The method of claim 15, wherein the antibody or antibody fragment to a cell surface protein other than C3d is an anti-CD33 antibody or antibody fragment. 47. The method of claim 46, wherein the cancer cell is a myeloid cell. 48. The method of claim 46, wherein the anti-CD33 antibody or antibody fragment is emtuzumab or lintuzumab. 49. The method of claim 15, wherein the antibody or antibody fragment to a cell surface protein other than C3d is an anti-CD38 antibody or antibody fragment. 50. The method of claim 49, wherein the cancer cell is a plasma cell. 51. The method of claim 49, wherein the anti-CD38 antibody or antibody fragment is daratumumab. 52. The method of claim 15, wherein the antibody or antibody fragment to a cell surface protein other than C3d is an anti-EGFR antibody or antibody fragment. 53. The method of claim 52, wherein the cancer cell is from gut, colon, lung, breast, head, neck, pancreas, ovary, endometrium, or brain tissue. 54. The method of claim 52, wherein the anti-EGFR antibody or antibody fragment is cetuximab or panitumumab. 55. The method of claim 15, wherein the antibody or antibody fragment to a cell surface protein other than C3d is an anti-ERBB2 antibody or antibody fragment. 56. The method of claim 55, wherein the cancer cell is from gut, colon, lung, breast, head, neck, pancreas, ovary, endometrium, or brain tissue. 57. The method of claim 55, wherein the anti-ERBB2 antibody or antibody fragment is trastuzumab.
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An anti-C3d antibody or antibody fragment; method for use thereof to kill cancer cells; and related methods and compositions.1.-14. (canceled) 15. A method of killing a cancer cell having C3d complement protein on the surface thereof in a subject, the method comprising administering to the subject (1) an anti-C3d antibody or antibody fragment comprising a heavy chain variable region comprising
SEQ ID NO: 1 as heavy chain complementary determining region-1 (CDRH1); SEQ ID NO: 2 as heavy chain complementary determining region-2 (CDRH2); and SEQ ID NO: 3 or 4 as heavy chain complementary determining region-3 (CDRH3); and
a light chain variable region comprising
SEQ ID NO: 5 as light chain complementary determining region-1 (CDRL1);
SEQ ID NO: 6 as light chain complementary determining region-2 (CDRL2); and
SEQ ID NO: 7 as light chain complementary determining region-3 (CDRL3), and
(2) an antibody or antibody fragment to a cell surface protein other than C3d selected from the group consisting of an anti-CD33 antibody or antibody fragment, an anti-CD38 antibody or antibody fragment, an anti-EGFR antibody or antibody fragment, and an anti-ERBB2 antibody or antibody fragment,
wherein administration of the antibody or antibody fragment to a cell surface protein other than C3d induces formation of C3d complement protein the surface of the cancer cell. 16.-38. (canceled) 39. The method of claim 15, wherein the heavy chain variable region of the anti-C3d antibody or antibody fragment comprises SEQ ID NO: 3 as heavy chain complementary determining region-3 (CDRH3). 40. The method of claim 15, wherein the heavy chain variable region of the anti-C3d antibody or antibody fragment comprises SEQ ID NO: 4 as heavy chain complementary determining region-3 (CDRH3). 41. The method of claim 15, wherein the anti-C3d antibody or antibody fragment comprises a heavy chain comprising SEQ ID NO: 8 and a light chain comprising SEQ ID NO: 9. 42. The method of claim 15, wherein the anti-C3d antibody or antibody fragment comprises a heavy chain comprising SEQ ID NO: 10 and a light chain comprising SEQ ID NO: 11. 43. The method of claim 15, wherein the anti-C3d antibody or antibody fragment is selected from the group consisting of IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, IgM, scFv, IgGACH2, F(ab′)2, scFv2CH3, F(ab), scFv4, scFv3, scFv2, dsFv, Fv, scFv-Fc, (scFv)2, a diabody, a T-body, a multispecific antibody, and a multivalent antibody. 44. The method of claim 15, wherein the anti-CD33 antibody or antibody fragment is administered simultaneously with the administration of the antibody or antibody fragment to a cell surface protein other than C3d. 45. The method of claim 15, wherein the anti-CD33 antibody or antibody fragment is administered sequentially in any order with the administration of the antibody or antibody fragment to a cell surface protein other than C3d. 46. The method of claim 15, wherein the antibody or antibody fragment to a cell surface protein other than C3d is an anti-CD33 antibody or antibody fragment. 47. The method of claim 46, wherein the cancer cell is a myeloid cell. 48. The method of claim 46, wherein the anti-CD33 antibody or antibody fragment is emtuzumab or lintuzumab. 49. The method of claim 15, wherein the antibody or antibody fragment to a cell surface protein other than C3d is an anti-CD38 antibody or antibody fragment. 50. The method of claim 49, wherein the cancer cell is a plasma cell. 51. The method of claim 49, wherein the anti-CD38 antibody or antibody fragment is daratumumab. 52. The method of claim 15, wherein the antibody or antibody fragment to a cell surface protein other than C3d is an anti-EGFR antibody or antibody fragment. 53. The method of claim 52, wherein the cancer cell is from gut, colon, lung, breast, head, neck, pancreas, ovary, endometrium, or brain tissue. 54. The method of claim 52, wherein the anti-EGFR antibody or antibody fragment is cetuximab or panitumumab. 55. The method of claim 15, wherein the antibody or antibody fragment to a cell surface protein other than C3d is an anti-ERBB2 antibody or antibody fragment. 56. The method of claim 55, wherein the cancer cell is from gut, colon, lung, breast, head, neck, pancreas, ovary, endometrium, or brain tissue. 57. The method of claim 55, wherein the anti-ERBB2 antibody or antibody fragment is trastuzumab.
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1,203 | 16,000,717 | 1,618 |
A molecular probe for labeling myelin includes a fluorescent trans-stilbene derivative.
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1. A molecular probe for use in the detection of myelin in a subject comprising the general formula:
wherein R1 and R2 are each independently a hydrophilic or lipophilic group; wherein X1 is a double or triple bond; each R4-R13 is independently selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, an alkylene group, an alkenyl group, an alkynyl group, an alkoxy group, an aryl group, an aryloxy group, an alkaryl group, an aralkyl group, O, (CH2)nOR′ (wherein n=1, 2, or 3), CF3, CH2—CH2X, O—CH2—CH2X, CH2—CH2—CH2X, O—CH2—CH2X (wherein X=F, Cl, Br, or I), CN, C═O, (C═O)—R′, N(R′)2, NO2, (C═O)N(R′)2, O(CO)R′, OR′, SR′, COOR′, Rph, CR′═CR′—Rph, CR2′—CR2′—Rph (wherein Rph represents an unsubstituted or substituted phenyl group, wherein R′ is H or a lower alkyl group); wherein R10 and R11 and/or R12 and R13 may be linked to form a cyclic ring, wherein the cyclic ring is aromatic, alicyclic, heteroaromatic, or heteroalicyclic; or a pharmaceutically acceptable salt thereof. 2. The molecular probe of claim 1, wherein R1 and R2 are each independently selected from the group consisting of H, NO2, NH2, NHCH3, N(CH3)2, OH, OCH3, COOCH3, SH, SCH3, and alkyl derivatives thereof and each R4-R13 is H. 3. The molecular probe of claim 1, wherein R1 and R2 are each independently selected from the group consisting of H, NO2, NH2, NHCH3, N(CH3)2, OH, OCH3, COOCH3, SH, SCH3, and alkyl derivatives thereof, X1 is a double bond, and R10 and R11 are linked to form a heterocylic ring. 4. The molecular probe of claim 1, further comprising a radiolabel. 5. The molecular probe of claim 4, the radiolabel including a 3H, 125I, 11C, or 18F. 6. The molecular probe of claim 1, further comprising a chelating group or a near infrared imaging group. 7. The molecular probe of claim 1, wherein X1 is a double bond. 8. The molecular probe of claim 1, wherein R1 and R2 are amines or alkyl derivates thereof. 9. A method of detecting myelin in vivo in an animal, the method comprising:
(i) administering to the animal a molecular probe including the general formula:
wherein R1 and R2 are each independently a hydrophilic or lipophilic group; wherein X1 is a double or triple bond; each R4-R13 is independently selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, an alkylene group, an alkenyl group, an alkynyl group, an alkoxy group, an aryl group, an aryloxy group, an alkaryl group, an aralkyl group, O, (CH2)nOR′ (wherein n=1, 2, or 3), CF3, CH2—CH2X, O—CH2—CH2X, CH2—CH2—CH2X, O—CH2—CH2X (wherein X=F, Cl, Br, or I), CN, C═O, (C═O)—R′, N(R′)2, NO2, (C═O)N(R′)2, O(CO)R′, OR′, SR′, COOR′, Rph, CR′═CR′—Rph, CR2′—CR2′—Rph (wherein Rph represents an unsubstituted or substituted phenyl group, wherein R′ is H or a lower alkyl group); wherein R10 and R11 and/or R12 and R13 may be linked to form a cyclic ring, wherein the cyclic ring is aromatic, alicyclic, heteroaromatic, or heteroalicyclic; or a pharmaceutically acceptable salt thereof;
(ii) visualizing the myelin in the animal using an in vivo imaging modality. 10. The method of claim 9, the in vivo imaging modality comprising a Positron Emission Tomography (PET) imaging modality. 11. The method of claim 9, the in vivo imaging modality comprising a micro Positron Emission Tomography (microPET) imaging modality. 12. The method of claim 9, further comprising the step of administering the molecular probe to the animal parenterally. 13. The method of claim 9, wherein R1 and R2 are each independently selected from the group consisting of H, NO2, NH2, NHCH3, N(CH3)2, OH, OCH3, COOCH3, SH, SCH3, and alkyl derivatives thereof; and wherein each R4-R13 is H. 14. The molecular probe of claim 9, wherein R1 and R2 are each independently selected from the group consisting of H, NO2, NH2, NHCH3, N(CH3)2, OH, OCH3, COOCH3, SH, SCH3, and alkyl derivatives thereof, X1 is a double bond, and R10 and R11 are linked to form a heterocylic ring. 15. The method of claim 9, wherein the molecular probe further comprises a radiolabel. 16. The method of claim 15, the radiolabel including a 3H, 125I, 11C, or 18F. 17. The method of claim 9, wherein the molecular probe further comprises a chelating group or a near infrared imaging group. 18. The molecular probe of claim 9, wherein X1 is a double bond. 19. The molecular probe of claim 9, wherein R1 and R2 are amines or alkyl derivates thereof. 20. A method of detecting a myelin related disorder in an animal, the method comprising the steps of:
(i) administering to an animal's brain a molecular probe including the general formula:
wherein R1 and R2 are each independently a hydrophilic or lipophilic group; wherein X1 is a double or triple bond; each R4-R13 is independently selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, an alkylene group, an alkenyl group, an alkynyl group, an alkoxy group, an aryl group, an aryloxy group, an alkaryl group, an aralkyl group, O, (CH2)nOR′ (wherein n=1, 2, or 3), CF3, CH2—CH2X, O—CH2—CH2X, CH2—CH2—CH2X, O—CH2—CH2X (wherein X=F, Cl, Br, or I), CN, C═O, (C═O)—R′, N(R′)2, NO2, (C═O)N(R′)2, O(CO)R′, OR′, SR′, COOR′, Rph, CR′═CR′—Rph, CR2′—CR2′—Rph (wherein Rph represents an unsubstituted or substituted phenyl group, wherein R′ is H or a lower alkyl group); wherein R10 and R11 and/or R12 and R13 may be linked to form a cyclic ring, wherein the cyclic ring is aromatic, alicyclic, heteroaromatic, or heteroalicyclic; or a pharmaceutically acceptable salt thereof;
(ii) visualizing a distribution of the molecular probe in the animal's tissue; and
(iii) correlating the distribution of the molecular probe with a myelin related disorder in the animal. 21. The method of claim 20, wherein the myelin related disorder is a neurodegenerative autoimmune disease. 22. The method of claim 21, wherein the neurodegenerative autoimmune disease is multiple sclerosis. 23. The method of claim 20, the step of visualizing the distribution of the molecular probe in the animal's tissue comprising the use of an in vivo imaging modality. 24. The method of claim 20, wherein R1 and R2 are each independently selected from the group consisting of H, NO2, NH2, NHCH3, N(CH3)2, OH, OCH3, COOCH3, SH, SCH3, and alkyl derivatives thereof; and wherein each R4-R13 is H. 25. The molecular probe of claim 20, wherein R1 and R2 are each independently selected from the group consisting of H, NO2, NH2, NHCH3, N(CH3)2, OH, OCH3, COOCH3, SH, SCH3, and alkyl derivatives thereof, X1 is a double bond, and R10 and R11 are linked to form a heterocylic ring. 26. The method of claim 20, wherein the molecular probe further comprises a radiolabel. 27. The method of claim 20, the radiolabel the radiolabel including a 3H, 125I, 11C, or 18F. 28. The method of claim 20, wherein the molecular probe further comprises a chelating group or a near infrared imaging group. 29. The method of claim 20, wherein X1 is a double bond. 30. The method of claim 20, wherein R1 and R2 are amines or alkyl derivates thereof.
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A molecular probe for labeling myelin includes a fluorescent trans-stilbene derivative.1. A molecular probe for use in the detection of myelin in a subject comprising the general formula:
wherein R1 and R2 are each independently a hydrophilic or lipophilic group; wherein X1 is a double or triple bond; each R4-R13 is independently selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, an alkylene group, an alkenyl group, an alkynyl group, an alkoxy group, an aryl group, an aryloxy group, an alkaryl group, an aralkyl group, O, (CH2)nOR′ (wherein n=1, 2, or 3), CF3, CH2—CH2X, O—CH2—CH2X, CH2—CH2—CH2X, O—CH2—CH2X (wherein X=F, Cl, Br, or I), CN, C═O, (C═O)—R′, N(R′)2, NO2, (C═O)N(R′)2, O(CO)R′, OR′, SR′, COOR′, Rph, CR′═CR′—Rph, CR2′—CR2′—Rph (wherein Rph represents an unsubstituted or substituted phenyl group, wherein R′ is H or a lower alkyl group); wherein R10 and R11 and/or R12 and R13 may be linked to form a cyclic ring, wherein the cyclic ring is aromatic, alicyclic, heteroaromatic, or heteroalicyclic; or a pharmaceutically acceptable salt thereof. 2. The molecular probe of claim 1, wherein R1 and R2 are each independently selected from the group consisting of H, NO2, NH2, NHCH3, N(CH3)2, OH, OCH3, COOCH3, SH, SCH3, and alkyl derivatives thereof and each R4-R13 is H. 3. The molecular probe of claim 1, wherein R1 and R2 are each independently selected from the group consisting of H, NO2, NH2, NHCH3, N(CH3)2, OH, OCH3, COOCH3, SH, SCH3, and alkyl derivatives thereof, X1 is a double bond, and R10 and R11 are linked to form a heterocylic ring. 4. The molecular probe of claim 1, further comprising a radiolabel. 5. The molecular probe of claim 4, the radiolabel including a 3H, 125I, 11C, or 18F. 6. The molecular probe of claim 1, further comprising a chelating group or a near infrared imaging group. 7. The molecular probe of claim 1, wherein X1 is a double bond. 8. The molecular probe of claim 1, wherein R1 and R2 are amines or alkyl derivates thereof. 9. A method of detecting myelin in vivo in an animal, the method comprising:
(i) administering to the animal a molecular probe including the general formula:
wherein R1 and R2 are each independently a hydrophilic or lipophilic group; wherein X1 is a double or triple bond; each R4-R13 is independently selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, an alkylene group, an alkenyl group, an alkynyl group, an alkoxy group, an aryl group, an aryloxy group, an alkaryl group, an aralkyl group, O, (CH2)nOR′ (wherein n=1, 2, or 3), CF3, CH2—CH2X, O—CH2—CH2X, CH2—CH2—CH2X, O—CH2—CH2X (wherein X=F, Cl, Br, or I), CN, C═O, (C═O)—R′, N(R′)2, NO2, (C═O)N(R′)2, O(CO)R′, OR′, SR′, COOR′, Rph, CR′═CR′—Rph, CR2′—CR2′—Rph (wherein Rph represents an unsubstituted or substituted phenyl group, wherein R′ is H or a lower alkyl group); wherein R10 and R11 and/or R12 and R13 may be linked to form a cyclic ring, wherein the cyclic ring is aromatic, alicyclic, heteroaromatic, or heteroalicyclic; or a pharmaceutically acceptable salt thereof;
(ii) visualizing the myelin in the animal using an in vivo imaging modality. 10. The method of claim 9, the in vivo imaging modality comprising a Positron Emission Tomography (PET) imaging modality. 11. The method of claim 9, the in vivo imaging modality comprising a micro Positron Emission Tomography (microPET) imaging modality. 12. The method of claim 9, further comprising the step of administering the molecular probe to the animal parenterally. 13. The method of claim 9, wherein R1 and R2 are each independently selected from the group consisting of H, NO2, NH2, NHCH3, N(CH3)2, OH, OCH3, COOCH3, SH, SCH3, and alkyl derivatives thereof; and wherein each R4-R13 is H. 14. The molecular probe of claim 9, wherein R1 and R2 are each independently selected from the group consisting of H, NO2, NH2, NHCH3, N(CH3)2, OH, OCH3, COOCH3, SH, SCH3, and alkyl derivatives thereof, X1 is a double bond, and R10 and R11 are linked to form a heterocylic ring. 15. The method of claim 9, wherein the molecular probe further comprises a radiolabel. 16. The method of claim 15, the radiolabel including a 3H, 125I, 11C, or 18F. 17. The method of claim 9, wherein the molecular probe further comprises a chelating group or a near infrared imaging group. 18. The molecular probe of claim 9, wherein X1 is a double bond. 19. The molecular probe of claim 9, wherein R1 and R2 are amines or alkyl derivates thereof. 20. A method of detecting a myelin related disorder in an animal, the method comprising the steps of:
(i) administering to an animal's brain a molecular probe including the general formula:
wherein R1 and R2 are each independently a hydrophilic or lipophilic group; wherein X1 is a double or triple bond; each R4-R13 is independently selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, an alkylene group, an alkenyl group, an alkynyl group, an alkoxy group, an aryl group, an aryloxy group, an alkaryl group, an aralkyl group, O, (CH2)nOR′ (wherein n=1, 2, or 3), CF3, CH2—CH2X, O—CH2—CH2X, CH2—CH2—CH2X, O—CH2—CH2X (wherein X=F, Cl, Br, or I), CN, C═O, (C═O)—R′, N(R′)2, NO2, (C═O)N(R′)2, O(CO)R′, OR′, SR′, COOR′, Rph, CR′═CR′—Rph, CR2′—CR2′—Rph (wherein Rph represents an unsubstituted or substituted phenyl group, wherein R′ is H or a lower alkyl group); wherein R10 and R11 and/or R12 and R13 may be linked to form a cyclic ring, wherein the cyclic ring is aromatic, alicyclic, heteroaromatic, or heteroalicyclic; or a pharmaceutically acceptable salt thereof;
(ii) visualizing a distribution of the molecular probe in the animal's tissue; and
(iii) correlating the distribution of the molecular probe with a myelin related disorder in the animal. 21. The method of claim 20, wherein the myelin related disorder is a neurodegenerative autoimmune disease. 22. The method of claim 21, wherein the neurodegenerative autoimmune disease is multiple sclerosis. 23. The method of claim 20, the step of visualizing the distribution of the molecular probe in the animal's tissue comprising the use of an in vivo imaging modality. 24. The method of claim 20, wherein R1 and R2 are each independently selected from the group consisting of H, NO2, NH2, NHCH3, N(CH3)2, OH, OCH3, COOCH3, SH, SCH3, and alkyl derivatives thereof; and wherein each R4-R13 is H. 25. The molecular probe of claim 20, wherein R1 and R2 are each independently selected from the group consisting of H, NO2, NH2, NHCH3, N(CH3)2, OH, OCH3, COOCH3, SH, SCH3, and alkyl derivatives thereof, X1 is a double bond, and R10 and R11 are linked to form a heterocylic ring. 26. The method of claim 20, wherein the molecular probe further comprises a radiolabel. 27. The method of claim 20, the radiolabel the radiolabel including a 3H, 125I, 11C, or 18F. 28. The method of claim 20, wherein the molecular probe further comprises a chelating group or a near infrared imaging group. 29. The method of claim 20, wherein X1 is a double bond. 30. The method of claim 20, wherein R1 and R2 are amines or alkyl derivates thereof.
| 1,600 |
1,204 | 14,441,135 | 1,653 |
Disclosed is a hydrogel comprising a hydrophilic gelling agent that includes a nonionic cellulose ether, and active thermolysin, wherein the proteolytic activity of the thermolysin does not decrease by more than 20% when stored at room temperature for 6 months.
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1. A hydrogel comprising:
(a) a hydrophilic gelling agent that includes a nonionic cellulose ether; and (b) active thermolysin, wherein the proteolytic activity of the thermolysin does not decrease by more than 20% when stored at room temperature for 6 months. 2. The hydrogel of claim 1, wherein the proteolytic activity of the thermolysin does not decrease by more than 10% when stored at room temperature for 6 months. 3. The hydrogel of claim 1, wherein the proteolytic activity of the thermolysin does not decrease by more than 10% when stored at room temperature for 24 months. 4. The hydrogel of claim 1, wherein the nonionic cellulose ether is a hydroxyalkyl cellulose ether. 5. The hydrogel of claim 4, wherein the hydroxyalkyl cellulose ether is hydroxyethylcellulose, hydroxypropylcellulose, or hydroxypropylmethylcellulose, or any combination thereof. 6. The hydrogel of claim 1, comprising 0.1 to 10.0% w/w or 0.1 to 5% w/w of the nonionic cellulose ether. 7. The hydrogel of claim 1, wherein the nonionic cellulose ether comprises hydroxyethylcellulose, and wherein the hydrogel comprises 2.5 to 4.5% w/w of the hydroxyethylcellulose. 8. The hydrogel of claim 1, wherein the nonionic cellulose ether comprises hydroxypropylcellulose, and wherein the hydrogel comprises 0.01 to 10% w/w of the hydroxypropylcellulose. 9. The hydrogel of claim 1, wherein the nonionic cellulose ether is hydroxypropylmethylcellulose, and wherein the hydrogel comprises 1.5 to 2.5% w/w of the hydroxypropylmethylcellulose. 10. The hydrogel of claim 1, comprising 0.1 to 5% w/w or 0.5 to 1% w/w of the thermolysin. 11. The hydrogel of claim 1, further comprising a buffer having a pH of 7.0 to 8.0 or about 7.5. 12. The hydrogel of claim 1, wherein the hydrogel has a viscosity of 15,000 to 100,000 cps, as measured with a Brookfield RV Viscometer, spindle 14 with small sample adapter, at 10 rpm at room temperature read at 30 seconds. 13. The hydrogel of claim 1, wherein the hydrogel further comprises a metal salt. 14. The hydrogel of claim 13, wherein the metal salt is sodium chloride or calcium chloride or mixtures thereof. 15. The hydrogel of claim 1, wherein the hydrogel further comprises a preservative. 16. The hydrogel of claim 15, wherein the preservative is methylparaben, propylparaben, or phenoxyethanol, or mixtures thereof. 17. The hydrogel of claim 1, wherein the thermolysin is solubilized within the hydrogel. 18. The hydrogel of claim 1, wherein the thermolysin is suspended within the hydrogel. 19. The hydrogel of claim 1, wherein the thermolysin is partially solubilized and partially suspended within the hydrogel. 20. A method of debriding a wound comprising topically applying a composition according to claim 1 to a wound in need of debridement. 21. The method of claim 20, wherein the wound is a chronic wound. 22. The method of claim 21, wherein the chronic wound is a diabetic foot ulcer, a venous leg ulcer, an arterial leg ulcer, a decubitus ulcer, a stasis ulcer, a dermal ulcer, a burn, or a pressure ulcer. 23. The method of claim 20, wherein the wound includes necrotic tissue. 24. The method of claim 23, wherein the necrotic tissue is an eschar. 25. A method for stabilizing thermolysin comprising preparing a hydrogel according to claim 1.
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Disclosed is a hydrogel comprising a hydrophilic gelling agent that includes a nonionic cellulose ether, and active thermolysin, wherein the proteolytic activity of the thermolysin does not decrease by more than 20% when stored at room temperature for 6 months.1. A hydrogel comprising:
(a) a hydrophilic gelling agent that includes a nonionic cellulose ether; and (b) active thermolysin, wherein the proteolytic activity of the thermolysin does not decrease by more than 20% when stored at room temperature for 6 months. 2. The hydrogel of claim 1, wherein the proteolytic activity of the thermolysin does not decrease by more than 10% when stored at room temperature for 6 months. 3. The hydrogel of claim 1, wherein the proteolytic activity of the thermolysin does not decrease by more than 10% when stored at room temperature for 24 months. 4. The hydrogel of claim 1, wherein the nonionic cellulose ether is a hydroxyalkyl cellulose ether. 5. The hydrogel of claim 4, wherein the hydroxyalkyl cellulose ether is hydroxyethylcellulose, hydroxypropylcellulose, or hydroxypropylmethylcellulose, or any combination thereof. 6. The hydrogel of claim 1, comprising 0.1 to 10.0% w/w or 0.1 to 5% w/w of the nonionic cellulose ether. 7. The hydrogel of claim 1, wherein the nonionic cellulose ether comprises hydroxyethylcellulose, and wherein the hydrogel comprises 2.5 to 4.5% w/w of the hydroxyethylcellulose. 8. The hydrogel of claim 1, wherein the nonionic cellulose ether comprises hydroxypropylcellulose, and wherein the hydrogel comprises 0.01 to 10% w/w of the hydroxypropylcellulose. 9. The hydrogel of claim 1, wherein the nonionic cellulose ether is hydroxypropylmethylcellulose, and wherein the hydrogel comprises 1.5 to 2.5% w/w of the hydroxypropylmethylcellulose. 10. The hydrogel of claim 1, comprising 0.1 to 5% w/w or 0.5 to 1% w/w of the thermolysin. 11. The hydrogel of claim 1, further comprising a buffer having a pH of 7.0 to 8.0 or about 7.5. 12. The hydrogel of claim 1, wherein the hydrogel has a viscosity of 15,000 to 100,000 cps, as measured with a Brookfield RV Viscometer, spindle 14 with small sample adapter, at 10 rpm at room temperature read at 30 seconds. 13. The hydrogel of claim 1, wherein the hydrogel further comprises a metal salt. 14. The hydrogel of claim 13, wherein the metal salt is sodium chloride or calcium chloride or mixtures thereof. 15. The hydrogel of claim 1, wherein the hydrogel further comprises a preservative. 16. The hydrogel of claim 15, wherein the preservative is methylparaben, propylparaben, or phenoxyethanol, or mixtures thereof. 17. The hydrogel of claim 1, wherein the thermolysin is solubilized within the hydrogel. 18. The hydrogel of claim 1, wherein the thermolysin is suspended within the hydrogel. 19. The hydrogel of claim 1, wherein the thermolysin is partially solubilized and partially suspended within the hydrogel. 20. A method of debriding a wound comprising topically applying a composition according to claim 1 to a wound in need of debridement. 21. The method of claim 20, wherein the wound is a chronic wound. 22. The method of claim 21, wherein the chronic wound is a diabetic foot ulcer, a venous leg ulcer, an arterial leg ulcer, a decubitus ulcer, a stasis ulcer, a dermal ulcer, a burn, or a pressure ulcer. 23. The method of claim 20, wherein the wound includes necrotic tissue. 24. The method of claim 23, wherein the necrotic tissue is an eschar. 25. A method for stabilizing thermolysin comprising preparing a hydrogel according to claim 1.
| 1,600 |
1,205 | 14,769,754 | 1,653 |
Disclosed is a dissolvable, gel-forming film, and methods for its use, comprising a water-soluble cellulose ether, a hydrophilic rheological modifying agent, and an active proteolytic enzyme or other drug substance. The gel-forming film has a water content of less than 15% w/w and is capable of forming a hydrogel when contacted with water or other aqueous medium. The disclosed films achieve delivery of stable proteolytic enzymes to the desired site of action in a manner that provides uniform delivery of the enzymes.
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1. A dissolvable, gel-forming film comprising:
(a) a water-soluble cellulose ether; (b) a hydrophilic rheological modifying agent; and (c) a proteolytic enzyme, wherein the dissolvable, gel-forming film has a water content of less than 15% w/w, and the dissolvable, gel-forming film is capable of forming a hydrogel when contacted with water or other aqueous medium. 2. The dissolvable, gel-forming film of claim 1, wherein the proteolytic enzyme is in crystalline form. 3. The dissolvable, gel-forming film of any of claims 1-2, wherein the hydrogel that is formed has a viscosity of 1,000 to 100,000 cps, as measured using a Brookfield RV Model Viscometer using small sample adapter with spindle #SC4-14 and chamber #SC4-6R, at 10 rpm at room temperature, reading taken at 1 minute. 4. The dissolvable, gel-forming film of any of claims 1-3, wherein the proteolytic enzyme is themolysin, collagenase, or papain. 5. The dissolvable, gel-forming film of claim 4, wherein the proteolytic enzyme is thermolysin. 6. The dissolvable, gel-forming film of any of claims 1-5, wherein the thickness of the film ranges from 10 to 1000 μm. 7. The dissolvable, gel-forming film of any of claims 1-6, wherein the film is capable of dissolving in water at a rate from 100 to 0.1 mg/min. 8. The dissolvable, gel-forming film of claim 7, wherein the film is capable of dissolving in water at a rate from 0.5-10 mg/min. 9. The dissolvable, gel-forming film of any of claims 1-8, wherein the weight percent of the proteolytic enzyme is not less than 0.1% of the dry weight of the film and does not decrease by more than 10% when stored at room temperature for 24 months. 10. The dissolvable, gel-forming film of any one of claims 1-9, wherein the water-soluble cellulose ether is a hydroxyalkyl cellulose ether. 11. The dissolvable, gel-forming film of claim 10, wherein the hydroxyalkyl cellulose ether is hydroxyethylcellulose, hydroxypropylcellulose, or hydroxypropylmethylcellulose, or any combination thereof. 12. The dissolvable, gel-forming film of any one of claims 1-11, comprising 50 to 70% w/w or 55 to 65% w/w of the water-soluble cellulose ether or combinations thereof. 13. The dissolvable, gel-forming film of any one of claims 1-12, comprising 25 to 35% w/w of hydroxyethylcellulose and 25 to 35% w/w of hydroxypropylmethyl cellulose. 14. The dissolvable, gel-forming film of any one of claims 1-13, comprising 15 to 25% w/w of the hydrophilic rheological modifying agent. 15. The dissolvable, gel-forming film of claim 14, wherein the hydrophilic rheological modifying agent is a polyol. 16. The dissolvable, gel-forming film of claim 15, wherein the polyol is polyethylene glycol. 17. The dissolvable, gel-forming film of claim 16, wherein the polyethylene glycol is PEG-400. 18. The dissolvable, gel-forming film of any one of claims 1-17, comprising 5 to 15% w/w of the proteolytic enzyme. 19. The dissolvable, gel-forming film of any one of claims 1-18, wherein the hydrogel further comprises a metal salt. 20. The dissolvable, gel-forming film of claim 19, wherein the metal salt is sodium chloride or calcium chloride or mixtures thereof. 21. The dissolvable, gel-forming film of any one of claims 1-20, wherein the hydrogel further comprises a preservative. 22. The dissolvable, gel-forming film of claim 21, wherein the preservative is methylparaben, propylparaben, or phenoxyethanol, or mixtures thereof. 23. The dissolvable, gel-forming film of any one of claims 1-22, wherein the film is produced by:
(a) obtaining a first mixture comprising 3 to 7% w/w of the cellulose ether or combinations thereof, 1 to 3% w/w of the hydrophilic rheological modifying agent, and Tris Buffer (10 mM, pH=7.5); (b) obtaining a second mixture comprising a proteolytic enzyme, a metal salt, and Tris Buffer (10 mM, pH=7.5); (c) mixing the first and second mixtures together to obtain a hydrogel; and (d) drying the hydrogel from step (c) to obtain the dissolvable, gel-forming film. 24. The dissolvable, gel-forming film of claim 23, wherein the proteolytic enzyme is themolysin, collagenase, or papain. 25. The dissolvable, gel-forming film of claim 24, wherein the proteolytic enzyme is thermolysin. 26. A method of debriding a wound comprising topically applying the dissolvable, gel-forming film from any one of claims 1-25 to a wound in need of debridement. 27. The method of claim 26, wherein the wound is a chronic wound. 28. The method of claim 27, wherein the chronic wound is a diabetic foot ulcer, a venous leg ulcer, an arterial leg ulcer, a decubitus ulcer, a stasis ulcer, a dermal ulcer, a burn, or a pressure ulcer. 29. The method of any one of claims 26-28, wherein the wound includes necrotic tissue. 30. The method of claim 29, wherein the necrotic tissue is an eschar. 31. The method of any one of claims 26-30, wherein an aqueous medium is applied to the wound before the dissolvable, gel-forming film is applied to the wound or wherein an aqueous medium is applied to the dissolvable, gel-forming film after said film is applied to the wound. 32. The method of claim 31, wherein the aqueous medium is a saline solution. 33. The method of any one of claims 26-32, wherein a bandage, wound dressing, or gauze is applied onto the dissolvable, gel-forming film after said film is applied to the wound.
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Disclosed is a dissolvable, gel-forming film, and methods for its use, comprising a water-soluble cellulose ether, a hydrophilic rheological modifying agent, and an active proteolytic enzyme or other drug substance. The gel-forming film has a water content of less than 15% w/w and is capable of forming a hydrogel when contacted with water or other aqueous medium. The disclosed films achieve delivery of stable proteolytic enzymes to the desired site of action in a manner that provides uniform delivery of the enzymes.1. A dissolvable, gel-forming film comprising:
(a) a water-soluble cellulose ether; (b) a hydrophilic rheological modifying agent; and (c) a proteolytic enzyme, wherein the dissolvable, gel-forming film has a water content of less than 15% w/w, and the dissolvable, gel-forming film is capable of forming a hydrogel when contacted with water or other aqueous medium. 2. The dissolvable, gel-forming film of claim 1, wherein the proteolytic enzyme is in crystalline form. 3. The dissolvable, gel-forming film of any of claims 1-2, wherein the hydrogel that is formed has a viscosity of 1,000 to 100,000 cps, as measured using a Brookfield RV Model Viscometer using small sample adapter with spindle #SC4-14 and chamber #SC4-6R, at 10 rpm at room temperature, reading taken at 1 minute. 4. The dissolvable, gel-forming film of any of claims 1-3, wherein the proteolytic enzyme is themolysin, collagenase, or papain. 5. The dissolvable, gel-forming film of claim 4, wherein the proteolytic enzyme is thermolysin. 6. The dissolvable, gel-forming film of any of claims 1-5, wherein the thickness of the film ranges from 10 to 1000 μm. 7. The dissolvable, gel-forming film of any of claims 1-6, wherein the film is capable of dissolving in water at a rate from 100 to 0.1 mg/min. 8. The dissolvable, gel-forming film of claim 7, wherein the film is capable of dissolving in water at a rate from 0.5-10 mg/min. 9. The dissolvable, gel-forming film of any of claims 1-8, wherein the weight percent of the proteolytic enzyme is not less than 0.1% of the dry weight of the film and does not decrease by more than 10% when stored at room temperature for 24 months. 10. The dissolvable, gel-forming film of any one of claims 1-9, wherein the water-soluble cellulose ether is a hydroxyalkyl cellulose ether. 11. The dissolvable, gel-forming film of claim 10, wherein the hydroxyalkyl cellulose ether is hydroxyethylcellulose, hydroxypropylcellulose, or hydroxypropylmethylcellulose, or any combination thereof. 12. The dissolvable, gel-forming film of any one of claims 1-11, comprising 50 to 70% w/w or 55 to 65% w/w of the water-soluble cellulose ether or combinations thereof. 13. The dissolvable, gel-forming film of any one of claims 1-12, comprising 25 to 35% w/w of hydroxyethylcellulose and 25 to 35% w/w of hydroxypropylmethyl cellulose. 14. The dissolvable, gel-forming film of any one of claims 1-13, comprising 15 to 25% w/w of the hydrophilic rheological modifying agent. 15. The dissolvable, gel-forming film of claim 14, wherein the hydrophilic rheological modifying agent is a polyol. 16. The dissolvable, gel-forming film of claim 15, wherein the polyol is polyethylene glycol. 17. The dissolvable, gel-forming film of claim 16, wherein the polyethylene glycol is PEG-400. 18. The dissolvable, gel-forming film of any one of claims 1-17, comprising 5 to 15% w/w of the proteolytic enzyme. 19. The dissolvable, gel-forming film of any one of claims 1-18, wherein the hydrogel further comprises a metal salt. 20. The dissolvable, gel-forming film of claim 19, wherein the metal salt is sodium chloride or calcium chloride or mixtures thereof. 21. The dissolvable, gel-forming film of any one of claims 1-20, wherein the hydrogel further comprises a preservative. 22. The dissolvable, gel-forming film of claim 21, wherein the preservative is methylparaben, propylparaben, or phenoxyethanol, or mixtures thereof. 23. The dissolvable, gel-forming film of any one of claims 1-22, wherein the film is produced by:
(a) obtaining a first mixture comprising 3 to 7% w/w of the cellulose ether or combinations thereof, 1 to 3% w/w of the hydrophilic rheological modifying agent, and Tris Buffer (10 mM, pH=7.5); (b) obtaining a second mixture comprising a proteolytic enzyme, a metal salt, and Tris Buffer (10 mM, pH=7.5); (c) mixing the first and second mixtures together to obtain a hydrogel; and (d) drying the hydrogel from step (c) to obtain the dissolvable, gel-forming film. 24. The dissolvable, gel-forming film of claim 23, wherein the proteolytic enzyme is themolysin, collagenase, or papain. 25. The dissolvable, gel-forming film of claim 24, wherein the proteolytic enzyme is thermolysin. 26. A method of debriding a wound comprising topically applying the dissolvable, gel-forming film from any one of claims 1-25 to a wound in need of debridement. 27. The method of claim 26, wherein the wound is a chronic wound. 28. The method of claim 27, wherein the chronic wound is a diabetic foot ulcer, a venous leg ulcer, an arterial leg ulcer, a decubitus ulcer, a stasis ulcer, a dermal ulcer, a burn, or a pressure ulcer. 29. The method of any one of claims 26-28, wherein the wound includes necrotic tissue. 30. The method of claim 29, wherein the necrotic tissue is an eschar. 31. The method of any one of claims 26-30, wherein an aqueous medium is applied to the wound before the dissolvable, gel-forming film is applied to the wound or wherein an aqueous medium is applied to the dissolvable, gel-forming film after said film is applied to the wound. 32. The method of claim 31, wherein the aqueous medium is a saline solution. 33. The method of any one of claims 26-32, wherein a bandage, wound dressing, or gauze is applied onto the dissolvable, gel-forming film after said film is applied to the wound.
| 1,600 |
1,206 | 14,443,359 | 1,657 |
Methods are disclosed for treating post traumatic stress disorder (PTSD) in a subject. The methods include administering a therapeutically effective amount of a neurotoxin to a corrugator supercilli and/or a procerus muscle of the subject to cause paralysis of the corrugator supercilli and/or a procerus muscle in the subject, thereby treating PTSD. The neurotoxin can be Botulinum toxin A, such as at a dose of about 20 to about 50 units of Botulinum toxin A.
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1. A method for treating post traumatic stress disorder (PTSD) in a subject, comprising administering a therapeutically effective amount of a neurotoxin to a corrugator supercilli and/or a procerus muscle of the subject to cause paralysis of the corrugator supercilli and/or a procerus muscle, thereby treating the PTSD in the subject. 2. The method of claim 1, comprising administering a therapeutically effective amount of a neurotoxin to the corrugator supercilli and the procerus muscle. 3. The method of claim 1, wherein the subject does not have any other psychiatric disorder. 4. The method of claim 1, wherein the subject does not have a muscular disorder. 5. The method of claim 1, wherein the neurotoxin is a Botulinum toxin. 6. The method of claim 5, wherein the Botulinum toxin is Botulinum toxin A. 7. The method of claim 6, wherein about 20-50 Unit equivalents of Botulinum toxin type A are administered to the corrugator supercilli and the procerus muscle in the subject. 8. The method of claim 7, further comprising administering an additional dose of about 20-50 Unit equivalents of Botulinum toxin type A to the corrugator supercilli and the procerus muscle after about two to six months. 9. A method for treating post traumatic stress disorder (PTSD) in a subject, comprising
selecting a subject with PTSD, and administering a therapeutically effective amount of Botulinum toxin A to a corrugator supercilli muscle and a procerus muscle of the subject to cause paralysis of the corrugator supercilli muscle and procerus muscle, thereby treating the PTSD in the subject, wherein the subject does not have an underlying muscular physical condition. 10. The method of claim 9, wherein about 20 to about 40 Unit equivalents of Botulinum toxin type A are administered to the corrugator supercilli muscle and the procerus muscle of the subject. 11. The method of claim 9, wherein about 29 to about 40 Unit equivalents of Botulinum toxin type A are administered to the corrugator supercilli muscle and the procerus muscle of the subject. 12. The method of claim 10, further comprising administering an additional dose of about 30-60 Unit equivalents of Botulinum toxin type A to the corrugator supercilli muscle and the procerus muscle after about two to six months. 13. The method of claim 9, further comprising administering to the subject a therapeutically effective amount of an additional modality of treatment. 14. The method of claim 13, wherein the additional modality of treatment comprises administration of an antidepressant, psychotherapy, a beta blocker, or behavioral therapy. 15. The method of claim 13, wherein the additional modality of treatment comprises Selective Serotonin Reuptake Inhibitor (SSRI), an alpha adrenergic antagonist, an anti-convulsant, a mood stabilizer, an anti-psychotic, a beta blocker, a bezodiazepine, a glucocorticoid, monoamine-oxidase inhibitor (MAOIs), a heterocyclic anti-depressant, or a tricyclic anti-depressant. 16. The method of claim 9, further comprising performing a psychological assessment on the subject. 17. The method of claim 16, wherein the subject reports one or more of: (1) decreased efforts to avoid thoughts, feelings, or conversations associated with the trauma; (2) decreased efforts to avoid activities, places, or people that arouse recollections of the trauma; (3) increased recall of aspect of the trauma (memory); (4) increased interest or participation in significant activities; (5) fewer feelings of detachment or estrangement from others; (6) an increased range of affect (e.g., able to show loving feelings); and (7) a better sense of the future, following the administration of Botulinum toxin A. 18. The method of claim 16, wherein the subject reports one or more of the subject has (1) less difficulty falling or staying asleep; (2) less irritability or outbursts of anger; (3) less difficulty concentrating; (4) less hypervigilance; and (5) a less exaggerated startle response, following the administration of Botulinum toxin A. 19. The method of claim 1, wherein the subject is female. 20. The method of claim 9, wherein the subject is a female.
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Methods are disclosed for treating post traumatic stress disorder (PTSD) in a subject. The methods include administering a therapeutically effective amount of a neurotoxin to a corrugator supercilli and/or a procerus muscle of the subject to cause paralysis of the corrugator supercilli and/or a procerus muscle in the subject, thereby treating PTSD. The neurotoxin can be Botulinum toxin A, such as at a dose of about 20 to about 50 units of Botulinum toxin A.1. A method for treating post traumatic stress disorder (PTSD) in a subject, comprising administering a therapeutically effective amount of a neurotoxin to a corrugator supercilli and/or a procerus muscle of the subject to cause paralysis of the corrugator supercilli and/or a procerus muscle, thereby treating the PTSD in the subject. 2. The method of claim 1, comprising administering a therapeutically effective amount of a neurotoxin to the corrugator supercilli and the procerus muscle. 3. The method of claim 1, wherein the subject does not have any other psychiatric disorder. 4. The method of claim 1, wherein the subject does not have a muscular disorder. 5. The method of claim 1, wherein the neurotoxin is a Botulinum toxin. 6. The method of claim 5, wherein the Botulinum toxin is Botulinum toxin A. 7. The method of claim 6, wherein about 20-50 Unit equivalents of Botulinum toxin type A are administered to the corrugator supercilli and the procerus muscle in the subject. 8. The method of claim 7, further comprising administering an additional dose of about 20-50 Unit equivalents of Botulinum toxin type A to the corrugator supercilli and the procerus muscle after about two to six months. 9. A method for treating post traumatic stress disorder (PTSD) in a subject, comprising
selecting a subject with PTSD, and administering a therapeutically effective amount of Botulinum toxin A to a corrugator supercilli muscle and a procerus muscle of the subject to cause paralysis of the corrugator supercilli muscle and procerus muscle, thereby treating the PTSD in the subject, wherein the subject does not have an underlying muscular physical condition. 10. The method of claim 9, wherein about 20 to about 40 Unit equivalents of Botulinum toxin type A are administered to the corrugator supercilli muscle and the procerus muscle of the subject. 11. The method of claim 9, wherein about 29 to about 40 Unit equivalents of Botulinum toxin type A are administered to the corrugator supercilli muscle and the procerus muscle of the subject. 12. The method of claim 10, further comprising administering an additional dose of about 30-60 Unit equivalents of Botulinum toxin type A to the corrugator supercilli muscle and the procerus muscle after about two to six months. 13. The method of claim 9, further comprising administering to the subject a therapeutically effective amount of an additional modality of treatment. 14. The method of claim 13, wherein the additional modality of treatment comprises administration of an antidepressant, psychotherapy, a beta blocker, or behavioral therapy. 15. The method of claim 13, wherein the additional modality of treatment comprises Selective Serotonin Reuptake Inhibitor (SSRI), an alpha adrenergic antagonist, an anti-convulsant, a mood stabilizer, an anti-psychotic, a beta blocker, a bezodiazepine, a glucocorticoid, monoamine-oxidase inhibitor (MAOIs), a heterocyclic anti-depressant, or a tricyclic anti-depressant. 16. The method of claim 9, further comprising performing a psychological assessment on the subject. 17. The method of claim 16, wherein the subject reports one or more of: (1) decreased efforts to avoid thoughts, feelings, or conversations associated with the trauma; (2) decreased efforts to avoid activities, places, or people that arouse recollections of the trauma; (3) increased recall of aspect of the trauma (memory); (4) increased interest or participation in significant activities; (5) fewer feelings of detachment or estrangement from others; (6) an increased range of affect (e.g., able to show loving feelings); and (7) a better sense of the future, following the administration of Botulinum toxin A. 18. The method of claim 16, wherein the subject reports one or more of the subject has (1) less difficulty falling or staying asleep; (2) less irritability or outbursts of anger; (3) less difficulty concentrating; (4) less hypervigilance; and (5) a less exaggerated startle response, following the administration of Botulinum toxin A. 19. The method of claim 1, wherein the subject is female. 20. The method of claim 9, wherein the subject is a female.
| 1,600 |
1,207 | 15,335,547 | 1,617 |
Disclosed are compositions and methods for the treatment of a subject having an autism spectrum disorder. The disclosed compositions may contain racemic ketamine or S-ketamine. The disclosed methods of administering the compositions include intranasal administration to a subject having an autism spectrum disorder.
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1.-15. (canceled) 16. An intranasal delivery device comprising a composition comprising racemic ketamine, wherein said delivery device is capable of administering a unit dose of from about 20 to about 120 mg. 17. The device according to claim 16, wherein said composition is substantially free of R-ketamine. 18. The device according to claim 16 wherein said device delivers a dose of from about 20 to about 120 mg. 19-38. (canceled) 39. The device of claim 16, wherein said composition comprises a pharmaceutically acceptable carrier. 40. The device of claim 16, wherein said composition comprises an agent selected from a permeation enhancer, a polymer capable of increasing mucosal adhesion of the composition, or a combination thereof. 41. The device of claim 16, wherein said unit dose is about 20 mg of atomized ketamine per 0.1 cc spray.
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Disclosed are compositions and methods for the treatment of a subject having an autism spectrum disorder. The disclosed compositions may contain racemic ketamine or S-ketamine. The disclosed methods of administering the compositions include intranasal administration to a subject having an autism spectrum disorder.1.-15. (canceled) 16. An intranasal delivery device comprising a composition comprising racemic ketamine, wherein said delivery device is capable of administering a unit dose of from about 20 to about 120 mg. 17. The device according to claim 16, wherein said composition is substantially free of R-ketamine. 18. The device according to claim 16 wherein said device delivers a dose of from about 20 to about 120 mg. 19-38. (canceled) 39. The device of claim 16, wherein said composition comprises a pharmaceutically acceptable carrier. 40. The device of claim 16, wherein said composition comprises an agent selected from a permeation enhancer, a polymer capable of increasing mucosal adhesion of the composition, or a combination thereof. 41. The device of claim 16, wherein said unit dose is about 20 mg of atomized ketamine per 0.1 cc spray.
| 1,600 |
1,208 | 15,694,567 | 1,648 |
Disclosed herein are methods of eliciting an immune response against a polyomavirus (for example, BKV serotype I (BKV-I), BKV serotype II (BKV-II), BKV serotype III (BKV-III) and/or BKV serotype IV (BKV-IV)) and methods of treating or inhibiting polyomavirus-associated pathology (such as polyomavirus-associated nephropathy, BKV-associated hemorrhagic cystitis, or JC virus-associated progressive multifocal leukoencephalopathy; PML). Further disclosed are immunogenic compositions of use in the disclosed methods. Also disclosed are methods of selecting an organ transplant donor and/or recipient including detecting whether the prospective donor and/or recipient has BKV serotype-specific (such as BKV serotype IV-specific) neutralizing antibodies.
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1. A multivalent BK polyomavirus (BKV) immunogenic composition comprising:
a virus-like particle comprising at least one BKV serotype IV capsid polypeptide; a virus-like particle comprising at least one BKV serotype I capsid polypeptide; a pharmaceutically acceptable carrier; and an adjuvant. 2. The composition of claim 1, wherein the at least one BKV-IV capsid polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 4-6, 16, and 110-125 and the at least one isolated BKV-I capsid polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 1-3, 13-15, and 52-103. 3. The composition of claim 1, further comprising:
a virus-like particle comprising at least one BKV serotype II capsid polypeptide; a virus-like particle comprising at least one BKV serotype III capsid polypeptide; or a combination thereof. 4. The composition of claim 1, wherein the at least one capsid polypeptide comprises VP1, VP2, VP3, or a combination of two or more thereof. 5. The composition of claim 1, wherein the at least one BKV serotype IV capsid polypeptide comprises one or more of a BKV-IVb1 VP1 polypeptide and/or a BKV-IVc2 VP1 polypeptide. 6. The composition of claim 5, wherein the BKV-IVb1 VP1 polypeptide is encoded by a nucleic acid molecule comprising the sequence of SEQ ID NO: 47 and/or the BKV-IVc2 VP1 polypeptide is encoded by a nucleic acid molecule comprising the sequence of SEQ ID NO: 27 or 39. 7. The composition of claim 1, wherein the at least one BKV serotype I capsid polypeptide comprises one or more of a BKV-Ia VP1 polypeptide, a BKV-Ib1 VP1 polypeptide, a BKV-Ib2 VP1 polypeptide, and/or a BKV-Ic VP1 polypeptide. 8. The composition of claim 7, wherein the BKV-Ia VP1 polypeptide is encoded by a nucleic acid molecule comprising the sequence of SEQ ID NO: 42, the BKV-Ib1 VP1 polypeptide is encoded by a nucleic acid molecule comprising the sequence of SEQ ID NO: 24; the BKV-Ib2 VP1 polypeptide is encoded by a nucleic acid molecule comprising the sequence of SEQ ID NO: 43; and/or the BKV-Ic VP1 polypeptide is encoded by a nucleic acid molecule comprising the sequence of SEQ ID NO: 44. 9. The composition of claim 1, wherein the virus-like particle comprising at least one BKV-IV capsid polypeptide comprises a BKV-IV VP1 polypeptide, and the virus-like particle comprising at least one BKV-I capsid polypeptide comprises a BKV-Ia VP1 polypeptide and/or a BKV-Ib2 VP1 polypeptide. 10. The composition of claim 1, further comprising a virus-like particle comprising at least one JC polyomavirus capsid polypeptide. 11. A multivalent BK polyomavirus (BKV) immunogenic composition comprising:
a virus-like particle comprising at least one BKV serotype IV VP1 polypeptide, wherein the at least one BKV serotype IV VP1 polypeptide is encoded by a nucleic acid molecule comprising the sequence of SEQ ID NO: 39 or SEQ ID NO: 47; a virus-like particle comprising at least one BKV serotype I VP1polypeptide, wherein the at least one BKV serotype I VP1 polypeptide is encoded by a nucleic acid molecule comprising the sequence of one of SEQ ID NOs: 42-44; and a pharmaceutically acceptable carrier. 12. The composition of claim 11, wherein the at least one BKV-IV VP1 polypeptide comprises the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 16 and/ot the at least one isolated BKV-I VP1 polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 1 and 13-15. 13. The composition of claim 11, further comprising:
a virus-like particle comprising at least one BKV serotype II capsid polypeptide; a virus-like particle comprising at least one BKV serotype III capsid polypeptide; or a combination thereof. 14. The composition of claim 11, wherein the virus-like particle further comprises a VP2 polypeptide, a VP3 polypeptide, or a combination of two or more thereof. 15. The composition of claim 11, wherein the at least one BKV serotype IV VP1 polypeptide comprises one or more of a BKV-IVb1 VP1 polypeptide and/or a BKV-IVc2 VP1 polypeptide. 16. The composition of claim 11, wherein the at least one BKV serotype I VP1 polypeptide comprises one or more of a BKV-Ia VP1 polypeptide, a BKV-Ib1 VP1 polypeptide, a BKV-Ib2 VP1 polypeptide, and/or a BKV-Ic VP1 polypeptide. 17. The composition of claim 11, wherein the virus-like particle comprising at least one BKV-IV VP1 polypeptide comprises a BKV-IV VP1 polypeptide, and the virus-like particle comprising at least one BKV-I VP1 polypeptide comprises a BKV-Ia VP1 polypeptide and/or a BKV-Ib2 VP1 polypeptide. 18. The composition of claim 11, further comprising a virus-like particle comprising at least one JC polyomavirus capsid polypeptide. 19. The composition of claim 11, further comprising an adjuvant.
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Disclosed herein are methods of eliciting an immune response against a polyomavirus (for example, BKV serotype I (BKV-I), BKV serotype II (BKV-II), BKV serotype III (BKV-III) and/or BKV serotype IV (BKV-IV)) and methods of treating or inhibiting polyomavirus-associated pathology (such as polyomavirus-associated nephropathy, BKV-associated hemorrhagic cystitis, or JC virus-associated progressive multifocal leukoencephalopathy; PML). Further disclosed are immunogenic compositions of use in the disclosed methods. Also disclosed are methods of selecting an organ transplant donor and/or recipient including detecting whether the prospective donor and/or recipient has BKV serotype-specific (such as BKV serotype IV-specific) neutralizing antibodies.1. A multivalent BK polyomavirus (BKV) immunogenic composition comprising:
a virus-like particle comprising at least one BKV serotype IV capsid polypeptide; a virus-like particle comprising at least one BKV serotype I capsid polypeptide; a pharmaceutically acceptable carrier; and an adjuvant. 2. The composition of claim 1, wherein the at least one BKV-IV capsid polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 4-6, 16, and 110-125 and the at least one isolated BKV-I capsid polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 1-3, 13-15, and 52-103. 3. The composition of claim 1, further comprising:
a virus-like particle comprising at least one BKV serotype II capsid polypeptide; a virus-like particle comprising at least one BKV serotype III capsid polypeptide; or a combination thereof. 4. The composition of claim 1, wherein the at least one capsid polypeptide comprises VP1, VP2, VP3, or a combination of two or more thereof. 5. The composition of claim 1, wherein the at least one BKV serotype IV capsid polypeptide comprises one or more of a BKV-IVb1 VP1 polypeptide and/or a BKV-IVc2 VP1 polypeptide. 6. The composition of claim 5, wherein the BKV-IVb1 VP1 polypeptide is encoded by a nucleic acid molecule comprising the sequence of SEQ ID NO: 47 and/or the BKV-IVc2 VP1 polypeptide is encoded by a nucleic acid molecule comprising the sequence of SEQ ID NO: 27 or 39. 7. The composition of claim 1, wherein the at least one BKV serotype I capsid polypeptide comprises one or more of a BKV-Ia VP1 polypeptide, a BKV-Ib1 VP1 polypeptide, a BKV-Ib2 VP1 polypeptide, and/or a BKV-Ic VP1 polypeptide. 8. The composition of claim 7, wherein the BKV-Ia VP1 polypeptide is encoded by a nucleic acid molecule comprising the sequence of SEQ ID NO: 42, the BKV-Ib1 VP1 polypeptide is encoded by a nucleic acid molecule comprising the sequence of SEQ ID NO: 24; the BKV-Ib2 VP1 polypeptide is encoded by a nucleic acid molecule comprising the sequence of SEQ ID NO: 43; and/or the BKV-Ic VP1 polypeptide is encoded by a nucleic acid molecule comprising the sequence of SEQ ID NO: 44. 9. The composition of claim 1, wherein the virus-like particle comprising at least one BKV-IV capsid polypeptide comprises a BKV-IV VP1 polypeptide, and the virus-like particle comprising at least one BKV-I capsid polypeptide comprises a BKV-Ia VP1 polypeptide and/or a BKV-Ib2 VP1 polypeptide. 10. The composition of claim 1, further comprising a virus-like particle comprising at least one JC polyomavirus capsid polypeptide. 11. A multivalent BK polyomavirus (BKV) immunogenic composition comprising:
a virus-like particle comprising at least one BKV serotype IV VP1 polypeptide, wherein the at least one BKV serotype IV VP1 polypeptide is encoded by a nucleic acid molecule comprising the sequence of SEQ ID NO: 39 or SEQ ID NO: 47; a virus-like particle comprising at least one BKV serotype I VP1polypeptide, wherein the at least one BKV serotype I VP1 polypeptide is encoded by a nucleic acid molecule comprising the sequence of one of SEQ ID NOs: 42-44; and a pharmaceutically acceptable carrier. 12. The composition of claim 11, wherein the at least one BKV-IV VP1 polypeptide comprises the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 16 and/ot the at least one isolated BKV-I VP1 polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 1 and 13-15. 13. The composition of claim 11, further comprising:
a virus-like particle comprising at least one BKV serotype II capsid polypeptide; a virus-like particle comprising at least one BKV serotype III capsid polypeptide; or a combination thereof. 14. The composition of claim 11, wherein the virus-like particle further comprises a VP2 polypeptide, a VP3 polypeptide, or a combination of two or more thereof. 15. The composition of claim 11, wherein the at least one BKV serotype IV VP1 polypeptide comprises one or more of a BKV-IVb1 VP1 polypeptide and/or a BKV-IVc2 VP1 polypeptide. 16. The composition of claim 11, wherein the at least one BKV serotype I VP1 polypeptide comprises one or more of a BKV-Ia VP1 polypeptide, a BKV-Ib1 VP1 polypeptide, a BKV-Ib2 VP1 polypeptide, and/or a BKV-Ic VP1 polypeptide. 17. The composition of claim 11, wherein the virus-like particle comprising at least one BKV-IV VP1 polypeptide comprises a BKV-IV VP1 polypeptide, and the virus-like particle comprising at least one BKV-I VP1 polypeptide comprises a BKV-Ia VP1 polypeptide and/or a BKV-Ib2 VP1 polypeptide. 18. The composition of claim 11, further comprising a virus-like particle comprising at least one JC polyomavirus capsid polypeptide. 19. The composition of claim 11, further comprising an adjuvant.
| 1,600 |
1,209 | 15,308,085 | 1,633 |
It is an object of the present invention to provide a chicken B cell that expresses a variety of human antibodies. The solution to the problem in the present invention is a chicken B cell, in which, in an antibody light chain gene locus thereof, all or a part of a DNA sequence derived from a human antibody light chain variable region and a human antibody light chain constant region are inserted, or the antibody light chain gene locus is replaced with all or a part of a DNA sequence derived from a human antibody light chain variable region and a human antibody light chain constant region, and in an antibody heavy chain gene locus thereof, all or a part of a DNA sequence derived from a human antibody heavy chain variable region and a human antibody heavy chain constant region are inserted, or the antibody heavy chain gene locus is replaced with all or a part of a DNA sequence derived from a human antibody heavy chain variable region and a human antibody heavy chain constant region, and in an antibody light chain pseudogene locus thereof, two or more DNA sequences derived from human antibody light chain variable regions are inserted, or the antibody light chain pseudogene locus is replaced with two or more DNA sequences derived from human antibody light chain variable regions, and/or in an antibody heavy chain pseudogene locus thereof, two or more DNA sequences derived from human antibody heavy chain variable regions are inserted, or the antibody heavy chain pseudogene locus is replaced with two or more DNA sequences derived from human antibody heavy chain variable regions.
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1. A chicken B cell, in which in chicken antibody light chain gene locus is replaced by the DNA sequence derived from a human antibody light chain variable region and by the DNA sequence derived from a human antibody light chain constant region,
which in the chicken antibody heavy chain gene locus all or a part of the DNA sequence derived from a human antibody heavy chain variable region and of a human antibody heavy chain constant region are inserted, and in which the chicken antibody light chain pseudogene locus is replaced by 25 or more DNA sequences derived from human antibody light chain variable regions, and in which the chicken antibody heavy chain pseudogene locus is inserted by 30 or more DNA sequences derived from human antibody heavy chain variable regions,
wherein the chicken B cell has the ability to express a human antibody on the cell surface and also to secrete the human antibody into the culture solution. 2. (canceled) 3. (canceled) 4. (canceled) 5. (canceled) 6. The chicken B cell according to claim 1, wherein the DNA sequence derived from the human antibody light chain variable region inserted into the antibody light chain gene locus is at a position upstream from the DNA sequence derived from the human antibody light chain constant region, and the DNA sequence derived from the human antibody heavy chain variable region inserted into the antibody heavy chain gene locus is at a position upstream from the DNA sequence derived from the human antibody heavy chain constant region. 7. (canceled) 8. The chicken B cell according to claim 1, wherein the human antibody heavy chain is a γ chain. 9. The chicken B cell according to claim 1, wherein the human antibody light chain is a γ chain or a κ chain. 10. (canceled) 11. The chicken B cell according to claim 1, which is a DT40 cell. 12. The chicken B cell according to claim 1, which has been subjected to a treatment of relaxing chromatin. 13. The chicken B cell according to claim 12, wherein the treatment of relaxing chromatin is reduction or deletion of the function of histone deacetylase in the chicken B cell. 14. The chicken B cell according to claim 13, wherein the method for reducing or deleting the function of histone deacetylase is reduction or deletion of the expression of a histone deacetylase gene in the chicken B cell. 15. The chicken B cell according to claim 14, wherein the histone deacetylase is HDAC2. 16. The chicken B cell according to claim 13, wherein the method for reducing or deleting the function of histone deacetylase is a treatment with an HDAC inhibitor. 17. An antibody-producing cell library consisting of the chicken B cells according to claim 1. 18. A method for producing a human antibody or a humanized antibody from the chicken B cell according to claim 1, comprising culturing said chicken B cell under culturing conditions suitable for the cell to produce a human antibody or a humanized antibody and obtaining said antibody. 19. Antibodies reacting with various antigens, wherein said antibodies have been produced by the cell library according to claim 17. 20. A kit for producing the chicken B cells according to claim 1. 21. (canceled) 22. The method of claim 18, wherein the antibody is comprised in a pharmaceutical product.
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It is an object of the present invention to provide a chicken B cell that expresses a variety of human antibodies. The solution to the problem in the present invention is a chicken B cell, in which, in an antibody light chain gene locus thereof, all or a part of a DNA sequence derived from a human antibody light chain variable region and a human antibody light chain constant region are inserted, or the antibody light chain gene locus is replaced with all or a part of a DNA sequence derived from a human antibody light chain variable region and a human antibody light chain constant region, and in an antibody heavy chain gene locus thereof, all or a part of a DNA sequence derived from a human antibody heavy chain variable region and a human antibody heavy chain constant region are inserted, or the antibody heavy chain gene locus is replaced with all or a part of a DNA sequence derived from a human antibody heavy chain variable region and a human antibody heavy chain constant region, and in an antibody light chain pseudogene locus thereof, two or more DNA sequences derived from human antibody light chain variable regions are inserted, or the antibody light chain pseudogene locus is replaced with two or more DNA sequences derived from human antibody light chain variable regions, and/or in an antibody heavy chain pseudogene locus thereof, two or more DNA sequences derived from human antibody heavy chain variable regions are inserted, or the antibody heavy chain pseudogene locus is replaced with two or more DNA sequences derived from human antibody heavy chain variable regions.1. A chicken B cell, in which in chicken antibody light chain gene locus is replaced by the DNA sequence derived from a human antibody light chain variable region and by the DNA sequence derived from a human antibody light chain constant region,
which in the chicken antibody heavy chain gene locus all or a part of the DNA sequence derived from a human antibody heavy chain variable region and of a human antibody heavy chain constant region are inserted, and in which the chicken antibody light chain pseudogene locus is replaced by 25 or more DNA sequences derived from human antibody light chain variable regions, and in which the chicken antibody heavy chain pseudogene locus is inserted by 30 or more DNA sequences derived from human antibody heavy chain variable regions,
wherein the chicken B cell has the ability to express a human antibody on the cell surface and also to secrete the human antibody into the culture solution. 2. (canceled) 3. (canceled) 4. (canceled) 5. (canceled) 6. The chicken B cell according to claim 1, wherein the DNA sequence derived from the human antibody light chain variable region inserted into the antibody light chain gene locus is at a position upstream from the DNA sequence derived from the human antibody light chain constant region, and the DNA sequence derived from the human antibody heavy chain variable region inserted into the antibody heavy chain gene locus is at a position upstream from the DNA sequence derived from the human antibody heavy chain constant region. 7. (canceled) 8. The chicken B cell according to claim 1, wherein the human antibody heavy chain is a γ chain. 9. The chicken B cell according to claim 1, wherein the human antibody light chain is a γ chain or a κ chain. 10. (canceled) 11. The chicken B cell according to claim 1, which is a DT40 cell. 12. The chicken B cell according to claim 1, which has been subjected to a treatment of relaxing chromatin. 13. The chicken B cell according to claim 12, wherein the treatment of relaxing chromatin is reduction or deletion of the function of histone deacetylase in the chicken B cell. 14. The chicken B cell according to claim 13, wherein the method for reducing or deleting the function of histone deacetylase is reduction or deletion of the expression of a histone deacetylase gene in the chicken B cell. 15. The chicken B cell according to claim 14, wherein the histone deacetylase is HDAC2. 16. The chicken B cell according to claim 13, wherein the method for reducing or deleting the function of histone deacetylase is a treatment with an HDAC inhibitor. 17. An antibody-producing cell library consisting of the chicken B cells according to claim 1. 18. A method for producing a human antibody or a humanized antibody from the chicken B cell according to claim 1, comprising culturing said chicken B cell under culturing conditions suitable for the cell to produce a human antibody or a humanized antibody and obtaining said antibody. 19. Antibodies reacting with various antigens, wherein said antibodies have been produced by the cell library according to claim 17. 20. A kit for producing the chicken B cells according to claim 1. 21. (canceled) 22. The method of claim 18, wherein the antibody is comprised in a pharmaceutical product.
| 1,600 |
1,210 | 16,062,422 | 1,612 |
The present invention relates to a in the form of an emulsion, in particular a water-in-oil emulsion, in particular comprising a physiologically acceptable medium, in particular for coating keratin materials, more particularly for making up and/or caring for keratin materials, such as the skin, containing: —at least one aqueous phase in a content from 60% to 80% by weight relative to the total weight of the composition; and —at least one oily phase at a concentration of less than 30.0% by weight relative to the total weight of the composition and comprising at least one silicone oil; and —at least one hydrophobic coated pigment; and —optionally at least one moisturizing agent at a concentration ranging from 10% to 25% by weight relative to the total weight of the composition; and —at least one emulsifying surfactant. The invention also relates to a process for coating keratin materials, more particularly for making up and/or caring for keratin materials, such as the skin, characterized in that it comprises the application to the keratin materials of a composition as defined previously.
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1. A composition, in the form of an emulsion, comprising a physiologically acceptable medium, comprising:
at least one aqueous phase in a content from 60% to 80% by weight relative to the total weight of the composition; at least one oily phase at a concentration of less than 30.0% by weight relative to the total weight of the composition and comprising at least one silicone oil; at least one hydrophobic coated pigment; optionally at least one moisturizing agent at a concentration ranging from 10% to 25% by weight relative to the total weight of the composition; and at least one emulsifying surfactant. 2. The composition according to claim 1, comprising:
at least one aqueous phase in a content ranging from 60% to 80% by weight relative to the total weight of the composition; at least one oily phase, at a concentration of less than 30.0% by weight relative to the total weight of the composition and comprising at least one silicone oil; at least one hydrophobic coated pigment; and at least one emulsifying silicone elastomer. 3. The composition according to claim 1, comprising:
at least one aqueous phase in a content from 60% to 80% by weight relative to the total weight of the composition; at least one continuous oily phase at a concentration of less than 30.0% by weight relative to the total weight of the composition and comprising at least one silicone oil; at least one hydrophobic coated pigment; at least one moisturizing agent at a concentration ranging from 10% to 25% by weight relative to the total weight of the composition; and at least one emulsifying surfactant, said composition having a viscosity at 25° C. ranging from 0.1 to 10 Pa·s. 4. The composition according to claim 3, wherein the viscosity ranges from 0.5 to 5 Pa·s. 5. The composition according to claim 1, wherein the aqueous phase of the emulsion is characterized by a number of droplets of less than 200,000. 6. The composition according to claim 1, wherein the surfactant emulsifier is chosen from polyoxyalkylenated silicone elastomers and polyglycerolated silicone elastomers, and mixtures thereof. 7. The composition according to claim 1, wherein the emulsifying surfactant is present in a content of active material of less than 2.5% by weight relative to the total weight of said composition. 8. The composition according to claim 1, wherein the oily phase concentration is less than or equal to 25% by weight, relative to the total weight of the composition. 9. The composition according to claim 1, wherein the oily phase comprises at least one silicone oil chosen from:
volatile cyclic silicone oils having a viscosity at ambient temperature of less than 8 cst and containing from 4 to 7 silicone atoms, these silicones optionally comprising alkyl or alkoxy groups containing from 1 to 10 carbon atoms; volatile or non-volatile polydimethylsiloxanes (PDMSs); phenylated silicones; polydimethylsiloxanes comprising aliphatic groups, which are pendent and/or at the end of the silicone chain, these groups each comprising from 6 to 24 carbon atoms, and mixtures thereof. 10. The composition according to claim 1, wherein the oily phase comprises in addition at least one liquid lipophilic organic UV-screening agent, chosen from:
liquid lipophilic β,β-diphenylacrylate compounds, liquid lipophilic salicylate compounds, liquid lipophilic cinnamate compounds, and mixtures thereof. 11. The composition according to claim 1, wherein the oily phase comprises at least ethylhexyl methoxycinnamate and caprylyl methicone. 12. The composition according to claim 1, wherein the moisturizing agent is chosen from polyols, urea and its derivatives, hyaluronic acid, glycine, β-alanine, taurine, trimethyl glycine, and mixtures thereof. 13. The composition according to claim 1, wherein the moisturizing agent is chosen from polyols chosen from ethylene glycol, pentaerythritol, trimethylolpropane, propylene glycol, 1,3 propanediol, butylene glycol, isoprene glycol, pentylene glycol, hexylene glycol, glycerol, polyglycerols, polyethylene glycols, and mixtures thereof. 14. The composition according to claim 1, wherein the moisturizing agent is present in the composition in a content ranging from 15% to 20% by weight relative to the total weight of said composition. 15. The composition according to claim 1, wherein the hydrophobic coated pigments are present in a proportion ranging from 5% to 25% by weight, relative to the total weight of the composition. 16. The composition according to claim 1, wherein the hydrophobic coated pigments are hydrophobic coated pigments of iron oxide and/or of titanium dioxide. 17. The composition according to claim 1, wherein the hydrophobic coated pigments are titanium dioxides and/or iron oxides coated:
with an N-acylamino acid and/or a salt thereof; or with isopropyl titanium triisostearate. 18. A process for coating keratin materials, comprising applying the composition according to claim 1 to the keratin materials. 19. A process for preparing a water-in-oil emulsion, comprising:
at least one aqueous phase in a content from 60% to 80% by weight relative to the total weight of the composition; at least one oily phase at a concentration of less than 30.0% by weight relative to the total weight of the composition and comprising at least one silicone oil; at least one hydrophobic coated pigment; optionally at least one moisturizing agent at a concentration ranging from 10% to 25% by weight relative to the total weight of the composition; at least one surfactant emulsifier, the method comprising: a) preparing an aqueous phase by mixing the water, the optional moisturizing agent and the optional other ingredients, with magnetic stirring, at a temperature of from 50 to 60° C. from 3 to 10 minutes and then leaving to cool to 25-30° C.; b) preparing the oily phase, at a temperature ranging from 25 to 30° C., by mixing the hydrophobic coated pigment, the surfactant emulsifier and the oily component with rotor stator stirring (Moritz) for 15 to 25 minutes at a shear rate ranging from 2500 to 3500 revolutions/minute; then c) stirring the oily phase is stirred in a Rayneri deflocculating paddle mixer at a shear rate ranging from 300 to 500 revolutions/minute, at a temperature of from 25 to 30° C.; then d) adding the aqueous phase to said oily phase, over the course of a period of time not exceeding 1 minute, while increasing the stirring to a shear rate ranging from 700 to 1200 revolutions/minute, at a temperature of from 25 to 30° C.; and e) leaving the resulting mixture to stir for a further period of time ranging from 1 to 3 minutes, at a shear rate ranging from 700 to 1200 revolutions/minute, at a temperature ranging from 25 to 30° C.
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The present invention relates to a in the form of an emulsion, in particular a water-in-oil emulsion, in particular comprising a physiologically acceptable medium, in particular for coating keratin materials, more particularly for making up and/or caring for keratin materials, such as the skin, containing: —at least one aqueous phase in a content from 60% to 80% by weight relative to the total weight of the composition; and —at least one oily phase at a concentration of less than 30.0% by weight relative to the total weight of the composition and comprising at least one silicone oil; and —at least one hydrophobic coated pigment; and —optionally at least one moisturizing agent at a concentration ranging from 10% to 25% by weight relative to the total weight of the composition; and —at least one emulsifying surfactant. The invention also relates to a process for coating keratin materials, more particularly for making up and/or caring for keratin materials, such as the skin, characterized in that it comprises the application to the keratin materials of a composition as defined previously.1. A composition, in the form of an emulsion, comprising a physiologically acceptable medium, comprising:
at least one aqueous phase in a content from 60% to 80% by weight relative to the total weight of the composition; at least one oily phase at a concentration of less than 30.0% by weight relative to the total weight of the composition and comprising at least one silicone oil; at least one hydrophobic coated pigment; optionally at least one moisturizing agent at a concentration ranging from 10% to 25% by weight relative to the total weight of the composition; and at least one emulsifying surfactant. 2. The composition according to claim 1, comprising:
at least one aqueous phase in a content ranging from 60% to 80% by weight relative to the total weight of the composition; at least one oily phase, at a concentration of less than 30.0% by weight relative to the total weight of the composition and comprising at least one silicone oil; at least one hydrophobic coated pigment; and at least one emulsifying silicone elastomer. 3. The composition according to claim 1, comprising:
at least one aqueous phase in a content from 60% to 80% by weight relative to the total weight of the composition; at least one continuous oily phase at a concentration of less than 30.0% by weight relative to the total weight of the composition and comprising at least one silicone oil; at least one hydrophobic coated pigment; at least one moisturizing agent at a concentration ranging from 10% to 25% by weight relative to the total weight of the composition; and at least one emulsifying surfactant, said composition having a viscosity at 25° C. ranging from 0.1 to 10 Pa·s. 4. The composition according to claim 3, wherein the viscosity ranges from 0.5 to 5 Pa·s. 5. The composition according to claim 1, wherein the aqueous phase of the emulsion is characterized by a number of droplets of less than 200,000. 6. The composition according to claim 1, wherein the surfactant emulsifier is chosen from polyoxyalkylenated silicone elastomers and polyglycerolated silicone elastomers, and mixtures thereof. 7. The composition according to claim 1, wherein the emulsifying surfactant is present in a content of active material of less than 2.5% by weight relative to the total weight of said composition. 8. The composition according to claim 1, wherein the oily phase concentration is less than or equal to 25% by weight, relative to the total weight of the composition. 9. The composition according to claim 1, wherein the oily phase comprises at least one silicone oil chosen from:
volatile cyclic silicone oils having a viscosity at ambient temperature of less than 8 cst and containing from 4 to 7 silicone atoms, these silicones optionally comprising alkyl or alkoxy groups containing from 1 to 10 carbon atoms; volatile or non-volatile polydimethylsiloxanes (PDMSs); phenylated silicones; polydimethylsiloxanes comprising aliphatic groups, which are pendent and/or at the end of the silicone chain, these groups each comprising from 6 to 24 carbon atoms, and mixtures thereof. 10. The composition according to claim 1, wherein the oily phase comprises in addition at least one liquid lipophilic organic UV-screening agent, chosen from:
liquid lipophilic β,β-diphenylacrylate compounds, liquid lipophilic salicylate compounds, liquid lipophilic cinnamate compounds, and mixtures thereof. 11. The composition according to claim 1, wherein the oily phase comprises at least ethylhexyl methoxycinnamate and caprylyl methicone. 12. The composition according to claim 1, wherein the moisturizing agent is chosen from polyols, urea and its derivatives, hyaluronic acid, glycine, β-alanine, taurine, trimethyl glycine, and mixtures thereof. 13. The composition according to claim 1, wherein the moisturizing agent is chosen from polyols chosen from ethylene glycol, pentaerythritol, trimethylolpropane, propylene glycol, 1,3 propanediol, butylene glycol, isoprene glycol, pentylene glycol, hexylene glycol, glycerol, polyglycerols, polyethylene glycols, and mixtures thereof. 14. The composition according to claim 1, wherein the moisturizing agent is present in the composition in a content ranging from 15% to 20% by weight relative to the total weight of said composition. 15. The composition according to claim 1, wherein the hydrophobic coated pigments are present in a proportion ranging from 5% to 25% by weight, relative to the total weight of the composition. 16. The composition according to claim 1, wherein the hydrophobic coated pigments are hydrophobic coated pigments of iron oxide and/or of titanium dioxide. 17. The composition according to claim 1, wherein the hydrophobic coated pigments are titanium dioxides and/or iron oxides coated:
with an N-acylamino acid and/or a salt thereof; or with isopropyl titanium triisostearate. 18. A process for coating keratin materials, comprising applying the composition according to claim 1 to the keratin materials. 19. A process for preparing a water-in-oil emulsion, comprising:
at least one aqueous phase in a content from 60% to 80% by weight relative to the total weight of the composition; at least one oily phase at a concentration of less than 30.0% by weight relative to the total weight of the composition and comprising at least one silicone oil; at least one hydrophobic coated pigment; optionally at least one moisturizing agent at a concentration ranging from 10% to 25% by weight relative to the total weight of the composition; at least one surfactant emulsifier, the method comprising: a) preparing an aqueous phase by mixing the water, the optional moisturizing agent and the optional other ingredients, with magnetic stirring, at a temperature of from 50 to 60° C. from 3 to 10 minutes and then leaving to cool to 25-30° C.; b) preparing the oily phase, at a temperature ranging from 25 to 30° C., by mixing the hydrophobic coated pigment, the surfactant emulsifier and the oily component with rotor stator stirring (Moritz) for 15 to 25 minutes at a shear rate ranging from 2500 to 3500 revolutions/minute; then c) stirring the oily phase is stirred in a Rayneri deflocculating paddle mixer at a shear rate ranging from 300 to 500 revolutions/minute, at a temperature of from 25 to 30° C.; then d) adding the aqueous phase to said oily phase, over the course of a period of time not exceeding 1 minute, while increasing the stirring to a shear rate ranging from 700 to 1200 revolutions/minute, at a temperature of from 25 to 30° C.; and e) leaving the resulting mixture to stir for a further period of time ranging from 1 to 3 minutes, at a shear rate ranging from 700 to 1200 revolutions/minute, at a temperature ranging from 25 to 30° C.
| 1,600 |
1,211 | 14,649,803 | 1,634 |
The subject of the invention is a method for making an in vitro prognosis of severity for a patient in septic shock, including the following steps: (i) the level of expression of the expression product of at least one gene chosen from the lilrb2 and lilrb1 genes is measured in vitro on the basis of a biological sample taken from the patient, (ii) the level of expression of the expression product of the at least one gene is compared with a control level of expression, of the expression product of the same gene, with a good prognosis of severity, in which a level of expression of the expression product of the at least one gene below the control level of expression indicates a poor prognosis of severity for the patient, and also a kit for implementing the method.
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1. Method for making an in vitro prognosis of severity for a patient in septic shock, comprising the following steps:
(i) the level of expression of the expression product of at least one gene chosen from the lilrb2 and lilrb1 genes is measured in vitro on the basis of a biological sample taken from said patient, (ii) the level of expression of the expression product of said at least one gene is compared with a control level of expression, of the expression product of the same gene, with a good prognosis of severity, in which a level of expression of the expression product of said at least one gene below said control level of expression indicates a poor prognosis of severity for the patient. 2. Method according to claim 1, in which
(i) the level of expression of the expression product of the lilrb2 gene is measured, (ii) the level of expression of the expression product of the lilrb2 gene is compared with the control level of expression of the lilrb2 gene, in which a level of expression of the expression product of the lilrb2 gene in the patient below the control level of expression indicates a poor prognosis for the patient. 3. Method according to claim 1, in which
(i) the patient's level of expression of the expression product of the lilrb2 gene and the patient's level of expression of the expression product of the lilrb1 gene are measured, (ii) the patient's level of expression of the expression product of the lilrb2 gene and of the lilrb1 gene are compared respectively with the control level of expression of each gene, in which a level of expression of the expression product of the lilrb2 gene and of the lilrb1 gene in the patient respectively below the predetermined threshold control level of expression of each gene indicates a poor prognosis for the patient. 4. Method according to claim 1, in which said biological sample is chosen from blood, plasma, serum, saliva, urine, cerebrospinal fluid, pleural fluid and peritoneal fluid. 5. Method according to claim 1, in which the expression product of the gene is an RNA. 6. Method according to claim 1, in which the expression product is a protein or a polypeptide. 7. Method according to claim 5, in which the level of expression of the RNA is determined by means of at least one hybridization probe specific for the expression product. 8. Method according to claim 7, in which the level of expression of the RNA is determined by quantitative enzymatic amplification. 9. Method according to claim 6, in which the level of expression of the polypeptide is determined by a quantitative immunoassay. 10. Method for carrying out in vitro monitoring of a patient in septic shock, by measuring the change in the level of expression of the expression product of at least one gene chosen from the lilrb2 and lilrb1 genes in said patient, in which
(i) the level of expression of said at least one gene in a sample taken from the patient on D1 is measured, (ii) the level of expression of said at least one gene in a sample taken from the patient on Dx is measured, in which an increase in said level of expression of said at least one gene between D1 and Dx indicates that the patient is moving towards a good prognosis of severity. 11. Method according to claim 10, in which said level of expression is measured by quantitative amplification. 12. Method according to claim 10, in which the level of expression is measured by a quantitative immunoassay.
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The subject of the invention is a method for making an in vitro prognosis of severity for a patient in septic shock, including the following steps: (i) the level of expression of the expression product of at least one gene chosen from the lilrb2 and lilrb1 genes is measured in vitro on the basis of a biological sample taken from the patient, (ii) the level of expression of the expression product of the at least one gene is compared with a control level of expression, of the expression product of the same gene, with a good prognosis of severity, in which a level of expression of the expression product of the at least one gene below the control level of expression indicates a poor prognosis of severity for the patient, and also a kit for implementing the method.1. Method for making an in vitro prognosis of severity for a patient in septic shock, comprising the following steps:
(i) the level of expression of the expression product of at least one gene chosen from the lilrb2 and lilrb1 genes is measured in vitro on the basis of a biological sample taken from said patient, (ii) the level of expression of the expression product of said at least one gene is compared with a control level of expression, of the expression product of the same gene, with a good prognosis of severity, in which a level of expression of the expression product of said at least one gene below said control level of expression indicates a poor prognosis of severity for the patient. 2. Method according to claim 1, in which
(i) the level of expression of the expression product of the lilrb2 gene is measured, (ii) the level of expression of the expression product of the lilrb2 gene is compared with the control level of expression of the lilrb2 gene, in which a level of expression of the expression product of the lilrb2 gene in the patient below the control level of expression indicates a poor prognosis for the patient. 3. Method according to claim 1, in which
(i) the patient's level of expression of the expression product of the lilrb2 gene and the patient's level of expression of the expression product of the lilrb1 gene are measured, (ii) the patient's level of expression of the expression product of the lilrb2 gene and of the lilrb1 gene are compared respectively with the control level of expression of each gene, in which a level of expression of the expression product of the lilrb2 gene and of the lilrb1 gene in the patient respectively below the predetermined threshold control level of expression of each gene indicates a poor prognosis for the patient. 4. Method according to claim 1, in which said biological sample is chosen from blood, plasma, serum, saliva, urine, cerebrospinal fluid, pleural fluid and peritoneal fluid. 5. Method according to claim 1, in which the expression product of the gene is an RNA. 6. Method according to claim 1, in which the expression product is a protein or a polypeptide. 7. Method according to claim 5, in which the level of expression of the RNA is determined by means of at least one hybridization probe specific for the expression product. 8. Method according to claim 7, in which the level of expression of the RNA is determined by quantitative enzymatic amplification. 9. Method according to claim 6, in which the level of expression of the polypeptide is determined by a quantitative immunoassay. 10. Method for carrying out in vitro monitoring of a patient in septic shock, by measuring the change in the level of expression of the expression product of at least one gene chosen from the lilrb2 and lilrb1 genes in said patient, in which
(i) the level of expression of said at least one gene in a sample taken from the patient on D1 is measured, (ii) the level of expression of said at least one gene in a sample taken from the patient on Dx is measured, in which an increase in said level of expression of said at least one gene between D1 and Dx indicates that the patient is moving towards a good prognosis of severity. 11. Method according to claim 10, in which said level of expression is measured by quantitative amplification. 12. Method according to claim 10, in which the level of expression is measured by a quantitative immunoassay.
| 1,600 |
1,212 | 16,010,412 | 1,658 |
The subject invention is directed to a pharmaceutical composition comprising an open matrix network carrying a pharmaceutically active ingredient, wherein the open matrix network comprises levan.
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1-31. (canceled) 32. A pharmaceutical composition comprising:
(a) at least one matrix-forming agent that is levan to form an open matrix network; and (b) at least one pharmaceutically active ingredient,
wherein the composition is an orodispersible pharmaceutical dosage form. 33. The pharmaceutical composition according to claim 32, further comprising one or more secondary matrix-forming agents. 34. The pharmaceutical composition according to claim 33, wherein the one or more secondary matrix-forming agents is selected from the group consisting of trehalose, raffinose, and mannitol. 35. The pharmaceutical composition according to claim 33, wherein the one or more secondary matrix-forming agent is mannitol. 36. The pharmaceutical composition according to claim 33, wherein the one or more secondary matrix-forming agent is trehalose. 37. The pharmaceutical composition according to claim 33, wherein the one or more secondary matrix-forming agent is raffinose. 38. The pharmaceutical composition according to claim 32, wherein the at least one pharmaceutically active ingredient is chosen from desmopressin, desmopressin acetate, loratidine, famotidine, montelukast sodium, and ondansetron. 39. The pharmaceutical composition according to claim 32, wherein at least 80% of the composition dissolves within 10 seconds upon contact with an aqueous solution or with saliva. 40. The pharmaceutical composition according to claim 32, wherein the composition has a tensile strength from about 0.05 to about 1.6 N/mm2. 41. A pharmaceutical composition prepared by a process comprising at least a step of sublimating a solvent from a liquid preparation that comprises:
(a) at least one matrix-forming agent that is levan to form an open matrix network; and (b) at least one pharmaceutically active ingredient,
wherein the composition is an orodispersible pharmaceutical dosage form. 42. The pharmaceutical composition according to claim 41, wherein the liquid preparation further comprises one or more secondary matrix-forming agents. 43. The pharmaceutical composition according to claim 42, wherein the one or more secondary matrix-forming agent is mannitol. 44. The pharmaceutical composition according to claim 42, wherein the one or more secondary matrix-forming agent is trehalose. 45. The pharmaceutical composition according to claim 42, wherein the one or more secondary matrix-forming agent is raffinose. 46. The pharmaceutical composition according to claim 41, wherein the at least one pharmaceutically active ingredient is chosen from desmopressin, desmopressin acetate, loratidine, famotidine, montelukast sodium, and ondansetron. 47. A blister pack having one or more depressions disposed therein, wherein each of the one or more depressions comprises a pharmaceutical composition, the composition comprising:
(a) at least one matrix-forming agent that is levan to form an open matrix network; and (b) at least one pharmaceutically active ingredient,
wherein the composition is an orodispersible pharmaceutical dosage form. 48. The blister pack according to claim 47, which is prepared by a process comprising steps of:
(a) introducing a liquid preparation into one or more depressions of a blister pack, the liquid preparation comprising the matrix forming agent and the pharmaceutically active ingredient; and (b) sublimating the solvent from the liquid preparation in the one or more depressions. 49. The blister pack according to claim 47, wherein the composition further comprises one or more secondary matrix-forming agents. 50. The blister pack according to claim 48, wherein the one or more secondary matrix-forming agents is selected from the group consisting of trehalose, raffinose, and mannitol. 51. The blister pack according to claim 50, wherein the one or more secondary matrix-forming agent is mannitol. 52. The pharmaceutical composition according to claim 50, wherein the one or more secondary matrix-forming agent is trehalose. 53. The pharmaceutical composition according to claim 50, wherein the one or more secondary matrix-forming agent is raffinose. 54. The pharmaceutical composition according to claim 47, wherein the at least one pharmaceutically active ingredient is chosen from desmopressin, desmopressin acetate, loratidine, famotidine, montelukast sodium, and ondansetron.
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The subject invention is directed to a pharmaceutical composition comprising an open matrix network carrying a pharmaceutically active ingredient, wherein the open matrix network comprises levan.1-31. (canceled) 32. A pharmaceutical composition comprising:
(a) at least one matrix-forming agent that is levan to form an open matrix network; and (b) at least one pharmaceutically active ingredient,
wherein the composition is an orodispersible pharmaceutical dosage form. 33. The pharmaceutical composition according to claim 32, further comprising one or more secondary matrix-forming agents. 34. The pharmaceutical composition according to claim 33, wherein the one or more secondary matrix-forming agents is selected from the group consisting of trehalose, raffinose, and mannitol. 35. The pharmaceutical composition according to claim 33, wherein the one or more secondary matrix-forming agent is mannitol. 36. The pharmaceutical composition according to claim 33, wherein the one or more secondary matrix-forming agent is trehalose. 37. The pharmaceutical composition according to claim 33, wherein the one or more secondary matrix-forming agent is raffinose. 38. The pharmaceutical composition according to claim 32, wherein the at least one pharmaceutically active ingredient is chosen from desmopressin, desmopressin acetate, loratidine, famotidine, montelukast sodium, and ondansetron. 39. The pharmaceutical composition according to claim 32, wherein at least 80% of the composition dissolves within 10 seconds upon contact with an aqueous solution or with saliva. 40. The pharmaceutical composition according to claim 32, wherein the composition has a tensile strength from about 0.05 to about 1.6 N/mm2. 41. A pharmaceutical composition prepared by a process comprising at least a step of sublimating a solvent from a liquid preparation that comprises:
(a) at least one matrix-forming agent that is levan to form an open matrix network; and (b) at least one pharmaceutically active ingredient,
wherein the composition is an orodispersible pharmaceutical dosage form. 42. The pharmaceutical composition according to claim 41, wherein the liquid preparation further comprises one or more secondary matrix-forming agents. 43. The pharmaceutical composition according to claim 42, wherein the one or more secondary matrix-forming agent is mannitol. 44. The pharmaceutical composition according to claim 42, wherein the one or more secondary matrix-forming agent is trehalose. 45. The pharmaceutical composition according to claim 42, wherein the one or more secondary matrix-forming agent is raffinose. 46. The pharmaceutical composition according to claim 41, wherein the at least one pharmaceutically active ingredient is chosen from desmopressin, desmopressin acetate, loratidine, famotidine, montelukast sodium, and ondansetron. 47. A blister pack having one or more depressions disposed therein, wherein each of the one or more depressions comprises a pharmaceutical composition, the composition comprising:
(a) at least one matrix-forming agent that is levan to form an open matrix network; and (b) at least one pharmaceutically active ingredient,
wherein the composition is an orodispersible pharmaceutical dosage form. 48. The blister pack according to claim 47, which is prepared by a process comprising steps of:
(a) introducing a liquid preparation into one or more depressions of a blister pack, the liquid preparation comprising the matrix forming agent and the pharmaceutically active ingredient; and (b) sublimating the solvent from the liquid preparation in the one or more depressions. 49. The blister pack according to claim 47, wherein the composition further comprises one or more secondary matrix-forming agents. 50. The blister pack according to claim 48, wherein the one or more secondary matrix-forming agents is selected from the group consisting of trehalose, raffinose, and mannitol. 51. The blister pack according to claim 50, wherein the one or more secondary matrix-forming agent is mannitol. 52. The pharmaceutical composition according to claim 50, wherein the one or more secondary matrix-forming agent is trehalose. 53. The pharmaceutical composition according to claim 50, wherein the one or more secondary matrix-forming agent is raffinose. 54. The pharmaceutical composition according to claim 47, wherein the at least one pharmaceutically active ingredient is chosen from desmopressin, desmopressin acetate, loratidine, famotidine, montelukast sodium, and ondansetron.
| 1,600 |
1,213 | 14,577,028 | 1,613 |
Described are transdermal drug delivery compositions comprising amphetamine, methods of manufacturing transdermal drug delivery compositions comprising amphetamine, and therapeutic methods using transdermal drug delivery compositions comprising amphetamine, such as may be desired for achieving central nervous system stimulation, such as for the treatment of attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), or for the treatment of narcolepsy. In some embodiments, the compositions comprise an amount of polyurethane effective to control the presence of and/or prevent the formation of phenyl acetone in the compositions. The polyurethane may be present in a drug-containing polymer matrix or in a backing adjacent the drug-containing polymer matrix.
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1. A composition for the transdermal delivery of amphetamine in the form of a flexible finite system for topical application, comprising a polymer matrix comprising a polymer and amphetamine or a pharmaceutically acceptable salt or prodrug thereof, wherein the composition comprises polyurethane in an amount effective to control the presence of and/or prevent the formation of phenyl acetone in the polymer matrix. 2. The composition of claim 1, wherein the amphetamine includes amphetamine free base. 3. The composition of claim 1, wherein the polyurethane is a reaction product of an isocyanate and a polyol. 4. The composition of claim 1, wherein the polyurethane is a reaction product of (i) an isocyanate selected from the group consisting of diphenylmethane diisocyanate, toluene diisocyanate, p-phenylene diisocyanate, naphthalene diisocyanate, hexamethylene diisocyanate, isophorone diisocyanate, dicyclohexylmethane-4,4′-diisocyanate, meta-tetramethylxylylene diisocyanate and transcyclohexane diisocyanate and (ii) a polyol. 5. The composition of claim 4, wherein the polyol is a momomeric polyol. 6. The composition of claim 5, wherein the momomeric polyol is selected from the group consisting of glycerin, ethylene glycol, pentaerythritol, and sucrose. 7. The composition of claim 4, wherein the polyol is a polymeric polyol. 8. The composition of claim 7, wherein the polymeric polyol is selected from the group consisting of natural oil polyols, polyols obtained by polymerization of diols and dicarboxylic acids, polyether polyols, polyols obtained from reacting glycerin with propylene oxide or ethylene oxide or a combination thereof, polycarbonate polyols, polycaprolactone polyols, polybutadiene polyols, and polysulfide polyols. 9. The composition of claim 4, wherein the polyol is a combination of a monomeric polyol and a polymeric polyol. 10. The composition of claim 1, wherein the composition includes an amount of polyurethane from about 1/100 to about 100 times the amount of amphetamine in the composition. 11. The composition of claim 1, wherein the polymer matrix comprises polyurethane. 12. The composition of claim 1, further comprising a backing. 13. The composition of claim 12, wherein the backing comprises polyurethane. 14. The composition of claim 13, wherein the backing comprises a polyurethane film layer adjacent the polymer matrix. 15. The composition of claim 13, wherein the backing comprises a layer adjacent the polymer matrix comprising a polyurethane fiber, particle or powder. 16. The transdermal drug delivery system according to claim 12, further comprising a release liner. 17. A method of manufacturing a composition according to claim 1, comprising forming a polymer matrix comprising a polymer and amphetamine or a pharmaceutically acceptable salt or prodrug thereof, wherein the polymer matrix comprises polyurethane. 18. A method of manufacturing a composition according to claim 1, comprising providing a polymer matrix comprising a polymer and amphetamine with a backing comprising polyurethane. 19. The method of claim 19, wherein the backing comprises a polyurethane film layer adjacent the polymer matrix. 20. A composition for the transdermal delivery of amphetamine made by a method according to claim 17. 21. A composition for the transdermal delivery of amphetamine made by a method according to claim 18. 22. A method of transdermally administering amphetamine comprising topically applying to the skin or mucosa of a subject in need thereof a composition according to claim 1.
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Described are transdermal drug delivery compositions comprising amphetamine, methods of manufacturing transdermal drug delivery compositions comprising amphetamine, and therapeutic methods using transdermal drug delivery compositions comprising amphetamine, such as may be desired for achieving central nervous system stimulation, such as for the treatment of attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), or for the treatment of narcolepsy. In some embodiments, the compositions comprise an amount of polyurethane effective to control the presence of and/or prevent the formation of phenyl acetone in the compositions. The polyurethane may be present in a drug-containing polymer matrix or in a backing adjacent the drug-containing polymer matrix.1. A composition for the transdermal delivery of amphetamine in the form of a flexible finite system for topical application, comprising a polymer matrix comprising a polymer and amphetamine or a pharmaceutically acceptable salt or prodrug thereof, wherein the composition comprises polyurethane in an amount effective to control the presence of and/or prevent the formation of phenyl acetone in the polymer matrix. 2. The composition of claim 1, wherein the amphetamine includes amphetamine free base. 3. The composition of claim 1, wherein the polyurethane is a reaction product of an isocyanate and a polyol. 4. The composition of claim 1, wherein the polyurethane is a reaction product of (i) an isocyanate selected from the group consisting of diphenylmethane diisocyanate, toluene diisocyanate, p-phenylene diisocyanate, naphthalene diisocyanate, hexamethylene diisocyanate, isophorone diisocyanate, dicyclohexylmethane-4,4′-diisocyanate, meta-tetramethylxylylene diisocyanate and transcyclohexane diisocyanate and (ii) a polyol. 5. The composition of claim 4, wherein the polyol is a momomeric polyol. 6. The composition of claim 5, wherein the momomeric polyol is selected from the group consisting of glycerin, ethylene glycol, pentaerythritol, and sucrose. 7. The composition of claim 4, wherein the polyol is a polymeric polyol. 8. The composition of claim 7, wherein the polymeric polyol is selected from the group consisting of natural oil polyols, polyols obtained by polymerization of diols and dicarboxylic acids, polyether polyols, polyols obtained from reacting glycerin with propylene oxide or ethylene oxide or a combination thereof, polycarbonate polyols, polycaprolactone polyols, polybutadiene polyols, and polysulfide polyols. 9. The composition of claim 4, wherein the polyol is a combination of a monomeric polyol and a polymeric polyol. 10. The composition of claim 1, wherein the composition includes an amount of polyurethane from about 1/100 to about 100 times the amount of amphetamine in the composition. 11. The composition of claim 1, wherein the polymer matrix comprises polyurethane. 12. The composition of claim 1, further comprising a backing. 13. The composition of claim 12, wherein the backing comprises polyurethane. 14. The composition of claim 13, wherein the backing comprises a polyurethane film layer adjacent the polymer matrix. 15. The composition of claim 13, wherein the backing comprises a layer adjacent the polymer matrix comprising a polyurethane fiber, particle or powder. 16. The transdermal drug delivery system according to claim 12, further comprising a release liner. 17. A method of manufacturing a composition according to claim 1, comprising forming a polymer matrix comprising a polymer and amphetamine or a pharmaceutically acceptable salt or prodrug thereof, wherein the polymer matrix comprises polyurethane. 18. A method of manufacturing a composition according to claim 1, comprising providing a polymer matrix comprising a polymer and amphetamine with a backing comprising polyurethane. 19. The method of claim 19, wherein the backing comprises a polyurethane film layer adjacent the polymer matrix. 20. A composition for the transdermal delivery of amphetamine made by a method according to claim 17. 21. A composition for the transdermal delivery of amphetamine made by a method according to claim 18. 22. A method of transdermally administering amphetamine comprising topically applying to the skin or mucosa of a subject in need thereof a composition according to claim 1.
| 1,600 |
1,214 | 16,207,546 | 1,617 |
Provided is a method for producing an antithrombotic coating material in which a high molecular weight polymer can be obtained by a solution polymerization using a radical polymerization initiator. The above-mentioned task is achieved by a method for producing an antithrombotic coating material, including steps of: preparing a methanol solution containing a monomer represented by formula (1):
wherein in formula (1), R 1 , R 2 , and R 3 are the same as those described in the specification, respectively; adding a radical polymerization initiator having a 10-hour half-life temperature of 60° C. or less to the methanol solution to prepare a polymerization reaction liquid; and polymerizing the monomer.
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1. An antithrombotic coating material, comprising:
polyalkoxyalkyl (meth)acrylate that contains a structural unit (A) represented by formula (2):
wherein in formula (2), R1 represents a hydrogen atom or a methyl group, R2 represents an alkylene group having 1 to 4 carbon atoms, and R3 represents an alkyl group having 1 to 4 carbon atoms,
wherein the polyalkoxyalkyl (meth)acrylate has a weight average molecular weight of 200,000 or more, and
wherein the polyalkoxyalkyl (meth)acrylate is dissolved in methanol or a mixture comprising water and methanol. 2. The antithrombotic coating material according to claim 1, wherein a ratio of intermediate water calculated by equation (1) below with respect to the polyalkoxyalkyl (meth)acrylate that is equilibrium-hydrated, exceeds 32%:
Ratio (%) of Intermediate Water=(a/x)×100 Equation (1):
wherein in equation (1), a and x represent an intermediate water content (wt %) and an equilibrium water content (wt %), respectively, in the polyalkoxyalkyl (meth)acrylate that is equilibrium-hydrated. 3. The antithrombotic coating material according to claim 1, wherein the weight average molecular weight of the polyalkoxyalkyl (meth)acrylate is less than 1,000,000. 4. The antithrombotic coating material according to claim 1, wherein the weight average molecular weight of the polyalkoxyalkyl (meth)acrylate is 400,000 or more and 800,000 or less. 5. The antithrombotic coating material according to claim 1, wherein in formula (1), R1 is a hydrogen atom, R2 is a methylene group or an ethylene group, and R3 is a methyl group. 6. The antithrombotic coating material according to claim 1, wherein the polymer is contained in the antithrombotic coating material in an amount of 0.2 to 10 wt % based on the antithrombotic coating material material. 7. The antithrombotic coating material according to claim 1, wherein the polyalkoxyalkyl (meth)acrylate is dissolved in a solvent consisting of methanol or a solvent mixture consisting of water and methanol. 8. A medical device, comprising:
a substrate comprising a polymer material, and the antithrombotic coating material according to claim 1, wherein the antithrombotic coating material is coated on a surface of the substrate.
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Provided is a method for producing an antithrombotic coating material in which a high molecular weight polymer can be obtained by a solution polymerization using a radical polymerization initiator. The above-mentioned task is achieved by a method for producing an antithrombotic coating material, including steps of: preparing a methanol solution containing a monomer represented by formula (1):
wherein in formula (1), R 1 , R 2 , and R 3 are the same as those described in the specification, respectively; adding a radical polymerization initiator having a 10-hour half-life temperature of 60° C. or less to the methanol solution to prepare a polymerization reaction liquid; and polymerizing the monomer.1. An antithrombotic coating material, comprising:
polyalkoxyalkyl (meth)acrylate that contains a structural unit (A) represented by formula (2):
wherein in formula (2), R1 represents a hydrogen atom or a methyl group, R2 represents an alkylene group having 1 to 4 carbon atoms, and R3 represents an alkyl group having 1 to 4 carbon atoms,
wherein the polyalkoxyalkyl (meth)acrylate has a weight average molecular weight of 200,000 or more, and
wherein the polyalkoxyalkyl (meth)acrylate is dissolved in methanol or a mixture comprising water and methanol. 2. The antithrombotic coating material according to claim 1, wherein a ratio of intermediate water calculated by equation (1) below with respect to the polyalkoxyalkyl (meth)acrylate that is equilibrium-hydrated, exceeds 32%:
Ratio (%) of Intermediate Water=(a/x)×100 Equation (1):
wherein in equation (1), a and x represent an intermediate water content (wt %) and an equilibrium water content (wt %), respectively, in the polyalkoxyalkyl (meth)acrylate that is equilibrium-hydrated. 3. The antithrombotic coating material according to claim 1, wherein the weight average molecular weight of the polyalkoxyalkyl (meth)acrylate is less than 1,000,000. 4. The antithrombotic coating material according to claim 1, wherein the weight average molecular weight of the polyalkoxyalkyl (meth)acrylate is 400,000 or more and 800,000 or less. 5. The antithrombotic coating material according to claim 1, wherein in formula (1), R1 is a hydrogen atom, R2 is a methylene group or an ethylene group, and R3 is a methyl group. 6. The antithrombotic coating material according to claim 1, wherein the polymer is contained in the antithrombotic coating material in an amount of 0.2 to 10 wt % based on the antithrombotic coating material material. 7. The antithrombotic coating material according to claim 1, wherein the polyalkoxyalkyl (meth)acrylate is dissolved in a solvent consisting of methanol or a solvent mixture consisting of water and methanol. 8. A medical device, comprising:
a substrate comprising a polymer material, and the antithrombotic coating material according to claim 1, wherein the antithrombotic coating material is coated on a surface of the substrate.
| 1,600 |
1,215 | 16,278,025 | 1,656 |
The present invention provides a microorganism-derived soluble coenzyme-binding glucose dehydrogenase which catalyzes a reaction for oxidizing glucose in the presence of an electron acceptor, has an activity to maltose as low as 5% or less, and is inhibited by 1,10-phenanthroline. The invention also provides a method for producing the coenzyme-binding glucose dehydrogenase, and a method and a reagent for measuring employing the coenzyme-binding glucose dehydrogenase. According to the invention, the coenzyme-binding glucose dehydrogenase can be applied to an industrial field, and a use becomes possible also in a material production or analysis including a method for measuring or eliminating glucose in a sample using the coenzyme-binding glucose dehydrogenase as well as a method for producing an organic compound. It became also possible to provide a glucose sensor capable of accurately measuring a blood sugar level. Therefore, it became possible to provide an enzyme having a high utility, such as an ability of being used for modifying a material in the fields of pharmaceuticals, clinical studies and food products.
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1-22. (canceled) 23. A method for producing a biosensor for measuring glucose in a sample liquid comprising:
(i) obtaining a soluble flavin compound-binding glucose dehydrogenase secreted from an Aspergillus fungal body, which has enzymatic activity to glucose comprising catalyzing a reaction for oxidizing glucose in the presence of an electron acceptor, and (ii) forming a biosensor comprising an electrode system and an enzymatic reaction layer on an electrode of the electrode system, the enzymatic reaction layer comprising the soluble flavin compound-binding glucose dehydrogenase and an electron acceptor, wherein: (a) enzymatic activity to maltose is 5% or less relative to the enzymatic activity to glucose, and (b) enzymatic activity to D-fructose is not more than the enzymatic activity to maltose. 24. The method for producing a biosensor of claim 23, wherein the enzymatic activity to maltose is 3% or less relative to the enzymatic activity to glucose.
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The present invention provides a microorganism-derived soluble coenzyme-binding glucose dehydrogenase which catalyzes a reaction for oxidizing glucose in the presence of an electron acceptor, has an activity to maltose as low as 5% or less, and is inhibited by 1,10-phenanthroline. The invention also provides a method for producing the coenzyme-binding glucose dehydrogenase, and a method and a reagent for measuring employing the coenzyme-binding glucose dehydrogenase. According to the invention, the coenzyme-binding glucose dehydrogenase can be applied to an industrial field, and a use becomes possible also in a material production or analysis including a method for measuring or eliminating glucose in a sample using the coenzyme-binding glucose dehydrogenase as well as a method for producing an organic compound. It became also possible to provide a glucose sensor capable of accurately measuring a blood sugar level. Therefore, it became possible to provide an enzyme having a high utility, such as an ability of being used for modifying a material in the fields of pharmaceuticals, clinical studies and food products.1-22. (canceled) 23. A method for producing a biosensor for measuring glucose in a sample liquid comprising:
(i) obtaining a soluble flavin compound-binding glucose dehydrogenase secreted from an Aspergillus fungal body, which has enzymatic activity to glucose comprising catalyzing a reaction for oxidizing glucose in the presence of an electron acceptor, and (ii) forming a biosensor comprising an electrode system and an enzymatic reaction layer on an electrode of the electrode system, the enzymatic reaction layer comprising the soluble flavin compound-binding glucose dehydrogenase and an electron acceptor, wherein: (a) enzymatic activity to maltose is 5% or less relative to the enzymatic activity to glucose, and (b) enzymatic activity to D-fructose is not more than the enzymatic activity to maltose. 24. The method for producing a biosensor of claim 23, wherein the enzymatic activity to maltose is 3% or less relative to the enzymatic activity to glucose.
| 1,600 |
1,216 | 14,395,396 | 1,616 |
Provided herein relates to silk fibroin-based compositions comprising non-hydrolyzed silk fibroin and a humectant agent and methods of making the same. In some embodiments, the silk fibroin-based compositions can be formulated for personal care products, e.g., but not limited to, cosmetic products, skin care products, body care products, and/or hair products. In some embodiments, the silk fibroin-based compositions can be formulated for food applications.
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1. A silk fibroin-based composition comprising non-hydrolyzed silk fibroin and a humectant agent. 2. The silk fibroin-based composition of claim 1, wherein the non-hydrolyzed silk fibroin has an average molecular weight of at least about 20 kDa or higher. 3. The silk fibroin-based composition of any of claims 1-3, wherein the non-hydrolyzed silk fibroin and humectant agent are present in a volume ratio of about 1:2 to about 1:100. 4. The silk fibroin-based composition of any of claims 1-4, wherein the non-hydrolyzed silk fibroin and humectant agent are present in a volume ratio of about 1:2 to about 1:10. 5. The silk fibroin-based composition of any of claims 1-5, wherein the non-hydrolyzed silk fibroin is present in an amount of about 1% (w/v or w/w) to about 30% (w/v or w/w). 6. The silk fibroin-based composition of any of claims 1-6, wherein the non-hydrolyzed silk fibroin is present in an amount of about 1% (w/v or w/w) to about 10% (w/v or w/w). 7. The silk fibroin-based composition of any of claims 1-7, wherein the humectant agent is selected from the group consisting of phospholipid (e.g., lecithin, panthenol (pro-vitamin B5), glycerin (glycerol)), aloe vera, sorbitol, urea, alpha-hydroxy acids, sodium pyroglutamate, N-acetyl-ethanolamine, sodium lactate, isopropanol, polyalkylene glycols (e.g., ethylene glycol, propylene glycol, hexylene glycol, butylene glycol, dipropylene glycol, triethylene glycol), 1,3-propanediol, polyethylene glycols, synthetic alcohols (e.g., glyceryl coconate, hydroxystearate, myristate, oleate), and any combinations thereof. 8. The silk fibroin-based composition of any of claims 1-8, wherein the humectant agent comprises phospholipid (e.g., lecithin, panthenol (pro-vitamin B5), glycerin), aloe vera, sorbital, alpha-hydroxy acids, or any combinations thereof. 9. The silk fibroin-based composition of any of claims 1-8, wherein the humectant agent comprises glycerin (glycerol). 10. The silk fibroin-based composition of claim 9, wherein the glycerin is present in an amount of about 50% (w/v or w/w) to about 99% (w/v or w/w). 11. The silk fibroin-based composition of any of claims 1-10, wherein the composition is a gel or hydrogel, a paste, a lotion, a cream, an ointment, an oil, a liquid, a serum, a shampoo, a foam or mousse, a spray, an aerosol, a scrub, or any combinations thereof. 12. The silk fibroin-based composition of any of claims 1-11, wherein the composition is translucent. 13. The silk fibroin-based composition of any of claims 1-12, wherein the composition is flowable. 14. The silk fibroin-based composition of any of claims 1-13, wherein the composition does not precipitate when exposed to shear. 15. The silk fibroin-based composition of any of claims 1-14, wherein the composition has a larger amount of silk fibroin in random coil conformation, as compared to a composition comprising the non-hydrolyzed silk fibroin in the absence of the humectant agent. 16. The silk fibroin-based composition of any of claims 1-15, wherein the composition has a smaller amount of silk fibroin in beta-sheet conformation, as compared to a composition comprising the non-hydrolyzed silk fibroin in the absence of the humectant agent. 17. The silk fibroin-based composition of any of claims 1-16, wherein the composition does not have a peak in the amide II region (between ˜1475 cm−1 and ˜1560 cm−1), as determined in a Fourier Transform Infrared Spectroscopy (FTIR) spectrum. 18. The silk fibroin-based composition of any of claims 1-17, further comprising an additive. 19. The silk fibroin-based composition of claim 18, wherein the additive comprises aqueous-soluble components, oil-soluble components, wax-soluble components, essential oils, emulsifiers, surfactants, flavors, fragrance, nutraceuticals, vitamins, therapeutic agents, cosmeceuticals, preservatives, botanical extracts or distillates, antioxidants, anti-bacterial agents, anti-inflammatory agents, cosmetically-acceptable agents, skin-lightening agents, skin-evening agents, anti-reddening agents, viscosity modifiers, emollients, or any combinations thereof. 20. The silk fibroin-based composition of any of claims 1-19, wherein the composition is formulated for use in a personal care product (e.g., a cosmetic, skincare, body care, or hair product). 21. The silk fibroin-based composition of any of claims 1-20, wherein the composition is formulated for use in a food product. 22. The silk fibroin-based composition of any of claims 1-21, wherein the composition is stable (e.g., no brittle gel formation) for at least about 1 month at room temperature. 23. A composition comprising an aqueous-based phase, an oil-based phase or a wax-based phase, and an emulsifier, wherein the aqueous-based phase comprises non-hydrolyzed silk fibroin and a humectant agent. 24. The composition of claim 23, wherein the non-hydrolyzed silk fibroin has an average molecular weight of at least about 20 kDa or higher. 25. The composition of any of claims 23-24, wherein the non-hydrolyzed silk fibroin and humectant agent are present in a volume ratio of about 1:2 to about 1:100 in the aqueous-based phase. 26. The composition of any of claims 23-25, wherein the non-hydrolyzed silk fibroin and humectant agent are present in a volume ratio of about 1:2 to about 1:10 in the aqueous-based phase. 27. The composition of any of claims 23-26, wherein the non-hydrolyzed silk fibroin is present in an amount of about 1% (w/v or w/w) to about 30% (w/v or w/w) of the aqueous phase. 28. The composition of any of claims 23-27, wherein the non-hydrolyzed silk fibroin is present in an amount of about 1% (w/v or w/w) to about 10% (w/v or w/w) of the aqueous phase. 29. The composition of any of claims 23-28, wherein the humectant agent is selected from the group consisting of phospholipid (e.g., lecithin, panthenol (pro-vitamin B5), glycerin (glycerol)), aloe vera, sorbitol, urea, alpha-hydroxy acids, sodium pyroglutamate, N-acetyl-ethanolamine, sodium lactate, isopropanol, polyalkylene glycols (e.g., ethylene glycol, propylene glycol, hexylene glycol, butylene glycol, dipropylene glycol, triethylene glycol), 1,3-propanediol, polyethylene glycols, synthetic alcohols (e.g., glyceryl coconate, hydroxystearate, myristate, oleate), and any combinations thereof. 30. The composition of any of claims 23-29, wherein the humectant agent comprises phospholipid (e.g., lecithin, panthenol (pro-vitamin B5), glycerin), aloe vera, sorbital, alpha-hydroxy acids, or any combinations thereof. 31. The composition of any of claims 23-28, wherein the humectant agent comprises glycerin (glycerol). 32. The composition of claim 31, wherein the humectant agent is present in an amount of about 50% (w/v or w/w) to about 99% (w/v or w/w) in the aqueous-based phase. 33. The composition of any of claims 23-32, wherein the oil-based phase comprises a carrier oil. 34. The composition of claim 33, wherein the carrier oil is a synthetic or natural oil derived from seeds, nuts, fruits, flowers, plant-based materials, or any combinations thereof. 35. The composition of any of claims 23-32, wherein the wax-based phase comprises butters, wax, paraffin wax, paraffin oil, petrolatum, or any combinations thereof. 36. The composition of any of claims 23-35, wherein at least one or both of the aqueous-based phase and the oil-based phase or the wax-based phase further comprise an additive. 37. The composition of claim 36, wherein the additive comprises aqueous-soluble components, oil-soluble components, wax-soluble components, essential oils, surfactants, flavors, fragrance, nutraceuticals, vitamins, therapeutic agents, preservatives, botanical extracts or distillates, antioxidants, anti-bacterial agents, anti-inflammatory agents, cosmetically-acceptable agents, cosmeceuticals, skin-lightening agents, skin-evening agents, anti-reddening agents, viscosity modifiers, emollients, or any combinations thereof. 38. The composition of any of claims 23-37, wherein the ratio of the aqueous-based phase to the oil-based phase is about 1:100 to about 100:1. 39. The composition of any of claims 23-38, wherein the emulsifier is selected from the group consisting of liquid soy lecithin, solid soy lecithin, honey, beeswax, cetyl alcohol, or any combinations thereof. 40. The composition of any of claims 23-39, wherein the composition is a gel or hydrogel, a paste, a lotion, a cream, an ointment, an oil, a liquid, a serum, a shampoo, a foam or mousse, a spray, an aerosol, a stick, a balm, a bar, a scrub, or any combinations thereof. 41. The composition of any of claims 23-40, wherein the composition is translucent. 42. The composition of any of claims 23-41, wherein the composition is flowable. 43. The composition of any of claims 23-42, wherein the composition does not precipitate when exposed to shear. 44. The composition of any of claims 23-43, wherein the composition is formulated for use in a personal care product (e.g., a cosmetic, skincare, body care, or hair product). 45. The composition of any of claims 23-44, wherein the composition is formulated for use in a food product. 46. A method of producing a silk fibroin-based composition comprising:
mixing a non-hydrolyzed silk fibroin solution and a humectant agent in a volume ratio of about 1:2 to about 1:100. 47. The method of claim 46, wherein the volume ratio of the non-hydrolyzed silk fibroin solution to the humectant agent is about 1:2 to about 1:10. 48. The method of claim 46 or 47, wherein the humectant agent is selected from the group consisting of phospholipid (e.g., lecithin, panthenol (pro-vitamin B5), glycerin (glycerol)), aloe vera, sorbitol, urea, alpha-hydroxy acids, sodium pyroglutamate, N-acetyl-ethanolamine, sodium lactate, isopropanol, polyalkylene glycols (e.g., ethylene glycol, propylene glycol, hexylene glycol, butylene glycol, dipropylene glycol, triethylene glycol), 1,3-propanediol, polyethylene glycols, synthetic alcohols (e.g., glyceryl coconate, hydroxystearate, myristate, oleate), and any combinations thereof. 49. The method of any of claims 46-48, wherein the humectant agent comprises phospholipid (e.g., lecithin, panthenol (pro-vitamin B5), glycerin), aloe vera, sorbital, alpha-hydroxy acids, or any combinations thereof. 50. The method of any of claims 46-49, wherein the non-hydrolyzed silk fibroin solution has a concentration of about 1% (w/v or w/w) to about 30% (w/v or w/w). 51. The method of any of claims 46-50, wherein the non-hydrolyzed silk fibroin solution has a concentration of about 1% (w/v or w/w) to about 10% (w/v or w/w). 52. The method of any of claims 46-51, further comprising mixing an additive with the humectant agent and the non-hydrolyzed silk fibroin solution. 53. The method of claim 52, wherein the additive is mixed with the humectant agent prior to said mixing with the non-hydrolyzed silk fibroin solution. 54. The method of any of claims 46-53, further comprising mixing an aqueous mixture comprising the non-hydrolyzed silk fibroin solution and the humectant agent with an oil-based phase or a wax-based phase. 55. The method of claim 54, wherein the oil-based phase comprises a carrier oil and an emulsifier. 56. The method of claim 55, wherein the carrier oil is a synthetic or natural oil derived from seeds, nuts, fruits, flowers, plant-based materials, or any combinations thereof. 57. The method of claim 54, wherein the wax-based phase comprises butters, wax, paraffin wax, paraffin oil, petrolatum, or any combinations thereof. 58. The method of any of claims 55-57, wherein the emulsifier is selected from the group consisting of liquid soy lecithin, solid soy lecithin, honey, beeswax, cetyl alcohol, or any combinations thereof. 59. The method of any of claims 55-58, wherein the volume ratio of the carrier oil to the emulsifier is about 2:1 to about 100:1. 60. The method of any of claims 54-59, wherein the oil-based phase further comprises an additive. 61. The method of claim 52 or 60, wherein the aqueous-soluble or the oil-soluble additive is selected from the group consisting of essential oils, flavors, fragrance, nutraceuticals, therapeutic agents, preservatives, botanical extracts or distillates, antioxidants, anti-bacterial agents, anti-inflammatory agents, cosmetically-acceptable agents, viscosity modifiers, emollients, or any combinations thereof. 62. A composition produced by the method of any of claims 46-61. 63. The composition of claim 62, wherein the composition is formulated for use in a personal care product (e.g., a cosmetic, skincare, body care, or hair product). 64. The composition of claim 62, wherein the composition is formulated for use in a food product. 65. A method comprising:
applying on a target surface a composition of any of claim 1-45 or 62-64. 66. The method of claim 65, wherein the applying comprises rubbing. 67. The method of claim 65 or 66, wherein the target surface is skin or hair of a subject. 68. The method of any of claims 65-67, further comprising maintaining the composition at room temperature for at least about 1 month, wherein the composition remains stable thereafter.
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Provided herein relates to silk fibroin-based compositions comprising non-hydrolyzed silk fibroin and a humectant agent and methods of making the same. In some embodiments, the silk fibroin-based compositions can be formulated for personal care products, e.g., but not limited to, cosmetic products, skin care products, body care products, and/or hair products. In some embodiments, the silk fibroin-based compositions can be formulated for food applications.1. A silk fibroin-based composition comprising non-hydrolyzed silk fibroin and a humectant agent. 2. The silk fibroin-based composition of claim 1, wherein the non-hydrolyzed silk fibroin has an average molecular weight of at least about 20 kDa or higher. 3. The silk fibroin-based composition of any of claims 1-3, wherein the non-hydrolyzed silk fibroin and humectant agent are present in a volume ratio of about 1:2 to about 1:100. 4. The silk fibroin-based composition of any of claims 1-4, wherein the non-hydrolyzed silk fibroin and humectant agent are present in a volume ratio of about 1:2 to about 1:10. 5. The silk fibroin-based composition of any of claims 1-5, wherein the non-hydrolyzed silk fibroin is present in an amount of about 1% (w/v or w/w) to about 30% (w/v or w/w). 6. The silk fibroin-based composition of any of claims 1-6, wherein the non-hydrolyzed silk fibroin is present in an amount of about 1% (w/v or w/w) to about 10% (w/v or w/w). 7. The silk fibroin-based composition of any of claims 1-7, wherein the humectant agent is selected from the group consisting of phospholipid (e.g., lecithin, panthenol (pro-vitamin B5), glycerin (glycerol)), aloe vera, sorbitol, urea, alpha-hydroxy acids, sodium pyroglutamate, N-acetyl-ethanolamine, sodium lactate, isopropanol, polyalkylene glycols (e.g., ethylene glycol, propylene glycol, hexylene glycol, butylene glycol, dipropylene glycol, triethylene glycol), 1,3-propanediol, polyethylene glycols, synthetic alcohols (e.g., glyceryl coconate, hydroxystearate, myristate, oleate), and any combinations thereof. 8. The silk fibroin-based composition of any of claims 1-8, wherein the humectant agent comprises phospholipid (e.g., lecithin, panthenol (pro-vitamin B5), glycerin), aloe vera, sorbital, alpha-hydroxy acids, or any combinations thereof. 9. The silk fibroin-based composition of any of claims 1-8, wherein the humectant agent comprises glycerin (glycerol). 10. The silk fibroin-based composition of claim 9, wherein the glycerin is present in an amount of about 50% (w/v or w/w) to about 99% (w/v or w/w). 11. The silk fibroin-based composition of any of claims 1-10, wherein the composition is a gel or hydrogel, a paste, a lotion, a cream, an ointment, an oil, a liquid, a serum, a shampoo, a foam or mousse, a spray, an aerosol, a scrub, or any combinations thereof. 12. The silk fibroin-based composition of any of claims 1-11, wherein the composition is translucent. 13. The silk fibroin-based composition of any of claims 1-12, wherein the composition is flowable. 14. The silk fibroin-based composition of any of claims 1-13, wherein the composition does not precipitate when exposed to shear. 15. The silk fibroin-based composition of any of claims 1-14, wherein the composition has a larger amount of silk fibroin in random coil conformation, as compared to a composition comprising the non-hydrolyzed silk fibroin in the absence of the humectant agent. 16. The silk fibroin-based composition of any of claims 1-15, wherein the composition has a smaller amount of silk fibroin in beta-sheet conformation, as compared to a composition comprising the non-hydrolyzed silk fibroin in the absence of the humectant agent. 17. The silk fibroin-based composition of any of claims 1-16, wherein the composition does not have a peak in the amide II region (between ˜1475 cm−1 and ˜1560 cm−1), as determined in a Fourier Transform Infrared Spectroscopy (FTIR) spectrum. 18. The silk fibroin-based composition of any of claims 1-17, further comprising an additive. 19. The silk fibroin-based composition of claim 18, wherein the additive comprises aqueous-soluble components, oil-soluble components, wax-soluble components, essential oils, emulsifiers, surfactants, flavors, fragrance, nutraceuticals, vitamins, therapeutic agents, cosmeceuticals, preservatives, botanical extracts or distillates, antioxidants, anti-bacterial agents, anti-inflammatory agents, cosmetically-acceptable agents, skin-lightening agents, skin-evening agents, anti-reddening agents, viscosity modifiers, emollients, or any combinations thereof. 20. The silk fibroin-based composition of any of claims 1-19, wherein the composition is formulated for use in a personal care product (e.g., a cosmetic, skincare, body care, or hair product). 21. The silk fibroin-based composition of any of claims 1-20, wherein the composition is formulated for use in a food product. 22. The silk fibroin-based composition of any of claims 1-21, wherein the composition is stable (e.g., no brittle gel formation) for at least about 1 month at room temperature. 23. A composition comprising an aqueous-based phase, an oil-based phase or a wax-based phase, and an emulsifier, wherein the aqueous-based phase comprises non-hydrolyzed silk fibroin and a humectant agent. 24. The composition of claim 23, wherein the non-hydrolyzed silk fibroin has an average molecular weight of at least about 20 kDa or higher. 25. The composition of any of claims 23-24, wherein the non-hydrolyzed silk fibroin and humectant agent are present in a volume ratio of about 1:2 to about 1:100 in the aqueous-based phase. 26. The composition of any of claims 23-25, wherein the non-hydrolyzed silk fibroin and humectant agent are present in a volume ratio of about 1:2 to about 1:10 in the aqueous-based phase. 27. The composition of any of claims 23-26, wherein the non-hydrolyzed silk fibroin is present in an amount of about 1% (w/v or w/w) to about 30% (w/v or w/w) of the aqueous phase. 28. The composition of any of claims 23-27, wherein the non-hydrolyzed silk fibroin is present in an amount of about 1% (w/v or w/w) to about 10% (w/v or w/w) of the aqueous phase. 29. The composition of any of claims 23-28, wherein the humectant agent is selected from the group consisting of phospholipid (e.g., lecithin, panthenol (pro-vitamin B5), glycerin (glycerol)), aloe vera, sorbitol, urea, alpha-hydroxy acids, sodium pyroglutamate, N-acetyl-ethanolamine, sodium lactate, isopropanol, polyalkylene glycols (e.g., ethylene glycol, propylene glycol, hexylene glycol, butylene glycol, dipropylene glycol, triethylene glycol), 1,3-propanediol, polyethylene glycols, synthetic alcohols (e.g., glyceryl coconate, hydroxystearate, myristate, oleate), and any combinations thereof. 30. The composition of any of claims 23-29, wherein the humectant agent comprises phospholipid (e.g., lecithin, panthenol (pro-vitamin B5), glycerin), aloe vera, sorbital, alpha-hydroxy acids, or any combinations thereof. 31. The composition of any of claims 23-28, wherein the humectant agent comprises glycerin (glycerol). 32. The composition of claim 31, wherein the humectant agent is present in an amount of about 50% (w/v or w/w) to about 99% (w/v or w/w) in the aqueous-based phase. 33. The composition of any of claims 23-32, wherein the oil-based phase comprises a carrier oil. 34. The composition of claim 33, wherein the carrier oil is a synthetic or natural oil derived from seeds, nuts, fruits, flowers, plant-based materials, or any combinations thereof. 35. The composition of any of claims 23-32, wherein the wax-based phase comprises butters, wax, paraffin wax, paraffin oil, petrolatum, or any combinations thereof. 36. The composition of any of claims 23-35, wherein at least one or both of the aqueous-based phase and the oil-based phase or the wax-based phase further comprise an additive. 37. The composition of claim 36, wherein the additive comprises aqueous-soluble components, oil-soluble components, wax-soluble components, essential oils, surfactants, flavors, fragrance, nutraceuticals, vitamins, therapeutic agents, preservatives, botanical extracts or distillates, antioxidants, anti-bacterial agents, anti-inflammatory agents, cosmetically-acceptable agents, cosmeceuticals, skin-lightening agents, skin-evening agents, anti-reddening agents, viscosity modifiers, emollients, or any combinations thereof. 38. The composition of any of claims 23-37, wherein the ratio of the aqueous-based phase to the oil-based phase is about 1:100 to about 100:1. 39. The composition of any of claims 23-38, wherein the emulsifier is selected from the group consisting of liquid soy lecithin, solid soy lecithin, honey, beeswax, cetyl alcohol, or any combinations thereof. 40. The composition of any of claims 23-39, wherein the composition is a gel or hydrogel, a paste, a lotion, a cream, an ointment, an oil, a liquid, a serum, a shampoo, a foam or mousse, a spray, an aerosol, a stick, a balm, a bar, a scrub, or any combinations thereof. 41. The composition of any of claims 23-40, wherein the composition is translucent. 42. The composition of any of claims 23-41, wherein the composition is flowable. 43. The composition of any of claims 23-42, wherein the composition does not precipitate when exposed to shear. 44. The composition of any of claims 23-43, wherein the composition is formulated for use in a personal care product (e.g., a cosmetic, skincare, body care, or hair product). 45. The composition of any of claims 23-44, wherein the composition is formulated for use in a food product. 46. A method of producing a silk fibroin-based composition comprising:
mixing a non-hydrolyzed silk fibroin solution and a humectant agent in a volume ratio of about 1:2 to about 1:100. 47. The method of claim 46, wherein the volume ratio of the non-hydrolyzed silk fibroin solution to the humectant agent is about 1:2 to about 1:10. 48. The method of claim 46 or 47, wherein the humectant agent is selected from the group consisting of phospholipid (e.g., lecithin, panthenol (pro-vitamin B5), glycerin (glycerol)), aloe vera, sorbitol, urea, alpha-hydroxy acids, sodium pyroglutamate, N-acetyl-ethanolamine, sodium lactate, isopropanol, polyalkylene glycols (e.g., ethylene glycol, propylene glycol, hexylene glycol, butylene glycol, dipropylene glycol, triethylene glycol), 1,3-propanediol, polyethylene glycols, synthetic alcohols (e.g., glyceryl coconate, hydroxystearate, myristate, oleate), and any combinations thereof. 49. The method of any of claims 46-48, wherein the humectant agent comprises phospholipid (e.g., lecithin, panthenol (pro-vitamin B5), glycerin), aloe vera, sorbital, alpha-hydroxy acids, or any combinations thereof. 50. The method of any of claims 46-49, wherein the non-hydrolyzed silk fibroin solution has a concentration of about 1% (w/v or w/w) to about 30% (w/v or w/w). 51. The method of any of claims 46-50, wherein the non-hydrolyzed silk fibroin solution has a concentration of about 1% (w/v or w/w) to about 10% (w/v or w/w). 52. The method of any of claims 46-51, further comprising mixing an additive with the humectant agent and the non-hydrolyzed silk fibroin solution. 53. The method of claim 52, wherein the additive is mixed with the humectant agent prior to said mixing with the non-hydrolyzed silk fibroin solution. 54. The method of any of claims 46-53, further comprising mixing an aqueous mixture comprising the non-hydrolyzed silk fibroin solution and the humectant agent with an oil-based phase or a wax-based phase. 55. The method of claim 54, wherein the oil-based phase comprises a carrier oil and an emulsifier. 56. The method of claim 55, wherein the carrier oil is a synthetic or natural oil derived from seeds, nuts, fruits, flowers, plant-based materials, or any combinations thereof. 57. The method of claim 54, wherein the wax-based phase comprises butters, wax, paraffin wax, paraffin oil, petrolatum, or any combinations thereof. 58. The method of any of claims 55-57, wherein the emulsifier is selected from the group consisting of liquid soy lecithin, solid soy lecithin, honey, beeswax, cetyl alcohol, or any combinations thereof. 59. The method of any of claims 55-58, wherein the volume ratio of the carrier oil to the emulsifier is about 2:1 to about 100:1. 60. The method of any of claims 54-59, wherein the oil-based phase further comprises an additive. 61. The method of claim 52 or 60, wherein the aqueous-soluble or the oil-soluble additive is selected from the group consisting of essential oils, flavors, fragrance, nutraceuticals, therapeutic agents, preservatives, botanical extracts or distillates, antioxidants, anti-bacterial agents, anti-inflammatory agents, cosmetically-acceptable agents, viscosity modifiers, emollients, or any combinations thereof. 62. A composition produced by the method of any of claims 46-61. 63. The composition of claim 62, wherein the composition is formulated for use in a personal care product (e.g., a cosmetic, skincare, body care, or hair product). 64. The composition of claim 62, wherein the composition is formulated for use in a food product. 65. A method comprising:
applying on a target surface a composition of any of claim 1-45 or 62-64. 66. The method of claim 65, wherein the applying comprises rubbing. 67. The method of claim 65 or 66, wherein the target surface is skin or hair of a subject. 68. The method of any of claims 65-67, further comprising maintaining the composition at room temperature for at least about 1 month, wherein the composition remains stable thereafter.
| 1,600 |
1,217 | 14,394,051 | 1,644 |
The present invention provides a composition for treating and/or preventing type I diabetes and an application thereof. The active ingredient of the composition is 1.) or 2.) or 3.), as follows: 1.) a mixture of a type I diabetes protein antigen and an immunosuppressor, 2.) a mixture of a type I diabetes protein antigenic epitope polypeptide and an immunosuppressor, 3.) a mixture of a type I diabetes protein antigen, a type I diabetes protein antigenic epitope polypeptide, and an immunosuppressor; the type I diabetes protein antigen is at least one of insulin, glutamic acid decarboxylase, and islet amyloid polypeptide, and the immunosuppressor is at least one of dexamethasone, cyclosporine A, tacrolimus, mycophenolate mofetil, azathioprine, prednisone, early prednisolone, anti-CD4 monoclonal antibody, and anti-CD3 monoclonal antibody.
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1-11. (canceled) 12. A composition capable of eliciting a suppressive immune response against type 1 diabetes (TID), comprising an antigen and immunosuppressive agent. 13. The composition of claim 12, wherein the antigen is a protein antigen. 14. The composition of claim 12, wherein the antigen is a peptide antigen. 15. The composition of claim 12, comprising a mixture of a protein antigen and a peptide antigen. 16. The composition of claim 13, wherein the protein antigen is selected from the group consisting of Insulin, Glutamic Acid Decarboxylase (GAD65) and Islet Amyloid Polypeptide (IAPP), or a fragment thereof. 17. The composition of claim 12, wherein the immunosuppressive agent is selected from the group consisting of Dexamethasone (Dex), tacrolimus (FK506), cyclosporine (CsA), mycophenolate mofetil (MMF), azathiopurine (Aza), prednisone (Pred), methylprednisolone (MP), and a monoclonal antibody against CD3 or CD4, or a combination thereof. 18. The composition of claim 14, wherein the peptide antigen comprises at least one epitopic sequence from insulin, GAD65, IAPP, or a combination thereof. 19. The composition of claim 12, wherein the antigen is from human, dog or cat. 20. The composition of claim 12, wherein the antigen is a native protein or peptide. 21. The composition of claim 12, wherein the antigen is chemically synthesized. 22. The composition of claim 18, wherein the epitopic sequence from insulin comprises an amino acid sequence set forth in SEQ ID NOS: 1, 2, 3, 4, 5, 6, 7, 12, or 13. 23. The composition of claim 18, wherein the epitopic sequence from human GAD65 comprises an amino acid sequence set forth in SEQ ID NO: 8. 24. The composition of claim 18, wherein the epitopic sequence from human IAPP comprises an amino acid sequence set forth in SEQ ID NO: 9. 25. The composition of claim 18, wherein the epitopic sequence from dog IAPP comprises an amino acid sequence set forth in SEQ ID NO: 10. 26. The composition of claim 18, wherein the epitopic sequence from cat IAPP comprises an amino acid sequence set forth in SEQ ID NO: 11. 27. The composition of claim 12, wherein the weight ratio of the antigen to the immunosuppressive agent is about 1:20 to about 20:1. 28. A method of vaccination comprising administering the composition of claim 12 to a subject in need thereof. 29. The method of claim 28, wherein the administering route is selected from the group consisting of intramuscular, intra subcutaneous, and intradermal. 30. The method of claim 28, wherein one or more of the functions listed below are elicited:
(1) Treatment and/or prevention of TID; (2) Enhance the proliferation of CD4+ CD25+Treg population; (3) Increase the ratio of CD4+CD25+Treg to CD4+T cells; (4) Increase the IL-10 secretion in T cells; (5) Inhibit the cytotoxicity effect of auto reactive CD8+T cells; (6) Control the blood glucose for TID patient; (7) Up-regulate the transcription level of IL-10 and/or TGF-β in PBMC and/or spleen cells; (8) Inhibit the DC maturation; and (9) Decrease the expression of at least one protein of CD40, CD80, CD83, or CD86 in DC.
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The present invention provides a composition for treating and/or preventing type I diabetes and an application thereof. The active ingredient of the composition is 1.) or 2.) or 3.), as follows: 1.) a mixture of a type I diabetes protein antigen and an immunosuppressor, 2.) a mixture of a type I diabetes protein antigenic epitope polypeptide and an immunosuppressor, 3.) a mixture of a type I diabetes protein antigen, a type I diabetes protein antigenic epitope polypeptide, and an immunosuppressor; the type I diabetes protein antigen is at least one of insulin, glutamic acid decarboxylase, and islet amyloid polypeptide, and the immunosuppressor is at least one of dexamethasone, cyclosporine A, tacrolimus, mycophenolate mofetil, azathioprine, prednisone, early prednisolone, anti-CD4 monoclonal antibody, and anti-CD3 monoclonal antibody.1-11. (canceled) 12. A composition capable of eliciting a suppressive immune response against type 1 diabetes (TID), comprising an antigen and immunosuppressive agent. 13. The composition of claim 12, wherein the antigen is a protein antigen. 14. The composition of claim 12, wherein the antigen is a peptide antigen. 15. The composition of claim 12, comprising a mixture of a protein antigen and a peptide antigen. 16. The composition of claim 13, wherein the protein antigen is selected from the group consisting of Insulin, Glutamic Acid Decarboxylase (GAD65) and Islet Amyloid Polypeptide (IAPP), or a fragment thereof. 17. The composition of claim 12, wherein the immunosuppressive agent is selected from the group consisting of Dexamethasone (Dex), tacrolimus (FK506), cyclosporine (CsA), mycophenolate mofetil (MMF), azathiopurine (Aza), prednisone (Pred), methylprednisolone (MP), and a monoclonal antibody against CD3 or CD4, or a combination thereof. 18. The composition of claim 14, wherein the peptide antigen comprises at least one epitopic sequence from insulin, GAD65, IAPP, or a combination thereof. 19. The composition of claim 12, wherein the antigen is from human, dog or cat. 20. The composition of claim 12, wherein the antigen is a native protein or peptide. 21. The composition of claim 12, wherein the antigen is chemically synthesized. 22. The composition of claim 18, wherein the epitopic sequence from insulin comprises an amino acid sequence set forth in SEQ ID NOS: 1, 2, 3, 4, 5, 6, 7, 12, or 13. 23. The composition of claim 18, wherein the epitopic sequence from human GAD65 comprises an amino acid sequence set forth in SEQ ID NO: 8. 24. The composition of claim 18, wherein the epitopic sequence from human IAPP comprises an amino acid sequence set forth in SEQ ID NO: 9. 25. The composition of claim 18, wherein the epitopic sequence from dog IAPP comprises an amino acid sequence set forth in SEQ ID NO: 10. 26. The composition of claim 18, wherein the epitopic sequence from cat IAPP comprises an amino acid sequence set forth in SEQ ID NO: 11. 27. The composition of claim 12, wherein the weight ratio of the antigen to the immunosuppressive agent is about 1:20 to about 20:1. 28. A method of vaccination comprising administering the composition of claim 12 to a subject in need thereof. 29. The method of claim 28, wherein the administering route is selected from the group consisting of intramuscular, intra subcutaneous, and intradermal. 30. The method of claim 28, wherein one or more of the functions listed below are elicited:
(1) Treatment and/or prevention of TID; (2) Enhance the proliferation of CD4+ CD25+Treg population; (3) Increase the ratio of CD4+CD25+Treg to CD4+T cells; (4) Increase the IL-10 secretion in T cells; (5) Inhibit the cytotoxicity effect of auto reactive CD8+T cells; (6) Control the blood glucose for TID patient; (7) Up-regulate the transcription level of IL-10 and/or TGF-β in PBMC and/or spleen cells; (8) Inhibit the DC maturation; and (9) Decrease the expression of at least one protein of CD40, CD80, CD83, or CD86 in DC.
| 1,600 |
1,218 | 15,573,214 | 1,632 |
The invention provides an adeno-associated viral (AAV) vector comprising a capsid comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 9, wherein the AAV vector further comprises a heterologous nucleic acid sequence, and wherein the heterologous nucleic acid sequence can encode the NGF-PTH fusion polypeptide or methylmalonyl CoA mutase enzyme. The invention also provides a polypeptide comprising nerve growth factor (NGF) signal peptide and parathyroid hormone (PTH), wherein the polypeptide can comprise, consist essentially of, or consist of the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2. The invention provides a nucleic acid encoding the polypeptide, a vector comprising the nucleic acid, and a composition comprising the polypeptide, nucleic acid, or vector, as well as treatment methods comprising the polypeptide, nucleic acid, vector, or composition. The invention further provides a method of treating methylmalonic acidaemia (MMA) in a mammal comprising administering an AAV vector comprising a heterologous nucleic acid sequence encoding methylmalonyl CoA mutase enzyme to the mammal.
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1. An adeno-associated viral (AAV) vector comprising a capsid comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 9, wherein the AAV vector further comprises a heterologous nucleic acid sequence. 2. The AAV vector of claim 1, wherein the heterologous nucleic acid sequence is operably linked to regulatory sequences which direct its expression in a host cell. 3. The AAV vector of claim 1, wherein the heterologous gene is flanked by one or more inverted terminal repeat (ITR) sequences. 4. The AAV vector of claim 1, wherein the capsid is encoded by the nucleic acid sequence of SEQ ID NO: 5. 5. The AAV vector of claim 1, wherein the heterologous nucleic acid sequence encodes methylmalonyl CoA mutase enzyme. 6. The AAV vector of claim 1, wherein the heterologous nucleic acid sequence encodes a polypeptide comprising nerve growth factor (NGF) signal peptide and parathyroid hormone (PTH). 7. The AAV vector of claim 6, wherein the polypeptide comprises the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2. 8. A composition comprising the AAV vector of claim 1 and a pharmaceutically acceptable carrier. 9. A polypeptide comprising nerve growth factor (NGF) signal peptide and parathyroid hormone (PTH). 10. The polypeptide of claim 9 comprising the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2. 11. A nucleic acid encoding the polypeptide of claim 9. 12. A vector comprising the nucleic acid of claim 11. 13. The vector of claim 12, wherein the nucleic acid sequence is operably linked to regulatory sequences which direct its expression in a host cell. 14. The vector of claim 12, wherein the vector is a viral vector. 15. The vector of claim 14, wherein the viral vector is an adeno-associated viral vector. 16. The vector of claim 15, wherein the adeno-associated viral vector comprises a capsid protein (i) comprising the amino acid sequence of SEQ ID NO: 4 or (ii) the nucleic acid sequence of SEQ ID NO: 5. 17. The vector of claim 15, wherein the adeno-associated viral vector comprises a capsid protein comprising the amino acid sequence of SEQ ID NO: 9. 18. The vector of claim 12, wherein the nucleic acid sequence encoding the polypeptide comprising NGF signal peptide and PTH is flanked by one or more inverted terminal repeat (ITR) sequences. 19. The vector of claim 12 comprising the nucleic acid sequence of SEQ ID NO: 3. 20. A composition comprising the polypeptide of claim 9 and a pharmaceutically acceptable carrier. 21. A method of treating hypoparathyroidism in a mammal comprising administering the AAV vector of claim 6 to the salivary glands of the mammal, thereby treating hypoparathyroidism in the mammal. 22. (canceled) 23. A method of treating methylmalonic acidaemia (MMA) in a mammal comprising administering the vector of claim 5 to the mammal, thereby treating MMA in the mammal.
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The invention provides an adeno-associated viral (AAV) vector comprising a capsid comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 9, wherein the AAV vector further comprises a heterologous nucleic acid sequence, and wherein the heterologous nucleic acid sequence can encode the NGF-PTH fusion polypeptide or methylmalonyl CoA mutase enzyme. The invention also provides a polypeptide comprising nerve growth factor (NGF) signal peptide and parathyroid hormone (PTH), wherein the polypeptide can comprise, consist essentially of, or consist of the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2. The invention provides a nucleic acid encoding the polypeptide, a vector comprising the nucleic acid, and a composition comprising the polypeptide, nucleic acid, or vector, as well as treatment methods comprising the polypeptide, nucleic acid, vector, or composition. The invention further provides a method of treating methylmalonic acidaemia (MMA) in a mammal comprising administering an AAV vector comprising a heterologous nucleic acid sequence encoding methylmalonyl CoA mutase enzyme to the mammal.1. An adeno-associated viral (AAV) vector comprising a capsid comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 9, wherein the AAV vector further comprises a heterologous nucleic acid sequence. 2. The AAV vector of claim 1, wherein the heterologous nucleic acid sequence is operably linked to regulatory sequences which direct its expression in a host cell. 3. The AAV vector of claim 1, wherein the heterologous gene is flanked by one or more inverted terminal repeat (ITR) sequences. 4. The AAV vector of claim 1, wherein the capsid is encoded by the nucleic acid sequence of SEQ ID NO: 5. 5. The AAV vector of claim 1, wherein the heterologous nucleic acid sequence encodes methylmalonyl CoA mutase enzyme. 6. The AAV vector of claim 1, wherein the heterologous nucleic acid sequence encodes a polypeptide comprising nerve growth factor (NGF) signal peptide and parathyroid hormone (PTH). 7. The AAV vector of claim 6, wherein the polypeptide comprises the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2. 8. A composition comprising the AAV vector of claim 1 and a pharmaceutically acceptable carrier. 9. A polypeptide comprising nerve growth factor (NGF) signal peptide and parathyroid hormone (PTH). 10. The polypeptide of claim 9 comprising the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2. 11. A nucleic acid encoding the polypeptide of claim 9. 12. A vector comprising the nucleic acid of claim 11. 13. The vector of claim 12, wherein the nucleic acid sequence is operably linked to regulatory sequences which direct its expression in a host cell. 14. The vector of claim 12, wherein the vector is a viral vector. 15. The vector of claim 14, wherein the viral vector is an adeno-associated viral vector. 16. The vector of claim 15, wherein the adeno-associated viral vector comprises a capsid protein (i) comprising the amino acid sequence of SEQ ID NO: 4 or (ii) the nucleic acid sequence of SEQ ID NO: 5. 17. The vector of claim 15, wherein the adeno-associated viral vector comprises a capsid protein comprising the amino acid sequence of SEQ ID NO: 9. 18. The vector of claim 12, wherein the nucleic acid sequence encoding the polypeptide comprising NGF signal peptide and PTH is flanked by one or more inverted terminal repeat (ITR) sequences. 19. The vector of claim 12 comprising the nucleic acid sequence of SEQ ID NO: 3. 20. A composition comprising the polypeptide of claim 9 and a pharmaceutically acceptable carrier. 21. A method of treating hypoparathyroidism in a mammal comprising administering the AAV vector of claim 6 to the salivary glands of the mammal, thereby treating hypoparathyroidism in the mammal. 22. (canceled) 23. A method of treating methylmalonic acidaemia (MMA) in a mammal comprising administering the vector of claim 5 to the mammal, thereby treating MMA in the mammal.
| 1,600 |
1,219 | 15,569,073 | 1,612 |
Disclosed are high-porosity protein particles useful for carrying one or more agents of interest, methods for their manufacture and use, and products comprising them.
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1. A method for preparing a porous protein particle, comprising:
providing a protein isolate; forming a protein isolate emulsion with an oil; drying the protein isolate emulsion to produce a powder; and extracting the oil from the powder to produce the porous protein particle. 2. The method of claim 1, wherein the protein isolate emulsion is formed by a procedure comprising one of:
(i) emulsifying an oil with one or more surfactants with an HLB of 8 to 18; (ii) emulsifying an oil with a surfactant having an HLB of 14 to 18 in the water phase and surfactant with an HLB of 1 to 6 in the oil phase; or (iii) mixing a surfactant stabilized emulsion with the protein isolate. 3. The method of claim 1, wherein the forming of the protein isolate emulsion comprises any of procedures (a)-(e):
(a) i) providing a mixture comprising an oil, a surfactant and water;
ii) homogenizing or fluidizing the mixture to form a surfactant stabilized emulsion;
iii) combining the protein isolate and the surfactant stabilized emulsion to form a protein isolate-surfactant stabilized emulsion; and
iv) optionally combining the protein isolate-surfactant stabilized emulsion with a further component;
(b) i) providing a mixture comprising the protein isolate, a modified cellulose, and water; and
ii) combining the mixture with an oil to form an emulsion; and
iii) homogenizing or fluidizing the emulsion;
(c) i) providing a mixture comprising the protein isolate and a surfactant; and
ii) combining the mixture with an oil to form an emulsion; and
iii) homogenizing or fluidizing the emulsion;
(d) i) providing a mixture comprising an oil, an amphipathic surfactant, and water to form an emulsion;
ii) homogenizing or fluidizing the emulsion; and
iii) combining the protein isolate and the emulsion;
(e) i) combining an oil with the protein isolate together with water; and
ii) homogenizing or fluidizing the mixture to form an emulsion. 4. The method of claim 1, wherein the protein isolate is dissolved or suspended in water. 5. The method of claim 1, wherein the protein isolate is at least one protein isolate chosen from whey protein isolate, soy protein isolate, casein, sodium caseinate, egg white proteins, ovalbumin, rice protein isolate, potato protein isolates, canola protein isolates, pea protein isolates and bovine serum albumin; each of which can be either native or denatured. 6-8. (canceled) 9. The method of claim 1, wherein the oil is selected from rapeseed oil, soybean oil, triglyceride oils and medium-chain triglyceride oil. 10-11. (canceled) 12. The method of claim 3, wherein the modified cellulose comprises one or more of hydroxypropyl methyl cellulose, methyl cellulose, and hydroxypropyl cellulose. 13. (canceled) 14. The method of claim 1, wherein the extracting of the powder comprises extracting with supercritical carbon dioxide or extracting with an organic solvent. 15. (canceled) 16. (canceled) 17. The method of claim 1, wherein the emulsion is homogenized to produce an average droplet diameter of from 100 nm to 1000 nm; or 100 nm to 300 nm, or about 200 nm. 18-26. (canceled) 27. A method for loading one or more active substances into a porous protein particle, comprising contacting said active substances with a porous protein particle, for a time and under conditions effective to load the active substances; wherein the porous protein particle is prepared by the method of claim 1. 28-29. (canceled) 30. The method of claim 27, wherein each active substance is independently selected from flavors, fragrances, nutrients, active substances, taste-masking substances, biocides, pesticides vitamins and personal care substances. 31. (canceled) 32. A porous protein particle prepared by the method of claim 1; wherein the protein particle has an average diameter of from 500 nm to 20 μm; and has one or more characteristics selected from: a specific surface area of 3-16 m2/g, or 5-14 m2/g, or 7-12 m2/g; an internal surface area of 20-80 m2/g, or 30-70 m2/g, or 40-60 m2/g; and a pore volume of 0.1-0.6 ml/g, or 0.2-0.5 ml/g, or 0.3-0.4 ml/g. 33-37. (canceled) 38. The porous protein particle according claim 32, further comprising an agent of interest loaded therein; wherein the agent of interest is independently selected from flavors, fragrances, nutrients, active substances, taste-masking substances, biocides, pesticides, vitamins, and personal care substances. 39. (canceled) 40. (canceled) 41. A composition comprising a plurality of porous protein particles according to claim 32. 42. The composition of claim 41, wherein said composition is an antiperspirant or deodorant composition comprising (i) at least one of an antiperspirant active, a deodorant active, and free fragrance, and (ii) a plurality of protein particles containing a fragrance. 43-45. (canceled) 46. The composition of claim 41 wherein the composition is:
a soap for personal care; wherein the porous protein particles comprise a fragrance and/or antibacterial agent loaded therein; or
a laundry additive composition, wherein the porous protein particles comprise a fragrance loaded therein; and the laundry additive composition optionally further comprises one of a water soluble carrier or a dryer sheet. 47-54. (canceled) 55. The composition of claim 46, further comprising at least one fabric conditioning material chosen from a fabric softener and a silicone. 56-57. (canceled) 58. A method for adding fragrance to laundry comprising adding a composition according to claim 46 to laundry. 59-61. (canceled) 62. The composition of claim 41, wherein the composition is a dentifrice, a toothpaste or a chewing gum. 63. (canceled) 64. (canceled) 65. The composition of claim 41 wherein at least two of said protein particles carry different agents of interest. 66. A food substance, confectionary, beverage, pharmaceutical, biocide, pesticide, personal care product, oral care product or laundry product comprising a porous protein particle according to claim 32. 67. (canceled)
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Disclosed are high-porosity protein particles useful for carrying one or more agents of interest, methods for their manufacture and use, and products comprising them.1. A method for preparing a porous protein particle, comprising:
providing a protein isolate; forming a protein isolate emulsion with an oil; drying the protein isolate emulsion to produce a powder; and extracting the oil from the powder to produce the porous protein particle. 2. The method of claim 1, wherein the protein isolate emulsion is formed by a procedure comprising one of:
(i) emulsifying an oil with one or more surfactants with an HLB of 8 to 18; (ii) emulsifying an oil with a surfactant having an HLB of 14 to 18 in the water phase and surfactant with an HLB of 1 to 6 in the oil phase; or (iii) mixing a surfactant stabilized emulsion with the protein isolate. 3. The method of claim 1, wherein the forming of the protein isolate emulsion comprises any of procedures (a)-(e):
(a) i) providing a mixture comprising an oil, a surfactant and water;
ii) homogenizing or fluidizing the mixture to form a surfactant stabilized emulsion;
iii) combining the protein isolate and the surfactant stabilized emulsion to form a protein isolate-surfactant stabilized emulsion; and
iv) optionally combining the protein isolate-surfactant stabilized emulsion with a further component;
(b) i) providing a mixture comprising the protein isolate, a modified cellulose, and water; and
ii) combining the mixture with an oil to form an emulsion; and
iii) homogenizing or fluidizing the emulsion;
(c) i) providing a mixture comprising the protein isolate and a surfactant; and
ii) combining the mixture with an oil to form an emulsion; and
iii) homogenizing or fluidizing the emulsion;
(d) i) providing a mixture comprising an oil, an amphipathic surfactant, and water to form an emulsion;
ii) homogenizing or fluidizing the emulsion; and
iii) combining the protein isolate and the emulsion;
(e) i) combining an oil with the protein isolate together with water; and
ii) homogenizing or fluidizing the mixture to form an emulsion. 4. The method of claim 1, wherein the protein isolate is dissolved or suspended in water. 5. The method of claim 1, wherein the protein isolate is at least one protein isolate chosen from whey protein isolate, soy protein isolate, casein, sodium caseinate, egg white proteins, ovalbumin, rice protein isolate, potato protein isolates, canola protein isolates, pea protein isolates and bovine serum albumin; each of which can be either native or denatured. 6-8. (canceled) 9. The method of claim 1, wherein the oil is selected from rapeseed oil, soybean oil, triglyceride oils and medium-chain triglyceride oil. 10-11. (canceled) 12. The method of claim 3, wherein the modified cellulose comprises one or more of hydroxypropyl methyl cellulose, methyl cellulose, and hydroxypropyl cellulose. 13. (canceled) 14. The method of claim 1, wherein the extracting of the powder comprises extracting with supercritical carbon dioxide or extracting with an organic solvent. 15. (canceled) 16. (canceled) 17. The method of claim 1, wherein the emulsion is homogenized to produce an average droplet diameter of from 100 nm to 1000 nm; or 100 nm to 300 nm, or about 200 nm. 18-26. (canceled) 27. A method for loading one or more active substances into a porous protein particle, comprising contacting said active substances with a porous protein particle, for a time and under conditions effective to load the active substances; wherein the porous protein particle is prepared by the method of claim 1. 28-29. (canceled) 30. The method of claim 27, wherein each active substance is independently selected from flavors, fragrances, nutrients, active substances, taste-masking substances, biocides, pesticides vitamins and personal care substances. 31. (canceled) 32. A porous protein particle prepared by the method of claim 1; wherein the protein particle has an average diameter of from 500 nm to 20 μm; and has one or more characteristics selected from: a specific surface area of 3-16 m2/g, or 5-14 m2/g, or 7-12 m2/g; an internal surface area of 20-80 m2/g, or 30-70 m2/g, or 40-60 m2/g; and a pore volume of 0.1-0.6 ml/g, or 0.2-0.5 ml/g, or 0.3-0.4 ml/g. 33-37. (canceled) 38. The porous protein particle according claim 32, further comprising an agent of interest loaded therein; wherein the agent of interest is independently selected from flavors, fragrances, nutrients, active substances, taste-masking substances, biocides, pesticides, vitamins, and personal care substances. 39. (canceled) 40. (canceled) 41. A composition comprising a plurality of porous protein particles according to claim 32. 42. The composition of claim 41, wherein said composition is an antiperspirant or deodorant composition comprising (i) at least one of an antiperspirant active, a deodorant active, and free fragrance, and (ii) a plurality of protein particles containing a fragrance. 43-45. (canceled) 46. The composition of claim 41 wherein the composition is:
a soap for personal care; wherein the porous protein particles comprise a fragrance and/or antibacterial agent loaded therein; or
a laundry additive composition, wherein the porous protein particles comprise a fragrance loaded therein; and the laundry additive composition optionally further comprises one of a water soluble carrier or a dryer sheet. 47-54. (canceled) 55. The composition of claim 46, further comprising at least one fabric conditioning material chosen from a fabric softener and a silicone. 56-57. (canceled) 58. A method for adding fragrance to laundry comprising adding a composition according to claim 46 to laundry. 59-61. (canceled) 62. The composition of claim 41, wherein the composition is a dentifrice, a toothpaste or a chewing gum. 63. (canceled) 64. (canceled) 65. The composition of claim 41 wherein at least two of said protein particles carry different agents of interest. 66. A food substance, confectionary, beverage, pharmaceutical, biocide, pesticide, personal care product, oral care product or laundry product comprising a porous protein particle according to claim 32. 67. (canceled)
| 1,600 |
1,220 | 14,815,251 | 1,631 |
Systems, devices, methods, and kits for monitoring one or more physiologic and/or physical signals from a subject are disclosed. A system including patches and corresponding modules for wirelessly monitoring physiologic and/or physical signals is disclosed. A service system for managing the collection of physiologic data from a customer is disclosed. An isolating patch for providing a barrier between a handheld monitoring device with a plurality of contact pads and a subject is disclosed.
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1. A patch interface, comprising:
a substrate with a surface; an adhesive coupled to the substrate formulated for attachment to the skin of a subject; an interconnect embedded into or coupled to the substrate for attachment of the patch to a microcircuit; and a plurality microelectrodes attached to or embedded into the surface of the substrate, the microelectrodes arranged, configured, and dimensioned to interface with the subject when the adhesive is attached thereto, the microelectrodes electrically coupled with at least one of the interconnect and the microcircuit; wherein the patch interface is configured to monitor neural activity from the skin of the subject. 2. The patch interface in accordance with claim 1, wherein the adhesive is patterned onto the substrate so as to form one or more exposed regions of the substrate, one or more of the plurality of microelectrodes arranged within the exposed regions; and wherein the adhesive comprises one of an electrically conducting and an ionically conducting component. 3. The patch interface in accordance with claim 1, wherein the adhesive provides a macroelectrode function comprising one or more macroelectrodes for interfacing with the subject when attached thereto, the one or more macroelectrodes electrically coupled to at least one of the interconnect and the microcircuit. 4. The patch interface in accordance with claim 3, wherein the one or more macroelectrodes provide at least one of a guard function, a reference function, and a counter electrode function for one or more of the microelectrodes. 5. The patch interface in accordance with claim 1, wherein one or more of the plurality of microelectrodes is configured to penetrate into the skin when the adhesive is attached to the subject. 6. The patch interface in accordance with claim 1, wherein one or more of the plurality of microelectrodes has a needle-like shape, the microelectrode comprising an insulated region and an exposed region. 7. The patch interface in accordance with claim 6, wherein a given one of the plurality of microelectrodes has a length such that the exposed region is positioned within at least one of an epidermal layer, a dermal layer, and a hypodermal layer of the skin upon attachment of the patch to the surface thereof. 8. The patch interface in accordance with claim 6, wherein one or more of the plurality of microelectrodes is shaped so as to penetrate down a root of a follicle to reach at least one of a sweat gland, a sebaceous gland, a muscle, a vessel, and an arrector pili follicular muscle upon attachment of the patch interface to the skin. 9. The patch interface in accordance with claim 1, wherein one or more of the plurality of microelectrodes comprises an electrode feature arranged so as to improve the electrical connection between the microelectrode or an exposed region thereof and the skin upon placement on a subject; and wherein the improved electrical connection is achieved after pressure is applied to the microelectrode. 10. The patch interface in accordance with claim 1, wherein the microcircuit comprises a switch bank and an amplifier comprising two or more inputs, the switch bank adaptably configurable to couple one or more of the plurality of microelectrodes with an input of the amplifier, and couple one or more alternative ones of the plurality of microelectrodes and the one or more macroelectrodes to another input of the amplifier. 11. The patch interface in accordance with claim 10, wherein the switch bank is adaptively configurable to connect one or more clusters of the plurality of microelectrodes to a single input of the amplifier. 12. The patch interface in accordance with claim 1, wherein one or more of the plurality of microelectrodes are configured and shaped so as to penetrate into the skin during engagement therewith one of less than 3 mm, less than 2 mm into the skin, less than 1 mm, less than 0.5 mm, and less than 0.2 mm. 13. The patch interface in accordance with claim 1, wherein one or more of the plurality of microelectrodes and exposed regions thereof has an active surface area of one of less than 4 mm2, less than 1 mm2, less than 100,000 um2, less than 10,000 um2, less than 1,000 um2, and less than 100 um2. 14. The patch interface in accordance with claim 3, wherein the one or more macroelectrodes has an active surface area of one of greater than 5 mm2, greater than 50 mm2, greater than 100 mm2, and greater than 500 mm2. 15. The patch interface in accordance with claim 14, wherein the one or more macroelectrodes is shaped and patterned on the substrate so as to reduce movement artifacts, monitor a macroscopic electrophysiologic field, provide a reference electrode function, provide a guard electrode function, provide a drive electrode function, or a combination thereof during use. 16. The patch interface in accordance with claim 1, further comprising a sensor coupled with the substrate, and electrically coupled with the microcircuit, the sensor configured to monitor one or more physiologic parameters of the subject when coupled thereto. 17. The patch interface in accordance with claim 16, wherein the sensor comprises an electrophysiologic sensor, a temperature sensor, a thermal gradient sensor, a barometer, an altimeter, an accelerometer, a gyroscope, a humidity sensor, a magnetometer, an inclinometer, an oximeter, a colorimetric monitor, a sweat analyte sensor, a perfusion sensor, a galvanic skin response sensor, a hydration sensor, an interfacial pressure sensor, a flow sensor, a stretch sensor, a microphone, or a combination thereof. 18. The patch interface in accordance with claim 1, further comprising a stimulating device selected from an electrical stimulator, a thermoregulating device, a heating coil, a thermoelectric device, a Peltier device, a tactile stimulating component, a vibratory stimulating element, or a combination thereof arranged along the substrate so as to interface with the skin of the subject when the adhesive is attached thereto. 19. The patch interface in accordance with claim 18, further comprising a feedback sensor coupled with the stimulating device, configured and arranged so as to monitor the interaction of the stimulating device with the skin during activation thereof. 20. The patch interface in accordance with claim 1, further comprising one or more stretchable electrically conducting traces attached to the substrate, arranged so as to couple one or more sensors, microelectrodes, and macroelectrodes with one of the interconnect and the microcircuit. 21. The patch interface in accordance with claim 1, wherein the patch interface is sufficiently physically frail such that it cannot retain a predetermined shape in a free standing state. 22. The patch interface in accordance with claim 21, further comprising a temporary stiffening member attached to the substrate, the temporary stiffening member configured to provide retention of the shape of the patch interface prior to attachment to the subject, the stiffening member being removable from the substrate after attachment to the subject. 23. The patch interface in accordance with claim 1, wherein the substrate is formed from a soft pseudo-elastic material and the patch interface is configured to maintain operation when stretched to one of more than 25%, more than 50%, and more than 80%. 24. The patch interface in accordance with claim 1, wherein the patch interface is configured with a moisture vapor transmission rate of one of: between 200 g/m2/24 hrs and 20,000 g/m2/24 hrs; between 500 g/m2/24 hrs and 12,000 g/m2/24 hrs; and between 1,000 g/m2/24 hrs and 8,000 g/m2/24 hrs. 25. The patch interface in accordance with claim 1, wherein the adhesive includes one of an endothermic-reactive specie, an exothermic-reactive specie, a local analgesic, a neuro-blocker, a neurotoxin, a neural antagonist, and a neural agonist. 26. A module, comprising:
a housing; a circuit board comprising one or more microcircuits, the circuit board coupled to the housing; and a module interconnect coupled to one or more of the microcircuits configured for placement and coupling of the module onto a patch interface, the patch interface comprising:
a substrate with a surface;
an adhesive coupled to the substrate formulated for attachment to the skin of a subject;
an interconnect embedded into or coupled to the substrate for attachment of the patch to a microcircuit; and
a plurality microelectrodes attached to or embedded into the surface of the substrate, the microelectrodes arranged, configured, and dimensioned to interface with the subject when the adhesive is attached thereto, the microelectrodes electrically coupled with at least one of the interconnect and the microcircuit;
wherein the module is configured to monitor one or more physiologic signals, physical signals, skin based neural activity, and electrophysiological signals from the subject. 27. The module in accordance with claim 26, wherein the module comprises at least one of: one or more sensors; and one or more microelectronics, configured to interface with a sensor included on the patch interface, at least one of the one or more sensors comprising at least one of: an electrophysiologic sensor, a temperature sensor, a thermal gradient sensor, a barometer, an altimeter, an accelerometer, a gyroscope, a humidity sensor, a magnetometer, an inclinometer, an oximeter, a colorimetric monitor, a perfusion sensor, a sweat analyte sensor, a galvanic skin response sensor, an interfacial pressure sensor, a flow sensor, a stretch sensor, and a microphone. 28. The module in accordance with claim 26 further, comprising a stimulating device selected from an electrical stimulator, a thermoregulating device, a heating coil, a thermoelectric device, a Peltier device, a tactile stimulating component, a vibratory stimulating element, or a combination thereof arranged along the substrate so as to interface with the skin of the subject when coupled to the patch interface. 29. The module in accordance with claim 26, wherein the module is hermetically sealed. 30. The module in accordance with claim 26, further comprising a gasket coupled to the circuit board, the gasket shaped so as to isolate the region formed by the module interconnect and the patch from a surrounding environment, when the module is coupled with the patch.
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Systems, devices, methods, and kits for monitoring one or more physiologic and/or physical signals from a subject are disclosed. A system including patches and corresponding modules for wirelessly monitoring physiologic and/or physical signals is disclosed. A service system for managing the collection of physiologic data from a customer is disclosed. An isolating patch for providing a barrier between a handheld monitoring device with a plurality of contact pads and a subject is disclosed.1. A patch interface, comprising:
a substrate with a surface; an adhesive coupled to the substrate formulated for attachment to the skin of a subject; an interconnect embedded into or coupled to the substrate for attachment of the patch to a microcircuit; and a plurality microelectrodes attached to or embedded into the surface of the substrate, the microelectrodes arranged, configured, and dimensioned to interface with the subject when the adhesive is attached thereto, the microelectrodes electrically coupled with at least one of the interconnect and the microcircuit; wherein the patch interface is configured to monitor neural activity from the skin of the subject. 2. The patch interface in accordance with claim 1, wherein the adhesive is patterned onto the substrate so as to form one or more exposed regions of the substrate, one or more of the plurality of microelectrodes arranged within the exposed regions; and wherein the adhesive comprises one of an electrically conducting and an ionically conducting component. 3. The patch interface in accordance with claim 1, wherein the adhesive provides a macroelectrode function comprising one or more macroelectrodes for interfacing with the subject when attached thereto, the one or more macroelectrodes electrically coupled to at least one of the interconnect and the microcircuit. 4. The patch interface in accordance with claim 3, wherein the one or more macroelectrodes provide at least one of a guard function, a reference function, and a counter electrode function for one or more of the microelectrodes. 5. The patch interface in accordance with claim 1, wherein one or more of the plurality of microelectrodes is configured to penetrate into the skin when the adhesive is attached to the subject. 6. The patch interface in accordance with claim 1, wherein one or more of the plurality of microelectrodes has a needle-like shape, the microelectrode comprising an insulated region and an exposed region. 7. The patch interface in accordance with claim 6, wherein a given one of the plurality of microelectrodes has a length such that the exposed region is positioned within at least one of an epidermal layer, a dermal layer, and a hypodermal layer of the skin upon attachment of the patch to the surface thereof. 8. The patch interface in accordance with claim 6, wherein one or more of the plurality of microelectrodes is shaped so as to penetrate down a root of a follicle to reach at least one of a sweat gland, a sebaceous gland, a muscle, a vessel, and an arrector pili follicular muscle upon attachment of the patch interface to the skin. 9. The patch interface in accordance with claim 1, wherein one or more of the plurality of microelectrodes comprises an electrode feature arranged so as to improve the electrical connection between the microelectrode or an exposed region thereof and the skin upon placement on a subject; and wherein the improved electrical connection is achieved after pressure is applied to the microelectrode. 10. The patch interface in accordance with claim 1, wherein the microcircuit comprises a switch bank and an amplifier comprising two or more inputs, the switch bank adaptably configurable to couple one or more of the plurality of microelectrodes with an input of the amplifier, and couple one or more alternative ones of the plurality of microelectrodes and the one or more macroelectrodes to another input of the amplifier. 11. The patch interface in accordance with claim 10, wherein the switch bank is adaptively configurable to connect one or more clusters of the plurality of microelectrodes to a single input of the amplifier. 12. The patch interface in accordance with claim 1, wherein one or more of the plurality of microelectrodes are configured and shaped so as to penetrate into the skin during engagement therewith one of less than 3 mm, less than 2 mm into the skin, less than 1 mm, less than 0.5 mm, and less than 0.2 mm. 13. The patch interface in accordance with claim 1, wherein one or more of the plurality of microelectrodes and exposed regions thereof has an active surface area of one of less than 4 mm2, less than 1 mm2, less than 100,000 um2, less than 10,000 um2, less than 1,000 um2, and less than 100 um2. 14. The patch interface in accordance with claim 3, wherein the one or more macroelectrodes has an active surface area of one of greater than 5 mm2, greater than 50 mm2, greater than 100 mm2, and greater than 500 mm2. 15. The patch interface in accordance with claim 14, wherein the one or more macroelectrodes is shaped and patterned on the substrate so as to reduce movement artifacts, monitor a macroscopic electrophysiologic field, provide a reference electrode function, provide a guard electrode function, provide a drive electrode function, or a combination thereof during use. 16. The patch interface in accordance with claim 1, further comprising a sensor coupled with the substrate, and electrically coupled with the microcircuit, the sensor configured to monitor one or more physiologic parameters of the subject when coupled thereto. 17. The patch interface in accordance with claim 16, wherein the sensor comprises an electrophysiologic sensor, a temperature sensor, a thermal gradient sensor, a barometer, an altimeter, an accelerometer, a gyroscope, a humidity sensor, a magnetometer, an inclinometer, an oximeter, a colorimetric monitor, a sweat analyte sensor, a perfusion sensor, a galvanic skin response sensor, a hydration sensor, an interfacial pressure sensor, a flow sensor, a stretch sensor, a microphone, or a combination thereof. 18. The patch interface in accordance with claim 1, further comprising a stimulating device selected from an electrical stimulator, a thermoregulating device, a heating coil, a thermoelectric device, a Peltier device, a tactile stimulating component, a vibratory stimulating element, or a combination thereof arranged along the substrate so as to interface with the skin of the subject when the adhesive is attached thereto. 19. The patch interface in accordance with claim 18, further comprising a feedback sensor coupled with the stimulating device, configured and arranged so as to monitor the interaction of the stimulating device with the skin during activation thereof. 20. The patch interface in accordance with claim 1, further comprising one or more stretchable electrically conducting traces attached to the substrate, arranged so as to couple one or more sensors, microelectrodes, and macroelectrodes with one of the interconnect and the microcircuit. 21. The patch interface in accordance with claim 1, wherein the patch interface is sufficiently physically frail such that it cannot retain a predetermined shape in a free standing state. 22. The patch interface in accordance with claim 21, further comprising a temporary stiffening member attached to the substrate, the temporary stiffening member configured to provide retention of the shape of the patch interface prior to attachment to the subject, the stiffening member being removable from the substrate after attachment to the subject. 23. The patch interface in accordance with claim 1, wherein the substrate is formed from a soft pseudo-elastic material and the patch interface is configured to maintain operation when stretched to one of more than 25%, more than 50%, and more than 80%. 24. The patch interface in accordance with claim 1, wherein the patch interface is configured with a moisture vapor transmission rate of one of: between 200 g/m2/24 hrs and 20,000 g/m2/24 hrs; between 500 g/m2/24 hrs and 12,000 g/m2/24 hrs; and between 1,000 g/m2/24 hrs and 8,000 g/m2/24 hrs. 25. The patch interface in accordance with claim 1, wherein the adhesive includes one of an endothermic-reactive specie, an exothermic-reactive specie, a local analgesic, a neuro-blocker, a neurotoxin, a neural antagonist, and a neural agonist. 26. A module, comprising:
a housing; a circuit board comprising one or more microcircuits, the circuit board coupled to the housing; and a module interconnect coupled to one or more of the microcircuits configured for placement and coupling of the module onto a patch interface, the patch interface comprising:
a substrate with a surface;
an adhesive coupled to the substrate formulated for attachment to the skin of a subject;
an interconnect embedded into or coupled to the substrate for attachment of the patch to a microcircuit; and
a plurality microelectrodes attached to or embedded into the surface of the substrate, the microelectrodes arranged, configured, and dimensioned to interface with the subject when the adhesive is attached thereto, the microelectrodes electrically coupled with at least one of the interconnect and the microcircuit;
wherein the module is configured to monitor one or more physiologic signals, physical signals, skin based neural activity, and electrophysiological signals from the subject. 27. The module in accordance with claim 26, wherein the module comprises at least one of: one or more sensors; and one or more microelectronics, configured to interface with a sensor included on the patch interface, at least one of the one or more sensors comprising at least one of: an electrophysiologic sensor, a temperature sensor, a thermal gradient sensor, a barometer, an altimeter, an accelerometer, a gyroscope, a humidity sensor, a magnetometer, an inclinometer, an oximeter, a colorimetric monitor, a perfusion sensor, a sweat analyte sensor, a galvanic skin response sensor, an interfacial pressure sensor, a flow sensor, a stretch sensor, and a microphone. 28. The module in accordance with claim 26 further, comprising a stimulating device selected from an electrical stimulator, a thermoregulating device, a heating coil, a thermoelectric device, a Peltier device, a tactile stimulating component, a vibratory stimulating element, or a combination thereof arranged along the substrate so as to interface with the skin of the subject when coupled to the patch interface. 29. The module in accordance with claim 26, wherein the module is hermetically sealed. 30. The module in accordance with claim 26, further comprising a gasket coupled to the circuit board, the gasket shaped so as to isolate the region formed by the module interconnect and the patch from a surrounding environment, when the module is coupled with the patch.
| 1,600 |
1,221 | 15,321,770 | 1,622 |
In an oxychlorination process of the type where ethylene is converted to 1,2-dichloroethane in the presence of a supported copper catalyst, the improvement comprising: the use of a supported catalyst prepared by (i) impregnating, within a first step, an alumina support with a first aqueous solution including copper, to thereby form a first catalyst component; and (ii) impregnating, within a subsequent step, the first catalyst component with a second aqueous solution including copper and alkaline earth metal, to thereby form the supported catalyst.
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1. In an oxychlorination process of the type where ethylene is converted to 1,2-dichloroethane in the presence of a supported copper catalyst, the improvement comprising: the use of a supported catalyst prepared by (i) impregnating, within a first step, an alumina support with a first aqueous solution including copper and a transition metal, to thereby form a first catalyst component; and (ii) impregnating, within a subsequent step, the first catalyst component with a second aqueous solution including copper and alkaline earth metal to thereby form the supported catalyst. 2. The process of claim 1, where the oxychlorination process is conducted within a fluid-bed reactor. 3. The process of claim 1, where the fluid bed reactor is a baffled-bed reactor. 4. The process of claim 1, where the supported catalyst includes from about 5.0 to about 12 weight percent copper 5. The process of claim 1, where the supported catalyst includes from about 0.25 to about 3.0 weight percent alkaline earth metal. 6. The process of claim 1, where the supported catalyst includes from about 0.25 to about 1.6 weight percent alkaline earth metal. 7. The process of claim 1, where the supported catalyst includes from about 0.5 to about 2.25 weight percent transition metal. 8. The process of claim 1, where the alkaline earth metal is magnesium. 9. The process of claim 1, where the first solution includes an alkali metal. 10. The process of claim 1, where the alkali metal is potassium. 11. The process of claim 1, where the first solution includes an alkaline earth metal. 12. The process of claim 1, where the alkaline earth metal is magnesium. 13. The process of claim 1, where the second aqueous solution is substantially devoid of alkali metal. 14. The process of claim 1, where transition metal is manganese. 15. A process for producing a catalyst for the oxychlorination of ethylene to 1,2-dichloroethane, the process comprising the steps of:
(i) impregnating, within a first step, an alumina support with a first aqueous solution including copper and a transition metal to thereby form a first catalyst component; and (ii) impregnating, within a subsequent step, the first catalyst component with a second aqueous solution including copper and alkaline earth metal, to thereby form the supported catalyst. 16. The process of claim 15, where the first solution further includes an alkali metal and an alkaline earth metal. 17. The process of claim 16, where the second aqueous solution is substantially devoid of alkali metal. 18. An oxychlorination process comprising the step of:
converting ethylene to 1,2-dichloroethane in the presence of a catalyst, oxygen, and hydrogen chloride, where the catalyst is produced by: (1) impregnating, within a first step, an alumina support with a first aqueous solution including copper and a transition metal to thereby form a first catalyst component; and (ii) impregnating, within a subsequent step, the first catalyst component with a second aqueous solution including copper and alkaline earth metal, to thereby form the supported catalyst. 19. The process of claim 18, where the first solution further includes an alkali metal and an alkaline earth metal. 20. The process of claim 19, where the second aqueous solution is substantially devoid of alkali metal.
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In an oxychlorination process of the type where ethylene is converted to 1,2-dichloroethane in the presence of a supported copper catalyst, the improvement comprising: the use of a supported catalyst prepared by (i) impregnating, within a first step, an alumina support with a first aqueous solution including copper, to thereby form a first catalyst component; and (ii) impregnating, within a subsequent step, the first catalyst component with a second aqueous solution including copper and alkaline earth metal, to thereby form the supported catalyst.1. In an oxychlorination process of the type where ethylene is converted to 1,2-dichloroethane in the presence of a supported copper catalyst, the improvement comprising: the use of a supported catalyst prepared by (i) impregnating, within a first step, an alumina support with a first aqueous solution including copper and a transition metal, to thereby form a first catalyst component; and (ii) impregnating, within a subsequent step, the first catalyst component with a second aqueous solution including copper and alkaline earth metal to thereby form the supported catalyst. 2. The process of claim 1, where the oxychlorination process is conducted within a fluid-bed reactor. 3. The process of claim 1, where the fluid bed reactor is a baffled-bed reactor. 4. The process of claim 1, where the supported catalyst includes from about 5.0 to about 12 weight percent copper 5. The process of claim 1, where the supported catalyst includes from about 0.25 to about 3.0 weight percent alkaline earth metal. 6. The process of claim 1, where the supported catalyst includes from about 0.25 to about 1.6 weight percent alkaline earth metal. 7. The process of claim 1, where the supported catalyst includes from about 0.5 to about 2.25 weight percent transition metal. 8. The process of claim 1, where the alkaline earth metal is magnesium. 9. The process of claim 1, where the first solution includes an alkali metal. 10. The process of claim 1, where the alkali metal is potassium. 11. The process of claim 1, where the first solution includes an alkaline earth metal. 12. The process of claim 1, where the alkaline earth metal is magnesium. 13. The process of claim 1, where the second aqueous solution is substantially devoid of alkali metal. 14. The process of claim 1, where transition metal is manganese. 15. A process for producing a catalyst for the oxychlorination of ethylene to 1,2-dichloroethane, the process comprising the steps of:
(i) impregnating, within a first step, an alumina support with a first aqueous solution including copper and a transition metal to thereby form a first catalyst component; and (ii) impregnating, within a subsequent step, the first catalyst component with a second aqueous solution including copper and alkaline earth metal, to thereby form the supported catalyst. 16. The process of claim 15, where the first solution further includes an alkali metal and an alkaline earth metal. 17. The process of claim 16, where the second aqueous solution is substantially devoid of alkali metal. 18. An oxychlorination process comprising the step of:
converting ethylene to 1,2-dichloroethane in the presence of a catalyst, oxygen, and hydrogen chloride, where the catalyst is produced by: (1) impregnating, within a first step, an alumina support with a first aqueous solution including copper and a transition metal to thereby form a first catalyst component; and (ii) impregnating, within a subsequent step, the first catalyst component with a second aqueous solution including copper and alkaline earth metal, to thereby form the supported catalyst. 19. The process of claim 18, where the first solution further includes an alkali metal and an alkaline earth metal. 20. The process of claim 19, where the second aqueous solution is substantially devoid of alkali metal.
| 1,600 |
1,222 | 15,559,237 | 1,651 |
Provided is a cell culture support using a water-soluble polymer, which is a support to which cells are attached to culture the cells, and which includes: a fibrous web having a plurality of pores in which fibers containing a water-soluble polymer and a synthetic polymer obtained by electrospinning are accumulated, and into which a culture solution is penetrated, and the water-soluble polymer of the fibers gradually dissolves in the culture solution so that the cells can be grown and eluted from the fibrous web, thereby gradually reducing the diameters of the fibers.
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1. A cell culture support using a water-soluble polymer, the cell culture support, which is a support to which cells are attached to culture the cells, the cell culture support comprising:
a fibrous web having a plurality of pores in which fibers containing a water-soluble polymer and a synthetic polymer obtained by electrospinning are accumulated, and into which a culture solution is penetrated, and the water-soluble polymer of the fibers gradually dissolves in the culture solution so that the cells can be grown and eluted from the fibrous web, thereby gradually reducing the diameters of the fibers. 2. The cell culture support using a water-soluble polymer of claim 1, wherein the fibers contain 10 wt % to 50 wt % of the water-soluble polymer. 3. The cell culture support using a water-soluble polymer of claim 1, wherein the water-soluble polymer is one or a mixture of two or more selected from among PVA (polyvinyl alcohol), PVP (polyvinyl pyrrolidone), polyethylene oxide (PEO), carboxyl methyl cellulose (CMC), starch, polyacrylic acid (PAA), and hyaluronic acid. 4. The cell culture support using a water-soluble polymer of claim 1, wherein the diameter of each of the fibers is 100 nm to 10 μm. 5. The cell culture support using a water-soluble polymer of claim 1, wherein the synthetic polymer is a biodegradable polymer. 6. The cell culture support using a water-soluble polymer of claim 5, wherein the biodegradable polymer is one of PLA, PLLA, PGA, PLGA, PCL and PDO. 7. The cell culture support using a water-soluble polymer of claim 1, wherein the fibers an additive for hydrophilic treatment. 8. The cell culture support using a water-soluble polymer of claim 7, wherein the hydrophilic treatment additive is one of Tween 80, Pluronic, and PVP. 9. The cell culture support using a water-soluble polymer of claim 1, further comprising a plurality of beads formed on the fibers in order to secure spaces in which the cells penetrate into the fibrous web and grow therein. 10. The cell culture support using a water-soluble polymer of claim 9, wherein the fibrous web is a web obtained by electrospinning a spinning solution in which the water-soluble polymer, the synthetic polymer and a solvent are mixed, and a viscosity of the spinning solution is from 50 cps to 2000 cps. 11. The cell culture support using a water-soluble polymer of claim 9, wherein the diameters of the beads are larger than the diameters of the fibers. 12. A cell culture support using a water-soluble polymer, the cell culture support comprising:
a first fibrous web made by accumulating first fibers containing a water-soluble polymer and a synthetic polymer, and formed with beads; a second fibrous web made by accumulating second fibers containing a water-soluble polymer and a synthetic polymer, and formed with beads, on the first fibrous web; and a third fibrous web made by accumulating third fibers containing a water-soluble polymer and a synthetic polymer, and formed with beads, on the second fibrous web. 13. The cell culture support using a water-soluble polymer of claim 12, wherein the diameters of the second fibers are smaller than the diameters of the first and third fibers. 14. The cell culture support using a water-soluble polymer of claim 12, wherein the thicknesses of the first and third fibrous webs are thinner than the thickness of the second fibrous web.
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Provided is a cell culture support using a water-soluble polymer, which is a support to which cells are attached to culture the cells, and which includes: a fibrous web having a plurality of pores in which fibers containing a water-soluble polymer and a synthetic polymer obtained by electrospinning are accumulated, and into which a culture solution is penetrated, and the water-soluble polymer of the fibers gradually dissolves in the culture solution so that the cells can be grown and eluted from the fibrous web, thereby gradually reducing the diameters of the fibers.1. A cell culture support using a water-soluble polymer, the cell culture support, which is a support to which cells are attached to culture the cells, the cell culture support comprising:
a fibrous web having a plurality of pores in which fibers containing a water-soluble polymer and a synthetic polymer obtained by electrospinning are accumulated, and into which a culture solution is penetrated, and the water-soluble polymer of the fibers gradually dissolves in the culture solution so that the cells can be grown and eluted from the fibrous web, thereby gradually reducing the diameters of the fibers. 2. The cell culture support using a water-soluble polymer of claim 1, wherein the fibers contain 10 wt % to 50 wt % of the water-soluble polymer. 3. The cell culture support using a water-soluble polymer of claim 1, wherein the water-soluble polymer is one or a mixture of two or more selected from among PVA (polyvinyl alcohol), PVP (polyvinyl pyrrolidone), polyethylene oxide (PEO), carboxyl methyl cellulose (CMC), starch, polyacrylic acid (PAA), and hyaluronic acid. 4. The cell culture support using a water-soluble polymer of claim 1, wherein the diameter of each of the fibers is 100 nm to 10 μm. 5. The cell culture support using a water-soluble polymer of claim 1, wherein the synthetic polymer is a biodegradable polymer. 6. The cell culture support using a water-soluble polymer of claim 5, wherein the biodegradable polymer is one of PLA, PLLA, PGA, PLGA, PCL and PDO. 7. The cell culture support using a water-soluble polymer of claim 1, wherein the fibers an additive for hydrophilic treatment. 8. The cell culture support using a water-soluble polymer of claim 7, wherein the hydrophilic treatment additive is one of Tween 80, Pluronic, and PVP. 9. The cell culture support using a water-soluble polymer of claim 1, further comprising a plurality of beads formed on the fibers in order to secure spaces in which the cells penetrate into the fibrous web and grow therein. 10. The cell culture support using a water-soluble polymer of claim 9, wherein the fibrous web is a web obtained by electrospinning a spinning solution in which the water-soluble polymer, the synthetic polymer and a solvent are mixed, and a viscosity of the spinning solution is from 50 cps to 2000 cps. 11. The cell culture support using a water-soluble polymer of claim 9, wherein the diameters of the beads are larger than the diameters of the fibers. 12. A cell culture support using a water-soluble polymer, the cell culture support comprising:
a first fibrous web made by accumulating first fibers containing a water-soluble polymer and a synthetic polymer, and formed with beads; a second fibrous web made by accumulating second fibers containing a water-soluble polymer and a synthetic polymer, and formed with beads, on the first fibrous web; and a third fibrous web made by accumulating third fibers containing a water-soluble polymer and a synthetic polymer, and formed with beads, on the second fibrous web. 13. The cell culture support using a water-soluble polymer of claim 12, wherein the diameters of the second fibers are smaller than the diameters of the first and third fibers. 14. The cell culture support using a water-soluble polymer of claim 12, wherein the thicknesses of the first and third fibrous webs are thinner than the thickness of the second fibrous web.
| 1,600 |
1,223 | 15,890,610 | 1,617 |
Novel pharmaceutical compositions of mometasone or a pharmaceutically acceptable derivate thereof in the form of an oil-in-water emulsion, notably a cream. The composition has excellent stability and therapeutic effect. The compositions contain mometasone in micronised form, butylene glycol and water and the weight ratio between the butylene glycol and water contained in the oil-in-water emulsion is from 1:1 to about 1:3.
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1-32. (canceled) 33. A topical mometasone pharmaceutical composition in the form of an oil-in-water emulsion, comprising:
0.05%-0.2% w/w mometasone or a pharmaceutically acceptable ester thereof, calculated as mometasone furoate; 15-45% w/w of butylene glycol; 3-30% w/w vegetable oil; 1-15% w/w of one or more emulsifying agents optionally, 0.1-1% w/w of a pH adjusting agent, optionally, 5-15% w/w viscosity increasing agent, and water. 34. The composition of claim 33, comprising:
0.06-0.15% w/w of mometasone or a pharmaceutically acceptable ester thereof, calculated as mometasone furoate, 20-40% w/w of butylene glycol, 5-15% w/w of a vegetable oil, 1-10% w/w of one or more emulsifying agents, 0.1-1% w/w of a pH adjusting agent to adjust the pH of the emulsion to about 4-6, optionally, 5-15% w/w viscosity increasing agent, and water. 35. The composition of claim 33, comprising:
0.1% w/w of mometasone or a pharmaceutically acceptable ester thereof, calculated as mometasone furoate, 20-30% w/w of butylene glycol, 5-10% w/w of a vegetable oil, 5-10% w/w of one or more emulsifying agents, 0.1-1% w/w of a pH adjusting agent to adjust the pH of the emulsion to about 4-6, 5-10% w/w viscosity increasing agent, and water. 36. The composition of claim 33, wherein the composition does not contain any preservative other than butylene glycol. 37. The composition of claim 33, wherein, after topical application, the composition achieves an AUC (area under the curve) of blanching index as a function of time that is at least 85% that of Elocon® cream 0.1%, which contains mometasone furoate USP in an amount of 1 mg/g of cream in a cream base comprising hexylene glycol NF, phosphoric acid NF, propylene glycol stearate having a monoester content of 55%, stearyl alcohol, ceteareth-20, titanium dioxide USP, gamma-irradiated aluminium starch octenylsuccinate, white wax NF, white petrolatum USP, and purified water USP. 38. The composition of claim 33, wherein the weight ratio of butylene glycol to water in the oil-in-water emulsion is from about 1:1 to about 1:3. 39. The composition of claim 33, wherein the weight ratio of butylene glycol to water in the oil-in-water emulsion is from about 1:1.5 to about 1:2.5. 40. The composition of claim 33, wherein the weight ratio of butylene glycol to mometasone or pharmaceutically acceptable ester thereof in the oil-in-water emulsion is from about 100:1 to about 600:1. 41. The composition of claim 33, wherein the composition does not contain N-methyl-2-pyrrolidone. 42. The composition of claim 33, wherein the composition does not contain chlorocresol. 43. A topical mometasone pharmaceutical composition in the form of an oil-in-water emulsion, comprising:
0.1% w/w micronized momentasone furoate, wherein 100% of the micronized particles have a particle size≤20 μm, 99% have a particle size≤15 μm, and 80% have a particle size≤5 μm; 8.0% w/w coconut oil; 2.0% w/w stearic acids; 3.0% w/w macrogol stearate; 3.0% w/w glycerol monostearate 40-55; 7.0% w/w cetostearyl alcohol; 25.0% w/w butylene glycol; 0.27% w/w sodium citrate; 0.25% w/w citric acid, monohydrate; and water. 44. A topical mometasone pharmaceutical composition in the form of an oil-in-water emulsion, consisting of:
0.1% w/w micronized momentasone furoate, wherein 100% of the micronized particles have a particle size≤20 μm, 99% have a particle size≤15 μm, and 80% have a particle size≤5 μm; 8.0% w/w coconut oil; 2.0% w/w stearic acids; 3.0% w/w macrogol stearate; 3.0% w/w glycerol monostearate 40-55; 7.0% w/w cetostearyl alcohol; 25.0% w/w butylene glycol; 0.27% w/w sodium citrate; 0.25% w/w citric acid, monohydrate; and water.
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Novel pharmaceutical compositions of mometasone or a pharmaceutically acceptable derivate thereof in the form of an oil-in-water emulsion, notably a cream. The composition has excellent stability and therapeutic effect. The compositions contain mometasone in micronised form, butylene glycol and water and the weight ratio between the butylene glycol and water contained in the oil-in-water emulsion is from 1:1 to about 1:3.1-32. (canceled) 33. A topical mometasone pharmaceutical composition in the form of an oil-in-water emulsion, comprising:
0.05%-0.2% w/w mometasone or a pharmaceutically acceptable ester thereof, calculated as mometasone furoate; 15-45% w/w of butylene glycol; 3-30% w/w vegetable oil; 1-15% w/w of one or more emulsifying agents optionally, 0.1-1% w/w of a pH adjusting agent, optionally, 5-15% w/w viscosity increasing agent, and water. 34. The composition of claim 33, comprising:
0.06-0.15% w/w of mometasone or a pharmaceutically acceptable ester thereof, calculated as mometasone furoate, 20-40% w/w of butylene glycol, 5-15% w/w of a vegetable oil, 1-10% w/w of one or more emulsifying agents, 0.1-1% w/w of a pH adjusting agent to adjust the pH of the emulsion to about 4-6, optionally, 5-15% w/w viscosity increasing agent, and water. 35. The composition of claim 33, comprising:
0.1% w/w of mometasone or a pharmaceutically acceptable ester thereof, calculated as mometasone furoate, 20-30% w/w of butylene glycol, 5-10% w/w of a vegetable oil, 5-10% w/w of one or more emulsifying agents, 0.1-1% w/w of a pH adjusting agent to adjust the pH of the emulsion to about 4-6, 5-10% w/w viscosity increasing agent, and water. 36. The composition of claim 33, wherein the composition does not contain any preservative other than butylene glycol. 37. The composition of claim 33, wherein, after topical application, the composition achieves an AUC (area under the curve) of blanching index as a function of time that is at least 85% that of Elocon® cream 0.1%, which contains mometasone furoate USP in an amount of 1 mg/g of cream in a cream base comprising hexylene glycol NF, phosphoric acid NF, propylene glycol stearate having a monoester content of 55%, stearyl alcohol, ceteareth-20, titanium dioxide USP, gamma-irradiated aluminium starch octenylsuccinate, white wax NF, white petrolatum USP, and purified water USP. 38. The composition of claim 33, wherein the weight ratio of butylene glycol to water in the oil-in-water emulsion is from about 1:1 to about 1:3. 39. The composition of claim 33, wherein the weight ratio of butylene glycol to water in the oil-in-water emulsion is from about 1:1.5 to about 1:2.5. 40. The composition of claim 33, wherein the weight ratio of butylene glycol to mometasone or pharmaceutically acceptable ester thereof in the oil-in-water emulsion is from about 100:1 to about 600:1. 41. The composition of claim 33, wherein the composition does not contain N-methyl-2-pyrrolidone. 42. The composition of claim 33, wherein the composition does not contain chlorocresol. 43. A topical mometasone pharmaceutical composition in the form of an oil-in-water emulsion, comprising:
0.1% w/w micronized momentasone furoate, wherein 100% of the micronized particles have a particle size≤20 μm, 99% have a particle size≤15 μm, and 80% have a particle size≤5 μm; 8.0% w/w coconut oil; 2.0% w/w stearic acids; 3.0% w/w macrogol stearate; 3.0% w/w glycerol monostearate 40-55; 7.0% w/w cetostearyl alcohol; 25.0% w/w butylene glycol; 0.27% w/w sodium citrate; 0.25% w/w citric acid, monohydrate; and water. 44. A topical mometasone pharmaceutical composition in the form of an oil-in-water emulsion, consisting of:
0.1% w/w micronized momentasone furoate, wherein 100% of the micronized particles have a particle size≤20 μm, 99% have a particle size≤15 μm, and 80% have a particle size≤5 μm; 8.0% w/w coconut oil; 2.0% w/w stearic acids; 3.0% w/w macrogol stearate; 3.0% w/w glycerol monostearate 40-55; 7.0% w/w cetostearyl alcohol; 25.0% w/w butylene glycol; 0.27% w/w sodium citrate; 0.25% w/w citric acid, monohydrate; and water.
| 1,600 |
1,224 | 15,696,282 | 1,612 |
An anhydrous stick composition, including deodorant active, an antiperspirant active, or a combination thereof; a carrier; a structurant; and a cyclodextrin perfume complex, comprising cyclodextrin and a perfume, wherein the perfume comprises perfume raw materials and 10% or more, by weight of the perfume, of the perfume raw materials have: a cyclodextrin complex stability constant of about 3.0 or less, a C log P of about 2.5 or less; and a weight average molecular weight of about 200 Daltons or less.
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1. An anhydrous stick composition, comprising:
a) a deodorant active, an antiperspirant active, or a combination thereof; b) a carrier; c) a structurant; and d) a cyclodextrin perfume complex, comprising cyclodextrin and a perfume, wherein the perfume comprises perfume raw materials and 10% or more, by weight of the perfume, of the perfume raw materials have: a complex stability constant of about 3.0 or less, a C log P of about 2.5 or less; and a weight average molecular weight of about 200 Daltons or less. 2. The personal aerosol composition of claim 1, wherein the cyclodextrin complex stability constant (log k) is from about −2.0 to about 2.5. 3. The personal aerosol composition of any of claim 1, wherein the perfume raw materials are selected from the group consisting of: beta gamma hexanol; cis 3 hexenyl acetate; ethyl-2-methyl butyrate; amyl-acetate; vanillin; anethole; methyl isoeugenol; guaiacol; floralol; 2,6-nonadien-1-ol; coumarin; and a combination thereof. 4. The personal aerosol composition of any of claim 1, wherein the perfume raw materials comprise dimethyl anthranilate; iso-eugenyl acetate; canthoxal; 3,6-nonadien-1-ol, triplal; or a combination thereof. 5. The personal aerosol composition of any of claim 1, wherein the perfume raw materials comprise ethyl-2-methyl butyrate; beta gamma hexanol; iso amyl acetate; amyl acetate; cis-3-hexenyl acetate; gamma-octalactone; ethyl vanillin; vanillin; benzaldehyde; or a combination thereof. 6. The personal aerosol composition of claim 1, wherein 10% or more of the perfume raw materials also have an Odor Detection Threshold of about 7 to about 11.5-log molar concentration. 7. The personal aerosol composition of claim 1, wherein about 20% to about 100%, by weight of the perfume, of the perfume raw materials have: a complex stability constant of about 3.0 or less, a C log P of about 2.5 or less; and a weight average molecular weight of about 200 Daltons or less. 8. The personal aerosol composition of claim 1, wherein the perfume raw materials have a complex stability constant of about −1.5 to about 2.5. 9. The personal aerosol composition of claim 1, wherein the perfume raw materials have a C log P of about 2.0 or less. 10. The personal aerosol composition of claim 1, wherein the perfume raw materials have a weight average molecular weight of about 180 Daltons or less. 11. The personal aerosol composition of claim 1, wherein the cyclodextrin comprises hydroxypropyl alpha-cyclodextrin, hydroxypropyl beta-cyclodextrin, methylated-alpha-cyclodextrin, methylated-beta-cyclodextrin, or a combination thereof. 12. The personal aerosol composition of claim 1, wherein the percent of the perfume that is complexed with the cyclodextrin is greater than about 75%. 13. An anhydrous stick composition, comprising: deodorant active, an antiperspirant active, or a combination thereof a carrier; a structurant; and a cyclodextrin perfume complex, comprising cyclodextrin and a perfume, wherein the perfume comprises perfume raw materials wherein 20% or more, by weight of the perfume, of the perfume raw materials, are selected from the group consisting of: ethyl-2-methyl butyrate; beta gamma hexanol; iso amyl acetate; amyl acetate; cis-3-hexenyl acetate; gamma-octalactone; ethyl vanillin; vanillin; benzaldehyde; dimethyl anthranilate; iso-eugenyl acetate; canthoxal; 3,6-nonadien-1-ol, triplal; and combinations thereof. 14. The personal aerosol composition of claim 13, wherein the perfume raw materials are selected from the group consisting of dimethyl anthranilate; iso-eugenyl acetate; canthoxal; 3,6-nonadien-1-ol, triplal; and combinations thereof. 15. The personal aerosol composition of claim 13, wherein about 20% to about 100%, by weight of the perfume, of the perfume raw materials have: a complex stability constant of about 3.0 or less, a C log P of about 2.5 or less; and a weight average molecular weight of about 200 Daltons or less. 16. The personal aerosol composition of claim 13, wherein about 50% to about 100% of the perfume raw materials have a complex stability constant of about −1.5 to about 2.5. 17. The personal aerosol composition of claim 13, wherein about 50% to about 100% of the perfume raw materials have a C log P of about 2.0 or less. 18. The personal aerosol composition of claim 13, wherein about 20% to about 100% of the perfume raw materials have a weight average molecular weight of about 180 Daltons or less. 19. The personal aerosol composition of claim 13, wherein the percent of the perfume that is complexed with the cyclodextrin is greater than about 75%. 20. The perfume of claim 13, wherein the cyclodextrin comprises beta-cyclodextrin.
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An anhydrous stick composition, including deodorant active, an antiperspirant active, or a combination thereof; a carrier; a structurant; and a cyclodextrin perfume complex, comprising cyclodextrin and a perfume, wherein the perfume comprises perfume raw materials and 10% or more, by weight of the perfume, of the perfume raw materials have: a cyclodextrin complex stability constant of about 3.0 or less, a C log P of about 2.5 or less; and a weight average molecular weight of about 200 Daltons or less.1. An anhydrous stick composition, comprising:
a) a deodorant active, an antiperspirant active, or a combination thereof; b) a carrier; c) a structurant; and d) a cyclodextrin perfume complex, comprising cyclodextrin and a perfume, wherein the perfume comprises perfume raw materials and 10% or more, by weight of the perfume, of the perfume raw materials have: a complex stability constant of about 3.0 or less, a C log P of about 2.5 or less; and a weight average molecular weight of about 200 Daltons or less. 2. The personal aerosol composition of claim 1, wherein the cyclodextrin complex stability constant (log k) is from about −2.0 to about 2.5. 3. The personal aerosol composition of any of claim 1, wherein the perfume raw materials are selected from the group consisting of: beta gamma hexanol; cis 3 hexenyl acetate; ethyl-2-methyl butyrate; amyl-acetate; vanillin; anethole; methyl isoeugenol; guaiacol; floralol; 2,6-nonadien-1-ol; coumarin; and a combination thereof. 4. The personal aerosol composition of any of claim 1, wherein the perfume raw materials comprise dimethyl anthranilate; iso-eugenyl acetate; canthoxal; 3,6-nonadien-1-ol, triplal; or a combination thereof. 5. The personal aerosol composition of any of claim 1, wherein the perfume raw materials comprise ethyl-2-methyl butyrate; beta gamma hexanol; iso amyl acetate; amyl acetate; cis-3-hexenyl acetate; gamma-octalactone; ethyl vanillin; vanillin; benzaldehyde; or a combination thereof. 6. The personal aerosol composition of claim 1, wherein 10% or more of the perfume raw materials also have an Odor Detection Threshold of about 7 to about 11.5-log molar concentration. 7. The personal aerosol composition of claim 1, wherein about 20% to about 100%, by weight of the perfume, of the perfume raw materials have: a complex stability constant of about 3.0 or less, a C log P of about 2.5 or less; and a weight average molecular weight of about 200 Daltons or less. 8. The personal aerosol composition of claim 1, wherein the perfume raw materials have a complex stability constant of about −1.5 to about 2.5. 9. The personal aerosol composition of claim 1, wherein the perfume raw materials have a C log P of about 2.0 or less. 10. The personal aerosol composition of claim 1, wherein the perfume raw materials have a weight average molecular weight of about 180 Daltons or less. 11. The personal aerosol composition of claim 1, wherein the cyclodextrin comprises hydroxypropyl alpha-cyclodextrin, hydroxypropyl beta-cyclodextrin, methylated-alpha-cyclodextrin, methylated-beta-cyclodextrin, or a combination thereof. 12. The personal aerosol composition of claim 1, wherein the percent of the perfume that is complexed with the cyclodextrin is greater than about 75%. 13. An anhydrous stick composition, comprising: deodorant active, an antiperspirant active, or a combination thereof a carrier; a structurant; and a cyclodextrin perfume complex, comprising cyclodextrin and a perfume, wherein the perfume comprises perfume raw materials wherein 20% or more, by weight of the perfume, of the perfume raw materials, are selected from the group consisting of: ethyl-2-methyl butyrate; beta gamma hexanol; iso amyl acetate; amyl acetate; cis-3-hexenyl acetate; gamma-octalactone; ethyl vanillin; vanillin; benzaldehyde; dimethyl anthranilate; iso-eugenyl acetate; canthoxal; 3,6-nonadien-1-ol, triplal; and combinations thereof. 14. The personal aerosol composition of claim 13, wherein the perfume raw materials are selected from the group consisting of dimethyl anthranilate; iso-eugenyl acetate; canthoxal; 3,6-nonadien-1-ol, triplal; and combinations thereof. 15. The personal aerosol composition of claim 13, wherein about 20% to about 100%, by weight of the perfume, of the perfume raw materials have: a complex stability constant of about 3.0 or less, a C log P of about 2.5 or less; and a weight average molecular weight of about 200 Daltons or less. 16. The personal aerosol composition of claim 13, wherein about 50% to about 100% of the perfume raw materials have a complex stability constant of about −1.5 to about 2.5. 17. The personal aerosol composition of claim 13, wherein about 50% to about 100% of the perfume raw materials have a C log P of about 2.0 or less. 18. The personal aerosol composition of claim 13, wherein about 20% to about 100% of the perfume raw materials have a weight average molecular weight of about 180 Daltons or less. 19. The personal aerosol composition of claim 13, wherein the percent of the perfume that is complexed with the cyclodextrin is greater than about 75%. 20. The perfume of claim 13, wherein the cyclodextrin comprises beta-cyclodextrin.
| 1,600 |
1,225 | 15,671,217 | 1,646 |
Provided herein are proteins, antibodies, assays and methods useful for modulating growth factor levels and/or activities. In some embodiments, such growth factors are members of the TGF-β superfamily of proteins.
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1. An antibody produced by a method comprising the steps of:
i. expressing proGDF-8 (SEQ ID NO: 5); ii. forming a growth factor prodomain complex (GPC) by subjecting the expressed proGDF-8 (SEQ ID NO: 5) to enzymatic cleavage with one or more of furin, bone morphogenetic protein-1 (BMP-1), mammalian tolloid protein (mTLD), mammalian tolloid-like 1 (mTLL1), and mammalian tolloid-like 2 (mTLL2); iii. carrying out solid-phase or solution-phase enrichment with an antibody fragment phage display library, wherein the GPC formed by enzymatic cleavage is used as a target antigen; iv. selecting phage particles bound to the GPC formed by enzymatic cleavage; and v. producing recombinant antibodies having complementarity determining region (CDR) amino acid sequences derived from the antibody fragments expressed at the surface of the selected phage particles. 2. The antibody of claim 1, wherein said antibody is human or humanized. 3. The antibody of claim 1, wherein said antibody is subjected to affinity maturation. 4. The antibody of claim 1, wherein said method further comprises:
vi. screening the recombinant antibodies and selecting those which inhibit release of GDF-8 growth factor from GDF-8 GPCs. 5. The antibody of claim 4, wherein antibodies that inhibit GDF-8 activity are selected. 6. The antibody of claim 1, wherein said method further comprises:
vi. conducting a negative selection binding assay to exclude antibodies that bind to one or more undesired antigens. 7. The antibody of claim 6, wherein said one or more undesired antigens are selected from the group consisting of GDF-8 prodomain, GDF-8 growth factor, murine proGDF-8, proGDF-11, proTGF-β1, and a protein with an amino acid sequence selected from the group consisting of SEQ ID NOs: 207-230. 8. The antibody of claim 7, wherein said antibody is human or humanized. 9. The antibody of claim 7, wherein said antibody is subjected to affinity maturation. 10. The antibody of claim 1, wherein phage particle binding is determined using one or more binding assays selected from the group consisting of enzyme-linked immunosorbent assays, surface plasmon resonance assays, and flow cytometry assays. 11. The antibody of claim 1, wherein said enzymatic cleavage comprises sequential enzymatic cleavage with at least two enzymes. 12. The antibody of claim 11, wherein said antibody is human or humanized. 13. The antibody of claim 11, wherein said antibody is subjected to affinity maturation. 14. The antibody of claim 1, wherein at least one CDR amino acid sequence has at least one amino acid deletion, addition, or substitution relative to an amino acid sequence of said antibody fragments expressed at the surface of the selected phage particles. 15. The antibody of claim 1 comprising an isotype selected from the group consisting of IgG1, IgG2, IgG3, IgG4, IgA, IgGA2, IgD, IgE, and IgM. 16. The antibody of claim 1 comprising a bispecific antibody.
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Provided herein are proteins, antibodies, assays and methods useful for modulating growth factor levels and/or activities. In some embodiments, such growth factors are members of the TGF-β superfamily of proteins.1. An antibody produced by a method comprising the steps of:
i. expressing proGDF-8 (SEQ ID NO: 5); ii. forming a growth factor prodomain complex (GPC) by subjecting the expressed proGDF-8 (SEQ ID NO: 5) to enzymatic cleavage with one or more of furin, bone morphogenetic protein-1 (BMP-1), mammalian tolloid protein (mTLD), mammalian tolloid-like 1 (mTLL1), and mammalian tolloid-like 2 (mTLL2); iii. carrying out solid-phase or solution-phase enrichment with an antibody fragment phage display library, wherein the GPC formed by enzymatic cleavage is used as a target antigen; iv. selecting phage particles bound to the GPC formed by enzymatic cleavage; and v. producing recombinant antibodies having complementarity determining region (CDR) amino acid sequences derived from the antibody fragments expressed at the surface of the selected phage particles. 2. The antibody of claim 1, wherein said antibody is human or humanized. 3. The antibody of claim 1, wherein said antibody is subjected to affinity maturation. 4. The antibody of claim 1, wherein said method further comprises:
vi. screening the recombinant antibodies and selecting those which inhibit release of GDF-8 growth factor from GDF-8 GPCs. 5. The antibody of claim 4, wherein antibodies that inhibit GDF-8 activity are selected. 6. The antibody of claim 1, wherein said method further comprises:
vi. conducting a negative selection binding assay to exclude antibodies that bind to one or more undesired antigens. 7. The antibody of claim 6, wherein said one or more undesired antigens are selected from the group consisting of GDF-8 prodomain, GDF-8 growth factor, murine proGDF-8, proGDF-11, proTGF-β1, and a protein with an amino acid sequence selected from the group consisting of SEQ ID NOs: 207-230. 8. The antibody of claim 7, wherein said antibody is human or humanized. 9. The antibody of claim 7, wherein said antibody is subjected to affinity maturation. 10. The antibody of claim 1, wherein phage particle binding is determined using one or more binding assays selected from the group consisting of enzyme-linked immunosorbent assays, surface plasmon resonance assays, and flow cytometry assays. 11. The antibody of claim 1, wherein said enzymatic cleavage comprises sequential enzymatic cleavage with at least two enzymes. 12. The antibody of claim 11, wherein said antibody is human or humanized. 13. The antibody of claim 11, wherein said antibody is subjected to affinity maturation. 14. The antibody of claim 1, wherein at least one CDR amino acid sequence has at least one amino acid deletion, addition, or substitution relative to an amino acid sequence of said antibody fragments expressed at the surface of the selected phage particles. 15. The antibody of claim 1 comprising an isotype selected from the group consisting of IgG1, IgG2, IgG3, IgG4, IgA, IgGA2, IgD, IgE, and IgM. 16. The antibody of claim 1 comprising a bispecific antibody.
| 1,600 |
1,226 | 16,318,209 | 1,618 |
The present invention relates to radiolabeled IDO1 inhibitors or pharmaceutically acceptable salts thereof which are useful for the quantitative imaging of IDO enzymes in mammals.
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1. A radiolabeled compound having the following Formula I:
or a pharmaceutically acceptable salt thereof. 2. The radiolabeled compound of claim 1 having the following structure:
or a pharmaceutically acceptable salt thereof. 3. A pharmaceutical composition comprising a diagnostically effective amount of the radiolabeled compound of claim 2 and a pharmaceutically acceptable carrier therefor. 4. A method of in vivo imaging of mammalian tissues of known IDO1 expression to detect cancer cells comprising the steps of:
(a) administering the radiolabeled compound of claim 2 to a subject; and (b) imaging in vivo the distribution of the radiolabeled compound by positron emission tomography (PET) scanning. 5. A method for screening a non-radiolabeled compound to determine its affinity for occupying the binding site of the IDO1 enzyme in mammalian tissue comprising the steps of:
(a) administering the radiolabeled compound of claim 2 to a subject; (b) imaging in vivo tissues of known IDO1 expression by positron emission tomography (PET) to determine a baseline uptake of the radiolabeled compound; (c) administering the non-radiolabeled compound to said subject; (d) administering a second dose of the radiolabeled compound of claim 2 to said subject; (e) imaging in vivo the distribution of the radiolabeled compound of claim 2 in tissues that express IDO1 enzymes; (f) comparing the signal from PET scan data at baseline within the tissue that expresses IDO1 to PET scan data retrieved after administering the non-radiolabeled compound within the tissue that expresses IDO1 enzymes. 6. A method for monitoring the treatment of a cancer patient who is being treated with an IDO1 inhibitor comprising the steps of:
(a) administering to the patient the radiolabeled compound of claim 2; (b) obtaining an image of tissues in the patient that express IDO1 enzymes by positron emission tomography (PET); and (c) detecting to what degree said radiolabeled IDO1 inhibitor occupies the binding site of the IDO1 enzyme. 7. A method for tissue imaging comprising the steps of contacting a tissue that contains IDO1 enzymes with the radiolabeled compound of claim 2 and detecting the radiolabeled compound using positron emission tomography (PET) imaging. 8. The method of claim 7 wherein the compound is detected in vitro. 9. The method of claim 7 wherein the compound is detected in vivo. 10. A method for diagnosing the presence of a disease in a subject, comprising
(a) administering to a subject in need thereof the radiolabeled compound of claim 2 which binds to the IDO1 enzyme associated with the presence of the disease; and (b) obtaining a radio-image of at least a portion of the subject to detect the presence or absence of the radiolabeled compound; wherein the presence and location of the radiolabeled compound above background is indicative of the presence or absence of the disease. 11. A method for quantifying diseased cells or tissues in a subject, comprising
(a) administering to a subject having diseased cells or tissues the radiolabeled compound of claim 2 which binds to the IDO1 enzyme located within the diseased cells or tissues; and (b) detecting radioactive emissions of the radiolabeled compound in the diseased cells or tissues, wherein the level and distribution of the radioactive emissions in the diseased cells or tissues is a quantitative measure of the diseased cells or tissues.
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The present invention relates to radiolabeled IDO1 inhibitors or pharmaceutically acceptable salts thereof which are useful for the quantitative imaging of IDO enzymes in mammals.1. A radiolabeled compound having the following Formula I:
or a pharmaceutically acceptable salt thereof. 2. The radiolabeled compound of claim 1 having the following structure:
or a pharmaceutically acceptable salt thereof. 3. A pharmaceutical composition comprising a diagnostically effective amount of the radiolabeled compound of claim 2 and a pharmaceutically acceptable carrier therefor. 4. A method of in vivo imaging of mammalian tissues of known IDO1 expression to detect cancer cells comprising the steps of:
(a) administering the radiolabeled compound of claim 2 to a subject; and (b) imaging in vivo the distribution of the radiolabeled compound by positron emission tomography (PET) scanning. 5. A method for screening a non-radiolabeled compound to determine its affinity for occupying the binding site of the IDO1 enzyme in mammalian tissue comprising the steps of:
(a) administering the radiolabeled compound of claim 2 to a subject; (b) imaging in vivo tissues of known IDO1 expression by positron emission tomography (PET) to determine a baseline uptake of the radiolabeled compound; (c) administering the non-radiolabeled compound to said subject; (d) administering a second dose of the radiolabeled compound of claim 2 to said subject; (e) imaging in vivo the distribution of the radiolabeled compound of claim 2 in tissues that express IDO1 enzymes; (f) comparing the signal from PET scan data at baseline within the tissue that expresses IDO1 to PET scan data retrieved after administering the non-radiolabeled compound within the tissue that expresses IDO1 enzymes. 6. A method for monitoring the treatment of a cancer patient who is being treated with an IDO1 inhibitor comprising the steps of:
(a) administering to the patient the radiolabeled compound of claim 2; (b) obtaining an image of tissues in the patient that express IDO1 enzymes by positron emission tomography (PET); and (c) detecting to what degree said radiolabeled IDO1 inhibitor occupies the binding site of the IDO1 enzyme. 7. A method for tissue imaging comprising the steps of contacting a tissue that contains IDO1 enzymes with the radiolabeled compound of claim 2 and detecting the radiolabeled compound using positron emission tomography (PET) imaging. 8. The method of claim 7 wherein the compound is detected in vitro. 9. The method of claim 7 wherein the compound is detected in vivo. 10. A method for diagnosing the presence of a disease in a subject, comprising
(a) administering to a subject in need thereof the radiolabeled compound of claim 2 which binds to the IDO1 enzyme associated with the presence of the disease; and (b) obtaining a radio-image of at least a portion of the subject to detect the presence or absence of the radiolabeled compound; wherein the presence and location of the radiolabeled compound above background is indicative of the presence or absence of the disease. 11. A method for quantifying diseased cells or tissues in a subject, comprising
(a) administering to a subject having diseased cells or tissues the radiolabeled compound of claim 2 which binds to the IDO1 enzyme located within the diseased cells or tissues; and (b) detecting radioactive emissions of the radiolabeled compound in the diseased cells or tissues, wherein the level and distribution of the radioactive emissions in the diseased cells or tissues is a quantitative measure of the diseased cells or tissues.
| 1,600 |
1,227 | 15,299,085 | 1,641 |
The invention discloses a method for reduction of autofluorescence in biological samples, comprising the steps of:
a) providing a biological microscopy sample; b) irradiating the sample with visible light, wherein the visible light has a spectrum such that at least 50% of the light intensity emanates from a narrow wavelength interval within the visible range. The invention also discloses a method for autofluorescence reduction with triplet sensitizers irradiated with visible light.
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1. A method for reduction of autofluorescence in biological samples, comprising the steps of:
a) providing one or more biological microscopy sample; b) irradiating said one or more sample with visible light having a light intensity, wherein a large fraction of said light intensity emanates from a narrow wavelength interval within the visible range. 2. A method for reduction of autofluorescence in biological samples, comprising the steps of:
a) providing one or more biological microscopy sample; b) irradiating said one or more sample with visible light having a light intensity, wherein said visible light has a spectrum such that at least 50% of the light intensity emanates from a narrow wavelength interval within the visible range. 3. The method of claim 1, wherein at least 70%, such as at least 80% or at least 90%, of the light intensity emanates from said narrow wavelength interval. 4. The method of claim 1, wherein said narrow wavelength interval has a width of up to 80 nm, such as up to 70 nm. 5. The method of claim 1, wherein a total light intensity in step b) is 5-300 mW/cm2, such as 50-200 mW/cm2. 6. The method of claim 1, wherein step b) is conducted for 5-90 min, such as 10-60 min or 10-30 min. 7. The method of claim 1, wherein said visible light is provided by one or more light emitting diodes (LED). 8. The method of claim 1, wherein said light intensity is spatially uniform over said one or more biological samples. 9. The method of claim 1, wherein said one or more biological microscopy sample is fixed on a microscope slide. 10. The method of claim 1, wherein said one or more biological microscopy sample comprises tissue material, material from body fluids or cultivated cells. 11. The method of claim 1, wherein said one or more biological microscopy sample comprises a section of a formaldehyde fixed paraffin embedded (FFPE) tissue sample. 12. The method of claim 1, further comprising a step c) of staining said one or more sample with one or more fluorescent markers and imaging fluorescence from said one or more sample. 13. The method of claim 12, wherein said one or more fluorescent markers comprise a fluorescent histological stain, a fluorophore conjugated to an antibody, a fluorophore conjugated to a nucleic acid and/or a fluorophore conjugated to a lipid. 14. The method of claim 1, wherein said visible light is within a range of about 390-700 nm. 15. The method of claim 1, wherein said wavelength interval is 470-550 nm, such as 490-530 nm. 16. The method of claim 1, further comprising, before step b), a step a′) of contacting said one or more sample with a solution comprising a triplet sensitizer. 17. The method of claim 16, wherein said triplet sensitizer is selected from the group consisting of riboflavin, bilirubin, hypericin, methylene blue and hypocrellin. 18. A method for reduction of autofluorescence in biological samples, comprising the steps of:
i) providing one or more biological microscopy sample; ii) contacting said one or more sample with a solution comprising a triplet sensitizer; iii) irradiating said one or more sample with visible or near infrared (NIR) light. 19. The method of claim 18, wherein said triplet sensitizer is a conjugated aromatic ketone or imide. 20. The method of claim 18, wherein said triplet sensitizer is capable of absorbing visible or NIR light. 21. The method of claim 18, wherein said triplet sensitizer is selected from the group consisting of riboflavin, bilirubin, hypericin, methylene blue, hypocrellin A and hypocrellin B. 22. The method of claim 18, wherein in step ii) a concentration of said triplet sensitizer in said solution is 10−10 M to 10−5 M. 23. The method of claim 18, wherein said visible or NIR light is provided by one or more light emitting diodes (LED). 24. The method of claim 18, wherein the visible or NIR light in step iii) has a total light intensity of 25-300 mW/cm2, such as 50-200 mW/cm2. 25. The method of claim 18, wherein step iii) is conducted for 5-90 min, such as 10-60 min or 10-30 min. 26. A method for reduction of autofluorescence in biological samples, comprising the steps of:
I) providing one or more biological microscopy sample; II) irradiating said one or more sample with visible light from one or more light emitting diodes (LED), wherein said light emitting diodes emit light within the 470-550 nm interval. 27. An apparatus (1) for reduction of autofluorescence in biological samples (3), comprising a light box (2) with a plurality of LEDs (4), a plurality of beam spreader lenses (5) and a diffuser plate (6). 28. The apparatus of claim 27, wherein said LEDs emit visible light with at least 50% of the light intensity emanating from a wavelength interval with a width of up to 80 nm or up to 70 nm. 29. The apparatus of claim 27, wherein said LEDs emit visible light with at least 50% of the light intensity emanating from the 470-550 nm interval. 30. The apparatus of claim 29, wherein a total light intensity reaching said biological samples or a sample tray (7) is 5-300 mW/cm2. 31. The apparatus of claim 30, wherein said total light intensity is spatially uniform over said biological samples or sample tray. 32. The method of claim 26, performed using the apparatus of claim 27.
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The invention discloses a method for reduction of autofluorescence in biological samples, comprising the steps of:
a) providing a biological microscopy sample; b) irradiating the sample with visible light, wherein the visible light has a spectrum such that at least 50% of the light intensity emanates from a narrow wavelength interval within the visible range. The invention also discloses a method for autofluorescence reduction with triplet sensitizers irradiated with visible light.1. A method for reduction of autofluorescence in biological samples, comprising the steps of:
a) providing one or more biological microscopy sample; b) irradiating said one or more sample with visible light having a light intensity, wherein a large fraction of said light intensity emanates from a narrow wavelength interval within the visible range. 2. A method for reduction of autofluorescence in biological samples, comprising the steps of:
a) providing one or more biological microscopy sample; b) irradiating said one or more sample with visible light having a light intensity, wherein said visible light has a spectrum such that at least 50% of the light intensity emanates from a narrow wavelength interval within the visible range. 3. The method of claim 1, wherein at least 70%, such as at least 80% or at least 90%, of the light intensity emanates from said narrow wavelength interval. 4. The method of claim 1, wherein said narrow wavelength interval has a width of up to 80 nm, such as up to 70 nm. 5. The method of claim 1, wherein a total light intensity in step b) is 5-300 mW/cm2, such as 50-200 mW/cm2. 6. The method of claim 1, wherein step b) is conducted for 5-90 min, such as 10-60 min or 10-30 min. 7. The method of claim 1, wherein said visible light is provided by one or more light emitting diodes (LED). 8. The method of claim 1, wherein said light intensity is spatially uniform over said one or more biological samples. 9. The method of claim 1, wherein said one or more biological microscopy sample is fixed on a microscope slide. 10. The method of claim 1, wherein said one or more biological microscopy sample comprises tissue material, material from body fluids or cultivated cells. 11. The method of claim 1, wherein said one or more biological microscopy sample comprises a section of a formaldehyde fixed paraffin embedded (FFPE) tissue sample. 12. The method of claim 1, further comprising a step c) of staining said one or more sample with one or more fluorescent markers and imaging fluorescence from said one or more sample. 13. The method of claim 12, wherein said one or more fluorescent markers comprise a fluorescent histological stain, a fluorophore conjugated to an antibody, a fluorophore conjugated to a nucleic acid and/or a fluorophore conjugated to a lipid. 14. The method of claim 1, wherein said visible light is within a range of about 390-700 nm. 15. The method of claim 1, wherein said wavelength interval is 470-550 nm, such as 490-530 nm. 16. The method of claim 1, further comprising, before step b), a step a′) of contacting said one or more sample with a solution comprising a triplet sensitizer. 17. The method of claim 16, wherein said triplet sensitizer is selected from the group consisting of riboflavin, bilirubin, hypericin, methylene blue and hypocrellin. 18. A method for reduction of autofluorescence in biological samples, comprising the steps of:
i) providing one or more biological microscopy sample; ii) contacting said one or more sample with a solution comprising a triplet sensitizer; iii) irradiating said one or more sample with visible or near infrared (NIR) light. 19. The method of claim 18, wherein said triplet sensitizer is a conjugated aromatic ketone or imide. 20. The method of claim 18, wherein said triplet sensitizer is capable of absorbing visible or NIR light. 21. The method of claim 18, wherein said triplet sensitizer is selected from the group consisting of riboflavin, bilirubin, hypericin, methylene blue, hypocrellin A and hypocrellin B. 22. The method of claim 18, wherein in step ii) a concentration of said triplet sensitizer in said solution is 10−10 M to 10−5 M. 23. The method of claim 18, wherein said visible or NIR light is provided by one or more light emitting diodes (LED). 24. The method of claim 18, wherein the visible or NIR light in step iii) has a total light intensity of 25-300 mW/cm2, such as 50-200 mW/cm2. 25. The method of claim 18, wherein step iii) is conducted for 5-90 min, such as 10-60 min or 10-30 min. 26. A method for reduction of autofluorescence in biological samples, comprising the steps of:
I) providing one or more biological microscopy sample; II) irradiating said one or more sample with visible light from one or more light emitting diodes (LED), wherein said light emitting diodes emit light within the 470-550 nm interval. 27. An apparatus (1) for reduction of autofluorescence in biological samples (3), comprising a light box (2) with a plurality of LEDs (4), a plurality of beam spreader lenses (5) and a diffuser plate (6). 28. The apparatus of claim 27, wherein said LEDs emit visible light with at least 50% of the light intensity emanating from a wavelength interval with a width of up to 80 nm or up to 70 nm. 29. The apparatus of claim 27, wherein said LEDs emit visible light with at least 50% of the light intensity emanating from the 470-550 nm interval. 30. The apparatus of claim 29, wherein a total light intensity reaching said biological samples or a sample tray (7) is 5-300 mW/cm2. 31. The apparatus of claim 30, wherein said total light intensity is spatially uniform over said biological samples or sample tray. 32. The method of claim 26, performed using the apparatus of claim 27.
| 1,600 |
1,228 | 15,799,919 | 1,619 |
The invention relates to nail compositions including diisononyl 1,2-cyclohexanedicarboxylate, as well as to methods, kits and nail composition sets related to such compositions.
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1. A nail composition comprising at least 5% of diisononyl 1,2-cyclohexanedicarboxylate by weight with respect to the total weight of the composition. 2. The nail composition of claim 1, further comprising at least one cellulose compound, wherein the diisononyl 1,2-cyclohexanedicarboxylate and the cellulose compound are present in a weight ratio of 7:1 to 1:7. 3. The nail composition of claim 2, wherein the cellulose compound is nitrocellulose. 4. The nail composition of claim 2, wherein the composition has gloss properties, measured at 20°, of greater than about 55 GU. 5. The nail composition of claim 2, wherein the composition has gloss properties, measured at 60°, of greater than about 70 GU. 6. The nail composition of claim 2, further comprising at least one coloring agent. 7. The nail composition of claim 2, wherein the composition is a topcoat. 8. The nail composition of claim 2, which is substantially free of phthalates. 9. The nail composition of claim 2, which is substantially free of water. 10. A nail composition set comprising (a) at least one color coat comprising at least one coloring agent; and (b) at least one basecoat comprising at least 5% of diisononyl 1,2-cyclohexanedicarboxylate by weight with respect to the total weight of the basecoat and/or at least one topcoat comprising at least 5% of diisononyl 1,2-cyclohexanedicarboxylate by weight with respect to the total weight of the topcoat, wherein the nail composition set has at least one of the following properties:
a. the nail composition set has gloss properties, measured at 20°, of greater than about 55 GU; or b. the nail composition set has gloss properties, measured at 60°, of greater than about 70 GU. 11. A method of improving shine and hardness properties of a nail composition comprising adding at least 5% of diisononyl 1,2-cyclohexanedicarboxylate to the nail composition during preparation of the nail composition. 12. The method of claim 11, wherein the composition further comprises at least one cellulose compound, wherein the diisononyl 1,2-cyclohexanedicarboxylate and the cellulose compound are present in a weight ratio of 7:1 to 1:7. 13. The method of claim 12, wherein the cellulose compound is nitrocellulose. 14. The method of claim 12, wherein the composition has gloss properties, measured at 20°, of greater than about 55 GU. 15. The method of claim 12, wherein the composition has gloss properties, measured at 60°, of greater than about 70 GU. 16. The method of claim 12, wherein the composition further comprises at least one coloring agent. 17. The method of claim 12, wherein the composition is a topcoat. 18. The method of claim 12, wherein the composition is substantially free of phthalates. 19. The method of claim 12, wherein the composition is substantially free of water.
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The invention relates to nail compositions including diisononyl 1,2-cyclohexanedicarboxylate, as well as to methods, kits and nail composition sets related to such compositions.1. A nail composition comprising at least 5% of diisononyl 1,2-cyclohexanedicarboxylate by weight with respect to the total weight of the composition. 2. The nail composition of claim 1, further comprising at least one cellulose compound, wherein the diisononyl 1,2-cyclohexanedicarboxylate and the cellulose compound are present in a weight ratio of 7:1 to 1:7. 3. The nail composition of claim 2, wherein the cellulose compound is nitrocellulose. 4. The nail composition of claim 2, wherein the composition has gloss properties, measured at 20°, of greater than about 55 GU. 5. The nail composition of claim 2, wherein the composition has gloss properties, measured at 60°, of greater than about 70 GU. 6. The nail composition of claim 2, further comprising at least one coloring agent. 7. The nail composition of claim 2, wherein the composition is a topcoat. 8. The nail composition of claim 2, which is substantially free of phthalates. 9. The nail composition of claim 2, which is substantially free of water. 10. A nail composition set comprising (a) at least one color coat comprising at least one coloring agent; and (b) at least one basecoat comprising at least 5% of diisononyl 1,2-cyclohexanedicarboxylate by weight with respect to the total weight of the basecoat and/or at least one topcoat comprising at least 5% of diisononyl 1,2-cyclohexanedicarboxylate by weight with respect to the total weight of the topcoat, wherein the nail composition set has at least one of the following properties:
a. the nail composition set has gloss properties, measured at 20°, of greater than about 55 GU; or b. the nail composition set has gloss properties, measured at 60°, of greater than about 70 GU. 11. A method of improving shine and hardness properties of a nail composition comprising adding at least 5% of diisononyl 1,2-cyclohexanedicarboxylate to the nail composition during preparation of the nail composition. 12. The method of claim 11, wherein the composition further comprises at least one cellulose compound, wherein the diisononyl 1,2-cyclohexanedicarboxylate and the cellulose compound are present in a weight ratio of 7:1 to 1:7. 13. The method of claim 12, wherein the cellulose compound is nitrocellulose. 14. The method of claim 12, wherein the composition has gloss properties, measured at 20°, of greater than about 55 GU. 15. The method of claim 12, wherein the composition has gloss properties, measured at 60°, of greater than about 70 GU. 16. The method of claim 12, wherein the composition further comprises at least one coloring agent. 17. The method of claim 12, wherein the composition is a topcoat. 18. The method of claim 12, wherein the composition is substantially free of phthalates. 19. The method of claim 12, wherein the composition is substantially free of water.
| 1,600 |
1,229 | 15,167,822 | 1,644 |
The present invention relates to optimized Fc variants, methods for their generation, and antibodies and Fc fusions comprising optimized Fc variants.
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1.-67. (canceled) 68. A nucleic acid encoding a polypeptide comprising an Fc variant of a parent Fc polypeptide, said Fc variant comprising an amino acid substitution at position 332 in the Fc region, wherein numbering is according to the EU index. 69. The nucleic acid according to claim 68, wherein the substitution at position 332 is 332D. 70. The nucleic acid according to claim 68, wherein the substitution at position 332 is 332E. 71. The nucleic acid according to claim 68, wherein the parent Fc polypeptide is a human IgG1 Fc polypeptide. 72. An expression vector comprising the nucleic acid according to claim 68. 73. A host cell comprising a nucleic acid according to claim 68. 74. A host cell comprising an expression vector according to claim 72. 75. A method of producing a polypeptide comprising: a) culturing a host cell according to claim 73 under conditions wherein said polypeptide is produced; and b) purifying said polypeptide. 76. A method of producing a polypeptide comprising: a) culturing a host cell according to claim 74 under conditions wherein said polypeptide is produced; and b) purifying said polypeptide. 77. A nucleic acid encoding a heavy chain of an antibody comprising an Fc variant of a parent Fc polypeptide, said Fc variant comprising an amino acid substitution at position 332 in the Fc region, wherein numbering is according to the EU index. 78. The nucleic acid according to claim 77, wherein the substitution at position 332 is 332D. 79. The nucleic acid according to claim 77, wherein the substitution at position 332 is 332E. 80. The nucleic acid according to claim 77, wherein the parent Fc polypeptide is a human IgG1 Fc polypeptide. 81. The nucleic acid according to claim 77, wherein the antibody is a monoclonal antibody. 82. An expression vector comprising the nucleic acid according to claim 77. 83. A host cell comprising a nucleic acid according to claim 77. 84. A host cell comprising an expression vector according to claim 82. 85. A method of producing a polypeptide comprising: a) culturing a host cell according to claim 83 under conditions wherein said polypeptide is produced; and b) purifying said polypeptide. 86. A method of producing a polypeptide comprising: a) culturing a host cell according to claim 84 under conditions wherein said polypeptide is produced; and b) purifying said polypeptide. 87. A nucleic acid encoding a polypeptide comprising an Fc variant of a parent Fc polypeptide, said Fc variant comprising an amino acid substitution 332E in the Fc region, wherein said Fc variant exhibits increased FcγRIIIa binding, and wherein numbering is according to the EU index. 88. The nucleic acid according to claim 87, wherein the parent Fc polypeptide is a human IgG1 Fc polypeptide. 89. An expression vector comprising the nucleic acid according to claim 87. 90. A host cell comprising a nucleic acid according to claim 87. 91. A host cell comprising an expression vector according to claim 89. 92. A method of producing a polypeptide comprising: a) culturing a host cell according to claim 90 under conditions wherein said polypeptide is produced; and b) purifying said polypeptide. 93. A method of producing a polypeptide comprising: a) culturing a host cell according to claim 91 under conditions wherein said polypeptide is produced; and b) purifying said polypeptide. 94. A nucleic acid encoding a heavy chain of an antibody comprising an Fc variant of a parent Fc polypeptide, said Fc variant comprising an amino acid substitution 332E in the Fc region, wherein said Fc variant exhibits increased FcγRIIIa binding, and wherein numbering is according to the EU index. 95. The nucleic acid according to claim 94, wherein the parent Fc polypeptide is a human IgG1 Fc polypeptide. 96. The nucleic acid according to claim 94, wherein the antibody is a monoclonal antibody. 97. An expression vector comprising the nucleic acid according to claim 94. 98. A host cell comprising a nucleic acid according to claim 94. 99. A host cell comprising an expression vector according to claim 97. 100. A method of producing a polypeptide comprising: a) culturing a host cell according to claim 98 under conditions wherein said polypeptide is produced; and b) purifying said polypeptide. 101. A method of producing a polypeptide comprising: a) culturing a host cell according to claim 99 under conditions wherein said polypeptide is produced; and b) purifying said polypeptide.
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The present invention relates to optimized Fc variants, methods for their generation, and antibodies and Fc fusions comprising optimized Fc variants.1.-67. (canceled) 68. A nucleic acid encoding a polypeptide comprising an Fc variant of a parent Fc polypeptide, said Fc variant comprising an amino acid substitution at position 332 in the Fc region, wherein numbering is according to the EU index. 69. The nucleic acid according to claim 68, wherein the substitution at position 332 is 332D. 70. The nucleic acid according to claim 68, wherein the substitution at position 332 is 332E. 71. The nucleic acid according to claim 68, wherein the parent Fc polypeptide is a human IgG1 Fc polypeptide. 72. An expression vector comprising the nucleic acid according to claim 68. 73. A host cell comprising a nucleic acid according to claim 68. 74. A host cell comprising an expression vector according to claim 72. 75. A method of producing a polypeptide comprising: a) culturing a host cell according to claim 73 under conditions wherein said polypeptide is produced; and b) purifying said polypeptide. 76. A method of producing a polypeptide comprising: a) culturing a host cell according to claim 74 under conditions wherein said polypeptide is produced; and b) purifying said polypeptide. 77. A nucleic acid encoding a heavy chain of an antibody comprising an Fc variant of a parent Fc polypeptide, said Fc variant comprising an amino acid substitution at position 332 in the Fc region, wherein numbering is according to the EU index. 78. The nucleic acid according to claim 77, wherein the substitution at position 332 is 332D. 79. The nucleic acid according to claim 77, wherein the substitution at position 332 is 332E. 80. The nucleic acid according to claim 77, wherein the parent Fc polypeptide is a human IgG1 Fc polypeptide. 81. The nucleic acid according to claim 77, wherein the antibody is a monoclonal antibody. 82. An expression vector comprising the nucleic acid according to claim 77. 83. A host cell comprising a nucleic acid according to claim 77. 84. A host cell comprising an expression vector according to claim 82. 85. A method of producing a polypeptide comprising: a) culturing a host cell according to claim 83 under conditions wherein said polypeptide is produced; and b) purifying said polypeptide. 86. A method of producing a polypeptide comprising: a) culturing a host cell according to claim 84 under conditions wherein said polypeptide is produced; and b) purifying said polypeptide. 87. A nucleic acid encoding a polypeptide comprising an Fc variant of a parent Fc polypeptide, said Fc variant comprising an amino acid substitution 332E in the Fc region, wherein said Fc variant exhibits increased FcγRIIIa binding, and wherein numbering is according to the EU index. 88. The nucleic acid according to claim 87, wherein the parent Fc polypeptide is a human IgG1 Fc polypeptide. 89. An expression vector comprising the nucleic acid according to claim 87. 90. A host cell comprising a nucleic acid according to claim 87. 91. A host cell comprising an expression vector according to claim 89. 92. A method of producing a polypeptide comprising: a) culturing a host cell according to claim 90 under conditions wherein said polypeptide is produced; and b) purifying said polypeptide. 93. A method of producing a polypeptide comprising: a) culturing a host cell according to claim 91 under conditions wherein said polypeptide is produced; and b) purifying said polypeptide. 94. A nucleic acid encoding a heavy chain of an antibody comprising an Fc variant of a parent Fc polypeptide, said Fc variant comprising an amino acid substitution 332E in the Fc region, wherein said Fc variant exhibits increased FcγRIIIa binding, and wherein numbering is according to the EU index. 95. The nucleic acid according to claim 94, wherein the parent Fc polypeptide is a human IgG1 Fc polypeptide. 96. The nucleic acid according to claim 94, wherein the antibody is a monoclonal antibody. 97. An expression vector comprising the nucleic acid according to claim 94. 98. A host cell comprising a nucleic acid according to claim 94. 99. A host cell comprising an expression vector according to claim 97. 100. A method of producing a polypeptide comprising: a) culturing a host cell according to claim 98 under conditions wherein said polypeptide is produced; and b) purifying said polypeptide. 101. A method of producing a polypeptide comprising: a) culturing a host cell according to claim 99 under conditions wherein said polypeptide is produced; and b) purifying said polypeptide.
| 1,600 |
1,230 | 14,618,772 | 1,618 |
An automated HPLC-based quality control system to perform quality control testing on a radiopharmaceutical solution shortly after synthesis. An automated HPLC-based quality control system makes efficient use of sample volume and is compatible with a variety of radioisotopes and radiopharmaceutical compounds. In several embodiments, the automated nature of an automated HPLC-based quality control system allows for quality control tests to be conducted quickly and with minimal impact on user workflow. When used as part of an integrated PET biomarker radiopharmaceutical production system, the present general inventive concept permits a manufacturer to produce product and conduct quality control tests with lower per dose costs and shorter testing times.
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1. A method for conducting quality control tests on a radiopharmaceutical using an automated quality control system comprising:
conveying a first portion of a radiopharmaceutical solution to a radiopharmaceutical solution pumping mechanism; conveying a second portion of said radiopharmetutical solution to a series of collection vials for additional quality control testing; pumping said first portion of a radiopharmaceutical solution to an injection valve, said injection valve to direct the flow of said clarified radiopharmaceutical solution; directing a first aliquot of the clarified radiopharmaceutical solution into a first sample collection vessel, said first sample collection vessel to hold the first aliquot of the clarified radiopharmaceutical solution for endotoxicity testing; directing a second aliquot of the clarified radiopharmaceutical solution into at least one high performance liquid chromatography column, said high performance liquid chromatography column to separate chemical species within the second aliquot of the clarified radiopharmaceutical solution into a number of separated chemical species; measuring the optical qualities of the second aliquot of the sample radiopharmaceutical solution by means of an ultraviolet-light detector; using a refractive index detector to measure the amount of each separated chemical species from said high performance liquid chromatography column; and measuring the radioactivity of each separated chemical species from said high performance liquid chromatography column. 2. The method of claim 1 wherein measuring the radioactivity of each separated chemical species from said high performance liquid chromatography column is performed by means of a radiation detector, said radiation detector including at least two radiation probes, said at least two radiation probes including:
a first radiation probe to measure the radioactivity of the first aliquot of the sample radiopharmaceutical solution held in said first sample collection vessel; and
a second radiation probe to measure the radioactivity of each separated chemical species from said high performance liquid chromatography column. 3. The method of claim 1 further comprising measuring the pH of the clarified radiopharmaceutical solution in parallel to said high performance liquid chromatography column. 4. The method of claim 1 wherein said radioisotope is selected from the group consisting of carbon-11, nitrogen-13, oxygen-15, and fluorine-18, iodine-124, gallium-68. 5. The method of claim 1 wherein said radiopharmaceutical selected from the group consisting of [18F]-2-fluoro-2-deoxy-D-glucose, [18F]Sodium Floride, [18F]3′-deoxy-3′fluorothymidine, [18F]fluoromisonidazole, [18F]Florbetaben, [18F]Florbetapir, [18F]-fluoro-ethyl-tyrosine, [18F]flutemetamol, [18F]flurocholine, [18F]Fallypride, [18F]FDOPA, [11C]Choline, [11C]methionine, [11C]acetate, [11C]N-Methylspiperone, [11C]Carfentanil and [11C]Raclopride. 6. The method of claim 1 wherein said system can perform automated self-cleaning after completion of tests. 7. The method of claim 1 wherein said second aliquot in said high performance liquid chromatography column is measure for C1DG concentration. 8. The method of claim 1 wherein said second aliquot is measured by radiation detector for radionucleic identity, radionucleic purity, radiochemical identity, or radiochemical purity. 9. The method of claim 1 wherein said second aliquot is measured by a multichannel analyzer for radionucleic identity, radionucleic purity, radiochemical identity, or radiochemical purity. 10. The method of claim 1 wherein said second aliquot is measured by a colormetric detector for color and clarity. 11. The method of claim 1 wherein said first aliquot in collection vial is contained in Charles River Endotoxin tester. 12. The method of claim 1 wherein said high performance liquid chromatography column is in series with at least one other high performance liquid chromatography column. 13. The method of claim 1 wherein said high performance liquid chromatography column is in parallel with at least one other high performance liquid chromatography column. 14. The method of claim 1 wherein said automated quality control system is configured for a specific radiopharmaceutical. 15. The method of claim 1 wherein said automated quality control system further comprises a system for detecting the presence of a phase transfer catalyst in a radiopharmaceutical solution, comprising:
a reagent that will react with the catalyst when added to the radiopharmaceutical solution, said reagent to be mixed with the radiopharmaceutical solution, said reagent including iodine. 16. The method of claim 15 wherein the phase transfer catalyst is selected from the group consisting of Kryptofix 2.2.2, 18-Crown-6, and Quaternary amine-derivatives. 17. The method of claim 1 wherein said Automated Quality Control System for Radiopharmaceuticals supports a method for determining the concentration of a phase transfer catalyst in a radiopharmaceutical solution, comprising:
mixing a reagent including iodine with a radiopharmaceutical solution to form a mixture; and
measuring the absorbance of the mixture. 18. The method of claim 1 wherein said Automated Quality Control System for Radiopharmaceuticals supports a method for determining the concentration of a selected phase transfer catalyst in a radiopharmaceutical solution, comprising:
mixing a reagent including iodine with a radiopharmaceutical solution to form a mixture, said reagent to react with the selected catalyst;
measuring the visible light absorbance properties of the mixture; and
comparing the visible light absorbance of the mixture to previously established visible light absorbance properties for selected known concentrations of the selected catalyst. 19. The method of claim 1, wherein said means for measuring the concentration of said chemical species in said radiopharmaceutical solution include a gas chromatograph or electronic mems “nose” device. 20. The method of claim 1, wherein said quality control module includes means for detecting the concentration of potassium and crown ethers in said radiopharmaceutical solution. 21. The method of claim 22, wherein said means for detecting the concentration of potassium and crown ethers are adapted to detect the concentration of 1,10-diaza-4,7,13,16,21,24-hexaoxabicyclo[8.8.8]hexacosane. 22. The method of claim 22, wherein said means for detecting the concentration of potassium and crown ethers in said radiopharmaceutical solution include a silica gel with iodoplatinate and a color recognition sensor. 23. The method of claim 1 wherein said means for method for detecting the chemical purity of said radiopharmaceutical is measured using the electrical conductivity.
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An automated HPLC-based quality control system to perform quality control testing on a radiopharmaceutical solution shortly after synthesis. An automated HPLC-based quality control system makes efficient use of sample volume and is compatible with a variety of radioisotopes and radiopharmaceutical compounds. In several embodiments, the automated nature of an automated HPLC-based quality control system allows for quality control tests to be conducted quickly and with minimal impact on user workflow. When used as part of an integrated PET biomarker radiopharmaceutical production system, the present general inventive concept permits a manufacturer to produce product and conduct quality control tests with lower per dose costs and shorter testing times.1. A method for conducting quality control tests on a radiopharmaceutical using an automated quality control system comprising:
conveying a first portion of a radiopharmaceutical solution to a radiopharmaceutical solution pumping mechanism; conveying a second portion of said radiopharmetutical solution to a series of collection vials for additional quality control testing; pumping said first portion of a radiopharmaceutical solution to an injection valve, said injection valve to direct the flow of said clarified radiopharmaceutical solution; directing a first aliquot of the clarified radiopharmaceutical solution into a first sample collection vessel, said first sample collection vessel to hold the first aliquot of the clarified radiopharmaceutical solution for endotoxicity testing; directing a second aliquot of the clarified radiopharmaceutical solution into at least one high performance liquid chromatography column, said high performance liquid chromatography column to separate chemical species within the second aliquot of the clarified radiopharmaceutical solution into a number of separated chemical species; measuring the optical qualities of the second aliquot of the sample radiopharmaceutical solution by means of an ultraviolet-light detector; using a refractive index detector to measure the amount of each separated chemical species from said high performance liquid chromatography column; and measuring the radioactivity of each separated chemical species from said high performance liquid chromatography column. 2. The method of claim 1 wherein measuring the radioactivity of each separated chemical species from said high performance liquid chromatography column is performed by means of a radiation detector, said radiation detector including at least two radiation probes, said at least two radiation probes including:
a first radiation probe to measure the radioactivity of the first aliquot of the sample radiopharmaceutical solution held in said first sample collection vessel; and
a second radiation probe to measure the radioactivity of each separated chemical species from said high performance liquid chromatography column. 3. The method of claim 1 further comprising measuring the pH of the clarified radiopharmaceutical solution in parallel to said high performance liquid chromatography column. 4. The method of claim 1 wherein said radioisotope is selected from the group consisting of carbon-11, nitrogen-13, oxygen-15, and fluorine-18, iodine-124, gallium-68. 5. The method of claim 1 wherein said radiopharmaceutical selected from the group consisting of [18F]-2-fluoro-2-deoxy-D-glucose, [18F]Sodium Floride, [18F]3′-deoxy-3′fluorothymidine, [18F]fluoromisonidazole, [18F]Florbetaben, [18F]Florbetapir, [18F]-fluoro-ethyl-tyrosine, [18F]flutemetamol, [18F]flurocholine, [18F]Fallypride, [18F]FDOPA, [11C]Choline, [11C]methionine, [11C]acetate, [11C]N-Methylspiperone, [11C]Carfentanil and [11C]Raclopride. 6. The method of claim 1 wherein said system can perform automated self-cleaning after completion of tests. 7. The method of claim 1 wherein said second aliquot in said high performance liquid chromatography column is measure for C1DG concentration. 8. The method of claim 1 wherein said second aliquot is measured by radiation detector for radionucleic identity, radionucleic purity, radiochemical identity, or radiochemical purity. 9. The method of claim 1 wherein said second aliquot is measured by a multichannel analyzer for radionucleic identity, radionucleic purity, radiochemical identity, or radiochemical purity. 10. The method of claim 1 wherein said second aliquot is measured by a colormetric detector for color and clarity. 11. The method of claim 1 wherein said first aliquot in collection vial is contained in Charles River Endotoxin tester. 12. The method of claim 1 wherein said high performance liquid chromatography column is in series with at least one other high performance liquid chromatography column. 13. The method of claim 1 wherein said high performance liquid chromatography column is in parallel with at least one other high performance liquid chromatography column. 14. The method of claim 1 wherein said automated quality control system is configured for a specific radiopharmaceutical. 15. The method of claim 1 wherein said automated quality control system further comprises a system for detecting the presence of a phase transfer catalyst in a radiopharmaceutical solution, comprising:
a reagent that will react with the catalyst when added to the radiopharmaceutical solution, said reagent to be mixed with the radiopharmaceutical solution, said reagent including iodine. 16. The method of claim 15 wherein the phase transfer catalyst is selected from the group consisting of Kryptofix 2.2.2, 18-Crown-6, and Quaternary amine-derivatives. 17. The method of claim 1 wherein said Automated Quality Control System for Radiopharmaceuticals supports a method for determining the concentration of a phase transfer catalyst in a radiopharmaceutical solution, comprising:
mixing a reagent including iodine with a radiopharmaceutical solution to form a mixture; and
measuring the absorbance of the mixture. 18. The method of claim 1 wherein said Automated Quality Control System for Radiopharmaceuticals supports a method for determining the concentration of a selected phase transfer catalyst in a radiopharmaceutical solution, comprising:
mixing a reagent including iodine with a radiopharmaceutical solution to form a mixture, said reagent to react with the selected catalyst;
measuring the visible light absorbance properties of the mixture; and
comparing the visible light absorbance of the mixture to previously established visible light absorbance properties for selected known concentrations of the selected catalyst. 19. The method of claim 1, wherein said means for measuring the concentration of said chemical species in said radiopharmaceutical solution include a gas chromatograph or electronic mems “nose” device. 20. The method of claim 1, wherein said quality control module includes means for detecting the concentration of potassium and crown ethers in said radiopharmaceutical solution. 21. The method of claim 22, wherein said means for detecting the concentration of potassium and crown ethers are adapted to detect the concentration of 1,10-diaza-4,7,13,16,21,24-hexaoxabicyclo[8.8.8]hexacosane. 22. The method of claim 22, wherein said means for detecting the concentration of potassium and crown ethers in said radiopharmaceutical solution include a silica gel with iodoplatinate and a color recognition sensor. 23. The method of claim 1 wherein said means for method for detecting the chemical purity of said radiopharmaceutical is measured using the electrical conductivity.
| 1,600 |
1,231 | 15,300,686 | 1,633 |
The present invention relates to a novel gene expression system comprising: a) a first nucleotide sequence encoding a fusion polypeptide of: a1) a destabilizing domain (DD) based on DHFR, and a2) a GTPcyclohydrolase 1 (GCH1) polypeptide, or a biologically active fragment or variant thereof; and b) a second nucleotide sequence encoding a tyrosine hydroxylase (TH) polypeptide, or a biologically active fragment or variant thereof. The invention also relates to use of this gene expression system together with a ligand binding to a destabilizing domain (DD) based on dihydrofolate reductase (DHFR) for treatment of diseases associated with a reduced dopamine level, such as Parkinson's disease.
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1. A gene expression system comprising:
a first nucleotide sequence encoding a fusion polypeptide of:
a) a destabilizing domain (DD), and
b) a GTPcyclohydrolase 1 (GCH1) polypeptide, or a biologically active fragment or variant thereof; and
a second nucleotide sequence encoding a tyrosine hydroxylase (TH) polypeptide, or a biologically active fragment or variant thereof. 2-4. (canceled) 5. A gene expression system according to claim 1, wherein said gene expression system comprises two vectors each containing one expression cassette, wherein:
the expression cassette in the first vector comprises the first nucleotide sequence and a first promoter sequence operably linked to the first nucleotide sequence, and the expression cassette in the second vector comprises the second nucleotide and a second promoter sequence operably linked to the second nucleotide sequence. 6. A gene expression system according to claim 1, wherein said gene expression system comprises one vector comprising both the first nucleotide sequence and the second nucleotide sequence, wherein the vector comprises either:
i) one expression cassette, wherein
ia) a promotor is operably linked to either the first or the second nucleotide sequence, and wherein the nucleotide sequence to which the promotor is linked to the other of the first and second nucleotide sequence via a translation initiating nucleotide sequence, such as an internal ribosome entry site (IRES); or
ib) a promotor is operably linked to either the first or the second nucleotide sequence and wherein the nucleotide sequence to which the promotor is linked to the other of the first and the second nucleotide sequence via a 2A peptide; or
ii) two expression cassettes, wherein one expression cassette comprises the first nucleotide sequence and a first promoter sequence operably linked to first nucleotide sequence, and the other expression cassette comprises the second nucleotide and a second promoter sequence operably linked to the second nucleotide sequence; or iii) a fusion polypeptide of the first nucleotide sequence and the second nucleotide sequence. 7-13. (canceled) 14. A method of treating a disease or condition associated with a reduced dopamine level comprising administering a gene expression system and a ligand binding to a destabilizing domain (DD) to a patient in need thereof, wherein said gene expression system comprises:
a first nucleotide sequence encoding a fusion polypeptide of:
a) a DD, and
b) a GTPcyclohydrolase 1 (GCH1) polypeptide, or a biologically active fragment or variant thereof; and
a second nucleotide sequence encoding a tyrosine hydroxylase (TH) polypeptide, or a biologically active fragment or variant thereof. 15. A method of treating a disease or condition associated with a reduced dopamine level in a patient that previously has been subject to gene therapy using a ligand binding to a destabilizing domain (DD), whereby a gene expression system comprising:
a first nucleotide sequence encoding a fusion polypeptide of:
a) a DD, and
b) a GTPcyclohydrolase 1 (GCH1) polypeptide, or a biologically active fragment or variant thereof; and
a second nucleotide sequence encoding a tyrosine hydroxylase (TH) polypeptide, or a biologically active fragment or variant thereof, has been administered to the brain of the patient. 16. The method of claim 15, wherein the treatment involved controlling the DOPA synthesis in the brain of the patient. 17. The method of claim 14, wherein said gene expression system comprises two vectors each containing one expression cassette, wherein:
the expression cassette in the first vector comprises the first nucleotide sequence and a first promoter sequence operably linked to the first nucleotide sequence, and the expression cassette in the second vector comprises the second nucleotide and a second promoter sequence operably linked to the second nucleotide sequence. 18. The method of claim 15, wherein said gene expression system comprises two vectors each containing one expression cassette, wherein:
the expression cassette in the first vector comprises the first nucleotide sequence and a first promoter sequence operably linked to the first nucleotide sequence, and the expression cassette in the second vector comprises the second nucleotide and a second promoter sequence operably linked to the second nucleotide sequence. 19. The method of claim 14, wherein said gene expression system comprises one vector comprising both the first nucleotide sequence and the second nucleotide sequence, wherein the vector comprises either:
i) one expression cassette, wherein
ia) a promotor is operably linked to either the first or the second nucleotide sequence, and wherein the nucleotide sequence to which the promotor is linked to the other of the first and second nucleotide sequence via a translation initiating nucleotide sequence, such as an internal ribosome entry site (IRES); or
ib) a promotor is operably linked to either the first or the second nucleotide sequence and wherein the nucleotide sequence to which the promotor is linked to the other of the first and the second nucleotide sequence via a 2A peptide; or
ii) two expression cassettes, wherein one expression cassette comprises the first nucleotide sequence and a first promoter sequence operably linked to first nucleotide sequence, and the other expression cassette comprises the second nucleotide and a second promoter sequence operably linked to the second nucleotide sequence; or iii) a fusion polypeptide of the first nucleotide sequence and the second nucleotide sequence. 20. The method of claim 15, wherein said gene expression system comprises one vector comprising both the first nucleotide sequence and the second nucleotide sequence, wherein the vector comprises either:
i) one expression cassette, wherein
ia) a promotor is operably linked to either the first or the second nucleotide sequence, and wherein the nucleotide sequence to which the promotor is linked to the other of the first and second nucleotide sequence via a translation initiating nucleotide sequence, such as an internal ribosome entry site (IRES); or
ib) a promotor is operably linked to either the first or the second nucleotide sequence and wherein the nucleotide sequence to which the promotor is linked to the other of the first and the second nucleotide sequence via a 2A peptide; or
ii) two expression cassettes, wherein one expression cassette comprises the first nucleotide sequence and a first promoter sequence operably linked to first nucleotide sequence, and the other expression cassette comprises the second nucleotide and a second promoter sequence operably linked to the second nucleotide sequence; or iii) a fusion polypeptide of the first nucleotide sequence and the second nucleotide sequence. 21. The method of claim 14, wherein said ligand binding to a DD is trimethoprim (TMP) or an analogue or derivative thereof. 22. The method of claim 15, wherein said ligand binding to a DD is trimethoprim (TMP) or an analogue or derivative thereof. 23. The method of claim 17, wherein said ligand binding to a DD is trimethoprim (TMP) or an analogue or derivative thereof. 24. The method of claim 18, wherein said ligand binding to a DD is trimethoprim (TMP) or an analogue or derivative thereof. 25. The method of claim 19, wherein said ligand binding to a DD is trimethoprim (TMP) or an analogue or derivative thereof. 26. The method of claim 20, wherein said ligand binding to a DD is trimethoprim (TMP) or an analogue or derivative thereof. 27. The method of claim 14, wherein said disease or condition is selected from the group consisting of idiopathic or genetic forms of Parkinson's disease, Parkinsonism and related disorders, schizophrenia, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, and restless legs syndrome (RLS). 28. The method of claim 15, wherein said disease or condition is selected from the group consisting of idiopathic or genetic forms of Parkinson's disease, Parkinsonism and related disorders, schizophrenia, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, and restless legs syndrome (RLS). 29. The method of claim 17, wherein said disease or condition is selected from the group consisting of idiopathic or genetic forms of Parkinson's disease, Parkinsonism and related disorders, schizophrenia, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, and restless legs syndrome (RLS). 30. The method of claim 18, wherein said disease or condition is selected from the group consisting of idiopathic or genetic forms of Parkinson's disease, Parkinsonism and related disorders, schizophrenia, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, and restless legs syndrome (RLS). 31. The method of claim 19, wherein said disease or condition is selected from the group consisting of idiopathic or genetic forms of Parkinson's disease, Parkinsonism and related disorders, schizophrenia, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, and restless legs syndrome (RLS). 32. The method of claim 20, wherein said disease or condition is selected from the group consisting of idiopathic or genetic forms of Parkinson's disease, Parkinsonism and related disorders, schizophrenia, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, and restless legs syndrome (RLS). 33. A gene expression system according to claim 1, wherein the destabilizing domain (DD) is based on DHFR. 34-35. (canceled)
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The present invention relates to a novel gene expression system comprising: a) a first nucleotide sequence encoding a fusion polypeptide of: a1) a destabilizing domain (DD) based on DHFR, and a2) a GTPcyclohydrolase 1 (GCH1) polypeptide, or a biologically active fragment or variant thereof; and b) a second nucleotide sequence encoding a tyrosine hydroxylase (TH) polypeptide, or a biologically active fragment or variant thereof. The invention also relates to use of this gene expression system together with a ligand binding to a destabilizing domain (DD) based on dihydrofolate reductase (DHFR) for treatment of diseases associated with a reduced dopamine level, such as Parkinson's disease.1. A gene expression system comprising:
a first nucleotide sequence encoding a fusion polypeptide of:
a) a destabilizing domain (DD), and
b) a GTPcyclohydrolase 1 (GCH1) polypeptide, or a biologically active fragment or variant thereof; and
a second nucleotide sequence encoding a tyrosine hydroxylase (TH) polypeptide, or a biologically active fragment or variant thereof. 2-4. (canceled) 5. A gene expression system according to claim 1, wherein said gene expression system comprises two vectors each containing one expression cassette, wherein:
the expression cassette in the first vector comprises the first nucleotide sequence and a first promoter sequence operably linked to the first nucleotide sequence, and the expression cassette in the second vector comprises the second nucleotide and a second promoter sequence operably linked to the second nucleotide sequence. 6. A gene expression system according to claim 1, wherein said gene expression system comprises one vector comprising both the first nucleotide sequence and the second nucleotide sequence, wherein the vector comprises either:
i) one expression cassette, wherein
ia) a promotor is operably linked to either the first or the second nucleotide sequence, and wherein the nucleotide sequence to which the promotor is linked to the other of the first and second nucleotide sequence via a translation initiating nucleotide sequence, such as an internal ribosome entry site (IRES); or
ib) a promotor is operably linked to either the first or the second nucleotide sequence and wherein the nucleotide sequence to which the promotor is linked to the other of the first and the second nucleotide sequence via a 2A peptide; or
ii) two expression cassettes, wherein one expression cassette comprises the first nucleotide sequence and a first promoter sequence operably linked to first nucleotide sequence, and the other expression cassette comprises the second nucleotide and a second promoter sequence operably linked to the second nucleotide sequence; or iii) a fusion polypeptide of the first nucleotide sequence and the second nucleotide sequence. 7-13. (canceled) 14. A method of treating a disease or condition associated with a reduced dopamine level comprising administering a gene expression system and a ligand binding to a destabilizing domain (DD) to a patient in need thereof, wherein said gene expression system comprises:
a first nucleotide sequence encoding a fusion polypeptide of:
a) a DD, and
b) a GTPcyclohydrolase 1 (GCH1) polypeptide, or a biologically active fragment or variant thereof; and
a second nucleotide sequence encoding a tyrosine hydroxylase (TH) polypeptide, or a biologically active fragment or variant thereof. 15. A method of treating a disease or condition associated with a reduced dopamine level in a patient that previously has been subject to gene therapy using a ligand binding to a destabilizing domain (DD), whereby a gene expression system comprising:
a first nucleotide sequence encoding a fusion polypeptide of:
a) a DD, and
b) a GTPcyclohydrolase 1 (GCH1) polypeptide, or a biologically active fragment or variant thereof; and
a second nucleotide sequence encoding a tyrosine hydroxylase (TH) polypeptide, or a biologically active fragment or variant thereof, has been administered to the brain of the patient. 16. The method of claim 15, wherein the treatment involved controlling the DOPA synthesis in the brain of the patient. 17. The method of claim 14, wherein said gene expression system comprises two vectors each containing one expression cassette, wherein:
the expression cassette in the first vector comprises the first nucleotide sequence and a first promoter sequence operably linked to the first nucleotide sequence, and the expression cassette in the second vector comprises the second nucleotide and a second promoter sequence operably linked to the second nucleotide sequence. 18. The method of claim 15, wherein said gene expression system comprises two vectors each containing one expression cassette, wherein:
the expression cassette in the first vector comprises the first nucleotide sequence and a first promoter sequence operably linked to the first nucleotide sequence, and the expression cassette in the second vector comprises the second nucleotide and a second promoter sequence operably linked to the second nucleotide sequence. 19. The method of claim 14, wherein said gene expression system comprises one vector comprising both the first nucleotide sequence and the second nucleotide sequence, wherein the vector comprises either:
i) one expression cassette, wherein
ia) a promotor is operably linked to either the first or the second nucleotide sequence, and wherein the nucleotide sequence to which the promotor is linked to the other of the first and second nucleotide sequence via a translation initiating nucleotide sequence, such as an internal ribosome entry site (IRES); or
ib) a promotor is operably linked to either the first or the second nucleotide sequence and wherein the nucleotide sequence to which the promotor is linked to the other of the first and the second nucleotide sequence via a 2A peptide; or
ii) two expression cassettes, wherein one expression cassette comprises the first nucleotide sequence and a first promoter sequence operably linked to first nucleotide sequence, and the other expression cassette comprises the second nucleotide and a second promoter sequence operably linked to the second nucleotide sequence; or iii) a fusion polypeptide of the first nucleotide sequence and the second nucleotide sequence. 20. The method of claim 15, wherein said gene expression system comprises one vector comprising both the first nucleotide sequence and the second nucleotide sequence, wherein the vector comprises either:
i) one expression cassette, wherein
ia) a promotor is operably linked to either the first or the second nucleotide sequence, and wherein the nucleotide sequence to which the promotor is linked to the other of the first and second nucleotide sequence via a translation initiating nucleotide sequence, such as an internal ribosome entry site (IRES); or
ib) a promotor is operably linked to either the first or the second nucleotide sequence and wherein the nucleotide sequence to which the promotor is linked to the other of the first and the second nucleotide sequence via a 2A peptide; or
ii) two expression cassettes, wherein one expression cassette comprises the first nucleotide sequence and a first promoter sequence operably linked to first nucleotide sequence, and the other expression cassette comprises the second nucleotide and a second promoter sequence operably linked to the second nucleotide sequence; or iii) a fusion polypeptide of the first nucleotide sequence and the second nucleotide sequence. 21. The method of claim 14, wherein said ligand binding to a DD is trimethoprim (TMP) or an analogue or derivative thereof. 22. The method of claim 15, wherein said ligand binding to a DD is trimethoprim (TMP) or an analogue or derivative thereof. 23. The method of claim 17, wherein said ligand binding to a DD is trimethoprim (TMP) or an analogue or derivative thereof. 24. The method of claim 18, wherein said ligand binding to a DD is trimethoprim (TMP) or an analogue or derivative thereof. 25. The method of claim 19, wherein said ligand binding to a DD is trimethoprim (TMP) or an analogue or derivative thereof. 26. The method of claim 20, wherein said ligand binding to a DD is trimethoprim (TMP) or an analogue or derivative thereof. 27. The method of claim 14, wherein said disease or condition is selected from the group consisting of idiopathic or genetic forms of Parkinson's disease, Parkinsonism and related disorders, schizophrenia, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, and restless legs syndrome (RLS). 28. The method of claim 15, wherein said disease or condition is selected from the group consisting of idiopathic or genetic forms of Parkinson's disease, Parkinsonism and related disorders, schizophrenia, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, and restless legs syndrome (RLS). 29. The method of claim 17, wherein said disease or condition is selected from the group consisting of idiopathic or genetic forms of Parkinson's disease, Parkinsonism and related disorders, schizophrenia, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, and restless legs syndrome (RLS). 30. The method of claim 18, wherein said disease or condition is selected from the group consisting of idiopathic or genetic forms of Parkinson's disease, Parkinsonism and related disorders, schizophrenia, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, and restless legs syndrome (RLS). 31. The method of claim 19, wherein said disease or condition is selected from the group consisting of idiopathic or genetic forms of Parkinson's disease, Parkinsonism and related disorders, schizophrenia, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, and restless legs syndrome (RLS). 32. The method of claim 20, wherein said disease or condition is selected from the group consisting of idiopathic or genetic forms of Parkinson's disease, Parkinsonism and related disorders, schizophrenia, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, and restless legs syndrome (RLS). 33. A gene expression system according to claim 1, wherein the destabilizing domain (DD) is based on DHFR. 34-35. (canceled)
| 1,600 |
1,232 | 15,266,570 | 1,617 |
The present invention provides antimicrobial feed supplement compositions comprising clay, and methods of treating microbial infections in an animal using the antimicrobial compositions.
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1. A method for controlling microbes, the method comprising contacting the microbes with an antimicrobial effective amount of an antimicrobial clay, wherein the clay is mined clay. 2. The method of claim 1, wherein the antimicrobial clay is clay mined in the Crater Lake region of the Cascade Mountains of Oregon. 3. The method of claim 1, wherein the antimicrobial clay comprises an antimicrobial effective amount of a reducing agent. 4. The method of claim 1, wherein the antimicrobial clay comprises an antimicrobial effective amount of aluminum. 5. The method of claim 1, wherein the antimicrobial clay comprises about 1% to about 15% aluminum. 6. The method of claim 1, wherein the antimicrobial clay comprises about 2% to about 5% aluminum. 7. The method of claim 1, wherein the antimicrobial clay comprises about 3% to about 10% pyrite. 8. The method of claim 1, wherein the antimicrobial clay comprises about 1% to about 5% Fe3+. 9. The method of claim 1, wherein the antimicrobial clay comprises about 3% to about 10% pyrite, and about 1% to about 5% Fe3+. 10. The method of claim 1, wherein the antimicrobial clay comprises about 3% to about 10% pyrite, about 1% to about 5% Fe3+, and about 3% to about 15% aluminum. 11. The method of claim 1, wherein the antimicrobial clay is naturally mined, and the level of reducing agent in the clay is adjusted to provide antimicrobial effective amounts of the reducing agent. 12. The method of claim 1, wherein the average particle size of the antimicrobial clay is less than about 500 microns in diameter. 13. The method of claim 1, wherein the average particle size of the antimicrobial clay is less than about 300 microns in diameter. 14. The method of claim 1, wherein the average particle size of the antimicrobial clay is between about 20 microns and about 200 microns in diameter. 15. The method of claim 1, wherein the average particle size of the antimicrobial clay is between about 25 microns and about 150 microns in diameter. 16. The method of claim 1, further comprising administering the antimicrobial clay to an animal to inhibit the growth of bacteria in the animal. 17. The method of claim 16, wherein the bacteria are selected from the group consisting of Clostridium perfringens, Aeromonas hydrophila, Yersinia enterocolitica, Vibrio spp., Leptospira spp., Mycobacterium ulcerans, Listeria spp., pathogenic strains of E. coli, Pseudomonas spp., Staphylococcus spp., Streptococcus sp., Clostridia, and M. marinum, Lawsonia, Salmonella, Campylobacter, Enterococcus, Liver abscess bacteria. 18. The method of claim 16, wherein the administering is oral administration. 19. The method of claim 19, wherein the antimicrobial clay is formulated in a feed composition for oral administration to the animal. 20. The method of claim 20, wherein the amount of antimicrobial clay in a feed composition ranges from about 0.1% to about 0.5% of the feed composition. 21. The method of claim 1, wherein the antimicrobial clay is administered to an animal at a rate of about 3 to about 10 grams per animal per day. 22. The method of claim 1, wherein the antimicrobial clay is administered to an animal at a rate of about 0.3 to about 4 grams per animal per day. 23. The method of claim 1, wherein the antimicrobial clay is administered to an animal at a rate of about 0.05 to about 5 grams/lb body weight/day. 24. The method of claim 1, wherein the antimicrobial clay is administered to an animal at a rate of about 0.025 to about 0.2 grams/lb body weight/day. 25. The method of claim 17, wherein the antimicrobial clay is administered to a pig to control enterotoxigenic E. coli in the pig. 26. The method of claim 17, wherein the antimicrobial clay is administered to a chicken to control necrotic enteritis in the chicken. 27. The method of claim 17, wherein the antimicrobial clay is administered to a pig to control influenza in the pig. 28. The method of claim 17, wherein the antimicrobial clay is administered to a pig to control scouring in the pig. 29. The method of claim 1, the method comprising administering the antimicrobial clay to an animal to improve growth performance of the animal. 30. The method of claim 17, wherein the antimicrobial clay is administered at least once daily. 31. The method of claim 1, the method comprising contacting an animal's environment with the antimicrobial clay to control pathogenic microbes in the animal's environment. 32. The method of claim 1, the method comprising contacting a fermenting mixture with the antimicrobial clay to control bacteria during fermentation. 33. A method for treating a microbial infection in an animal, the method comprising administering a feed composition to the animal, wherein the composition comprises an antimicrobial effective amount of a mined antimicrobial clay, and wherein the clay is mined in the Crater Lake region of the Cascade Mountains of Oregon. 34. The method of claim 34, wherein the amount of antimicrobial clay in a feed composition ranges from about 0.1% to about 0.5%. 35. The method of claim 34, wherein the composition is administered at least once daily. 36. The method of claim 34, wherein the microbial infection is selected from enterotoxigenic E. coli in the pig, necrotic enteritis in the chicken, influenza in the pig, or scouring in the pig. 37. A method of improving growth performance of an animal, the method comprising orally administering a feed composition to the animal, wherein the composition comprises an antimicrobial effective amount of an antimicrobial clay, and wherein the clay is mined in the Crater Lake region of the Cascade Mountains of Oregon. 38. The method of claim 38, wherein the amount of antimicrobial clay in the feed composition ranges from about 0.1% to about 0.5%. 39. The method of claim 38, wherein the composition is administered at least once daily. 40. A method of controlling pathogenic microbes in an animal's environment, the method comprising contacting the animal's environment with an antimicrobial effective amount of an antimicrobial clay, wherein the clay is mined in the Crater Lake region of the Cascade Mountains of Oregon. 41. A method for controlling bacteria during fermentation, the method comprising contacting a fermentation mixture with an antimicrobial effective amount of an antimicrobial clay, wherein the clay is mined in the Crater Lake region of the Cascade Mountains of Oregon. 42. An antimicrobial feed composition comprising an antimicrobial effective amount of an antimicrobial clay, wherein the clay is mined clay. 43. The composition of claim 42, wherein the antimicrobial clay is clay mined in the Crater Lake region of the Cascade Mountains of Oregon. 44. The composition of claim 42, wherein the amount of antimicrobial clay in a feed composition ranges from about 0.1% to about 0.5%. 45. The composition of claim 42, wherein the antimicrobial clay comprises about 1% to about 15% aluminum. 46. The composition of claim 42, wherein the antimicrobial clay comprises about 2% to about 5% aluminum. 47. The composition of claim 42, wherein the antimicrobial clay comprises about 3% to about 10% pyrite. 48. The composition of claim 42, wherein the antimicrobial clay comprises about 1% to about 5% Fe3+. 49. The composition of claim 42, wherein the antimicrobial clay comprises about 3% to about 10% pyrite, and about 1% to about 5% Fe3+. 50. The composition of claim 42, wherein the antimicrobial clay comprises about 3% to about 10% pyrite, about 1% to about 5% Fe3+, and about 3% to about 15% aluminum. 51. A method of treating a microbial infection in an animal, the method comprising:
a. providing an antimicrobial clay, wherein the clay is mined clay; b. combining an antimicrobial effective amount of the antimicrobial clay with an animal feed composition to prepare an antimicrobial feed composition; and c. feeding the antimicrobial feed composition to the animal to treat the microbial infection. 52. The composition of claim 51, wherein the antimicrobial clay is clay mined in the Crater Lake region of the Cascade Mountains of Oregon. 53. The composition of claim 51, wherein the antimicrobial effective amount of antimicrobial clay is combined with the animal feed at the rate of about 0.1% to about 0.5% wt/wt of the antimicrobial feed composition. 54. The composition of claim 51, wherein the antimicrobial clay comprises about 3% to about 10% pyrite, and about 1% to about 5% Fe3+. 55. The composition of claim 51, wherein the antimicrobial clay comprises about 3% to about 10% pyrite, about 1% to about 5% Fe3+, and about 3% to about 15% aluminum. 56. A method of improving growth performance of an animal, the method comprising:
a. providing an antimicrobial clay, wherein the clay is mined clay; b. combining an antimicrobial effective amount of the antimicrobial clay with an animal feed composition to prepare an antimicrobial feed composition; and c. feeding the antimicrobial feed composition to the animal to improve growth performance of the animal. 57. The composition of claim 56, wherein the antimicrobial clay is clay mined in the Crater Lake region of the Cascade Mountains of Oregon. 58. The composition of claim 56, wherein the antimicrobial effective amount of antimicrobial clay is combined with the animal feed at the rate of about 0.1% to about 0.5% wt/wt of the antimicrobial feed composition. 59. The composition of claim 56, wherein the antimicrobial clay comprises about 3% to about 10% pyrite, and about 1% to about 5% Fe3+. 60. The composition of claim 56, wherein the antimicrobial clay comprises about 3% to about 10% pyrite, about 1% to about 5% Fe3+, and about 3% to about 15% aluminum. 61. The method of claim 53, wherein the antimicrobial feed composition is fed to the animal at least once daily.
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The present invention provides antimicrobial feed supplement compositions comprising clay, and methods of treating microbial infections in an animal using the antimicrobial compositions.1. A method for controlling microbes, the method comprising contacting the microbes with an antimicrobial effective amount of an antimicrobial clay, wherein the clay is mined clay. 2. The method of claim 1, wherein the antimicrobial clay is clay mined in the Crater Lake region of the Cascade Mountains of Oregon. 3. The method of claim 1, wherein the antimicrobial clay comprises an antimicrobial effective amount of a reducing agent. 4. The method of claim 1, wherein the antimicrobial clay comprises an antimicrobial effective amount of aluminum. 5. The method of claim 1, wherein the antimicrobial clay comprises about 1% to about 15% aluminum. 6. The method of claim 1, wherein the antimicrobial clay comprises about 2% to about 5% aluminum. 7. The method of claim 1, wherein the antimicrobial clay comprises about 3% to about 10% pyrite. 8. The method of claim 1, wherein the antimicrobial clay comprises about 1% to about 5% Fe3+. 9. The method of claim 1, wherein the antimicrobial clay comprises about 3% to about 10% pyrite, and about 1% to about 5% Fe3+. 10. The method of claim 1, wherein the antimicrobial clay comprises about 3% to about 10% pyrite, about 1% to about 5% Fe3+, and about 3% to about 15% aluminum. 11. The method of claim 1, wherein the antimicrobial clay is naturally mined, and the level of reducing agent in the clay is adjusted to provide antimicrobial effective amounts of the reducing agent. 12. The method of claim 1, wherein the average particle size of the antimicrobial clay is less than about 500 microns in diameter. 13. The method of claim 1, wherein the average particle size of the antimicrobial clay is less than about 300 microns in diameter. 14. The method of claim 1, wherein the average particle size of the antimicrobial clay is between about 20 microns and about 200 microns in diameter. 15. The method of claim 1, wherein the average particle size of the antimicrobial clay is between about 25 microns and about 150 microns in diameter. 16. The method of claim 1, further comprising administering the antimicrobial clay to an animal to inhibit the growth of bacteria in the animal. 17. The method of claim 16, wherein the bacteria are selected from the group consisting of Clostridium perfringens, Aeromonas hydrophila, Yersinia enterocolitica, Vibrio spp., Leptospira spp., Mycobacterium ulcerans, Listeria spp., pathogenic strains of E. coli, Pseudomonas spp., Staphylococcus spp., Streptococcus sp., Clostridia, and M. marinum, Lawsonia, Salmonella, Campylobacter, Enterococcus, Liver abscess bacteria. 18. The method of claim 16, wherein the administering is oral administration. 19. The method of claim 19, wherein the antimicrobial clay is formulated in a feed composition for oral administration to the animal. 20. The method of claim 20, wherein the amount of antimicrobial clay in a feed composition ranges from about 0.1% to about 0.5% of the feed composition. 21. The method of claim 1, wherein the antimicrobial clay is administered to an animal at a rate of about 3 to about 10 grams per animal per day. 22. The method of claim 1, wherein the antimicrobial clay is administered to an animal at a rate of about 0.3 to about 4 grams per animal per day. 23. The method of claim 1, wherein the antimicrobial clay is administered to an animal at a rate of about 0.05 to about 5 grams/lb body weight/day. 24. The method of claim 1, wherein the antimicrobial clay is administered to an animal at a rate of about 0.025 to about 0.2 grams/lb body weight/day. 25. The method of claim 17, wherein the antimicrobial clay is administered to a pig to control enterotoxigenic E. coli in the pig. 26. The method of claim 17, wherein the antimicrobial clay is administered to a chicken to control necrotic enteritis in the chicken. 27. The method of claim 17, wherein the antimicrobial clay is administered to a pig to control influenza in the pig. 28. The method of claim 17, wherein the antimicrobial clay is administered to a pig to control scouring in the pig. 29. The method of claim 1, the method comprising administering the antimicrobial clay to an animal to improve growth performance of the animal. 30. The method of claim 17, wherein the antimicrobial clay is administered at least once daily. 31. The method of claim 1, the method comprising contacting an animal's environment with the antimicrobial clay to control pathogenic microbes in the animal's environment. 32. The method of claim 1, the method comprising contacting a fermenting mixture with the antimicrobial clay to control bacteria during fermentation. 33. A method for treating a microbial infection in an animal, the method comprising administering a feed composition to the animal, wherein the composition comprises an antimicrobial effective amount of a mined antimicrobial clay, and wherein the clay is mined in the Crater Lake region of the Cascade Mountains of Oregon. 34. The method of claim 34, wherein the amount of antimicrobial clay in a feed composition ranges from about 0.1% to about 0.5%. 35. The method of claim 34, wherein the composition is administered at least once daily. 36. The method of claim 34, wherein the microbial infection is selected from enterotoxigenic E. coli in the pig, necrotic enteritis in the chicken, influenza in the pig, or scouring in the pig. 37. A method of improving growth performance of an animal, the method comprising orally administering a feed composition to the animal, wherein the composition comprises an antimicrobial effective amount of an antimicrobial clay, and wherein the clay is mined in the Crater Lake region of the Cascade Mountains of Oregon. 38. The method of claim 38, wherein the amount of antimicrobial clay in the feed composition ranges from about 0.1% to about 0.5%. 39. The method of claim 38, wherein the composition is administered at least once daily. 40. A method of controlling pathogenic microbes in an animal's environment, the method comprising contacting the animal's environment with an antimicrobial effective amount of an antimicrobial clay, wherein the clay is mined in the Crater Lake region of the Cascade Mountains of Oregon. 41. A method for controlling bacteria during fermentation, the method comprising contacting a fermentation mixture with an antimicrobial effective amount of an antimicrobial clay, wherein the clay is mined in the Crater Lake region of the Cascade Mountains of Oregon. 42. An antimicrobial feed composition comprising an antimicrobial effective amount of an antimicrobial clay, wherein the clay is mined clay. 43. The composition of claim 42, wherein the antimicrobial clay is clay mined in the Crater Lake region of the Cascade Mountains of Oregon. 44. The composition of claim 42, wherein the amount of antimicrobial clay in a feed composition ranges from about 0.1% to about 0.5%. 45. The composition of claim 42, wherein the antimicrobial clay comprises about 1% to about 15% aluminum. 46. The composition of claim 42, wherein the antimicrobial clay comprises about 2% to about 5% aluminum. 47. The composition of claim 42, wherein the antimicrobial clay comprises about 3% to about 10% pyrite. 48. The composition of claim 42, wherein the antimicrobial clay comprises about 1% to about 5% Fe3+. 49. The composition of claim 42, wherein the antimicrobial clay comprises about 3% to about 10% pyrite, and about 1% to about 5% Fe3+. 50. The composition of claim 42, wherein the antimicrobial clay comprises about 3% to about 10% pyrite, about 1% to about 5% Fe3+, and about 3% to about 15% aluminum. 51. A method of treating a microbial infection in an animal, the method comprising:
a. providing an antimicrobial clay, wherein the clay is mined clay; b. combining an antimicrobial effective amount of the antimicrobial clay with an animal feed composition to prepare an antimicrobial feed composition; and c. feeding the antimicrobial feed composition to the animal to treat the microbial infection. 52. The composition of claim 51, wherein the antimicrobial clay is clay mined in the Crater Lake region of the Cascade Mountains of Oregon. 53. The composition of claim 51, wherein the antimicrobial effective amount of antimicrobial clay is combined with the animal feed at the rate of about 0.1% to about 0.5% wt/wt of the antimicrobial feed composition. 54. The composition of claim 51, wherein the antimicrobial clay comprises about 3% to about 10% pyrite, and about 1% to about 5% Fe3+. 55. The composition of claim 51, wherein the antimicrobial clay comprises about 3% to about 10% pyrite, about 1% to about 5% Fe3+, and about 3% to about 15% aluminum. 56. A method of improving growth performance of an animal, the method comprising:
a. providing an antimicrobial clay, wherein the clay is mined clay; b. combining an antimicrobial effective amount of the antimicrobial clay with an animal feed composition to prepare an antimicrobial feed composition; and c. feeding the antimicrobial feed composition to the animal to improve growth performance of the animal. 57. The composition of claim 56, wherein the antimicrobial clay is clay mined in the Crater Lake region of the Cascade Mountains of Oregon. 58. The composition of claim 56, wherein the antimicrobial effective amount of antimicrobial clay is combined with the animal feed at the rate of about 0.1% to about 0.5% wt/wt of the antimicrobial feed composition. 59. The composition of claim 56, wherein the antimicrobial clay comprises about 3% to about 10% pyrite, and about 1% to about 5% Fe3+. 60. The composition of claim 56, wherein the antimicrobial clay comprises about 3% to about 10% pyrite, about 1% to about 5% Fe3+, and about 3% to about 15% aluminum. 61. The method of claim 53, wherein the antimicrobial feed composition is fed to the animal at least once daily.
| 1,600 |
1,233 | 14,187,997 | 1,618 |
Novel pharmaceutical compositions of mometasone or a pharmaceutically acceptable derivate thereof in the form of an oil-in-water emulsion, notably a cream. The composition has excellent stability and therapeutic effect. The compositions contain mometasone in micronised form, propylene glycol and water and the weight ratio between the propylene glycol and water contained in the oil-in-water emulsion is from 1:1 to about 1:3.
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1-29. (canceled) 30. An oil-in-water emulsion comprising mometasone or a pharmaceutically acceptable derivative thereof and propylene glycol, wherein the concentration of propylene glycol is from about 20 to about 45% w/w. 31. The oil-in-water emulsion according to claim 30, wherein the concentration of propylene glycol is from about 20 to about 40% w/w. 32. The oil-in-water emulsion according to claim 30, wherein the concentration of propylene glycol is from about 20 to about 30% w/w. 33. The oil-in-water emulsion according to claim 30, wherein the weight ratio of propylene glycol to water in the oil-in-water emulsion is from about 1:1 to about 1:3. 34. The oil-in-water emulsion according to claim 30, wherein the weight ratio of propylene glycol to water in the oil-in-water emulsion is from about 1:1.5 to about 1:2.5. 35. The oil-in-water emulsion according to claim 30, wherein the mometasone or pharmaceutically acceptable derivative thereof is the sole therapeutically active ingredient. 36. The oil-in-water emulsion according to claim 30, wherein a portion of the mometasone or pharmaceutically acceptable derivative thereof is present in undissolved form. 37. The oil-in-water emulsion according to claim 30, wherein the mometasone or pharmaceutically acceptable derivative thereof is present in the emulsion in micronized form. 38. The oil-in-water emulsion according to claim 30, wherein the oil phase comprises an oil selected from the group consisting of vegetable oils, animal oils, mineral oils, ester oils, and silicon oils. 39. The oil-in-water emulsion according to claim 38, wherein the oil is a vegetable oil. 40. The oil-in-water emulsion according to claim 39, wherein the vegetable oil is selected from the group consisting of coconut oil, olive oil, sunflower oil, canola oil, and mixtures thereof. 41. The oil-in-water emulsion according to claim 38, wherein the concentration of the oil in the oil-in-water emulsion is from about 3 to about 30% w/w. 42. The oil-in-water emulsion according to claim 30, further comprising one or more emulsifying agents. 43. The oil-in-water emulsion according to claim 42, comprising one or more emulsifying agents having a hydrophilic-lipophilic balance (HLB) in the range of 3-20. 44. The oil-in-water emulsion according to claim 43, comprising one or more emulsifying agents with a HLB of from about 11 to about 20. 45. The oil-in-water emulsion according to claim 43, comprising one or more emulsifying agents with a HLB of from about 3 to about 11. 46. The oil-in-water emulsion according to claim 42, wherein the one or more emulsifying agents are selected from the group consisting of glycerol alkyl esters, macrogol alkyl esters, polyoxyethyleneglycol alkyl esters, fatty acids, polyoxyethylene sorbitan esters, polyoxyethylene alkyl ethers, and galactolipids. 47. The oil-in-water emulsion according to claim 42, wherein the one or more emulsifying agents are selected from the group consisting of glycerol monostearate 40-55, macrogol stearate, and stearic acid. 48. The oil-in-water emulsion according to claim 42, wherein the concentration of each emulsifier in the emulsion ranges from 1-5% w/w. 49. The oil-in-water emulsion according to claim 30, further comprising a viscosity-increasing agent. 50. The oil-in-water emulsion according to claim 49, wherein the viscosity-increasing agent is a fatty alcohol. 51. The oil-in-water emulsion according to claim 49, wherein the viscosity-increasing agent is cetostearyl alcohol. 52. The oil-in-water emulsion according to claim 30, containing: 0.05-0.2% w/w of mometasone or a pharmaceutically acceptable derivative thereof (calculated as mometasone furoate); 20-45% w/w of propylene glycol; 3-30% w/w of a vegetable oil; 1-15% w/w of one or more emulsifying agents; optionally, 0.1-1% w/w of a pH adjusting agent; optionally, 5-15% w/w viscosity increasing agent; and water to constitute 100% w/w. 53. The oil-in-water emulsion of claim 30 containing about 0.01% to about 2% w/w of mometasone or a pharmaceutically acceptable derivative thereof. 54. The oil-in-water emulsion of claim 30 containing 0.06% to 0.15% of mometasone or a pharmaceutically acceptable derivative thereof. 55. The oil-in-water emulsion according to claim 30, wherein the emulsion does not contain N-methyl-2-pyrrolidone. 56. The oil-in-water emulsion according to claim 30, wherein the emulsion does not contain any preservative other than propylene glycol. 57. The oil-in-water emulsion according to claim 37, wherein the micronized mometasone or pharmaceutically acceptable derivative thereof has a particle size distribution such that 100% of the particles have a particle size ≦20 μm, 99% have a particle size <15 μm, and 80% have a particle size ≦5 μM. 58. The oil-in-water emulsion of claim 30, comprising a pharmaceutically acceptable ester derivative of mometasone. 59. The oil-in-water emulsion of claim 30, wherein the mometasone is mometasone furoate.
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Novel pharmaceutical compositions of mometasone or a pharmaceutically acceptable derivate thereof in the form of an oil-in-water emulsion, notably a cream. The composition has excellent stability and therapeutic effect. The compositions contain mometasone in micronised form, propylene glycol and water and the weight ratio between the propylene glycol and water contained in the oil-in-water emulsion is from 1:1 to about 1:3.1-29. (canceled) 30. An oil-in-water emulsion comprising mometasone or a pharmaceutically acceptable derivative thereof and propylene glycol, wherein the concentration of propylene glycol is from about 20 to about 45% w/w. 31. The oil-in-water emulsion according to claim 30, wherein the concentration of propylene glycol is from about 20 to about 40% w/w. 32. The oil-in-water emulsion according to claim 30, wherein the concentration of propylene glycol is from about 20 to about 30% w/w. 33. The oil-in-water emulsion according to claim 30, wherein the weight ratio of propylene glycol to water in the oil-in-water emulsion is from about 1:1 to about 1:3. 34. The oil-in-water emulsion according to claim 30, wherein the weight ratio of propylene glycol to water in the oil-in-water emulsion is from about 1:1.5 to about 1:2.5. 35. The oil-in-water emulsion according to claim 30, wherein the mometasone or pharmaceutically acceptable derivative thereof is the sole therapeutically active ingredient. 36. The oil-in-water emulsion according to claim 30, wherein a portion of the mometasone or pharmaceutically acceptable derivative thereof is present in undissolved form. 37. The oil-in-water emulsion according to claim 30, wherein the mometasone or pharmaceutically acceptable derivative thereof is present in the emulsion in micronized form. 38. The oil-in-water emulsion according to claim 30, wherein the oil phase comprises an oil selected from the group consisting of vegetable oils, animal oils, mineral oils, ester oils, and silicon oils. 39. The oil-in-water emulsion according to claim 38, wherein the oil is a vegetable oil. 40. The oil-in-water emulsion according to claim 39, wherein the vegetable oil is selected from the group consisting of coconut oil, olive oil, sunflower oil, canola oil, and mixtures thereof. 41. The oil-in-water emulsion according to claim 38, wherein the concentration of the oil in the oil-in-water emulsion is from about 3 to about 30% w/w. 42. The oil-in-water emulsion according to claim 30, further comprising one or more emulsifying agents. 43. The oil-in-water emulsion according to claim 42, comprising one or more emulsifying agents having a hydrophilic-lipophilic balance (HLB) in the range of 3-20. 44. The oil-in-water emulsion according to claim 43, comprising one or more emulsifying agents with a HLB of from about 11 to about 20. 45. The oil-in-water emulsion according to claim 43, comprising one or more emulsifying agents with a HLB of from about 3 to about 11. 46. The oil-in-water emulsion according to claim 42, wherein the one or more emulsifying agents are selected from the group consisting of glycerol alkyl esters, macrogol alkyl esters, polyoxyethyleneglycol alkyl esters, fatty acids, polyoxyethylene sorbitan esters, polyoxyethylene alkyl ethers, and galactolipids. 47. The oil-in-water emulsion according to claim 42, wherein the one or more emulsifying agents are selected from the group consisting of glycerol monostearate 40-55, macrogol stearate, and stearic acid. 48. The oil-in-water emulsion according to claim 42, wherein the concentration of each emulsifier in the emulsion ranges from 1-5% w/w. 49. The oil-in-water emulsion according to claim 30, further comprising a viscosity-increasing agent. 50. The oil-in-water emulsion according to claim 49, wherein the viscosity-increasing agent is a fatty alcohol. 51. The oil-in-water emulsion according to claim 49, wherein the viscosity-increasing agent is cetostearyl alcohol. 52. The oil-in-water emulsion according to claim 30, containing: 0.05-0.2% w/w of mometasone or a pharmaceutically acceptable derivative thereof (calculated as mometasone furoate); 20-45% w/w of propylene glycol; 3-30% w/w of a vegetable oil; 1-15% w/w of one or more emulsifying agents; optionally, 0.1-1% w/w of a pH adjusting agent; optionally, 5-15% w/w viscosity increasing agent; and water to constitute 100% w/w. 53. The oil-in-water emulsion of claim 30 containing about 0.01% to about 2% w/w of mometasone or a pharmaceutically acceptable derivative thereof. 54. The oil-in-water emulsion of claim 30 containing 0.06% to 0.15% of mometasone or a pharmaceutically acceptable derivative thereof. 55. The oil-in-water emulsion according to claim 30, wherein the emulsion does not contain N-methyl-2-pyrrolidone. 56. The oil-in-water emulsion according to claim 30, wherein the emulsion does not contain any preservative other than propylene glycol. 57. The oil-in-water emulsion according to claim 37, wherein the micronized mometasone or pharmaceutically acceptable derivative thereof has a particle size distribution such that 100% of the particles have a particle size ≦20 μm, 99% have a particle size <15 μm, and 80% have a particle size ≦5 μM. 58. The oil-in-water emulsion of claim 30, comprising a pharmaceutically acceptable ester derivative of mometasone. 59. The oil-in-water emulsion of claim 30, wherein the mometasone is mometasone furoate.
| 1,600 |
1,234 | 16,086,960 | 1,613 |
A cosmetic composition capable of forming a multilayer structure after application to a keratinous material, wherein the cosmetic composition comprises at least two immiscible components A and B, wherein the component A comprises at least one silicone and/or hydrocarbon-containing film-forming agent and wherein the component B comprises one or more silicone compounds.
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1: A cosmetic composition capable of forming a multilayer structure after application to a keratinous material, wherein the cosmetic composition comprises at least two immiscible components prior to application and wherein the at least two immiscible components are Component A and Component B. 2: A cosmetic composition capable of forming a multilayer structure after application to a keratinous material,
wherein the cosmetic composition comprises at least two immiscible components A and B: wherein component A comprises about 0.01% to 60% by weight with respect to the total weight of the composition of at least one silicone and/or hydrocarbon-containing film-forming agent having at least one glass transition temperature which is lower than 60° C.; and wherein component B comprises about 0.01% to 90% by weight with respect to the total weight of the composition of one or more silicone compounds in an amount sufficient to achieve a viscosity of about 1,000 cSt to 22,000,000 cSt; and wherein the weight ratio of silicone and/or hydrocarbon-containing film forming agent(s) in Component A to silicone compound(s) in Component B is from about 1:50 to 50:1. 3: The cosmetic composition according to claim 1, wherein the cosmetic composition comprises at least two immiscible components prior to application. 4: The cosmetic composition according to claim 1, further comprising at least one colorant. 5: The cosmetic composition according to claim 4, wherein the at least one colorant is an inorganic pigment. 6: The cosmetic composition according to claim 5, wherein the inorganic pigment is selected from the group consisting of iron oxide, titanium oxide, ultramarine blue, and combinations thereof. 7: The cosmetic composition according to claim 1, wherein the cosmetic composition is anhydrous. 8: The cosmetic composition according to claim 2, wherein the silicone compound comprises at least one compound selected from the group consisting of a silicone gum, a silicone fluid, and mixtures thereof. 9: The cosmetic composition according to claim 1, wherein the cosmetic composition further comprises a hydrocarbon-containing film-forming agent selected from the group consisting of polysaccharides, polybutenes, polyisobutenes, polyhydrogenated butenes, acrylic polymers, acrylate copolymers, vinyl pyrrolidone homopolymers, vinyl pyrrolidone copolymers, polyurethanes, polyolefins, and mixtures thereof. 10: The cosmetic composition according to claim 1, wherein the cosmetic composition comprises at least one film forming agent selected from the group consisting of silicone resins, silicone acrylate copolymers, and mixtures thereof. 11: A kit comprising: (a) the cosmetic composition according to claim 1; (b) at least one container which contains the cosmetic composition; and (c) at least one applicator. 12: The kit of claim 11, wherein the container is configured to mix Components A and B. 13: A method of applying the cosmetic composition according to claim 1 to a keratinous material comprising mixing the cosmetic composition to form a mixed composition in which Component A and Component B are temporarily miscible, and applying the mixed composition to the keratinous material.
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A cosmetic composition capable of forming a multilayer structure after application to a keratinous material, wherein the cosmetic composition comprises at least two immiscible components A and B, wherein the component A comprises at least one silicone and/or hydrocarbon-containing film-forming agent and wherein the component B comprises one or more silicone compounds.1: A cosmetic composition capable of forming a multilayer structure after application to a keratinous material, wherein the cosmetic composition comprises at least two immiscible components prior to application and wherein the at least two immiscible components are Component A and Component B. 2: A cosmetic composition capable of forming a multilayer structure after application to a keratinous material,
wherein the cosmetic composition comprises at least two immiscible components A and B: wherein component A comprises about 0.01% to 60% by weight with respect to the total weight of the composition of at least one silicone and/or hydrocarbon-containing film-forming agent having at least one glass transition temperature which is lower than 60° C.; and wherein component B comprises about 0.01% to 90% by weight with respect to the total weight of the composition of one or more silicone compounds in an amount sufficient to achieve a viscosity of about 1,000 cSt to 22,000,000 cSt; and wherein the weight ratio of silicone and/or hydrocarbon-containing film forming agent(s) in Component A to silicone compound(s) in Component B is from about 1:50 to 50:1. 3: The cosmetic composition according to claim 1, wherein the cosmetic composition comprises at least two immiscible components prior to application. 4: The cosmetic composition according to claim 1, further comprising at least one colorant. 5: The cosmetic composition according to claim 4, wherein the at least one colorant is an inorganic pigment. 6: The cosmetic composition according to claim 5, wherein the inorganic pigment is selected from the group consisting of iron oxide, titanium oxide, ultramarine blue, and combinations thereof. 7: The cosmetic composition according to claim 1, wherein the cosmetic composition is anhydrous. 8: The cosmetic composition according to claim 2, wherein the silicone compound comprises at least one compound selected from the group consisting of a silicone gum, a silicone fluid, and mixtures thereof. 9: The cosmetic composition according to claim 1, wherein the cosmetic composition further comprises a hydrocarbon-containing film-forming agent selected from the group consisting of polysaccharides, polybutenes, polyisobutenes, polyhydrogenated butenes, acrylic polymers, acrylate copolymers, vinyl pyrrolidone homopolymers, vinyl pyrrolidone copolymers, polyurethanes, polyolefins, and mixtures thereof. 10: The cosmetic composition according to claim 1, wherein the cosmetic composition comprises at least one film forming agent selected from the group consisting of silicone resins, silicone acrylate copolymers, and mixtures thereof. 11: A kit comprising: (a) the cosmetic composition according to claim 1; (b) at least one container which contains the cosmetic composition; and (c) at least one applicator. 12: The kit of claim 11, wherein the container is configured to mix Components A and B. 13: A method of applying the cosmetic composition according to claim 1 to a keratinous material comprising mixing the cosmetic composition to form a mixed composition in which Component A and Component B are temporarily miscible, and applying the mixed composition to the keratinous material.
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1,235 | 16,196,500 | 1,615 |
The present invention includes a pharmaceutical composition, and methods of making and using, a pharmaceutical composition comprising one or more thyroid hormone(s) or analogs thereof, wherein a first portion of thyroid hormone(s) is formulated for immediate release and a second portion of thyroid hormone(s) is formulated of modified release, e.g., by forming a drug-resin particle with an ion exchange resin.
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1. A mixed-release pharmaceutical composition effective to treat hypothyroidism comprising: (i) a first portion comprising one or more thyroid hormones is formulated for immediate release, and (ii) a second portion comprising one or more thyroid hormones is formulated for modified release that is greater than 10% by weight, wherein greater than 30%, 40%, 50%, 60%, 70%, or 80% by weight of the first portion of the one or more thyroid hormones is released within the first 45 minutes after the product is introduced into an in vitro dissolution assay, wherein the conditions of the dissolution assay are an initial dissolution medium of 0.1 N HCl, and after 2 hours, the medium is adjusted to a pH of about 6.8, and the dissolution assay is performed using a USP Apparatus 2. 2. The pharmaceutical composition of claim 1, wherein the composition is chewable. 3. The pharmaceutical composition of claim 1, wherein the composition comprises an immediate release portion of levothyroxine (T4) and liothyronine (T3) and a modified release portion of T4 and T3. 4. The composition of claim 1, wherein the composition has an in vivo fasted serum profile having a first and a second peak of the one or more thyroid hormones, wherein the first peak occurs within 3 hours after ingestion of the composition and the second peak occurs after 3 hours after ingestion of the composition. 5. The pharmaceutical composition of claim 1, wherein the composition comprises T4:T3 in a ratio of about 1:1 to about 20:1. 6. The pharmaceutical composition of claim 1, wherein the composition comprises a geometric blend of T4:T3 at a ratio of about 1:1 to about 20:1. 7. The pharmaceutical composition of claim 1, wherein the composition comprises modified release portion of T3:T4 in a ratio of about 1:1 to about 20:1, wherein the modified release portions comprises a multi-particulate formulation. 8. The pharmaceutical composition of claim 1, wherein the composition comprises a geometrically diluted multi-particulate pharmaceutical composition comprising an immediate release portion of T4:T3 in a ratio of about 1:1 to about 20:1 and a modified release portion of T4:T3 ratio of about 1:1 to about 20:1. 9. The pharmaceutical composition of claim 1, wherein at least one of the first or second portions of the thyroid hormone(s) are bound to an ion resin; or wherein the resin is ion-exchange resin particles that are: an acidic cation exchange resin, or a basic anion exchange resin, and they are optionally coated with a triggered-release coating that is triggered by a pH change or a non-pH dependent controlled release coating. 10. The pharmaceutical composition of claim 1, wherein the T4 and T4 are selected from T4 or T3 N-Methyl, T4 or T3 N-Ethyl, T4 or T3 N-Triphenyl, T4 or T3 N-Propyl, T4 or T3 N-Isopropyl, T4 or T3-N-Tertiary butyl, GC-1, DIPTA, Tetrac, or Triac. 11. The pharmaceutical composition of claim 1, wherein the composition further comprises one or more pharmaceutically acceptable carriers, one or more additional biologically active substances, and wherein the composition is adapted for the treatment of hypothyroidism. 12. The pharmaceutical composition of claim 1, wherein the T4 and T3 are mixed with an excipient into a multi-particulate composition, or wherein the binding of thyroid hormone to a resin contributes to the geometric dilution to aid in the ease of manufacturing and increase consistency in dosing. 13. The pharmaceutical composition of claim 1, wherein the composition is a swallowed tablet or capsule, orally disintegrating tablet, chewable tablet, liquid suspension or a sublingual dose. 14. The pharmaceutical composition of claim 1, wherein the amount of the one or more thyroid hormones is from 0.013 to 0.30 mg equivalent of levothyroxine sodium per dose. 15. The pharmaceutical composition of claim 1, wherein the composition is coated and the coating is selected from at least one of cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters, co-polymerized methacrylic acid/acrylic acid ethyl esters, or mixtures thereof. 16. A pharmaceutical composition comprising a first portion of levothyroxine (T4) and liothyronine (T3) is formulated for immediate release, and a second portion of T4 and T3 is formulated for modified release, wherein the T4 and T3 at a ratio of about 1:1 to about 20:1; wherein the formulation of T4 and T3 is in an amount effective to treat hypothyroidism. 17. The pharmaceutical composition of claim 16, wherein the composition comprises a geometric blend of T4:T3. 18. The pharmaceutical composition of claim 16, wherein the second portion of the T3:T4 comprises a multi-particulate formulation. 19. The pharmaceutical composition of claim 16, wherein greater than 30%, 40%, 50%, 60%, 70%, or 80% by weight of the first portion of the thyroid hormones is released within the first 45 minutes after the product is introduced into an in vitro dissolution assay, wherein the conditions of the dissolution assay are an initial dissolution medium of 0.1 N HCl, and after 2 hours, the medium is adjusted to a pH of about 6.8, and the dissolution assay is performed using a USP Apparatus 2. 20. The pharmaceutical composition of claim 16, wherein the composition is chewable. 21. The pharmaceutical composition of claim 16, wherein the composition has an in vivo fasted serum profile having a first and a second peak of the one or more thyroid hormones, wherein the first peak occurs within 3 hours after ingestion of the composition and the second peak occurs after 3 hours after ingestion of the composition. 22. The pharmaceutical composition of claim 16, wherein the composition comprises a geometrically diluted, multi-particulate pharmaceutical composition. 23. The pharmaceutical composition of claim 16, wherein at least one of the T4 or T3, or both T4 and T3 thyroid hormone(s) are bound to an ion resin. 24. The pharmaceutical composition of claim 16, wherein the thyroid hormones are selected from T4 or T3 N-Methyl, T4 or T3 N-Ethyl, T4 or T3 N-Triphenyl, T4 or T3 N-Propyl, T4 or T3 N-Isopropyl, T4 or T3-N-Tertiary butyl, GC-1, DIPTA, Tetrac, or Triac. 25. The pharmaceutical composition of claim 16, wherein the composition further comprises one or more pharmaceutically acceptable carriers, one or more additional biologically active substances, and wherein the composition is adapted for the treatment of hypothyroidism. 26. The pharmaceutical composition of claim 16, wherein the two thyroid hormones are mixed with an excipient into a multi-particulate composition. 27. The pharmaceutical composition of claim 16, wherein the T4, the T3, or both are bound to a resin that provides a geometric dilution to aid in the ease of manufacturing and increase consistency in dosing. 28. The pharmaceutical composition of claim 26, wherein the resin is ion-exchange resin particles that is an acidic cation exchange resin, or a basic anion exchange resin, and they are optionally coated with a triggered-release coating that is triggered by a pH change or a non-pH dependent controlled release coating. 29. The pharmaceutical composition of claim 16, wherein the amount of the one or more thyroid hormones is from 0.013 to 0.30 mg equivalent of levothyroxine sodium per dose. 30. The pharmaceutical composition of claim 16, wherein the composition is coated and the coating is selected from at least one of cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters, co-polymerized methacrylic acid/acrylic acid ethyl esters, or mixtures thereof.
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The present invention includes a pharmaceutical composition, and methods of making and using, a pharmaceutical composition comprising one or more thyroid hormone(s) or analogs thereof, wherein a first portion of thyroid hormone(s) is formulated for immediate release and a second portion of thyroid hormone(s) is formulated of modified release, e.g., by forming a drug-resin particle with an ion exchange resin.1. A mixed-release pharmaceutical composition effective to treat hypothyroidism comprising: (i) a first portion comprising one or more thyroid hormones is formulated for immediate release, and (ii) a second portion comprising one or more thyroid hormones is formulated for modified release that is greater than 10% by weight, wherein greater than 30%, 40%, 50%, 60%, 70%, or 80% by weight of the first portion of the one or more thyroid hormones is released within the first 45 minutes after the product is introduced into an in vitro dissolution assay, wherein the conditions of the dissolution assay are an initial dissolution medium of 0.1 N HCl, and after 2 hours, the medium is adjusted to a pH of about 6.8, and the dissolution assay is performed using a USP Apparatus 2. 2. The pharmaceutical composition of claim 1, wherein the composition is chewable. 3. The pharmaceutical composition of claim 1, wherein the composition comprises an immediate release portion of levothyroxine (T4) and liothyronine (T3) and a modified release portion of T4 and T3. 4. The composition of claim 1, wherein the composition has an in vivo fasted serum profile having a first and a second peak of the one or more thyroid hormones, wherein the first peak occurs within 3 hours after ingestion of the composition and the second peak occurs after 3 hours after ingestion of the composition. 5. The pharmaceutical composition of claim 1, wherein the composition comprises T4:T3 in a ratio of about 1:1 to about 20:1. 6. The pharmaceutical composition of claim 1, wherein the composition comprises a geometric blend of T4:T3 at a ratio of about 1:1 to about 20:1. 7. The pharmaceutical composition of claim 1, wherein the composition comprises modified release portion of T3:T4 in a ratio of about 1:1 to about 20:1, wherein the modified release portions comprises a multi-particulate formulation. 8. The pharmaceutical composition of claim 1, wherein the composition comprises a geometrically diluted multi-particulate pharmaceutical composition comprising an immediate release portion of T4:T3 in a ratio of about 1:1 to about 20:1 and a modified release portion of T4:T3 ratio of about 1:1 to about 20:1. 9. The pharmaceutical composition of claim 1, wherein at least one of the first or second portions of the thyroid hormone(s) are bound to an ion resin; or wherein the resin is ion-exchange resin particles that are: an acidic cation exchange resin, or a basic anion exchange resin, and they are optionally coated with a triggered-release coating that is triggered by a pH change or a non-pH dependent controlled release coating. 10. The pharmaceutical composition of claim 1, wherein the T4 and T4 are selected from T4 or T3 N-Methyl, T4 or T3 N-Ethyl, T4 or T3 N-Triphenyl, T4 or T3 N-Propyl, T4 or T3 N-Isopropyl, T4 or T3-N-Tertiary butyl, GC-1, DIPTA, Tetrac, or Triac. 11. The pharmaceutical composition of claim 1, wherein the composition further comprises one or more pharmaceutically acceptable carriers, one or more additional biologically active substances, and wherein the composition is adapted for the treatment of hypothyroidism. 12. The pharmaceutical composition of claim 1, wherein the T4 and T3 are mixed with an excipient into a multi-particulate composition, or wherein the binding of thyroid hormone to a resin contributes to the geometric dilution to aid in the ease of manufacturing and increase consistency in dosing. 13. The pharmaceutical composition of claim 1, wherein the composition is a swallowed tablet or capsule, orally disintegrating tablet, chewable tablet, liquid suspension or a sublingual dose. 14. The pharmaceutical composition of claim 1, wherein the amount of the one or more thyroid hormones is from 0.013 to 0.30 mg equivalent of levothyroxine sodium per dose. 15. The pharmaceutical composition of claim 1, wherein the composition is coated and the coating is selected from at least one of cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters, co-polymerized methacrylic acid/acrylic acid ethyl esters, or mixtures thereof. 16. A pharmaceutical composition comprising a first portion of levothyroxine (T4) and liothyronine (T3) is formulated for immediate release, and a second portion of T4 and T3 is formulated for modified release, wherein the T4 and T3 at a ratio of about 1:1 to about 20:1; wherein the formulation of T4 and T3 is in an amount effective to treat hypothyroidism. 17. The pharmaceutical composition of claim 16, wherein the composition comprises a geometric blend of T4:T3. 18. The pharmaceutical composition of claim 16, wherein the second portion of the T3:T4 comprises a multi-particulate formulation. 19. The pharmaceutical composition of claim 16, wherein greater than 30%, 40%, 50%, 60%, 70%, or 80% by weight of the first portion of the thyroid hormones is released within the first 45 minutes after the product is introduced into an in vitro dissolution assay, wherein the conditions of the dissolution assay are an initial dissolution medium of 0.1 N HCl, and after 2 hours, the medium is adjusted to a pH of about 6.8, and the dissolution assay is performed using a USP Apparatus 2. 20. The pharmaceutical composition of claim 16, wherein the composition is chewable. 21. The pharmaceutical composition of claim 16, wherein the composition has an in vivo fasted serum profile having a first and a second peak of the one or more thyroid hormones, wherein the first peak occurs within 3 hours after ingestion of the composition and the second peak occurs after 3 hours after ingestion of the composition. 22. The pharmaceutical composition of claim 16, wherein the composition comprises a geometrically diluted, multi-particulate pharmaceutical composition. 23. The pharmaceutical composition of claim 16, wherein at least one of the T4 or T3, or both T4 and T3 thyroid hormone(s) are bound to an ion resin. 24. The pharmaceutical composition of claim 16, wherein the thyroid hormones are selected from T4 or T3 N-Methyl, T4 or T3 N-Ethyl, T4 or T3 N-Triphenyl, T4 or T3 N-Propyl, T4 or T3 N-Isopropyl, T4 or T3-N-Tertiary butyl, GC-1, DIPTA, Tetrac, or Triac. 25. The pharmaceutical composition of claim 16, wherein the composition further comprises one or more pharmaceutically acceptable carriers, one or more additional biologically active substances, and wherein the composition is adapted for the treatment of hypothyroidism. 26. The pharmaceutical composition of claim 16, wherein the two thyroid hormones are mixed with an excipient into a multi-particulate composition. 27. The pharmaceutical composition of claim 16, wherein the T4, the T3, or both are bound to a resin that provides a geometric dilution to aid in the ease of manufacturing and increase consistency in dosing. 28. The pharmaceutical composition of claim 26, wherein the resin is ion-exchange resin particles that is an acidic cation exchange resin, or a basic anion exchange resin, and they are optionally coated with a triggered-release coating that is triggered by a pH change or a non-pH dependent controlled release coating. 29. The pharmaceutical composition of claim 16, wherein the amount of the one or more thyroid hormones is from 0.013 to 0.30 mg equivalent of levothyroxine sodium per dose. 30. The pharmaceutical composition of claim 16, wherein the composition is coated and the coating is selected from at least one of cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters, co-polymerized methacrylic acid/acrylic acid ethyl esters, or mixtures thereof.
| 1,600 |
1,236 | 14,917,098 | 1,623 |
The invention relates generally to the treatment of CYR61- and VEGF-mediated conditions and, more particularly to the treatment of such conditions by administering to an individual a CYR61 downregulator. In one embodiment, the invention provides a method of treating a CYR61-mediated condition in an individual in need of such treatment, the method comprising: administering to the individual an effective amount of at least one CYR61 downregulator (CYR61DR), wherein the effective amount is an amount sufficient to decrease expression of the CYR61 gene in the individual.
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1. A method of treating a CYR61-mediated condition in an individual in need of such treatment, the method comprising:
administering to the individual an effective amount of at least one CYR61 downregulator (CYR61DR), wherein the effective amount is an amount sufficient to decrease expression of the CYR61 gene in the individual. 2. The method of claim 1, wherein the CYR61-mediated condition is selected from a group consisting of: conditions involving neovascularization and conditions involving inflammation. 3. The method of claim 1, wherein the CYR61-mediated condition is selected from a group consisting of: proliferative diabetic retinopathy, neovascular glaucoma, macular degeneration, inflammatory neovascularization, Crohn's disease, ulcerative colitis, retinal neovascularization, retinal vascular disorders, tumor vascularization, cancer angiogenesis, metastasis, rheumatoid arthritis, and fibrosis. 4. The method of claim 1, wherein the at least one CYR61DR is selected from a group consisting of: anthracyclines and statins. 5. The method of claim 4, wherein the at least one CYR61DR includes at least one anthracycline selected from a group consisting of: doxorubicin, daunorubicin, epirubicin, idarubicin, valrubicin, and mitoxantrone. 6. The method of claim 4, wherein the at least one CYR61DR includes at least one statin selected from a group consisting of: simvastatin, pravastatin, fluvastatin, atrovastatin, cerivastatin, lovastatin, mevastatin, pitavastatin, and rosuvastatin. 7. The method of claim 1, wherein administering includes intravitreally administering. 8. The method of claim 1, wherein administering includes orally administering. 9. The method of claim 1, wherein administering includes administering intravenously. 10. A method of treating a VEGF-mediated condition in an individual in need of such treatment, the method comprising:
administering to the individual an effective amount of at least one CYR61 downregulator (CYR61DR), wherein the effective amount is an amount sufficient to decrease expression of both the CYR61 gene and the VEGF gene in the individual. 11. The method of claim 10, wherein the at least one CYR61DR is selected from a group consisting of: anthracyclines and statins. 12. The method of claim 11, wherein the at least one CYR61DR includes at least one anthracycline selected from a group consisting of: doxorubicin, daunorubicin, epirubicin, idarubicin, valrubicin, and mitoxantrone. 13. The method of claim 11, wherein the at least one CYR61DR includes at least one statin selected from a group consisting of: simvastatin, pravastatin, fluvastatin, atrovastatin, cerivastatin, lovastatin, mevastatin, pitavastatin, and rosuvastatin. 14. The method of claim 10, wherein administering includes intravitreally administering. 15. The method of claim 10, wherein administering includes orally administering. 16. A method of treating a VEGF-mediated condition in an individual in need of such treatment, the method comprising:
administering to the individual an effective amount of at least one CYR61 downregulator (CYR61DR), wherein the effective amount is an amount sufficient to decrease expression of the CYR61 gene and the VEGF gene in the individual.
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The invention relates generally to the treatment of CYR61- and VEGF-mediated conditions and, more particularly to the treatment of such conditions by administering to an individual a CYR61 downregulator. In one embodiment, the invention provides a method of treating a CYR61-mediated condition in an individual in need of such treatment, the method comprising: administering to the individual an effective amount of at least one CYR61 downregulator (CYR61DR), wherein the effective amount is an amount sufficient to decrease expression of the CYR61 gene in the individual.1. A method of treating a CYR61-mediated condition in an individual in need of such treatment, the method comprising:
administering to the individual an effective amount of at least one CYR61 downregulator (CYR61DR), wherein the effective amount is an amount sufficient to decrease expression of the CYR61 gene in the individual. 2. The method of claim 1, wherein the CYR61-mediated condition is selected from a group consisting of: conditions involving neovascularization and conditions involving inflammation. 3. The method of claim 1, wherein the CYR61-mediated condition is selected from a group consisting of: proliferative diabetic retinopathy, neovascular glaucoma, macular degeneration, inflammatory neovascularization, Crohn's disease, ulcerative colitis, retinal neovascularization, retinal vascular disorders, tumor vascularization, cancer angiogenesis, metastasis, rheumatoid arthritis, and fibrosis. 4. The method of claim 1, wherein the at least one CYR61DR is selected from a group consisting of: anthracyclines and statins. 5. The method of claim 4, wherein the at least one CYR61DR includes at least one anthracycline selected from a group consisting of: doxorubicin, daunorubicin, epirubicin, idarubicin, valrubicin, and mitoxantrone. 6. The method of claim 4, wherein the at least one CYR61DR includes at least one statin selected from a group consisting of: simvastatin, pravastatin, fluvastatin, atrovastatin, cerivastatin, lovastatin, mevastatin, pitavastatin, and rosuvastatin. 7. The method of claim 1, wherein administering includes intravitreally administering. 8. The method of claim 1, wherein administering includes orally administering. 9. The method of claim 1, wherein administering includes administering intravenously. 10. A method of treating a VEGF-mediated condition in an individual in need of such treatment, the method comprising:
administering to the individual an effective amount of at least one CYR61 downregulator (CYR61DR), wherein the effective amount is an amount sufficient to decrease expression of both the CYR61 gene and the VEGF gene in the individual. 11. The method of claim 10, wherein the at least one CYR61DR is selected from a group consisting of: anthracyclines and statins. 12. The method of claim 11, wherein the at least one CYR61DR includes at least one anthracycline selected from a group consisting of: doxorubicin, daunorubicin, epirubicin, idarubicin, valrubicin, and mitoxantrone. 13. The method of claim 11, wherein the at least one CYR61DR includes at least one statin selected from a group consisting of: simvastatin, pravastatin, fluvastatin, atrovastatin, cerivastatin, lovastatin, mevastatin, pitavastatin, and rosuvastatin. 14. The method of claim 10, wherein administering includes intravitreally administering. 15. The method of claim 10, wherein administering includes orally administering. 16. A method of treating a VEGF-mediated condition in an individual in need of such treatment, the method comprising:
administering to the individual an effective amount of at least one CYR61 downregulator (CYR61DR), wherein the effective amount is an amount sufficient to decrease expression of the CYR61 gene and the VEGF gene in the individual.
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1,237 | 15,316,188 | 1,642 |
The present invention relates to extracellular microvesicles biomarkers for determining the tumour transformation status or presence of a tumour in a subject, and to the uses of such biomarkers and to diagnostics methods using such biomarkers. In particular, the methods and uses of the invention involve isolation of TM9SF4-positive extracellular vesicles and detection of the expression of a second biomarker, preferably selected from the group consisting of CD9 protein, miR-21 and RNU6.
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1. A method for determining in vitro the presence of a tumour in a subject, such method comprising
a) providing a biological sample obtained from that subject, b) isolating extracellular vesicles from said sample, wherein this step of isolating extracellular vesicles comprises isolating TM9SF4-positive extracellular vesicles, c) determining, from the extracellular vesicles isolated in step b), a level or presence of a suitable biomarker, and d) comparing the level or presence of the biomarker determined in step c) with one or more reference values. 2. The method according to claim 1, wherein the TM9SF4-positive extracellular vesicles are isolated through binding to an anti-TM9SF4 antibody. 3. The method according to claim 1 wherein at least a portion of the extracellular vesicles are exosomes. 4. The method according to claim 1 wherein the tumour is selected from the colon cancer, gastric cancer, breast cancer, lung cancer, melanoma, pancreatic cancer, ovary cancer, prostate cancer, central nervous system tumour or malignant peripheral nerve sheet tumour MPNST. 5. The method according to claim 1, wherein the biomarker of step c) is selected from CD9 protein, miR-21 or RNU6. 6. A method for determining in vitro tumour transformation status in a subject, such method comprising:
a) providing a biological sample obtained from that subject, b) isolating extracellular vesicles from said sample, wherein this step of isolating extracellular vesicles comprises isolating TM9SF4-positive extracellular vesicles, c) determining, from the extracellular vesicles isolated in step b), level or presence of a suitable biomarker, and d) comparing the level or presence of the biomarker determined in step c) with one or more reference values. 7. The method according to claim 6, wherein the biological sample of step a) is obtained from a subject affected by a benign tumour. 8. The method according to claim 6, wherein the TM9SF4-positive extracellular vesicles are isolated through binding to an anti-TM9SF4 antibody. 9. The method according to claim 6 wherein at least a portion of the extracellular vesicles are exosomes. 10. The method according to claim 6, wherein the tumour transformation status is the transformation to an MPNST or to a colorectal cancer. 11. The method according to claim 6, wherein the suitable biomarker is selected from CD9 protein, miR-21 or RNU6. 12. TM9SF4-positive extracellular vesicles for use in a test to determine presence of a tumour or tumour transformation status in a subject. 13. The TM9SF4-positive extracellular vesicles according to claim 12, wherein the extracellular vesicles are exosomes. 14. The TM9SF4-positive extracellular vesicles according to claim 12, wherein the tumour is selected from colon cancer, gastric cancer, breast cancer, lung cancer, melanoma, pancreatic cancer, ovary cancer, prostate cancer, central nervous system tumour or MPNST. 15. The TM9SF4-positive extracellular vesicles according to claim 12, wherein the tumour transformation status is transformation to MPNST or to colorectal cancer. 16. A kit for use in determining in vitro presence of a tumour or a tumour transformation status in a subject, such kit comprising an anti-TM9SF4 antibody. 17. The kit according to claim 16 further comprising a reagent selected from an anti CD9-antibody, a miR-21 primer or a RNU6 primer. 18. The kit according to claim 16, wherein the tumour is selected from colon cancer, gastric cancer, breast cancer, lung cancer, melanoma, pancreatic cancer, ovary cancer, prostate cancer, central nervous system tumour or MPNST. 19. The kit according to claim 16, wherein the tumour transformation status is transformation to an MPNST or to a colorectal cancer. 20. The kit according to claim 16, further comprising instructions for suitable operational parameters in form of a label or separate insert.
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The present invention relates to extracellular microvesicles biomarkers for determining the tumour transformation status or presence of a tumour in a subject, and to the uses of such biomarkers and to diagnostics methods using such biomarkers. In particular, the methods and uses of the invention involve isolation of TM9SF4-positive extracellular vesicles and detection of the expression of a second biomarker, preferably selected from the group consisting of CD9 protein, miR-21 and RNU6.1. A method for determining in vitro the presence of a tumour in a subject, such method comprising
a) providing a biological sample obtained from that subject, b) isolating extracellular vesicles from said sample, wherein this step of isolating extracellular vesicles comprises isolating TM9SF4-positive extracellular vesicles, c) determining, from the extracellular vesicles isolated in step b), a level or presence of a suitable biomarker, and d) comparing the level or presence of the biomarker determined in step c) with one or more reference values. 2. The method according to claim 1, wherein the TM9SF4-positive extracellular vesicles are isolated through binding to an anti-TM9SF4 antibody. 3. The method according to claim 1 wherein at least a portion of the extracellular vesicles are exosomes. 4. The method according to claim 1 wherein the tumour is selected from the colon cancer, gastric cancer, breast cancer, lung cancer, melanoma, pancreatic cancer, ovary cancer, prostate cancer, central nervous system tumour or malignant peripheral nerve sheet tumour MPNST. 5. The method according to claim 1, wherein the biomarker of step c) is selected from CD9 protein, miR-21 or RNU6. 6. A method for determining in vitro tumour transformation status in a subject, such method comprising:
a) providing a biological sample obtained from that subject, b) isolating extracellular vesicles from said sample, wherein this step of isolating extracellular vesicles comprises isolating TM9SF4-positive extracellular vesicles, c) determining, from the extracellular vesicles isolated in step b), level or presence of a suitable biomarker, and d) comparing the level or presence of the biomarker determined in step c) with one or more reference values. 7. The method according to claim 6, wherein the biological sample of step a) is obtained from a subject affected by a benign tumour. 8. The method according to claim 6, wherein the TM9SF4-positive extracellular vesicles are isolated through binding to an anti-TM9SF4 antibody. 9. The method according to claim 6 wherein at least a portion of the extracellular vesicles are exosomes. 10. The method according to claim 6, wherein the tumour transformation status is the transformation to an MPNST or to a colorectal cancer. 11. The method according to claim 6, wherein the suitable biomarker is selected from CD9 protein, miR-21 or RNU6. 12. TM9SF4-positive extracellular vesicles for use in a test to determine presence of a tumour or tumour transformation status in a subject. 13. The TM9SF4-positive extracellular vesicles according to claim 12, wherein the extracellular vesicles are exosomes. 14. The TM9SF4-positive extracellular vesicles according to claim 12, wherein the tumour is selected from colon cancer, gastric cancer, breast cancer, lung cancer, melanoma, pancreatic cancer, ovary cancer, prostate cancer, central nervous system tumour or MPNST. 15. The TM9SF4-positive extracellular vesicles according to claim 12, wherein the tumour transformation status is transformation to MPNST or to colorectal cancer. 16. A kit for use in determining in vitro presence of a tumour or a tumour transformation status in a subject, such kit comprising an anti-TM9SF4 antibody. 17. The kit according to claim 16 further comprising a reagent selected from an anti CD9-antibody, a miR-21 primer or a RNU6 primer. 18. The kit according to claim 16, wherein the tumour is selected from colon cancer, gastric cancer, breast cancer, lung cancer, melanoma, pancreatic cancer, ovary cancer, prostate cancer, central nervous system tumour or MPNST. 19. The kit according to claim 16, wherein the tumour transformation status is transformation to an MPNST or to a colorectal cancer. 20. The kit according to claim 16, further comprising instructions for suitable operational parameters in form of a label or separate insert.
| 1,600 |
1,238 | 15,334,600 | 1,654 |
An agent for preventing or ameliorating vascular endothelial malfunction and arteriosclerosis-related symptoms caused by the progress of vascular endothelial malfunction (e.g., ischemic diseases such as myocardial infarction, angina, and peripheral artery occlusion) or low blood flow-related symptoms (e.g., stiff shoulders, excessive sensitivity to cold, swelling, erectile dysfunction, rough skin and decrease in exercise performance due to skeletal muscle hypoactivity), which has an improved NO production enhancing effect is provided. A NO production enhancer comprising citrulline or a salt thereof and glutathione or a salt thereof as active ingredients. An agent for preventing or ameliorating vascular endothelial malfunction, comprising citrulline or a salt thereof and glutathione or a salt thereof as active ingredients. An agent for preventing or ameliorating a symptom caused by vascular endothelial malfunction, comprising citrulline or a salt thereof and glutathione or a salt thereof as active ingredients.
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1-3. (canceled) 4. A method for long-lasting enhancement of NO production comprising, administering an agent comprising citrulline or a salt thereof and glutathione or a salt thereof to a subject in need thereof. 5. The method for long-lasting enhancement of NO production according to claim 4, wherein the enhancement occurs approximately at 1 hour after the administration of the agent. 6. The method for long-lasting enhancement of NO production according to claim 4, wherein the enhancement occurs approximately at 2 hours after the agent.
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An agent for preventing or ameliorating vascular endothelial malfunction and arteriosclerosis-related symptoms caused by the progress of vascular endothelial malfunction (e.g., ischemic diseases such as myocardial infarction, angina, and peripheral artery occlusion) or low blood flow-related symptoms (e.g., stiff shoulders, excessive sensitivity to cold, swelling, erectile dysfunction, rough skin and decrease in exercise performance due to skeletal muscle hypoactivity), which has an improved NO production enhancing effect is provided. A NO production enhancer comprising citrulline or a salt thereof and glutathione or a salt thereof as active ingredients. An agent for preventing or ameliorating vascular endothelial malfunction, comprising citrulline or a salt thereof and glutathione or a salt thereof as active ingredients. An agent for preventing or ameliorating a symptom caused by vascular endothelial malfunction, comprising citrulline or a salt thereof and glutathione or a salt thereof as active ingredients.1-3. (canceled) 4. A method for long-lasting enhancement of NO production comprising, administering an agent comprising citrulline or a salt thereof and glutathione or a salt thereof to a subject in need thereof. 5. The method for long-lasting enhancement of NO production according to claim 4, wherein the enhancement occurs approximately at 1 hour after the administration of the agent. 6. The method for long-lasting enhancement of NO production according to claim 4, wherein the enhancement occurs approximately at 2 hours after the agent.
| 1,600 |
1,239 | 15,759,587 | 1,632 |
A biological cell and/or tissue growth apparatus operable to create, in a chamber of the apparatus, a three-dimensional (3D) cell culture and to interact with a 3D structure of the cells in the chamber to, for example, apply materials to and/or remove materials from the cells or the chamber. The apparatus may include equipment for printing the 3D cell culture in a 3D cell growth medium. The 3D cell growth medium may be a granular gel material that undergoes a temporary phase change in response to an applied stress, such as a thixotropic or “yield stress” material. The apparatus may be operated such that the 3D printing equipment “prints” the 3D cell culture by depositing cells at particular locations in the 3D cell growth medium.
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1. An apparatus for culturing and interacting with biological cells and/or tissues, the apparatus comprising:
a chamber comprising a container holding a three-dimensional (3D) cell growth medium, the 3D cell growth medium being a thixotropic material; equipment to dispense biological cells and/or tissues at particular positions within the 3D cell growth medium in the container; and equipment to interact with the biological cells and/or tissues within the 3D cell growth medium in the container. 2. The apparatus of claim 1, further comprising:
equipment to dispense the 3D cell growth medium into the container. 3. The apparatus of claim 1, wherein the 3D cell growth medium comprises:
a plurality of hydrogel particles; and a liquid cell culture medium, wherein the hydrogel particles are swelled with the liquid cell culture medium to form a granular gel. 4. The apparatus of claim 3, wherein the concentration of hydrogel particles is between 0.05% to 1.0% by weight. 5. The apparatus of claim 3, wherein the hydrogel particles have a size in the range of 0.1 μm to 100 μm when swollen with the liquid cell culture medium. 6. The apparatus of claim 5, wherein the hydrogel particles have a size in the range of 1 μm to 10 μm when swollen with the liquid cell culture medium. 7. The apparatus of claim 1, wherein the equipment to interact with the biological cells and/or tissues within the 3D cell growth medium in the container comprises equipment to add, remove, and/or exchange fluid materials in the chamber. 8. The apparatus of claim 7, further comprising:
a bioreactor, wherein the bioreactor comprises the chamber and the equipment to interact. 9. The apparatus of claim 7, further comprising:
a controller to operate the equipment to interact with the biological cells and/or tissues within the 3D cell growth medium, wherein the controller is configured to move at least some of the equipment to interact to penetrate the 3D cell growth medium following dispensing of the biological cells and/or tissues by the equipment to dispense. 10. The apparatus of claim 1, wherein the equipment to interact with the biological cells and/or tissues within the 3D cell growth medium in the container comprises equipment to dispense a material in the chamber and/or in the 3D cell growth medium while the biological cells and/or tissues are disposed in the 3D cell growth medium. 11. The apparatus of claim 10, wherein the equipment to dispense a material in the chamber and/or in the 3D cell growth medium comprises equipment to dispense nutrients for the biological cells and/or tissues. 12. The apparatus of claim 10, wherein the equipment to dispense a material in the chamber and/or in the 3D cell growth medium comprises equipment to dispense a pharmaceutical or a combination of pharmaceuticals in the chamber and/or in the 3D cell growth medium. 13. The apparatus of claim 1, wherein the equipment to interact with the biological cells and/or tissues within the 3D cell growth medium in the container comprises equipment to remove a material from the chamber and/or from the 3D cell growth medium while the biological cells and/or tissues are disposed in the 3D cell growth medium. 14. The apparatus of claim 13, wherein the equipment to remove a material from the chamber and/or from the 3D cell growth medium comprises equipment to remove waste from the chamber and/or the 3D cell growth medium. 15. The apparatus of claim 13, wherein the equipment to remove a material from the chamber and/or from the 3D cell growth medium comprises equipment to remove from the chamber and/or the 3D cell growth medium a byproduct created by the biological cells and/or tissues. 16. A method of operating a bioreactor, the method comprising:
culturing cells and/or tissues in a 3D cell growth medium, the 3D cell growth medium being a thixotropic material; and while the cells and/or tissues are disposed in the 3D cell growth medium, removing byproduct of cellular activity from the 3D cell growth medium. 17. The method of claim 16, further comprising:
while the cells and/or tissues are disposed in the 3D cell growth medium, replenishing the 3D cell growth medium. 18. (canceled) 19. (cancelled) 20. (canceled) 21. (cancelled) 22. The method of claim 16, further comprising:
while the cells and/or tissues are disposed in the 3D cell growth medium, supplying a compound to the cells and/or tissues. 23. The method of claim 22, wherein supplying the compound to the cells and/or tissues comprises dispensing the compound in the 3D cell growth medium in an area adjacent to the cells and/or tissues. 24. The method of claim 22, wherein supplying the compound to the cells and/or tissues comprises dispensing the compound in an area of the 3D cell growth medium to enable the compound to diffuse across the 3D cell growth medium from the area to the cells and/or tissues. 25. The method of claim 22, wherein supplying the compound to the cells and/or tissues comprises supplying a first compound to a first portion of the cells and/or tissues and supplying a second compound to a second portion of the cells and/or tissues. 26. The method of claim 25, wherein:
the first compound is a solution comprising a first material in a first concentration; and the second compound is a solution comprising the first material in a second concentration. 27. The method of claim 22, further comprising:
assaying the cells and/or tissues while the cells and/or tissues are disposed in the 3D cell growth medium, wherein the assaying comprises the supplying the compound. 28. The method of claim 22, wherein supplying the compound comprises supplying one or more materials from a group consisting of: a nutrient, a stain, a fixative, and a pharmaceutical. 29. A method of operating a bioreactor to expose cells to a material, the method comprising:
suspending cells at locations within a 3D cell growth medium contained in a container of the bioreactor, the 3D cell growth medium being a thixotropic material; operating the bioreactor to culture the cells suspended in the 3D cell growth material; operating the bioreactor to dispense the material into the 3D cell growth medium; and following dispensing of the material, evaluating the cells for an impact of the dispensed material on the cells. 30. The method of claim 29, wherein evaluating the cells comprises evaluating the cells while the cells are suspended in the 3D cell growth medium. 31. The method of claim 30, wherein evaluating the cells comprises inserting into the 3D cell growth medium equipment to evaluate the cells. 32. The method of claim 29, wherein:
operating the bioreactor to dispense the material comprises operating the bioreactor to dispense the material so as to create a gradient of concentration of the material in the 3D cell growth medium and expose different cells to different concentrations of the material; and evaluating the cells for the impact of the dispensed material comprises evaluating the cells based on a position of the cells within the gradient. 33. The method of claim 29, wherein:
the 3D cell growth medium comprises a hydrogel and a cell growth material; and operating the bioreactor to culture the cells comprises adding cell growth material to the 3D cell growth medium during the culturing. 34. The method of claim 33, wherein operating the bioreactor to culture the cells comprises removing from the 3D cell growth medium waste created by the cells. 35. The method of claim 34, wherein removing the waste from the 3D cell growth medium comprises operating a pump and/or a centrifuge to impose a force on the 3D cell growth medium. 36. The method of claim 29, wherein suspending cells at locations within a 3D cell growth medium comprises creating a 3D cell culture by dispensing cells at the locations within the 3D cell growth medium.
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A biological cell and/or tissue growth apparatus operable to create, in a chamber of the apparatus, a three-dimensional (3D) cell culture and to interact with a 3D structure of the cells in the chamber to, for example, apply materials to and/or remove materials from the cells or the chamber. The apparatus may include equipment for printing the 3D cell culture in a 3D cell growth medium. The 3D cell growth medium may be a granular gel material that undergoes a temporary phase change in response to an applied stress, such as a thixotropic or “yield stress” material. The apparatus may be operated such that the 3D printing equipment “prints” the 3D cell culture by depositing cells at particular locations in the 3D cell growth medium.1. An apparatus for culturing and interacting with biological cells and/or tissues, the apparatus comprising:
a chamber comprising a container holding a three-dimensional (3D) cell growth medium, the 3D cell growth medium being a thixotropic material; equipment to dispense biological cells and/or tissues at particular positions within the 3D cell growth medium in the container; and equipment to interact with the biological cells and/or tissues within the 3D cell growth medium in the container. 2. The apparatus of claim 1, further comprising:
equipment to dispense the 3D cell growth medium into the container. 3. The apparatus of claim 1, wherein the 3D cell growth medium comprises:
a plurality of hydrogel particles; and a liquid cell culture medium, wherein the hydrogel particles are swelled with the liquid cell culture medium to form a granular gel. 4. The apparatus of claim 3, wherein the concentration of hydrogel particles is between 0.05% to 1.0% by weight. 5. The apparatus of claim 3, wherein the hydrogel particles have a size in the range of 0.1 μm to 100 μm when swollen with the liquid cell culture medium. 6. The apparatus of claim 5, wherein the hydrogel particles have a size in the range of 1 μm to 10 μm when swollen with the liquid cell culture medium. 7. The apparatus of claim 1, wherein the equipment to interact with the biological cells and/or tissues within the 3D cell growth medium in the container comprises equipment to add, remove, and/or exchange fluid materials in the chamber. 8. The apparatus of claim 7, further comprising:
a bioreactor, wherein the bioreactor comprises the chamber and the equipment to interact. 9. The apparatus of claim 7, further comprising:
a controller to operate the equipment to interact with the biological cells and/or tissues within the 3D cell growth medium, wherein the controller is configured to move at least some of the equipment to interact to penetrate the 3D cell growth medium following dispensing of the biological cells and/or tissues by the equipment to dispense. 10. The apparatus of claim 1, wherein the equipment to interact with the biological cells and/or tissues within the 3D cell growth medium in the container comprises equipment to dispense a material in the chamber and/or in the 3D cell growth medium while the biological cells and/or tissues are disposed in the 3D cell growth medium. 11. The apparatus of claim 10, wherein the equipment to dispense a material in the chamber and/or in the 3D cell growth medium comprises equipment to dispense nutrients for the biological cells and/or tissues. 12. The apparatus of claim 10, wherein the equipment to dispense a material in the chamber and/or in the 3D cell growth medium comprises equipment to dispense a pharmaceutical or a combination of pharmaceuticals in the chamber and/or in the 3D cell growth medium. 13. The apparatus of claim 1, wherein the equipment to interact with the biological cells and/or tissues within the 3D cell growth medium in the container comprises equipment to remove a material from the chamber and/or from the 3D cell growth medium while the biological cells and/or tissues are disposed in the 3D cell growth medium. 14. The apparatus of claim 13, wherein the equipment to remove a material from the chamber and/or from the 3D cell growth medium comprises equipment to remove waste from the chamber and/or the 3D cell growth medium. 15. The apparatus of claim 13, wherein the equipment to remove a material from the chamber and/or from the 3D cell growth medium comprises equipment to remove from the chamber and/or the 3D cell growth medium a byproduct created by the biological cells and/or tissues. 16. A method of operating a bioreactor, the method comprising:
culturing cells and/or tissues in a 3D cell growth medium, the 3D cell growth medium being a thixotropic material; and while the cells and/or tissues are disposed in the 3D cell growth medium, removing byproduct of cellular activity from the 3D cell growth medium. 17. The method of claim 16, further comprising:
while the cells and/or tissues are disposed in the 3D cell growth medium, replenishing the 3D cell growth medium. 18. (canceled) 19. (cancelled) 20. (canceled) 21. (cancelled) 22. The method of claim 16, further comprising:
while the cells and/or tissues are disposed in the 3D cell growth medium, supplying a compound to the cells and/or tissues. 23. The method of claim 22, wherein supplying the compound to the cells and/or tissues comprises dispensing the compound in the 3D cell growth medium in an area adjacent to the cells and/or tissues. 24. The method of claim 22, wherein supplying the compound to the cells and/or tissues comprises dispensing the compound in an area of the 3D cell growth medium to enable the compound to diffuse across the 3D cell growth medium from the area to the cells and/or tissues. 25. The method of claim 22, wherein supplying the compound to the cells and/or tissues comprises supplying a first compound to a first portion of the cells and/or tissues and supplying a second compound to a second portion of the cells and/or tissues. 26. The method of claim 25, wherein:
the first compound is a solution comprising a first material in a first concentration; and the second compound is a solution comprising the first material in a second concentration. 27. The method of claim 22, further comprising:
assaying the cells and/or tissues while the cells and/or tissues are disposed in the 3D cell growth medium, wherein the assaying comprises the supplying the compound. 28. The method of claim 22, wherein supplying the compound comprises supplying one or more materials from a group consisting of: a nutrient, a stain, a fixative, and a pharmaceutical. 29. A method of operating a bioreactor to expose cells to a material, the method comprising:
suspending cells at locations within a 3D cell growth medium contained in a container of the bioreactor, the 3D cell growth medium being a thixotropic material; operating the bioreactor to culture the cells suspended in the 3D cell growth material; operating the bioreactor to dispense the material into the 3D cell growth medium; and following dispensing of the material, evaluating the cells for an impact of the dispensed material on the cells. 30. The method of claim 29, wherein evaluating the cells comprises evaluating the cells while the cells are suspended in the 3D cell growth medium. 31. The method of claim 30, wherein evaluating the cells comprises inserting into the 3D cell growth medium equipment to evaluate the cells. 32. The method of claim 29, wherein:
operating the bioreactor to dispense the material comprises operating the bioreactor to dispense the material so as to create a gradient of concentration of the material in the 3D cell growth medium and expose different cells to different concentrations of the material; and evaluating the cells for the impact of the dispensed material comprises evaluating the cells based on a position of the cells within the gradient. 33. The method of claim 29, wherein:
the 3D cell growth medium comprises a hydrogel and a cell growth material; and operating the bioreactor to culture the cells comprises adding cell growth material to the 3D cell growth medium during the culturing. 34. The method of claim 33, wherein operating the bioreactor to culture the cells comprises removing from the 3D cell growth medium waste created by the cells. 35. The method of claim 34, wherein removing the waste from the 3D cell growth medium comprises operating a pump and/or a centrifuge to impose a force on the 3D cell growth medium. 36. The method of claim 29, wherein suspending cells at locations within a 3D cell growth medium comprises creating a 3D cell culture by dispensing cells at the locations within the 3D cell growth medium.
| 1,600 |
1,240 | 14,892,702 | 1,662 |
Methods are provided for hybrid seed production using 3-phyletic crosses between female, maintainer and male, particularly restorer lines, wherein the trait is introduced in the female line only at the stage of basic seed production via crossing of the female line with a maintainer line containing the gene or genes encoding the trait in homozygous state.
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1) A method for producing herbicide-tolerant hybrid seed using
a) a male-sterile plant line or A-line; b) a male-sterile plant line comprising a herbicide tolerance gene in heterozygous or hemizygous state or AHT-line; c) an isogenic maintainer plant line or B-line; d) an isogenic maintainer plant line comprising a herbicide tolerance gene in homozygous state or BHT-line; e) and a male fertile line which can be a restorer line or R-line comprising said herbicide tolerance gene in homozygous state; wherein said hybrid seed is produced by crossing plants grown from basic seed of the AHT-line and plants of the male fertile line or R-line and collecting the seeds produced on plants of the A-line, and wherein said basic seed of the AHT-line has been produced by crossing plants grown from pre-basic seed of the A-line with plants of the BHT-line and collecting the seeds produced on plants of the A-line, and wherein said pre-basic seed of the A-line has been produced by crossing plants grown from pre-basic seed of the A-line with plants of the B-line and collecting seeds produced on plants of the A-line. 2) A method for producing herbicide-tolerant hybrid seed using
a) a male-sterile plant line (A-line); b) a male-sterile plant line comprising a herbicide tolerance gene in heterozygous or hemizygous state (AHT-line); c) an isogenic maintainer plant line (B-line); d) an isogenic maintainer plant line comprising a herbicide tolerance gene in homozygous state (BHT-line); e) and a male fertile line which may be a restorer line comprising said herbicide tolerance gene in homozygous state (R-line); said method comprising the steps of i. producing pre-basic seed of the A-line by crossing plants grown from pre-basic seed of the A-line with plants of the B-line and collecting seeds produced on plants of the A-line; ii. producing basic seed of the AHT-line by crossing plants grown from said pre-basic seed of the A-line with plants of the BHT-line and collecting the seeds produced on plants of the A-line; and iii. producing hybrid seed by crossing plants grown from basic seed of the AHT-line and plants of the male fertile line or R-line and collecting the seeds produced on plants of the AHT-line. 3) In a method for producing herbicide tolerant hybrid seeds using a three-line hybridization system comprising a male-sterile plant line or A-line, an isogenic maintainer plant line or B-line and a male fertile line, particularly a restorer liner or R-line comprising a herbicide tolerance gene, the improvement of crossing a fourth isogenic maintainer line further comprising said herbicide tolerance gene in homozygous state with said male-sterile plant only at the stage of basic seed production and not at any pre-basic seed production stages. 4) The method of any one of claims 1 to 3, wherein said herbicide tolerance gene provides tolerance against a herbicide selected from the group of acetyl CoA carboxylase inhibitors, acetolactoate synthase inhibitors, glutamine synthetase inhibitors, 5-enoylpyruvyl-shikimate-3-phosphate inhibitors, photosynthesis II inhibitors, diterpene synthesis inhibitors, hydroxyphenylpyruvate dioxygenase inhibitors, protoporphorinogen oxidase inhibitors, photosystem I electron diverters, microtubule inhibitors, lipid synthesis inhibitors, long chain fatty acid inhibitors or synthetic auxins. 5) The method according to claim 4 wherein said acetyl CoA carboxylase inhibitor is an aryloxyphenoxypropionate including fenoxaprop, fluazifop or quizalafop. 6) The method according to claim 4 wherein said acetyl CoA carboxylase inhibitor is a cyclohanedione including clethodim or sethoxydim. 7) The method according to claim 4 wherein said acetolactoate synthase inhibitor is a sufonylurea such as chlorimuron, foramsulfuron, halosulfuron, iodosulfuron, nicosulfuron, primisulfuron, pro sulfuron, rimsulfuron, thifensulfuron or tribenuron. 8) The method according to claim 4 wherein said acetolactoate synthase inhibitor is a imidazolinone such as imazamox, imazaquin or imazethapyr. 9) The method according to claim 4 wherein said acetolactoate synthase inhibitor is a tryazolopyrimidine such as flumetsulam or cloransulam. 10) The method according to claim 4 wherein said acetolactoate synthase inhibitor is a triazolinone such as thiencarbazone. 11) The method according to claim 4 wherein said 5-enoylpyruvyl-shikimate-3-phosphate inhibitor is glyphosate. 12) The method according to claim 4 wherein said synthetic auxin is a phenoxy such as 2,4-D; or a benzoic acid such as dicamba or a carboxylic acid such as clopyralid or fluroxypyr, or a semicarbazone such as difluofenzopyr. 13) The method according to claim 4 wherein said photosynthesis system II inhibitor is a triazine such as atrazine or simazine. 14) The method according to claim 4 wherein said photosynthesis system II inhibitor is a triazinone such as metribuzin. 15) The method according to claim 4 wherein said photosynthesis system II inhibitor is a nitrile such as bromoxynil. 16) The method according to claim 4 wherein said photosynthesis system II inhibitor is a benzothiadazole such as bentazon. 17) The method according to claim 4 wherein said photosynthesis system II inhibitor is an urea such as linuron. 18) The method according to claim 4 wherein said glutamine synthase inhibitor is glufosinate. 19) The method according to claim 4 wherein said diterpene synthesis inhibitor is isoxazolidinone. 20) The method according to claim 4 wherein said HPPD inhibitor is an isoxazole including isoxaflutole or a pyrzolone including topramezone or a triketone including mesotrione and tembotrione. 21) The method according to claim 4 wherein said PPO inhibitor is a diphenylether including acifluorfen, formesafen, lactofen. 22) The method according to claim 4 wherein said PPO inhibitor is an N-phenylphtalimide including flumiclorac or flumioxazin. 23) The method according to claim 4 wherein said PPO inhibitor is an aryl triazinone including sulfentrazone, carfentrazone or fluthiacet-ethyl. 24) The method according to claim 4 wherein said PPO inhibitor is a pyrimidinedione such as saflufenacil. 25) The method according to claim 4 wherein said photosystem I electron diverter is a bipyridilium including paraquat. 26) The method according to claim 4 wherein said microtubule inhibitor is a dinitroaniline including ethalfluralin, pendimethalin or trifluralin. 27) The method according to claim 4, wherein said lipid synthesis inhibitor is a thiocarbamate including butylate or EPTC (S-ethyl-N,N-dipropylthiocarbamate). 28) The method according to claim 4, wherein said long-chain fatty acid inhibitor is a chloroacetamide including acetochlor, alachlor, metolachlor, dimethenamid or an oxyacetamide including flufenacet or a pyrazole including pyroxasulfone. 29) The method of any one of claims 1 to 3, wherein said herbicide tolerance is provided by a transgene. 30) The method of any one of claims 1 to 3, wherein said herbicide tolerance is provided by a variant allele endogenous to said plant. 31) The method of any one of claims 1 to 30 wherein said plant lines are plant lines of rice (Oryza sativa), wheat (Triticum aestivum), corn (Zea mays), cotton (Gossypium hirsutum or G. barbadense), soybean (Glycine max), sorghum (Sorghum bicolor), rapeseed (Brassica napus), mustard seed (Brassica juncea), barley (Hordeum vulgare), oat (Avena sativa), rye (Secale cereale), pearl millet (Pennisetum typhoides), alfalfa (Medicago sativa), tomato (Lycopersicon esculentum), sugar beet (Beta vulgaris), sunflower (Helianthus annuus), onion (Allium cepa), petunia (Petunia hybrida), carrot (Daucus carota), sorghum (Sorghum spp.), cabbage (Brassica oleracea), melons (Cucumis melo), watermelons (Citrillus lanatus) or cucumber (Cucumis sativus). 32) A method for producing hybrid seed comprising a trait of interest using
a) a male-sterile plant line or A-line; b) a male-sterile plant line comprising said trait of interest in heterozygous or hemizygous state or AGOI-line; c) an isogenic maintainer plant line or B-line; d) an isogenic maintainer plant line comprising said trait of interest in homozygous state or BGOI-line; e) and a male fertile line, particularly a restorer line or R-line comprising said trait of interest in homozygous state; wherein said hybrid seed is produced by crossing of basic seed of the AGOI-line and the male fertile line or R-line and collecting the seeds produced on plants of the A-line, and wherein said basic seed of the AGOI-line has been produced by crossing pre-basic seed of the A-line with pre-basic seed of the BGOI-line and collecting the seeds produced on plants of the AGOI-line, and wherein said pre-basic seed of the A-line has been produced by crossing pre-basic seed of the A-line with pre-basic seed of the B-line and collecting seeds produced on plants of the A-line. 33) The method of claim 32 wherein said agronomic trait of interest is selected from insect tolerance, herbicide tolerance, stress tolerance, yield increase, oil content increase, starch increase, drought tolerance, cold tolerance, fiber yield increase.
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Methods are provided for hybrid seed production using 3-phyletic crosses between female, maintainer and male, particularly restorer lines, wherein the trait is introduced in the female line only at the stage of basic seed production via crossing of the female line with a maintainer line containing the gene or genes encoding the trait in homozygous state.1) A method for producing herbicide-tolerant hybrid seed using
a) a male-sterile plant line or A-line; b) a male-sterile plant line comprising a herbicide tolerance gene in heterozygous or hemizygous state or AHT-line; c) an isogenic maintainer plant line or B-line; d) an isogenic maintainer plant line comprising a herbicide tolerance gene in homozygous state or BHT-line; e) and a male fertile line which can be a restorer line or R-line comprising said herbicide tolerance gene in homozygous state; wherein said hybrid seed is produced by crossing plants grown from basic seed of the AHT-line and plants of the male fertile line or R-line and collecting the seeds produced on plants of the A-line, and wherein said basic seed of the AHT-line has been produced by crossing plants grown from pre-basic seed of the A-line with plants of the BHT-line and collecting the seeds produced on plants of the A-line, and wherein said pre-basic seed of the A-line has been produced by crossing plants grown from pre-basic seed of the A-line with plants of the B-line and collecting seeds produced on plants of the A-line. 2) A method for producing herbicide-tolerant hybrid seed using
a) a male-sterile plant line (A-line); b) a male-sterile plant line comprising a herbicide tolerance gene in heterozygous or hemizygous state (AHT-line); c) an isogenic maintainer plant line (B-line); d) an isogenic maintainer plant line comprising a herbicide tolerance gene in homozygous state (BHT-line); e) and a male fertile line which may be a restorer line comprising said herbicide tolerance gene in homozygous state (R-line); said method comprising the steps of i. producing pre-basic seed of the A-line by crossing plants grown from pre-basic seed of the A-line with plants of the B-line and collecting seeds produced on plants of the A-line; ii. producing basic seed of the AHT-line by crossing plants grown from said pre-basic seed of the A-line with plants of the BHT-line and collecting the seeds produced on plants of the A-line; and iii. producing hybrid seed by crossing plants grown from basic seed of the AHT-line and plants of the male fertile line or R-line and collecting the seeds produced on plants of the AHT-line. 3) In a method for producing herbicide tolerant hybrid seeds using a three-line hybridization system comprising a male-sterile plant line or A-line, an isogenic maintainer plant line or B-line and a male fertile line, particularly a restorer liner or R-line comprising a herbicide tolerance gene, the improvement of crossing a fourth isogenic maintainer line further comprising said herbicide tolerance gene in homozygous state with said male-sterile plant only at the stage of basic seed production and not at any pre-basic seed production stages. 4) The method of any one of claims 1 to 3, wherein said herbicide tolerance gene provides tolerance against a herbicide selected from the group of acetyl CoA carboxylase inhibitors, acetolactoate synthase inhibitors, glutamine synthetase inhibitors, 5-enoylpyruvyl-shikimate-3-phosphate inhibitors, photosynthesis II inhibitors, diterpene synthesis inhibitors, hydroxyphenylpyruvate dioxygenase inhibitors, protoporphorinogen oxidase inhibitors, photosystem I electron diverters, microtubule inhibitors, lipid synthesis inhibitors, long chain fatty acid inhibitors or synthetic auxins. 5) The method according to claim 4 wherein said acetyl CoA carboxylase inhibitor is an aryloxyphenoxypropionate including fenoxaprop, fluazifop or quizalafop. 6) The method according to claim 4 wherein said acetyl CoA carboxylase inhibitor is a cyclohanedione including clethodim or sethoxydim. 7) The method according to claim 4 wherein said acetolactoate synthase inhibitor is a sufonylurea such as chlorimuron, foramsulfuron, halosulfuron, iodosulfuron, nicosulfuron, primisulfuron, pro sulfuron, rimsulfuron, thifensulfuron or tribenuron. 8) The method according to claim 4 wherein said acetolactoate synthase inhibitor is a imidazolinone such as imazamox, imazaquin or imazethapyr. 9) The method according to claim 4 wherein said acetolactoate synthase inhibitor is a tryazolopyrimidine such as flumetsulam or cloransulam. 10) The method according to claim 4 wherein said acetolactoate synthase inhibitor is a triazolinone such as thiencarbazone. 11) The method according to claim 4 wherein said 5-enoylpyruvyl-shikimate-3-phosphate inhibitor is glyphosate. 12) The method according to claim 4 wherein said synthetic auxin is a phenoxy such as 2,4-D; or a benzoic acid such as dicamba or a carboxylic acid such as clopyralid or fluroxypyr, or a semicarbazone such as difluofenzopyr. 13) The method according to claim 4 wherein said photosynthesis system II inhibitor is a triazine such as atrazine or simazine. 14) The method according to claim 4 wherein said photosynthesis system II inhibitor is a triazinone such as metribuzin. 15) The method according to claim 4 wherein said photosynthesis system II inhibitor is a nitrile such as bromoxynil. 16) The method according to claim 4 wherein said photosynthesis system II inhibitor is a benzothiadazole such as bentazon. 17) The method according to claim 4 wherein said photosynthesis system II inhibitor is an urea such as linuron. 18) The method according to claim 4 wherein said glutamine synthase inhibitor is glufosinate. 19) The method according to claim 4 wherein said diterpene synthesis inhibitor is isoxazolidinone. 20) The method according to claim 4 wherein said HPPD inhibitor is an isoxazole including isoxaflutole or a pyrzolone including topramezone or a triketone including mesotrione and tembotrione. 21) The method according to claim 4 wherein said PPO inhibitor is a diphenylether including acifluorfen, formesafen, lactofen. 22) The method according to claim 4 wherein said PPO inhibitor is an N-phenylphtalimide including flumiclorac or flumioxazin. 23) The method according to claim 4 wherein said PPO inhibitor is an aryl triazinone including sulfentrazone, carfentrazone or fluthiacet-ethyl. 24) The method according to claim 4 wherein said PPO inhibitor is a pyrimidinedione such as saflufenacil. 25) The method according to claim 4 wherein said photosystem I electron diverter is a bipyridilium including paraquat. 26) The method according to claim 4 wherein said microtubule inhibitor is a dinitroaniline including ethalfluralin, pendimethalin or trifluralin. 27) The method according to claim 4, wherein said lipid synthesis inhibitor is a thiocarbamate including butylate or EPTC (S-ethyl-N,N-dipropylthiocarbamate). 28) The method according to claim 4, wherein said long-chain fatty acid inhibitor is a chloroacetamide including acetochlor, alachlor, metolachlor, dimethenamid or an oxyacetamide including flufenacet or a pyrazole including pyroxasulfone. 29) The method of any one of claims 1 to 3, wherein said herbicide tolerance is provided by a transgene. 30) The method of any one of claims 1 to 3, wherein said herbicide tolerance is provided by a variant allele endogenous to said plant. 31) The method of any one of claims 1 to 30 wherein said plant lines are plant lines of rice (Oryza sativa), wheat (Triticum aestivum), corn (Zea mays), cotton (Gossypium hirsutum or G. barbadense), soybean (Glycine max), sorghum (Sorghum bicolor), rapeseed (Brassica napus), mustard seed (Brassica juncea), barley (Hordeum vulgare), oat (Avena sativa), rye (Secale cereale), pearl millet (Pennisetum typhoides), alfalfa (Medicago sativa), tomato (Lycopersicon esculentum), sugar beet (Beta vulgaris), sunflower (Helianthus annuus), onion (Allium cepa), petunia (Petunia hybrida), carrot (Daucus carota), sorghum (Sorghum spp.), cabbage (Brassica oleracea), melons (Cucumis melo), watermelons (Citrillus lanatus) or cucumber (Cucumis sativus). 32) A method for producing hybrid seed comprising a trait of interest using
a) a male-sterile plant line or A-line; b) a male-sterile plant line comprising said trait of interest in heterozygous or hemizygous state or AGOI-line; c) an isogenic maintainer plant line or B-line; d) an isogenic maintainer plant line comprising said trait of interest in homozygous state or BGOI-line; e) and a male fertile line, particularly a restorer line or R-line comprising said trait of interest in homozygous state; wherein said hybrid seed is produced by crossing of basic seed of the AGOI-line and the male fertile line or R-line and collecting the seeds produced on plants of the A-line, and wherein said basic seed of the AGOI-line has been produced by crossing pre-basic seed of the A-line with pre-basic seed of the BGOI-line and collecting the seeds produced on plants of the AGOI-line, and wherein said pre-basic seed of the A-line has been produced by crossing pre-basic seed of the A-line with pre-basic seed of the B-line and collecting seeds produced on plants of the A-line. 33) The method of claim 32 wherein said agronomic trait of interest is selected from insect tolerance, herbicide tolerance, stress tolerance, yield increase, oil content increase, starch increase, drought tolerance, cold tolerance, fiber yield increase.
| 1,600 |
1,241 | 15,502,924 | 1,631 |
The present disclosure describes systems and methods for determining sources of infection transmission. Phylogenetic methods are used for determining the evolutionary history and replication rates of infection isolates. The evolutionary distance and/or replication rate of an infection isolate maybe compared to other isolates. Based on a comparison of the evolutionary distance and/or replication rate, a determination of the source of infection transmission is made.
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1. A method, comprising:
receiving an electronic data representative of an infection isolate sequence; comparing the electronic data representative of the infection isolate sequence to at least one reference sequence stored in a database to determine variants between the infection isolate sequence and the at least one reference sequence; determining at least a portion of an evolutionary history of the infection isolate based, at least in part, on the variants; calculating, based at least in part on the portion of the evolutionary history, an phylogenetic metric of the infection isolate; comparing the phylogenetic metric of the infection isolate to a phylogenetic metric of the at least one reference sequence; determining, based at least in part, on a difference between the phylogenetic metric of the infection isolate and the phylogenetic metric of the at least one reference sequence, whether the infection isolate was transmitted by a first reservoir or a second reservoir; and providing an indication of whether the infection isolate was transmitted by the first reservoir or second reservoir. 2. The method of claim 1, wherein the indication provided is for quarantining the first reservoir or second reservoir based, at least in part, on the determination of whether the infection isolate was transmitted by the first reservoir or second reservoir. 3. The method of claim 1, wherein the indication is text on an electronic display. 4. The method of claim 1, wherein determining at least a portion of the evolutionary history includes calculating an evolutionary distance. 5. The method of claim 4, wherein the evolutionary distance is calculated by the Jukes-Cantor Method. 6. The method of claim 1, wherein the phylogenetic metric is a mutation rate calculated by the Mean Path Lengths Method. 7. (canceled) 8. (canceled) 9. (canceled) 10. (canceled) 11. (canceled) 12. (canceled) 13. (canceled) 14. A method, comprising:
comparing, with at least one processing unit, a sequence of an infection isolate stored in a memory accessible by the at least one processing unit to at least one reference sequence stored in a database accessible to the at least one processing unit to determine variants between the infection isolate sequence and the at least one reference sequence; determining, with the at least one processing unit, an evolutionary distance of the infection isolate from the at least one reference sequence, based at least in part, on the variants; comparing, with the at least one processing unit, the evolutionary distance of the infection isolate to a distribution of evolutionary distances of a plurality of sequences stored in the database from the at least one reference sequence to determine whether the infection isolate was transmitted by a first reservoir or a second reservoir, based at least in part, on a difference of the evolutionary distance of the infection isolate and the distribution of evolutionary distances of the plurality of sequences; and providing to a user, with a display, the determination of whether the infection isolate was transmitted by the first reservoir or second reservoir. 15. The method of claim 14, wherein the determination of whether the infection isolate was transmitted by a first reservoir or a second reservoir is based, at least in part, on whether the evolutionary distance of the infection isolate falls within a desired confidence interval of the distribution of evolutionary distances of the plurality of sequences. 16. The method of claim 15, wherein the confidence interval is 95%. 17. The method of claim 14, wherein the distribution of evolutionary distances of the plurality of sequences is a plurality of distributions based on evolutionary distances of the plurality of sequences. 18. The method of claim 17, wherein a first one of the plurality of distributions based on evolutionary distances of the plurality of sequences corresponds to the first reservoir, and a second one of the plurality of distributions based on evolutionary distances of the plurality of sequences corresponds to the second reservoir. 19. The method of claim 18, wherein the determination whether the infection isolate was transmitted by the first reservoir or the second reservoir is based, at least in part, on a probability of whether the evolutionary distance of the infection isolate is included in the first one or the second one of the plurality of distributions based on evolutionary distances of the plurality of sequences. 20. The method of claim 14, further comprising storing the infection isolate sequence in the database as one of the plurality of sequences for use in a future determination of whether a new infection isolate was transmitted by the first reservoir or second reservoir. 21. (canceled) 22. (canceled) 23. (canceled) 24. (canceled) 25. The method of claim 1, wherein the first reservoir is a living organism and the second reservoir is a non-living domain. 26. The method of claim 25, further comprising providing a notice to a user to disinfect a piece of equipment if the indication is the infection isolate was transmitted by the non-living domain.
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The present disclosure describes systems and methods for determining sources of infection transmission. Phylogenetic methods are used for determining the evolutionary history and replication rates of infection isolates. The evolutionary distance and/or replication rate of an infection isolate maybe compared to other isolates. Based on a comparison of the evolutionary distance and/or replication rate, a determination of the source of infection transmission is made.1. A method, comprising:
receiving an electronic data representative of an infection isolate sequence; comparing the electronic data representative of the infection isolate sequence to at least one reference sequence stored in a database to determine variants between the infection isolate sequence and the at least one reference sequence; determining at least a portion of an evolutionary history of the infection isolate based, at least in part, on the variants; calculating, based at least in part on the portion of the evolutionary history, an phylogenetic metric of the infection isolate; comparing the phylogenetic metric of the infection isolate to a phylogenetic metric of the at least one reference sequence; determining, based at least in part, on a difference between the phylogenetic metric of the infection isolate and the phylogenetic metric of the at least one reference sequence, whether the infection isolate was transmitted by a first reservoir or a second reservoir; and providing an indication of whether the infection isolate was transmitted by the first reservoir or second reservoir. 2. The method of claim 1, wherein the indication provided is for quarantining the first reservoir or second reservoir based, at least in part, on the determination of whether the infection isolate was transmitted by the first reservoir or second reservoir. 3. The method of claim 1, wherein the indication is text on an electronic display. 4. The method of claim 1, wherein determining at least a portion of the evolutionary history includes calculating an evolutionary distance. 5. The method of claim 4, wherein the evolutionary distance is calculated by the Jukes-Cantor Method. 6. The method of claim 1, wherein the phylogenetic metric is a mutation rate calculated by the Mean Path Lengths Method. 7. (canceled) 8. (canceled) 9. (canceled) 10. (canceled) 11. (canceled) 12. (canceled) 13. (canceled) 14. A method, comprising:
comparing, with at least one processing unit, a sequence of an infection isolate stored in a memory accessible by the at least one processing unit to at least one reference sequence stored in a database accessible to the at least one processing unit to determine variants between the infection isolate sequence and the at least one reference sequence; determining, with the at least one processing unit, an evolutionary distance of the infection isolate from the at least one reference sequence, based at least in part, on the variants; comparing, with the at least one processing unit, the evolutionary distance of the infection isolate to a distribution of evolutionary distances of a plurality of sequences stored in the database from the at least one reference sequence to determine whether the infection isolate was transmitted by a first reservoir or a second reservoir, based at least in part, on a difference of the evolutionary distance of the infection isolate and the distribution of evolutionary distances of the plurality of sequences; and providing to a user, with a display, the determination of whether the infection isolate was transmitted by the first reservoir or second reservoir. 15. The method of claim 14, wherein the determination of whether the infection isolate was transmitted by a first reservoir or a second reservoir is based, at least in part, on whether the evolutionary distance of the infection isolate falls within a desired confidence interval of the distribution of evolutionary distances of the plurality of sequences. 16. The method of claim 15, wherein the confidence interval is 95%. 17. The method of claim 14, wherein the distribution of evolutionary distances of the plurality of sequences is a plurality of distributions based on evolutionary distances of the plurality of sequences. 18. The method of claim 17, wherein a first one of the plurality of distributions based on evolutionary distances of the plurality of sequences corresponds to the first reservoir, and a second one of the plurality of distributions based on evolutionary distances of the plurality of sequences corresponds to the second reservoir. 19. The method of claim 18, wherein the determination whether the infection isolate was transmitted by the first reservoir or the second reservoir is based, at least in part, on a probability of whether the evolutionary distance of the infection isolate is included in the first one or the second one of the plurality of distributions based on evolutionary distances of the plurality of sequences. 20. The method of claim 14, further comprising storing the infection isolate sequence in the database as one of the plurality of sequences for use in a future determination of whether a new infection isolate was transmitted by the first reservoir or second reservoir. 21. (canceled) 22. (canceled) 23. (canceled) 24. (canceled) 25. The method of claim 1, wherein the first reservoir is a living organism and the second reservoir is a non-living domain. 26. The method of claim 25, further comprising providing a notice to a user to disinfect a piece of equipment if the indication is the infection isolate was transmitted by the non-living domain.
| 1,600 |
1,242 | 11,616,658 | 1,618 |
Provided, among other things, is a delivery composition comprising: an aqueous carrier; a lipid component suspended in the carrier comprising significant amounts of type A lipid, fatty acid, and bilayer-stabilizing steroid(s), wherein type A lipid is one or more of any of phospholipid, ceramide(s) sphingomyelin(s) and glucocerebroside(s); and a bioactive agent, wherein (a) the delivery composition is packaged with a label with directions for mucosal, pulmonary or oral administration, and/or (b)(i) the viscosity of the composition is adjusted to a viscosity appropriate for spraying and/or (ii) the type A lipid comprises conjugate(s) of lipid-phase anchoring hydrophobic moieties and flexible, soluble polymers, and/or (iii) comprises a stabilizing effective amount of soluble polymers.
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1. A delivery composition comprising:
an aqueous carrier; a lipid component suspended in the carrier comprising significant amounts of type A lipid, fatty acid, and bilayer-stabilizing steroid(s), wherein type A lipid is one or more of any of phospholipid, ceramide(s) sphingomyelin(s) and glucocerebroside(s); and a bioactive agent, wherein (a) the delivery composition is packaged with a label with directions for mucosal, pulmonary or oral administration, and/or (b)(i) the viscosity of the composition is adjusted to a viscosity appropriate for spraying and/or (ii) the type A lipid comprises conjugate(s) of lipid-phase anchoring hydrophobic moieties and flexible, soluble polymers, and/or (iii) comprises a stabilizing effective amount of soluble polymers. 2. The delivery composition of claim 1, wherein the lipid component comprises
a lipid particle component comprising significant amounts of said lipids; and optionally, a vesicle component comprising vesicles enclosed by substantially a single lipid bilayer, the bilayers comprising significant amounts of said lipids. 3. The delivery composition of claim 2, wherein the bioactive agent is sufficiently hydrophobic to associate with the lipid component. 4. The delivery composition of claim 2, wherein the bioactive agent is a polypeptide. 5. The delivery composition of claim 2, wherein the lipid component comprises the vesicle component. 6. The delivery composition of claim 5, wherein the vesicles of the vesicle component have average diameter of 500 nm or less. 7. The delivery composition of claim 5, wherein the lipid particle component present in an amount effective to increase retention of the vesicle component at a mucosal surface. 8. The delivery composition of claim 5, wherein the bioactive agent is sufficiently hydrophobic to associate with the lipid component. 9. The delivery composition of claim 5, wherein the bioactive agent is a polypeptide. 10. The delivery composition of claim 1, wherein the bioactive agent is sufficiently hydrophobic to associate with the lipid component. 11. The delivery composition of claim 1, wherein the bioactive agent is a polypeptide. 12. The delivery composition of claim 1, wherein (b) the type A lipid comprises conjugate(s) of lipid-phase anchoring hydrophobic moieties and flexible, soluble polymers. 13. The delivery composition of claim 12, wherein the lipid component comprises
a lipid particle component; and optionally, a vesicle component comprising vesicles enclosed by substantially a single lipid bilayer. 14. The delivery composition of claim 13, wherein the bioactive agent is sufficiently hydrophobic to associate with the lipid component. 15. The delivery composition of claim 13, wherein the bioactive agent is a polypeptide. 16. The delivery composition of claim 13, wherein the lipid component comprises the vesicle component. 17. The delivery composition of claim 16, wherein the vesicles of the vesicle component have average diameter of 500 nm or less. 18. The delivery composition of claim 16, wherein the lipid particle component present in an amount effective to increase retention of the vesicle component at a mucosal surface. 19. The delivery composition of claim 16, wherein the bioactive agent is sufficiently hydrophobic to associate with the lipid component. 20. The delivery composition of claim 16, wherein the bioactive agent is a polypeptide. 21. The delivery composition of claim 12, wherein the bioactive agent is sufficiently hydrophobic to associate with the lipid component. 22. The delivery composition of claim 12, wherein the bioactive agent is a polypeptide. 23. The delivery composition of claim 1, wherein the composition is packaged with a label with directions for nasal administration. 24. The delivery composition of claim 1, wherein the composition is packaged with a label with directions for pulmonary administration. 25. The delivery composition of claim 1, wherein the composition is packaged with a label with directions for oral administration. 26. The delivery composition of claim 2, wherein the composition is made by
(i) forming a first intermediate lipid component comprising significant amounts of type A lipid, fatty acid, and bilayer-stabilizing steroid(s) and substantially comprising the lipid particles; (ii) forming a second intermediate lipid component comprising significant amounts of type A lipid, fatty acid, and bilayer-stabilizing steroid(s) and substantially comprising the lipid vesicles; and (iii) mixing (i) and (ii). 27. A method of forming a delivery composition of claim 2 comprising:
(i) forming a first intermediate lipid component comprising significant amounts of type A lipid, fatty acid, and bilayer-stabilizing steroid(s) and substantially comprising the lipid particles; (ii) forming a second intermediate lipid component comprising significant amounts of type A lipid, fatty acid, and bilayer-stabilizing steroid(s) and substantially comprising the lipid vesicles; and (iii) mixing (i) and (ii). 28. A method of optimizing a delivery composition of claim 2 comprising:
forming two or more such delivery compositions by
(i) forming a first intermediate lipid component comprising significant amounts of type A lipid, fatty acid, and bilayer-stabilizing steroid(s) and substantially comprising the lipid particles,
(ii) forming a second intermediate lipid component comprising significant amounts of type A lipid, fatty acid, and bilayer-stabilizing steroid(s) and substantially comprising the lipid vesicles, and
(iii) mixing (i) and (ii),
wherein the two or more delivery compositions vary by the lipid composition of (i) or (ii), or by varying the incorporation of bioactive agent into said lipid vesicles;
testing one or more pharmacokinetic parameters of the delivery compositions; and identifying one or a subset of the delivery compositions with more favorable pharmacokinetic parameters. 29. A delivery device for a transmucosal composition comprising:
liquid vessel(s) containing the delivery composition of claim 1; and a sprayer situated to accept and spray delivery composition from the vessel. 30. A method of treating a disease, disorder or condition comprising administering the delivery composition of claim 1 to a mucosal, lung or intestinal surface of a subject in need of the bioactive agent. 31. The method of claim 30, wherein the composition is delivered to a nasal mucosal surface. 32. The method of claim 30, wherein the composition is delivered to the lung. 33. The method of claim 30, wherein the composition is delivered orally. 34. The method of claim 30, wherein the composition is delivered to a buccal mucosal surface. 35. A delivery composition comprising:
a composition formed from lyophilization to remove water comprising
a lipid component suspended in the carrier comprising significant amounts of type A lipid, fatty acid, and bilayer-stabilizing steroid(s), wherein type A lipid is one or more of any of phospholipid, ceramide(s) sphingomyelin(s) and glucocerebroside(s); and
a bioactive agent;
wherein the delivery composition has been formulated for oral delivery by compression, encapsulation, or coating. 36. A delivery composition comprising:
a composition formed from lyophilization to remove water comprising
a lipid component suspended in the carrier comprising significant amounts of type A lipid, fatty acid, and bilayer-stabilizing steroid(s), wherein type A lipid is one or more of any of phospholipid, ceramide(s) sphingomyelin(s) and glucocerebroside(s); and
a bioactive agent;
wherein the composition is packaged with a label with directions for pulmonary administration.
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Provided, among other things, is a delivery composition comprising: an aqueous carrier; a lipid component suspended in the carrier comprising significant amounts of type A lipid, fatty acid, and bilayer-stabilizing steroid(s), wherein type A lipid is one or more of any of phospholipid, ceramide(s) sphingomyelin(s) and glucocerebroside(s); and a bioactive agent, wherein (a) the delivery composition is packaged with a label with directions for mucosal, pulmonary or oral administration, and/or (b)(i) the viscosity of the composition is adjusted to a viscosity appropriate for spraying and/or (ii) the type A lipid comprises conjugate(s) of lipid-phase anchoring hydrophobic moieties and flexible, soluble polymers, and/or (iii) comprises a stabilizing effective amount of soluble polymers.1. A delivery composition comprising:
an aqueous carrier; a lipid component suspended in the carrier comprising significant amounts of type A lipid, fatty acid, and bilayer-stabilizing steroid(s), wherein type A lipid is one or more of any of phospholipid, ceramide(s) sphingomyelin(s) and glucocerebroside(s); and a bioactive agent, wherein (a) the delivery composition is packaged with a label with directions for mucosal, pulmonary or oral administration, and/or (b)(i) the viscosity of the composition is adjusted to a viscosity appropriate for spraying and/or (ii) the type A lipid comprises conjugate(s) of lipid-phase anchoring hydrophobic moieties and flexible, soluble polymers, and/or (iii) comprises a stabilizing effective amount of soluble polymers. 2. The delivery composition of claim 1, wherein the lipid component comprises
a lipid particle component comprising significant amounts of said lipids; and optionally, a vesicle component comprising vesicles enclosed by substantially a single lipid bilayer, the bilayers comprising significant amounts of said lipids. 3. The delivery composition of claim 2, wherein the bioactive agent is sufficiently hydrophobic to associate with the lipid component. 4. The delivery composition of claim 2, wherein the bioactive agent is a polypeptide. 5. The delivery composition of claim 2, wherein the lipid component comprises the vesicle component. 6. The delivery composition of claim 5, wherein the vesicles of the vesicle component have average diameter of 500 nm or less. 7. The delivery composition of claim 5, wherein the lipid particle component present in an amount effective to increase retention of the vesicle component at a mucosal surface. 8. The delivery composition of claim 5, wherein the bioactive agent is sufficiently hydrophobic to associate with the lipid component. 9. The delivery composition of claim 5, wherein the bioactive agent is a polypeptide. 10. The delivery composition of claim 1, wherein the bioactive agent is sufficiently hydrophobic to associate with the lipid component. 11. The delivery composition of claim 1, wherein the bioactive agent is a polypeptide. 12. The delivery composition of claim 1, wherein (b) the type A lipid comprises conjugate(s) of lipid-phase anchoring hydrophobic moieties and flexible, soluble polymers. 13. The delivery composition of claim 12, wherein the lipid component comprises
a lipid particle component; and optionally, a vesicle component comprising vesicles enclosed by substantially a single lipid bilayer. 14. The delivery composition of claim 13, wherein the bioactive agent is sufficiently hydrophobic to associate with the lipid component. 15. The delivery composition of claim 13, wherein the bioactive agent is a polypeptide. 16. The delivery composition of claim 13, wherein the lipid component comprises the vesicle component. 17. The delivery composition of claim 16, wherein the vesicles of the vesicle component have average diameter of 500 nm or less. 18. The delivery composition of claim 16, wherein the lipid particle component present in an amount effective to increase retention of the vesicle component at a mucosal surface. 19. The delivery composition of claim 16, wherein the bioactive agent is sufficiently hydrophobic to associate with the lipid component. 20. The delivery composition of claim 16, wherein the bioactive agent is a polypeptide. 21. The delivery composition of claim 12, wherein the bioactive agent is sufficiently hydrophobic to associate with the lipid component. 22. The delivery composition of claim 12, wherein the bioactive agent is a polypeptide. 23. The delivery composition of claim 1, wherein the composition is packaged with a label with directions for nasal administration. 24. The delivery composition of claim 1, wherein the composition is packaged with a label with directions for pulmonary administration. 25. The delivery composition of claim 1, wherein the composition is packaged with a label with directions for oral administration. 26. The delivery composition of claim 2, wherein the composition is made by
(i) forming a first intermediate lipid component comprising significant amounts of type A lipid, fatty acid, and bilayer-stabilizing steroid(s) and substantially comprising the lipid particles; (ii) forming a second intermediate lipid component comprising significant amounts of type A lipid, fatty acid, and bilayer-stabilizing steroid(s) and substantially comprising the lipid vesicles; and (iii) mixing (i) and (ii). 27. A method of forming a delivery composition of claim 2 comprising:
(i) forming a first intermediate lipid component comprising significant amounts of type A lipid, fatty acid, and bilayer-stabilizing steroid(s) and substantially comprising the lipid particles; (ii) forming a second intermediate lipid component comprising significant amounts of type A lipid, fatty acid, and bilayer-stabilizing steroid(s) and substantially comprising the lipid vesicles; and (iii) mixing (i) and (ii). 28. A method of optimizing a delivery composition of claim 2 comprising:
forming two or more such delivery compositions by
(i) forming a first intermediate lipid component comprising significant amounts of type A lipid, fatty acid, and bilayer-stabilizing steroid(s) and substantially comprising the lipid particles,
(ii) forming a second intermediate lipid component comprising significant amounts of type A lipid, fatty acid, and bilayer-stabilizing steroid(s) and substantially comprising the lipid vesicles, and
(iii) mixing (i) and (ii),
wherein the two or more delivery compositions vary by the lipid composition of (i) or (ii), or by varying the incorporation of bioactive agent into said lipid vesicles;
testing one or more pharmacokinetic parameters of the delivery compositions; and identifying one or a subset of the delivery compositions with more favorable pharmacokinetic parameters. 29. A delivery device for a transmucosal composition comprising:
liquid vessel(s) containing the delivery composition of claim 1; and a sprayer situated to accept and spray delivery composition from the vessel. 30. A method of treating a disease, disorder or condition comprising administering the delivery composition of claim 1 to a mucosal, lung or intestinal surface of a subject in need of the bioactive agent. 31. The method of claim 30, wherein the composition is delivered to a nasal mucosal surface. 32. The method of claim 30, wherein the composition is delivered to the lung. 33. The method of claim 30, wherein the composition is delivered orally. 34. The method of claim 30, wherein the composition is delivered to a buccal mucosal surface. 35. A delivery composition comprising:
a composition formed from lyophilization to remove water comprising
a lipid component suspended in the carrier comprising significant amounts of type A lipid, fatty acid, and bilayer-stabilizing steroid(s), wherein type A lipid is one or more of any of phospholipid, ceramide(s) sphingomyelin(s) and glucocerebroside(s); and
a bioactive agent;
wherein the delivery composition has been formulated for oral delivery by compression, encapsulation, or coating. 36. A delivery composition comprising:
a composition formed from lyophilization to remove water comprising
a lipid component suspended in the carrier comprising significant amounts of type A lipid, fatty acid, and bilayer-stabilizing steroid(s), wherein type A lipid is one or more of any of phospholipid, ceramide(s) sphingomyelin(s) and glucocerebroside(s); and
a bioactive agent;
wherein the composition is packaged with a label with directions for pulmonary administration.
| 1,600 |
1,243 | 15,632,233 | 1,615 |
The present disclosure is directed toward drug coated balloons, and in particular to drug coated balloons having a microcrystalline structure and techniques for increasing vascular permeability for drug application and retention. Particular aspects may be directed to a medical device including a balloon having an outer surface, and a drug coating layer on the outer surface of the balloon. The drug coating layer includes microcrystals in a haystack orientation having random and a substantial absence of uniformity in placement and/or angle on the outer surface of the balloon.
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1. A medical device comprising:
a balloon comprising an outer surface; and a drug coating layer on the outer surface of the balloon, wherein the drug coating layer comprises microcrystals in a haystack orientation having random and a substantial absence of uniformity in placement on the outer surface of the balloon. 2. The medical device of claim 1, wherein the microcrystals have a random and a substantial absence of uniformity in angles from the outer surface of the balloon. 3. The medical device of claim 1, wherein the drug coating comprises paclitaxel. 4. The medical device of claim 1, wherein the outer surface of the balloon comprises a non-porous polymer. 5. The medical device of claim 1, wherein the outer surface of the balloon comprises a porous polymer. 6. The medical device of claim 1, wherein the balloon comprises a layer material, wherein the layered material comprises a polymer layer adhered to a fluoropolymer layer comprising a porous microstructure, wherein layers are in overlying relationship to each other and the fluoropolymer layer is an outermost layer. 7. The medical device of claim 6, wherein the drug coating layer penetrates the outer surface of the balloon by an average penetration depth of from 2 to 10 m. 8. A medical balloon comprising:
a thermoplastic polymeric layer defining an interior chamber; a polymeric layer over at least a portion of the thermoplastic polymeric layer; and a coating layer on at least a portion of the polymeric layer, wherein the coating layer comprises a therapeutic agent and an excipient; and wherein the coating layer comprises microcrystals in a haystack orientation having random and a substantial absence of uniformity in placement on an outer surface of the polymeric layer. 9. The medical balloon of claim 8, wherein the polymeric layer is porous. 10. The medical balloon of claim 8, wherein the polymeric layer is non-porous. 11. The medical balloon of claim 8, wherein a majority of the microcrystals each have a major dimension length that is at least 10 times greater than a major dimension width of the microcrystal. 12. The medical balloon of claim 8, wherein the microcrystals have a random and a substantial absence of uniformity in angles from the outer surface of the polymeric layer, and a majority of the microcrystals project from the outer surface at an angle of 50 to 15°. 13. The medical balloon of claim 8, wherein the therapeutic agent comprises paclitaxel, docetaxel, protaxel, arsenic trioxide, thalidomide, atorvastatin, cerivastatin, fluvastatin, betamethasone diproprionate, dexamethasone 21-palmitate, sirolimus, everolimus, zotarolimus, biolimus or temsirolimus. 14. The medical balloon of claim 8, wherein the coating layer comprises the therapeutic agent and the excipient in a predetermined weight ratio of between 3:1 and 20:1. 15. The medical balloon of claim 8, wherein a majority of the microcrystals each have a major dimension length that is at least 13 or at least 15 times a major dimension width. 16. The medical balloon of claim 8, wherein a majority of the microcrystals each have a major dimension length that is between 12 μm and 22 μm, and the majority of the microcrystals each have a major dimension width that is between 0.5 μm and 2 μm. 17. The medical balloon of claim 8, wherein when the medical balloon is inflated in a vessel lumen for one minute, at least a portion of the coating layer transfers to at least a portion of the vessel lumen such that one hour after the inflation at least 14% of the portion of the vessel lumen is covered by the coating layer. 18. The medical balloon of claim 8, wherein when the medical balloon is inflated in a vessel lumen for one minute, at least a portion of the coating layer transfers to at least a portion of the vessel lumen such that one hour after the inflation at least 12% of a portion of a surface of the vessel lumen is covered by the coating layer. 19. The medical balloon of claim 8, wherein when the medical balloon is inflated in a vessel lumen for one minute, at least a portion of the coating layer uniformly transfers to the vessel lumen along a length of the vessel lumen. 20. A method for preparing a tissue for drug application whereby tissue retention is improved, comprising:
a) providing one or more medical devices comprising a balloon comprising an outer surface and a drug coating on the outer surface of the balloon; and b) sequentially treating a vascular treatment site n times with the one or more medical devices, wherein a dose amount of a drug from the drug coating that is retained by the tissue at one hour after the sequential treating is greater than the n times a dose amount retained by the tissue at one hour after a single treatment. 21. The method of claim 20, wherein the dose amount retained in the tissue at the one hour after the sequential treatment is about six times the dose amount retained by the tissue at the one hour after the single treatment, wherein the dose amount retained by the tissue at the one hour after the single treatment is from 1% to 10% of a loaded dose of the drug coating. 22. The method of claim 20, wherein a half-life of the drug retained in the tissue after the sequential treatment is greater than 13 hours. 23. The method of claim 20, wherein the balloon is configured to release from 65% to 85% of drug from the drug coating upon inflation. 24. The method of claim 20, wherein a dose amount of the drug retained in the tissue at the one hour after the sequentially treating is greater than 750 μg/g. 25. The method of claim 20, wherein a dose amount of the drug retained in the tissue at the one hour after the sequentially treating is greater than 1150 μg/g. 26. The method of claim 20, wherein the dose amount of the drug retained in the tissue at the one hour after the sequentially treating is greater than 50 μg/g. 27. The method of claim 20, wherein the dose amount of the drug retained in the tissue at the one day after the sequentially treating is greater than 1 μg/g. 28. A method for preparing a vessel for drug application whereby tissue retention is improved, comprising:
a) providing a medical device comprising a balloon comprising an outer surface and a drug coating on the outer surface of the balloon, wherein the drug coating comprises microcrystals in a haystack orientation having random and a substantial absence of uniformity in placement on the outer surface of the balloon; and b) treating a vascular treatment site with the medical device. 29. The method of claim 28, wherein the drug coating comprises paclitaxel, the treating includes inflating the balloon at the treatment site for 1 minute, and when the balloon is inflated at the treatment site for 1 minute, less than about 35% of the drug coating remains on the outer surface of the balloon. 30. The method of claim 28, wherein the balloon comprises a porous material, and wherein the drug coating comprises paclitaxel, the treating includes inflating the balloon at the treatment site for 1 minute, and when the balloon is inflated at the treatment site for 1 minute, between about 15% and about 30% of the drug coating remains on the outer surface of the balloon. 31. The method of claim 28, wherein the balloon comprises a non-porous material, and wherein the drug coating comprises paclitaxel, the treating includes inflating the balloon at the treatment site for 1 minute, and when the balloon is inflated at the treatment site for 1 minute, less than about 10% of the drug coating remains on the outer surface of the balloon. 32. The method of claim 28, wherein the drug coating comprises paclitaxel at a dose of 3-4 μg/mm2. 33. The method of claim 32, wherein a dose amount of a drug from the drug coating retained in the tissue at one hour after the treating is greater than 5% of a load dose amount on the balloon. 34. The method of claim 32, wherein the balloon comprises a porous material, and a dose amount of a drug from the drug coating retained in the tissue at 72 hours after the treating is greater than 2% of a load dose amount on the balloon. 35. The method of claim 32, wherein the balloon comprises a porous material, and a dose amount of a drug from the drug coating layer retained in the tissue at one hour after the treating is greater than 50 μg/g. 36. The method of claim 32, wherein the balloon comprises a non-porous material, and an enface tissue coating at one hour after the treating is greater than 12%. 37. The method of claim 32, wherein the balloon comprises a porous material, and an enface tissue coating at one hour after the treating is greater than 15%. 38. A medical device comprising:
a) an elongate catheter shaft having a proximal section, a distal section, and an inflation lumen; b) a balloon on the distal section of the shaft and comprising a balloon wall defining a chamber and comprising a layered material, wherein the layered material comprises a polymer layer adhered to a fluoropolymer layer comprising a porous microstructure, wherein the polymer layer and the fluoropolymer layer are in an overlying relationship to each other and the fluoropolymer layer is an outermost layer; and c) a drug coating on the fluoropolymer layer, wherein the drug coating has microcrystals in a haystack orientation having random and a substantial absence of uniformity in placement on the balloon. 39. The medical device of claim 38, wherein the drug coating comprises paclitaxel and an excipient. 40. The medical device of claim 39, wherein the drug coating comprises paclitaxel and the excipient in a predetermined weight ratio of between 3:1 and 20:1 41. The medical device of claim 38, wherein a dose density of the drug coating is from 2.0 to 7.0 μg/mm2. 42. The medical device of claim 38, wherein the balloon is configured to release from 70% to 85% of a drug from the drug coating upon an inflation time of about 60 seconds. 43. The medical device of claim 38, wherein the microcrystals have a random and a substantial absence of uniformity in angles from the fluoropolymer layer, and a majority of the microcrystals project from the outer surface at an angle of 5° to 15°. 44. The medical device of claim 38, wherein the drug coating penetrates the fluoropolymer layer by an average penetration depth of from 2 to 10 μm.
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The present disclosure is directed toward drug coated balloons, and in particular to drug coated balloons having a microcrystalline structure and techniques for increasing vascular permeability for drug application and retention. Particular aspects may be directed to a medical device including a balloon having an outer surface, and a drug coating layer on the outer surface of the balloon. The drug coating layer includes microcrystals in a haystack orientation having random and a substantial absence of uniformity in placement and/or angle on the outer surface of the balloon.1. A medical device comprising:
a balloon comprising an outer surface; and a drug coating layer on the outer surface of the balloon, wherein the drug coating layer comprises microcrystals in a haystack orientation having random and a substantial absence of uniformity in placement on the outer surface of the balloon. 2. The medical device of claim 1, wherein the microcrystals have a random and a substantial absence of uniformity in angles from the outer surface of the balloon. 3. The medical device of claim 1, wherein the drug coating comprises paclitaxel. 4. The medical device of claim 1, wherein the outer surface of the balloon comprises a non-porous polymer. 5. The medical device of claim 1, wherein the outer surface of the balloon comprises a porous polymer. 6. The medical device of claim 1, wherein the balloon comprises a layer material, wherein the layered material comprises a polymer layer adhered to a fluoropolymer layer comprising a porous microstructure, wherein layers are in overlying relationship to each other and the fluoropolymer layer is an outermost layer. 7. The medical device of claim 6, wherein the drug coating layer penetrates the outer surface of the balloon by an average penetration depth of from 2 to 10 m. 8. A medical balloon comprising:
a thermoplastic polymeric layer defining an interior chamber; a polymeric layer over at least a portion of the thermoplastic polymeric layer; and a coating layer on at least a portion of the polymeric layer, wherein the coating layer comprises a therapeutic agent and an excipient; and wherein the coating layer comprises microcrystals in a haystack orientation having random and a substantial absence of uniformity in placement on an outer surface of the polymeric layer. 9. The medical balloon of claim 8, wherein the polymeric layer is porous. 10. The medical balloon of claim 8, wherein the polymeric layer is non-porous. 11. The medical balloon of claim 8, wherein a majority of the microcrystals each have a major dimension length that is at least 10 times greater than a major dimension width of the microcrystal. 12. The medical balloon of claim 8, wherein the microcrystals have a random and a substantial absence of uniformity in angles from the outer surface of the polymeric layer, and a majority of the microcrystals project from the outer surface at an angle of 50 to 15°. 13. The medical balloon of claim 8, wherein the therapeutic agent comprises paclitaxel, docetaxel, protaxel, arsenic trioxide, thalidomide, atorvastatin, cerivastatin, fluvastatin, betamethasone diproprionate, dexamethasone 21-palmitate, sirolimus, everolimus, zotarolimus, biolimus or temsirolimus. 14. The medical balloon of claim 8, wherein the coating layer comprises the therapeutic agent and the excipient in a predetermined weight ratio of between 3:1 and 20:1. 15. The medical balloon of claim 8, wherein a majority of the microcrystals each have a major dimension length that is at least 13 or at least 15 times a major dimension width. 16. The medical balloon of claim 8, wherein a majority of the microcrystals each have a major dimension length that is between 12 μm and 22 μm, and the majority of the microcrystals each have a major dimension width that is between 0.5 μm and 2 μm. 17. The medical balloon of claim 8, wherein when the medical balloon is inflated in a vessel lumen for one minute, at least a portion of the coating layer transfers to at least a portion of the vessel lumen such that one hour after the inflation at least 14% of the portion of the vessel lumen is covered by the coating layer. 18. The medical balloon of claim 8, wherein when the medical balloon is inflated in a vessel lumen for one minute, at least a portion of the coating layer transfers to at least a portion of the vessel lumen such that one hour after the inflation at least 12% of a portion of a surface of the vessel lumen is covered by the coating layer. 19. The medical balloon of claim 8, wherein when the medical balloon is inflated in a vessel lumen for one minute, at least a portion of the coating layer uniformly transfers to the vessel lumen along a length of the vessel lumen. 20. A method for preparing a tissue for drug application whereby tissue retention is improved, comprising:
a) providing one or more medical devices comprising a balloon comprising an outer surface and a drug coating on the outer surface of the balloon; and b) sequentially treating a vascular treatment site n times with the one or more medical devices, wherein a dose amount of a drug from the drug coating that is retained by the tissue at one hour after the sequential treating is greater than the n times a dose amount retained by the tissue at one hour after a single treatment. 21. The method of claim 20, wherein the dose amount retained in the tissue at the one hour after the sequential treatment is about six times the dose amount retained by the tissue at the one hour after the single treatment, wherein the dose amount retained by the tissue at the one hour after the single treatment is from 1% to 10% of a loaded dose of the drug coating. 22. The method of claim 20, wherein a half-life of the drug retained in the tissue after the sequential treatment is greater than 13 hours. 23. The method of claim 20, wherein the balloon is configured to release from 65% to 85% of drug from the drug coating upon inflation. 24. The method of claim 20, wherein a dose amount of the drug retained in the tissue at the one hour after the sequentially treating is greater than 750 μg/g. 25. The method of claim 20, wherein a dose amount of the drug retained in the tissue at the one hour after the sequentially treating is greater than 1150 μg/g. 26. The method of claim 20, wherein the dose amount of the drug retained in the tissue at the one hour after the sequentially treating is greater than 50 μg/g. 27. The method of claim 20, wherein the dose amount of the drug retained in the tissue at the one day after the sequentially treating is greater than 1 μg/g. 28. A method for preparing a vessel for drug application whereby tissue retention is improved, comprising:
a) providing a medical device comprising a balloon comprising an outer surface and a drug coating on the outer surface of the balloon, wherein the drug coating comprises microcrystals in a haystack orientation having random and a substantial absence of uniformity in placement on the outer surface of the balloon; and b) treating a vascular treatment site with the medical device. 29. The method of claim 28, wherein the drug coating comprises paclitaxel, the treating includes inflating the balloon at the treatment site for 1 minute, and when the balloon is inflated at the treatment site for 1 minute, less than about 35% of the drug coating remains on the outer surface of the balloon. 30. The method of claim 28, wherein the balloon comprises a porous material, and wherein the drug coating comprises paclitaxel, the treating includes inflating the balloon at the treatment site for 1 minute, and when the balloon is inflated at the treatment site for 1 minute, between about 15% and about 30% of the drug coating remains on the outer surface of the balloon. 31. The method of claim 28, wherein the balloon comprises a non-porous material, and wherein the drug coating comprises paclitaxel, the treating includes inflating the balloon at the treatment site for 1 minute, and when the balloon is inflated at the treatment site for 1 minute, less than about 10% of the drug coating remains on the outer surface of the balloon. 32. The method of claim 28, wherein the drug coating comprises paclitaxel at a dose of 3-4 μg/mm2. 33. The method of claim 32, wherein a dose amount of a drug from the drug coating retained in the tissue at one hour after the treating is greater than 5% of a load dose amount on the balloon. 34. The method of claim 32, wherein the balloon comprises a porous material, and a dose amount of a drug from the drug coating retained in the tissue at 72 hours after the treating is greater than 2% of a load dose amount on the balloon. 35. The method of claim 32, wherein the balloon comprises a porous material, and a dose amount of a drug from the drug coating layer retained in the tissue at one hour after the treating is greater than 50 μg/g. 36. The method of claim 32, wherein the balloon comprises a non-porous material, and an enface tissue coating at one hour after the treating is greater than 12%. 37. The method of claim 32, wherein the balloon comprises a porous material, and an enface tissue coating at one hour after the treating is greater than 15%. 38. A medical device comprising:
a) an elongate catheter shaft having a proximal section, a distal section, and an inflation lumen; b) a balloon on the distal section of the shaft and comprising a balloon wall defining a chamber and comprising a layered material, wherein the layered material comprises a polymer layer adhered to a fluoropolymer layer comprising a porous microstructure, wherein the polymer layer and the fluoropolymer layer are in an overlying relationship to each other and the fluoropolymer layer is an outermost layer; and c) a drug coating on the fluoropolymer layer, wherein the drug coating has microcrystals in a haystack orientation having random and a substantial absence of uniformity in placement on the balloon. 39. The medical device of claim 38, wherein the drug coating comprises paclitaxel and an excipient. 40. The medical device of claim 39, wherein the drug coating comprises paclitaxel and the excipient in a predetermined weight ratio of between 3:1 and 20:1 41. The medical device of claim 38, wherein a dose density of the drug coating is from 2.0 to 7.0 μg/mm2. 42. The medical device of claim 38, wherein the balloon is configured to release from 70% to 85% of a drug from the drug coating upon an inflation time of about 60 seconds. 43. The medical device of claim 38, wherein the microcrystals have a random and a substantial absence of uniformity in angles from the fluoropolymer layer, and a majority of the microcrystals project from the outer surface at an angle of 5° to 15°. 44. The medical device of claim 38, wherein the drug coating penetrates the fluoropolymer layer by an average penetration depth of from 2 to 10 μm.
| 1,600 |
1,244 | 14,549,467 | 1,636 |
Provided are detection means and method specific for the genus Cronobacter ( E. sakazakii ) which are sensitive by using a target molecule which is multiple existent in Cronobacter cells.
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1-15. (canceled) 16. A kit for the detection of the genus Cronobacter comprising
a nucleic acid comprising SEQ ID NO:2 or a variant thereof, together with a nucleic acid comprising SEQ ID NO:3 or a variant thereof, wherein the variant is
a) a sequence which is at least 90% identical to SEQ ID NO:2 or SEQ ID NO:3, respectively or
b) the complement of a). 17. The kit of claim 16, further comprising
a nucleic acid comprising SEQ ID NOs:8 and 9 or a variant thereof, together with a nucleic acid comprising SEQ ID NO:21 or a variant thereof, wherein the variant is
c) a sequence which is at least 90% identical to SEQ ID NO:8 or 9, or SEQ ID NO:21, respectively or
d) the complement of c). 18. The kit of claim 16, further comprising one or more nucleic acids comprising SEQ ID NOs: 4 to 7 or a variant thereof, together with a nucleic acid comprising SEQ ID NO:20 or a variant thereof,
wherein the variant is
e) a sequence which is at least 90% identical to any of SEQ ID NOs:4 to 7, or SEQ ID NO:20, respectively or
f) the complement of e). 19. The kit of claim 17, further comprising one or more nucleic acids comprising SEQ ID NOs: 4 to 7 or a variant thereof, together with a nucleic acid comprising SEQ ID NO:20 or a variant thereof,
wherein the variant is
e) sequence which is at least 90% identical to any of SEQ ID NOs:4 to 7, or SEQ ID NO:20, respectively or
f) the complement of e). 20. A method of using the kit of claim 16 for the detection of the genus Cronobacter. 21. A method of using the kit of claim 17 for the detection of the genus Cronobacter, wherein the kit is suitable for discrimination of Cronobacter turicensis against other species. 22. A method for amplifying bacterial DNA of the taxonomic unit genus Cronobacter, using primers, in which
a) in a first amplification step the DNA of the genus Cronobacter is amplified with primers, wherein the primers used in the first amplification step comprise the nucleic acids of the kit as defined in claim 16. 23. The method of claim 22, wherein
b) in a further detection step, the DNA fragments obtained by amplification step a) which are specific for the genus Cronobacter are detected by means of probes, wherein the probes used in step b) comprise nucleic acids comprising SEQ ID NOs:8 and 9 or a variant thereof, wherein the variant is a sequence which is at least 90% identical to SEQ ID NO:8 or 9, respectively, which are specific for the genus Cronobacter. 24. The method of claim 22, wherein
c) in a further detection step, the DNA fragments obtained by amplification step a) which are specific for the species Cronobacter turicensis are detected by means of probes, wherein the probes used in step c) comprise a nucleic acid comprising SEQ ID NO:21 or a variant thereof, wherein the variant is a sequence which is at least 90% identical to SEQ ID NO:21. 25. The method of claim 22, wherein
d) in at least one further amplification step the DNA of the taxonomic unit Enterobacteriaceae is amplified with conserved primers. 26. The method of claim 25, wherein
e) in a further detection step, the DNA fragments obtained by amplification step d), which are specific for the genus Enterobacteriaceae, are detected by means of probes. 27. The method of claim 22, including a step of amplifying an amplification control nucleic acid, which is added during amplification step a), wherein the amplification control nucleic acid is SEQ ID NO:22. 28. The method of claim 23, further including a melting curve analysis, wherein C. turicensis is discriminated against other Cronobacter species. 29. The method of claim 22, wherein viable cells of the genus Cronobacter or of other Enterobacteriaceae are discriminated against respective non-viable Cronobacter or other non-viable Enterobacteriaceae cells.
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Provided are detection means and method specific for the genus Cronobacter ( E. sakazakii ) which are sensitive by using a target molecule which is multiple existent in Cronobacter cells.1-15. (canceled) 16. A kit for the detection of the genus Cronobacter comprising
a nucleic acid comprising SEQ ID NO:2 or a variant thereof, together with a nucleic acid comprising SEQ ID NO:3 or a variant thereof, wherein the variant is
a) a sequence which is at least 90% identical to SEQ ID NO:2 or SEQ ID NO:3, respectively or
b) the complement of a). 17. The kit of claim 16, further comprising
a nucleic acid comprising SEQ ID NOs:8 and 9 or a variant thereof, together with a nucleic acid comprising SEQ ID NO:21 or a variant thereof, wherein the variant is
c) a sequence which is at least 90% identical to SEQ ID NO:8 or 9, or SEQ ID NO:21, respectively or
d) the complement of c). 18. The kit of claim 16, further comprising one or more nucleic acids comprising SEQ ID NOs: 4 to 7 or a variant thereof, together with a nucleic acid comprising SEQ ID NO:20 or a variant thereof,
wherein the variant is
e) a sequence which is at least 90% identical to any of SEQ ID NOs:4 to 7, or SEQ ID NO:20, respectively or
f) the complement of e). 19. The kit of claim 17, further comprising one or more nucleic acids comprising SEQ ID NOs: 4 to 7 or a variant thereof, together with a nucleic acid comprising SEQ ID NO:20 or a variant thereof,
wherein the variant is
e) sequence which is at least 90% identical to any of SEQ ID NOs:4 to 7, or SEQ ID NO:20, respectively or
f) the complement of e). 20. A method of using the kit of claim 16 for the detection of the genus Cronobacter. 21. A method of using the kit of claim 17 for the detection of the genus Cronobacter, wherein the kit is suitable for discrimination of Cronobacter turicensis against other species. 22. A method for amplifying bacterial DNA of the taxonomic unit genus Cronobacter, using primers, in which
a) in a first amplification step the DNA of the genus Cronobacter is amplified with primers, wherein the primers used in the first amplification step comprise the nucleic acids of the kit as defined in claim 16. 23. The method of claim 22, wherein
b) in a further detection step, the DNA fragments obtained by amplification step a) which are specific for the genus Cronobacter are detected by means of probes, wherein the probes used in step b) comprise nucleic acids comprising SEQ ID NOs:8 and 9 or a variant thereof, wherein the variant is a sequence which is at least 90% identical to SEQ ID NO:8 or 9, respectively, which are specific for the genus Cronobacter. 24. The method of claim 22, wherein
c) in a further detection step, the DNA fragments obtained by amplification step a) which are specific for the species Cronobacter turicensis are detected by means of probes, wherein the probes used in step c) comprise a nucleic acid comprising SEQ ID NO:21 or a variant thereof, wherein the variant is a sequence which is at least 90% identical to SEQ ID NO:21. 25. The method of claim 22, wherein
d) in at least one further amplification step the DNA of the taxonomic unit Enterobacteriaceae is amplified with conserved primers. 26. The method of claim 25, wherein
e) in a further detection step, the DNA fragments obtained by amplification step d), which are specific for the genus Enterobacteriaceae, are detected by means of probes. 27. The method of claim 22, including a step of amplifying an amplification control nucleic acid, which is added during amplification step a), wherein the amplification control nucleic acid is SEQ ID NO:22. 28. The method of claim 23, further including a melting curve analysis, wherein C. turicensis is discriminated against other Cronobacter species. 29. The method of claim 22, wherein viable cells of the genus Cronobacter or of other Enterobacteriaceae are discriminated against respective non-viable Cronobacter or other non-viable Enterobacteriaceae cells.
| 1,600 |
1,245 | 14,773,038 | 1,619 |
Disclosed herein is an aqueous hair care composition capable of providing durable non-permanent hair styling and/or wash-resistant retention of shape of hair fibers comprising a polyelectrolyte complex having a gel matrix structure or a mixture of gel matrix and microgel formed by electrostatic attraction, wherein the polyelectrolyte complex comprises a complex between: (A) about 0.01 wt. % to about 20 wt. % of at least one anionic polymer containing monoacid, diacid, triacid, half-acid/half-ester, acid anhydride functionality, or salts thereof having a molecular weight of from about 100,000 Daltons to about 5000,000 Daltons; and (B) about 0.1 wt. % to about 20 wt. % of at least one cationic or pseudo cationic polymer having a (i) molecular weight range of about 80,000 Daltons to about 5,000,000 Daltons, and (ii) a charge density of less than about 4.0 meg/gram, and wherein, the charge ratio of (B):(A) is more than about 0.70.
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1. An aqueous hair care composition capable of providing durable non-permanent hair styling and/or wash-resistant retention of shape of hair fibers comprising a polyelectrolyte complex having a gel matrix structure or a mixture of gel matrix and microgel formed by electrostatic attraction, wherein the polyelectrolyte complex comprises a complex between:
A. about 0.01 wt. % to about 20 wt. % of at least one anionic polymer containing monoacid, diacid, triacid, half-acid/half-ester, acid anhydride, alkyl vinyl ether, vinylpyrrolidone functionality or salts thereof having a molecular weight of from about 100,000 Daltons to about 5000,000 Daltons; and B. about 0.1 wt. % to about 20 wt. % of at least one cationic polymer having a (i) molecular weight range of about 80,000 Daltons to about 5,000,000 Daltons, and (ii) a charge density of less than about 4.0 meg/gram, and;
wherein, the charge ratio of (B):(A) is more than about 0.70. 2. The hair care composition according to claim 1, wherein said mixture of gel matrix and microgel comprises about 10% of microgel to about 90% of gel matrix to about 90% of microgel to about 10% of gel matrix, and wherein, the average particle size of gel matrix is more than about 15 microns, and the average particles size of microgel is less than about 7 microns. 3. The hair care composition according to claim 1, wherein said gel matrix structure or a mixture of gel matrix and microgel is formed by mixing about 0.01 wt. % to about 20 wt. % of at least one anionic polymer selected from (A) and about 0.1 wt. % to about 20 wt. % of at least one cationic or pseudo cationic polymer selected from (B) wherein A is added to B or B is added to A at room temperature, and wherein said A is pre-neutralized to a pH of about 5 to about 10 before mixing with B. 4. The hair care composition according to claim 1, wherein said gel matrix structure is capable of forming a water-resistant film after drying and/or after heating to a temperature of about 90° C. or more. 5. The hair care composition according to claim 1, wherein the molecular weight of anionic polymer (A) is from about 1,000,000,000 Daltons to about 3,000,000 Daltons. 6. The hair care composition according to claim 1, wherein the molecular weight of cationic or pseudocationic polymer is from about 200,000 Daltons to about 2,000,000 Daltons. 7. The hair care composition according to claim 1, wherein the charge ratio of (B):(A) is more than about 1.0. 8. The hair care composition according to claim 1, wherein said anionic polymer (A) is selected from the group consisting of carboxylic acids, maleic acids, phosphoric acids, sulfonic acids, acetylacetones, half-esters, half-acids, maleic acid anhydrides, methyl vinyl ethers, vinylpyrrolidone based compounds or their salts, and combinations thereof. 9. The hair care composition according to claim 1, wherein said anionic polymer (A) is selected from the group consisting of copolymers of alkyl vinyl ethers and maleic anhydride, polyvinylmethyl/maleic acid (PVM/MA) copolymer, a half-ester/half-salt of methyl vinyl ether/maleic anhydride (PVM/MA) copolymers, dodecyl vinyl ether/maleic acid copolymer, carbomers, acrylate polymers, acrylic acid/vinylpyrrolidone copolymer, polyvinylmethyl/maleic acid (PVM/MA) decadiene crosspolymer, vinyl acrylate/butyl maleate/isobornyl acrylate copolymers, vinylpyrrolidone/acrylates/lauryl methacrylate copolymer, salts thereof, alone or in combinations thereof. 10. The hair care composition according to claim 1 wherein said cationic polymer is selected from the group consisting of (i) polyquaternium compounds, (ii) pseudocationic polymers having amine functionality, and/or (iii) cationic polysaccharides. 11. The hair care composition according to claim 9, wherein said polyquaternium compound is selected from the group consisting of polyquaternium (PQ)-2, PQ-4, PQ-5, PQ-6, PQ-7, PQ-10, PQ-11, PQ-16, PQ-17, PQ-18, PQ-21, PQ-22, PQ-24, PQ-28, PQ-37, PQ-39, PQ-44, PQ-46, PQ-47, PQ-53, PQ-55, PQ-67, PQ-68, PQ-69, PQ-86, or PQ-95. 12. The hair care composition according to claim 10, wherein said pseudocationic polymer is selected from the group consisting of:
i. vinyl pyrrolidone-co-dimethylaminopropyl methacrylamide, poly(N-vinyl-2-pyrrolidone-co-dimethylaminoethyl-methacrylamide), PVP/tert-butylaminoethyl methacrylate (TBAMEA) copolymer, poly primary fatty amines, poly secondary fatty amines, poly tertiary fatty amines, polyaminoamides; or ii. polymers derived from polymerization of at least two or more monomer selected from the group consisting of N-tert-butylaminoethyl(meth)acrylamide, N-[2-(dimethylamino)ethyl]acrylamide, N-[2-(dimethylamino)ethyl]methacrylamide, N-[3-(dimethylamino)propyl]acrylamide, N-[3-(dimethylamino)propyl]-methacrylamide, N-[4-(dimethylamino)butyl]acrylamide, N-[4-(dimethylamino)-butyl]methacrylamide, N-[2-(diethylamino)ethyl]acrylamide, N-[4-(dimethylamino)cyclohexyl]acrylamide and N-[4-(dimethylamino)cyclohexyl]-methacrylamide, N-[12-(dimethylamino) dodecyl]methacrylamide, N-[18-(dimethylamino) octadecyl]methacrylamide, N-[8-(dimethylamino) octyl]methacrylamide, N-[7-(dimethylamino) heptyl]acrylamide, N-[14-(dimethylamino)tetradecyl]acrylamide, N-[3-(dimethylamino) propyl]methacrylamide, N-[3-(diethylamino) propyl]acrylamide, N-(4-(dipropylamino)butyl]methacrylamide, N-[3-(methyl butyl amino) propyl]acrylamide, N-(2-[3-(dimethylamino) propyl]ethyl)acrylamide, and N-(4-[4-(diethylamino)butyl]butyl)acrylamide. 13. The hair care composition according to claim 10 wherein said cationic polysaccharide is selected from the group consisting of cationic cellulose, quaternized hydroxyethyl cellulose (polyquaternium-10), quaternary ammonium salts of hydroxyethyl cellulose reacted with lauryl dimethyl ammonium-substituted epoxide (polyquaternium-24, polyquaternium-67), cationic guars, guar hydroxypropyltrimonium chloride, hydroxypropylated cationic guar derivatives and diallyldimethyl ammonium chloride substituted hydroxyethylcellulose (polyquaternium-4), acrylamidopropyl trimonium chloride/acrylamide copolymer, cationic starches, and corn starch/acrylamide/sodium acrylate copolymer. 14. The hair care composition according to claim 1 comprising a complex of:
i. polyvinyl methyl ether/maleic acid (PVM/MA) copolymer and polyquaternium-55 (PQ-55); or
ii. polyvinyl methyl ether/maleic acid (PVM/MA) copolymer and PVP/DMAPA acrylate copolymer; or
iii. polyvinyl methyl ether/maleic acid copolymer and PVP/tert-butylaminoethyl methacrylate (TBAMEA); or
iv. vinylpyrrolidone/acrylic acid/lauryl methacrylate copolymer and polyquatermium-55 (PQ-55); or
v. vinylpyrrolidone/acrylic acid/lauryl methacrylate copolymer and PVP/DMAPA acrylate copolymer;
vi. polyvinyl methyl ether/maleic acid (PVM/MA) copolymer and guar hydroxypropyltrimonium chloride; or
vii. polyvinyl dodecyl ether/maleic acid copolymer and polyquaternium-55 (PQ-55); or
viii. polyvinyl dodecyl ether/maleic acid copolymer and PVP/DMAPA acrylate copolymer; or
ix. polyvinyl dodecyl ether/maleic acid copolymer and PVP/TBAMEA; or
x. butyl half ester of polyvinyl methyl ether/maleic acid (PVM/MA) copolymer and polyquaternium-55 (PQ-55); or
xi. butyl half ester of polyvinyl dodecyl ether/maleic acid copolymer and PVP/DMAPA acrylate copolymer; or
xii. butyl half ester of polyvinyl dodecyl ether/maleic acid copolymer and PVP/TBAMEA; or
xiii. ethyl half ester of polyvinyl methyl ether/maleic acid (PVM/MA) copolymer and polyquaternium-55 (PQ-55); or
xiv. ethyl half ester of polyvinyl dodecyl ether/maleic acid copolymer and PVP/DMAPA acrylate copolymer; or
xv. ethyl half ester of polyvinyl dodecyl ether/maleic acid copolymer and PVP/TBAMEA. 15. The hair care composition according to claim 1 further comprises at least one cosmetically acceptable additive selected from the group consisting of: thickeners, viscosifiers, surfactants, cationic surfactants, emulsifiers, perfumes, preservatives, UV protectants, chelating agents, cleansing agents, wetting agents, hair conditioning ingredients, flexibility enhancers, split modifiers, conditioning ingredients, humectants, propellants, compressed gases, proteins, amino acids, shine enhancers, neutralizing agents, texturizing agents, water-proofing agents, solubilizers, suspension agents, suspended materials, cosmetically active ingredients, hair polymers, silicons, silicone-containing polymers, light protection agents, bleaches, gel formers, care agents, colorants, tinting agents, tanning agents, dyes, pigments, bodying agents, moisturizers, refatting agents, collagen, protein/keratin hydrolyzates, lipids, antioxidants, defoamers, antistatics, emollients, softeners, anti-dandruff agents, hair growth agents, anti-inflammatory agents, anti-microbial agents, foam stabilizers, rheology modifiers, water softening agents, hydrotropes, polyalkylene glycols, acids, bases, buffers and blends thereof. 16. The hair care composition according to claim 15, wherein said thickener is selected from the group consisting of hydroxypropylcellulose, hydroxyethylcellulose, cetyl modified hydroxyethylcellulose, carboxymethylcellulose, methylcellulose and hydroxypropyl methylcellulose, lightly to highly crosslinked polyacrylic acid polymers, hydrophobically modified crosslinked polyacrylic acid polymers, alkali swellable crosslinked polyacrylic acid polymers, and its derivatives, and combinations thereof. 17. The hair care composition according to claim 15, wherein said cationic surfactant is selected from the group consisting of quaternary ammonium compounds having at least one C8-C40 alkyl or alkenyl group, cetyl trimethylammonium chloride, stearyl dimethyl benzyl ammonium chloride, cetylpyridinium chloride, behentrimonium methosulfate, quaternium-18, quaternium-22, quaternium-26, quaternium-31, amine quaternary ammonium compounds, dialkyoylalkyl dimethylammonium halides, primary fatty amines, secondary fatty amines, tertiary fatty amines, and combinations thereof. 18. The hair care composition according to claim 1, wherein said polyelectrolyte complex is used in an amount of from about 0.1 wt. % to about 10 wt. % of total composition. 19. The hair care composition according to claim 1, wherein said composition is formulated as rinse-off or leave-in type of composition. 20. The hair care composition according to claim 19, wherein said rinse-off composition is a shampoo, conditioner, hair straightners, permanent wave or hair color. 21. The hair care composition according to claim 20, wherein said shampoo is capable of providing ease of styling, style durability, anti-frizz, manageability, increased conditioning, better volume, and/or better appearance in comparison with a shampoo that do not comprise said polyelectrolyte complex. 22. The hair care composition according to claim 20, wherein said conditioner is capable of providing greater styleability, style durability, anti-frizz, conditioning, dry conditioning, wet combing, and/or better volume in comparison with a conditioner that do not comprise said polyelectrolyte complex. 23. The hair care composition according to claim 19, wherein said leave-in composition is a mousse, a hair lacquer, a hair gel, a hair lotion, a hair wax, a styling cream, a pomade, a tonic, a hair spray, a working spray, a finishing spray, a blow-dry protectant spray, a flat-iron spray, a thermal protectant spray, or a curl-enhancing spray. 24. The hair care composition according to claim 23, wherein said leave-in type compositions are capable of providing better styleability, durability of style, anti-frizz, volume, shine, hair protection from styling appliances, better conditioning, anti-static, anti-frizz benefit in comparison with a leave-in hair care composition that does not comprise said polyelectrolyte complex. 25. A method for providing durable non-permanent hair styling and/or wash resistant retention of shape of hair fibers comprising the steps of:
i. applying durable non-permanent styling hair care composition to the hair fibers comprising a polyelectrolyte complex having a gel matrix structure or a mixture of gel matrix and microgel formed by electrostatic attraction, wherein the polyelectrolyte complex comprises a complex between: (A) about 0.01 wt. % to about 20 wt. % of at least one anionic polymer containing monoacid, diacid, triacid, half-acid/half-ester, acid anhydride, alkyl vinyl ether, vinylpyrrolidone functionality or salts thereof having a molecular weight of from about 100,000 Daltons to about 5000,000 Daltons; and (B) about 0.1 wt. % to about 20 wt. % of at least one cationic polymer having a (i) molecular weight range of about 80,000 Daltons to about 5,000,000 Daltons, and (ii) a charge density of less than about 4.0 meq/gram; wherein the charge ratio of (B):(A) is more than about 0.70; ii. drying the hair fibers with a hair drier and/or style the dried hair to the desired shape; iii. optionally, heating the hair fibers to a temperature ranging from about 90° C. to about 240° C. employing a hair heating device including hot flat iron, curling iron and/or a hair drier; and iv. shampooing the hair next day or two followed by drying and styling to desired shape with no further application of hair care composition of step (i) until re-application of composition is necessitated after multiple shampoo washes and conditioner rinse-cycles, which is typically a 3 to 5 wash cycles or more. 26. The method according to claim 25, wherein said durable non-permanent hair styling of hair fibers is capable of exhibiting styleability, volume, shine, manageability, durability of style, softness, ease of styling, anti-frizz, hair alignment, greater wet conditioning, dry conditioning, wet combing, ease of use with styling appliances, or hair protection from styling appliances in comparison with a method which comprises a hair composition that does not comprise said polyelectrolyte complex. 27. A process for preparing an aqueous hair care composition capable of providing durable non-permanent hair styling and/or wash-resistant retention of shape of hair fibers comprising the steps of:
i. preparing an aqueous solution of about 0.1 wt. % to about 20 wt. % of at least one cationic/pseudo-cationic polymer (B); ii. adding about 0.1 wt. % to about 3 wt. % of thickeners to the solution of step (i) and mixing continuously until to form an uniform mixture; iii. mixing the oil phase ingredients of (a) about 0.1 wt. % to about 10 wt. % of emulsifier, (b) about 0.1 wt. % to 10 wt. % of cationic surfactants and (c) optionally, about 0.5 wt. % to about 5 wt. % of silicone in a different container and heating the mixture to 70° C. to 75° C. to form a uniform mixture of oil phase and adding the resultant mixture oil phase to the uniform mixture of step (ii) then combined mixture is heated at 70° C. to 75° C. with continuous mixing for about 20 to about 30 minutes, and allowing the resultant to cool to 35° C. and slow down mixing; iv. neutralizing about 0.01% wt. % to about 20 wt. % of at least one anionic polymer (A) employing an aqueous alkali medium to bring the pH of about 7.0 and adding this resultant solution to the resultant of step (iii) at 35° C. with continuous mixing until to form an uniform mixture; and v. adding at least one about 0.5 wt. % to 5 wt. % of preservative to the resultant of step (iv) and pass through homogenizer if required. 28. The process according to claim 27, wherein the cationic polymer (B) is at least one cationic or pseudo cationic polymer having a (i) molecular weight range of about 80,000 Daltons to about 5,000,000 Daltons, and (ii) a charge density of less than about 4.0 meg/gram. 29. The process according to claim 27, wherein the anionic polymer (A) is at least one anionic polymer containing monoacid, diacid, triacid, half-acid/half-ester, acid anhydride, alkyl vinyl ether, vinylpyrrolidone functionality, or salts thereof having a molecular weight of from about 100,000 Daltons to about 5000,000 Daltons. 30. The process according to claim 27, wherein the thickener is selected from the group consisting of hydroxypropylcellulose, hydroxyethylcellulose, cetyl modified hydroxyethylcellulose, carboxymethylcellulose, methylcellulose and hydroxypropyl methylcellulose, lightly to highly crosslinked polyacrylic acid polymers, hydrophobically modified crosslinked polyacrylic acid polymers, alkali swellable crosslinked polyacrylic acid polymers, and its derivatives, and combinations thereof. 31. The process according to claim 27, wherein the cationic surfactant is selected from the group consisting of quaternary ammonium compounds having at least one C8-C40 alkyl or alkenyl group, cetyl trimethylammonium chloride, stearyl dimethyl benzyl ammonium chloride, cetylpyridinium chloride, behentrimonium methosulfate, quaternium-18, quaternium-22, quaternium-26, quaternium-31, amine quaternary ammonium compounds, dialkyoylalkyl dimethylammonium halides, and combinations thereof. 32. The process according to claim 27, wherein the emulsifier is selected from the group consisting of condensation products of aliphatic (C8 to C40) primary or secondary linear or branched-chain alcohols or phenols with alkylene oxides, C6-C100 ethylene oxide (EO), glycol distearate, sorbitan trioleate, propylene glycol isostearate, glycol stearate, sorbitan sesquioleate, glyceryl stearate, lecithin, sorbitan oleate, sorbitan monostearate NF, sorbitan stearate, sorbitan isostearate, steareth-2, oleth-2, glyceryl laurate, ceteth-2, PEG-30 dipolyhydroxystearate, glyceryl stearate SE, sorbitan stearate, sucrose cocoate, PEG-4 dilaurate, methyl glucose sesquistearate, PEG-8 dioleate, sorbitan laurate, PEG-40 sorbitan peroleate, laureth-4, PEG-7 glyceryl cocoate, PEG-20 almond glycerides, PEG-25 hydrogenated castor oil, stearamide MEA, glyceryl stearate, PEG-100 stearate, polysorbate 85, PEG-7 olivate, cetearyl glucoside, PEG-8 oleate, polyglyceryl-3 methyglucose distearate, Oleth-10, Oleth-10/polyoxyl 10 oleyl ether NF, ceteth-10, PEG-8 laurate, cocamide MEA, polysorbate 60 NF, polysorbate 60, polysorbate 80, isosteareth-20, PEG-60 almond glycerides, polysorbate 80 NF, PEG-20 methyl glucose sesquistearate, ceteareth-20, oleth-20, steareth-20, steareth-21, ceteth-20, isoceteth-20, polysorbate 20, polysorbate 20 NF, laureth-23, PEG-100 stearate, steareth-100, PEG-80 sorbitan laurate alone or in combinations thereof. 33. The process according to claim 27, wherein said preservative is selected from the group consisting of triazoles, imidazoles, naphthalene derivatives, benzimidazoles, morphline derivatives, dithiocarbamates, benzisothiazoles, benzamides, boron compounds, formaldehyde donors, isothiazolones, thiocyanates, quaternary ammonium compounds, iodine derivates, phenol derivatives, phenoxyethanol and caprylyl glycol, micobicides, pyridines, dialkylthiocarbamates, nitriles, parabens, alkyl parabens and salts thereof alone or in combination.
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Disclosed herein is an aqueous hair care composition capable of providing durable non-permanent hair styling and/or wash-resistant retention of shape of hair fibers comprising a polyelectrolyte complex having a gel matrix structure or a mixture of gel matrix and microgel formed by electrostatic attraction, wherein the polyelectrolyte complex comprises a complex between: (A) about 0.01 wt. % to about 20 wt. % of at least one anionic polymer containing monoacid, diacid, triacid, half-acid/half-ester, acid anhydride functionality, or salts thereof having a molecular weight of from about 100,000 Daltons to about 5000,000 Daltons; and (B) about 0.1 wt. % to about 20 wt. % of at least one cationic or pseudo cationic polymer having a (i) molecular weight range of about 80,000 Daltons to about 5,000,000 Daltons, and (ii) a charge density of less than about 4.0 meg/gram, and wherein, the charge ratio of (B):(A) is more than about 0.70.1. An aqueous hair care composition capable of providing durable non-permanent hair styling and/or wash-resistant retention of shape of hair fibers comprising a polyelectrolyte complex having a gel matrix structure or a mixture of gel matrix and microgel formed by electrostatic attraction, wherein the polyelectrolyte complex comprises a complex between:
A. about 0.01 wt. % to about 20 wt. % of at least one anionic polymer containing monoacid, diacid, triacid, half-acid/half-ester, acid anhydride, alkyl vinyl ether, vinylpyrrolidone functionality or salts thereof having a molecular weight of from about 100,000 Daltons to about 5000,000 Daltons; and B. about 0.1 wt. % to about 20 wt. % of at least one cationic polymer having a (i) molecular weight range of about 80,000 Daltons to about 5,000,000 Daltons, and (ii) a charge density of less than about 4.0 meg/gram, and;
wherein, the charge ratio of (B):(A) is more than about 0.70. 2. The hair care composition according to claim 1, wherein said mixture of gel matrix and microgel comprises about 10% of microgel to about 90% of gel matrix to about 90% of microgel to about 10% of gel matrix, and wherein, the average particle size of gel matrix is more than about 15 microns, and the average particles size of microgel is less than about 7 microns. 3. The hair care composition according to claim 1, wherein said gel matrix structure or a mixture of gel matrix and microgel is formed by mixing about 0.01 wt. % to about 20 wt. % of at least one anionic polymer selected from (A) and about 0.1 wt. % to about 20 wt. % of at least one cationic or pseudo cationic polymer selected from (B) wherein A is added to B or B is added to A at room temperature, and wherein said A is pre-neutralized to a pH of about 5 to about 10 before mixing with B. 4. The hair care composition according to claim 1, wherein said gel matrix structure is capable of forming a water-resistant film after drying and/or after heating to a temperature of about 90° C. or more. 5. The hair care composition according to claim 1, wherein the molecular weight of anionic polymer (A) is from about 1,000,000,000 Daltons to about 3,000,000 Daltons. 6. The hair care composition according to claim 1, wherein the molecular weight of cationic or pseudocationic polymer is from about 200,000 Daltons to about 2,000,000 Daltons. 7. The hair care composition according to claim 1, wherein the charge ratio of (B):(A) is more than about 1.0. 8. The hair care composition according to claim 1, wherein said anionic polymer (A) is selected from the group consisting of carboxylic acids, maleic acids, phosphoric acids, sulfonic acids, acetylacetones, half-esters, half-acids, maleic acid anhydrides, methyl vinyl ethers, vinylpyrrolidone based compounds or their salts, and combinations thereof. 9. The hair care composition according to claim 1, wherein said anionic polymer (A) is selected from the group consisting of copolymers of alkyl vinyl ethers and maleic anhydride, polyvinylmethyl/maleic acid (PVM/MA) copolymer, a half-ester/half-salt of methyl vinyl ether/maleic anhydride (PVM/MA) copolymers, dodecyl vinyl ether/maleic acid copolymer, carbomers, acrylate polymers, acrylic acid/vinylpyrrolidone copolymer, polyvinylmethyl/maleic acid (PVM/MA) decadiene crosspolymer, vinyl acrylate/butyl maleate/isobornyl acrylate copolymers, vinylpyrrolidone/acrylates/lauryl methacrylate copolymer, salts thereof, alone or in combinations thereof. 10. The hair care composition according to claim 1 wherein said cationic polymer is selected from the group consisting of (i) polyquaternium compounds, (ii) pseudocationic polymers having amine functionality, and/or (iii) cationic polysaccharides. 11. The hair care composition according to claim 9, wherein said polyquaternium compound is selected from the group consisting of polyquaternium (PQ)-2, PQ-4, PQ-5, PQ-6, PQ-7, PQ-10, PQ-11, PQ-16, PQ-17, PQ-18, PQ-21, PQ-22, PQ-24, PQ-28, PQ-37, PQ-39, PQ-44, PQ-46, PQ-47, PQ-53, PQ-55, PQ-67, PQ-68, PQ-69, PQ-86, or PQ-95. 12. The hair care composition according to claim 10, wherein said pseudocationic polymer is selected from the group consisting of:
i. vinyl pyrrolidone-co-dimethylaminopropyl methacrylamide, poly(N-vinyl-2-pyrrolidone-co-dimethylaminoethyl-methacrylamide), PVP/tert-butylaminoethyl methacrylate (TBAMEA) copolymer, poly primary fatty amines, poly secondary fatty amines, poly tertiary fatty amines, polyaminoamides; or ii. polymers derived from polymerization of at least two or more monomer selected from the group consisting of N-tert-butylaminoethyl(meth)acrylamide, N-[2-(dimethylamino)ethyl]acrylamide, N-[2-(dimethylamino)ethyl]methacrylamide, N-[3-(dimethylamino)propyl]acrylamide, N-[3-(dimethylamino)propyl]-methacrylamide, N-[4-(dimethylamino)butyl]acrylamide, N-[4-(dimethylamino)-butyl]methacrylamide, N-[2-(diethylamino)ethyl]acrylamide, N-[4-(dimethylamino)cyclohexyl]acrylamide and N-[4-(dimethylamino)cyclohexyl]-methacrylamide, N-[12-(dimethylamino) dodecyl]methacrylamide, N-[18-(dimethylamino) octadecyl]methacrylamide, N-[8-(dimethylamino) octyl]methacrylamide, N-[7-(dimethylamino) heptyl]acrylamide, N-[14-(dimethylamino)tetradecyl]acrylamide, N-[3-(dimethylamino) propyl]methacrylamide, N-[3-(diethylamino) propyl]acrylamide, N-(4-(dipropylamino)butyl]methacrylamide, N-[3-(methyl butyl amino) propyl]acrylamide, N-(2-[3-(dimethylamino) propyl]ethyl)acrylamide, and N-(4-[4-(diethylamino)butyl]butyl)acrylamide. 13. The hair care composition according to claim 10 wherein said cationic polysaccharide is selected from the group consisting of cationic cellulose, quaternized hydroxyethyl cellulose (polyquaternium-10), quaternary ammonium salts of hydroxyethyl cellulose reacted with lauryl dimethyl ammonium-substituted epoxide (polyquaternium-24, polyquaternium-67), cationic guars, guar hydroxypropyltrimonium chloride, hydroxypropylated cationic guar derivatives and diallyldimethyl ammonium chloride substituted hydroxyethylcellulose (polyquaternium-4), acrylamidopropyl trimonium chloride/acrylamide copolymer, cationic starches, and corn starch/acrylamide/sodium acrylate copolymer. 14. The hair care composition according to claim 1 comprising a complex of:
i. polyvinyl methyl ether/maleic acid (PVM/MA) copolymer and polyquaternium-55 (PQ-55); or
ii. polyvinyl methyl ether/maleic acid (PVM/MA) copolymer and PVP/DMAPA acrylate copolymer; or
iii. polyvinyl methyl ether/maleic acid copolymer and PVP/tert-butylaminoethyl methacrylate (TBAMEA); or
iv. vinylpyrrolidone/acrylic acid/lauryl methacrylate copolymer and polyquatermium-55 (PQ-55); or
v. vinylpyrrolidone/acrylic acid/lauryl methacrylate copolymer and PVP/DMAPA acrylate copolymer;
vi. polyvinyl methyl ether/maleic acid (PVM/MA) copolymer and guar hydroxypropyltrimonium chloride; or
vii. polyvinyl dodecyl ether/maleic acid copolymer and polyquaternium-55 (PQ-55); or
viii. polyvinyl dodecyl ether/maleic acid copolymer and PVP/DMAPA acrylate copolymer; or
ix. polyvinyl dodecyl ether/maleic acid copolymer and PVP/TBAMEA; or
x. butyl half ester of polyvinyl methyl ether/maleic acid (PVM/MA) copolymer and polyquaternium-55 (PQ-55); or
xi. butyl half ester of polyvinyl dodecyl ether/maleic acid copolymer and PVP/DMAPA acrylate copolymer; or
xii. butyl half ester of polyvinyl dodecyl ether/maleic acid copolymer and PVP/TBAMEA; or
xiii. ethyl half ester of polyvinyl methyl ether/maleic acid (PVM/MA) copolymer and polyquaternium-55 (PQ-55); or
xiv. ethyl half ester of polyvinyl dodecyl ether/maleic acid copolymer and PVP/DMAPA acrylate copolymer; or
xv. ethyl half ester of polyvinyl dodecyl ether/maleic acid copolymer and PVP/TBAMEA. 15. The hair care composition according to claim 1 further comprises at least one cosmetically acceptable additive selected from the group consisting of: thickeners, viscosifiers, surfactants, cationic surfactants, emulsifiers, perfumes, preservatives, UV protectants, chelating agents, cleansing agents, wetting agents, hair conditioning ingredients, flexibility enhancers, split modifiers, conditioning ingredients, humectants, propellants, compressed gases, proteins, amino acids, shine enhancers, neutralizing agents, texturizing agents, water-proofing agents, solubilizers, suspension agents, suspended materials, cosmetically active ingredients, hair polymers, silicons, silicone-containing polymers, light protection agents, bleaches, gel formers, care agents, colorants, tinting agents, tanning agents, dyes, pigments, bodying agents, moisturizers, refatting agents, collagen, protein/keratin hydrolyzates, lipids, antioxidants, defoamers, antistatics, emollients, softeners, anti-dandruff agents, hair growth agents, anti-inflammatory agents, anti-microbial agents, foam stabilizers, rheology modifiers, water softening agents, hydrotropes, polyalkylene glycols, acids, bases, buffers and blends thereof. 16. The hair care composition according to claim 15, wherein said thickener is selected from the group consisting of hydroxypropylcellulose, hydroxyethylcellulose, cetyl modified hydroxyethylcellulose, carboxymethylcellulose, methylcellulose and hydroxypropyl methylcellulose, lightly to highly crosslinked polyacrylic acid polymers, hydrophobically modified crosslinked polyacrylic acid polymers, alkali swellable crosslinked polyacrylic acid polymers, and its derivatives, and combinations thereof. 17. The hair care composition according to claim 15, wherein said cationic surfactant is selected from the group consisting of quaternary ammonium compounds having at least one C8-C40 alkyl or alkenyl group, cetyl trimethylammonium chloride, stearyl dimethyl benzyl ammonium chloride, cetylpyridinium chloride, behentrimonium methosulfate, quaternium-18, quaternium-22, quaternium-26, quaternium-31, amine quaternary ammonium compounds, dialkyoylalkyl dimethylammonium halides, primary fatty amines, secondary fatty amines, tertiary fatty amines, and combinations thereof. 18. The hair care composition according to claim 1, wherein said polyelectrolyte complex is used in an amount of from about 0.1 wt. % to about 10 wt. % of total composition. 19. The hair care composition according to claim 1, wherein said composition is formulated as rinse-off or leave-in type of composition. 20. The hair care composition according to claim 19, wherein said rinse-off composition is a shampoo, conditioner, hair straightners, permanent wave or hair color. 21. The hair care composition according to claim 20, wherein said shampoo is capable of providing ease of styling, style durability, anti-frizz, manageability, increased conditioning, better volume, and/or better appearance in comparison with a shampoo that do not comprise said polyelectrolyte complex. 22. The hair care composition according to claim 20, wherein said conditioner is capable of providing greater styleability, style durability, anti-frizz, conditioning, dry conditioning, wet combing, and/or better volume in comparison with a conditioner that do not comprise said polyelectrolyte complex. 23. The hair care composition according to claim 19, wherein said leave-in composition is a mousse, a hair lacquer, a hair gel, a hair lotion, a hair wax, a styling cream, a pomade, a tonic, a hair spray, a working spray, a finishing spray, a blow-dry protectant spray, a flat-iron spray, a thermal protectant spray, or a curl-enhancing spray. 24. The hair care composition according to claim 23, wherein said leave-in type compositions are capable of providing better styleability, durability of style, anti-frizz, volume, shine, hair protection from styling appliances, better conditioning, anti-static, anti-frizz benefit in comparison with a leave-in hair care composition that does not comprise said polyelectrolyte complex. 25. A method for providing durable non-permanent hair styling and/or wash resistant retention of shape of hair fibers comprising the steps of:
i. applying durable non-permanent styling hair care composition to the hair fibers comprising a polyelectrolyte complex having a gel matrix structure or a mixture of gel matrix and microgel formed by electrostatic attraction, wherein the polyelectrolyte complex comprises a complex between: (A) about 0.01 wt. % to about 20 wt. % of at least one anionic polymer containing monoacid, diacid, triacid, half-acid/half-ester, acid anhydride, alkyl vinyl ether, vinylpyrrolidone functionality or salts thereof having a molecular weight of from about 100,000 Daltons to about 5000,000 Daltons; and (B) about 0.1 wt. % to about 20 wt. % of at least one cationic polymer having a (i) molecular weight range of about 80,000 Daltons to about 5,000,000 Daltons, and (ii) a charge density of less than about 4.0 meq/gram; wherein the charge ratio of (B):(A) is more than about 0.70; ii. drying the hair fibers with a hair drier and/or style the dried hair to the desired shape; iii. optionally, heating the hair fibers to a temperature ranging from about 90° C. to about 240° C. employing a hair heating device including hot flat iron, curling iron and/or a hair drier; and iv. shampooing the hair next day or two followed by drying and styling to desired shape with no further application of hair care composition of step (i) until re-application of composition is necessitated after multiple shampoo washes and conditioner rinse-cycles, which is typically a 3 to 5 wash cycles or more. 26. The method according to claim 25, wherein said durable non-permanent hair styling of hair fibers is capable of exhibiting styleability, volume, shine, manageability, durability of style, softness, ease of styling, anti-frizz, hair alignment, greater wet conditioning, dry conditioning, wet combing, ease of use with styling appliances, or hair protection from styling appliances in comparison with a method which comprises a hair composition that does not comprise said polyelectrolyte complex. 27. A process for preparing an aqueous hair care composition capable of providing durable non-permanent hair styling and/or wash-resistant retention of shape of hair fibers comprising the steps of:
i. preparing an aqueous solution of about 0.1 wt. % to about 20 wt. % of at least one cationic/pseudo-cationic polymer (B); ii. adding about 0.1 wt. % to about 3 wt. % of thickeners to the solution of step (i) and mixing continuously until to form an uniform mixture; iii. mixing the oil phase ingredients of (a) about 0.1 wt. % to about 10 wt. % of emulsifier, (b) about 0.1 wt. % to 10 wt. % of cationic surfactants and (c) optionally, about 0.5 wt. % to about 5 wt. % of silicone in a different container and heating the mixture to 70° C. to 75° C. to form a uniform mixture of oil phase and adding the resultant mixture oil phase to the uniform mixture of step (ii) then combined mixture is heated at 70° C. to 75° C. with continuous mixing for about 20 to about 30 minutes, and allowing the resultant to cool to 35° C. and slow down mixing; iv. neutralizing about 0.01% wt. % to about 20 wt. % of at least one anionic polymer (A) employing an aqueous alkali medium to bring the pH of about 7.0 and adding this resultant solution to the resultant of step (iii) at 35° C. with continuous mixing until to form an uniform mixture; and v. adding at least one about 0.5 wt. % to 5 wt. % of preservative to the resultant of step (iv) and pass through homogenizer if required. 28. The process according to claim 27, wherein the cationic polymer (B) is at least one cationic or pseudo cationic polymer having a (i) molecular weight range of about 80,000 Daltons to about 5,000,000 Daltons, and (ii) a charge density of less than about 4.0 meg/gram. 29. The process according to claim 27, wherein the anionic polymer (A) is at least one anionic polymer containing monoacid, diacid, triacid, half-acid/half-ester, acid anhydride, alkyl vinyl ether, vinylpyrrolidone functionality, or salts thereof having a molecular weight of from about 100,000 Daltons to about 5000,000 Daltons. 30. The process according to claim 27, wherein the thickener is selected from the group consisting of hydroxypropylcellulose, hydroxyethylcellulose, cetyl modified hydroxyethylcellulose, carboxymethylcellulose, methylcellulose and hydroxypropyl methylcellulose, lightly to highly crosslinked polyacrylic acid polymers, hydrophobically modified crosslinked polyacrylic acid polymers, alkali swellable crosslinked polyacrylic acid polymers, and its derivatives, and combinations thereof. 31. The process according to claim 27, wherein the cationic surfactant is selected from the group consisting of quaternary ammonium compounds having at least one C8-C40 alkyl or alkenyl group, cetyl trimethylammonium chloride, stearyl dimethyl benzyl ammonium chloride, cetylpyridinium chloride, behentrimonium methosulfate, quaternium-18, quaternium-22, quaternium-26, quaternium-31, amine quaternary ammonium compounds, dialkyoylalkyl dimethylammonium halides, and combinations thereof. 32. The process according to claim 27, wherein the emulsifier is selected from the group consisting of condensation products of aliphatic (C8 to C40) primary or secondary linear or branched-chain alcohols or phenols with alkylene oxides, C6-C100 ethylene oxide (EO), glycol distearate, sorbitan trioleate, propylene glycol isostearate, glycol stearate, sorbitan sesquioleate, glyceryl stearate, lecithin, sorbitan oleate, sorbitan monostearate NF, sorbitan stearate, sorbitan isostearate, steareth-2, oleth-2, glyceryl laurate, ceteth-2, PEG-30 dipolyhydroxystearate, glyceryl stearate SE, sorbitan stearate, sucrose cocoate, PEG-4 dilaurate, methyl glucose sesquistearate, PEG-8 dioleate, sorbitan laurate, PEG-40 sorbitan peroleate, laureth-4, PEG-7 glyceryl cocoate, PEG-20 almond glycerides, PEG-25 hydrogenated castor oil, stearamide MEA, glyceryl stearate, PEG-100 stearate, polysorbate 85, PEG-7 olivate, cetearyl glucoside, PEG-8 oleate, polyglyceryl-3 methyglucose distearate, Oleth-10, Oleth-10/polyoxyl 10 oleyl ether NF, ceteth-10, PEG-8 laurate, cocamide MEA, polysorbate 60 NF, polysorbate 60, polysorbate 80, isosteareth-20, PEG-60 almond glycerides, polysorbate 80 NF, PEG-20 methyl glucose sesquistearate, ceteareth-20, oleth-20, steareth-20, steareth-21, ceteth-20, isoceteth-20, polysorbate 20, polysorbate 20 NF, laureth-23, PEG-100 stearate, steareth-100, PEG-80 sorbitan laurate alone or in combinations thereof. 33. The process according to claim 27, wherein said preservative is selected from the group consisting of triazoles, imidazoles, naphthalene derivatives, benzimidazoles, morphline derivatives, dithiocarbamates, benzisothiazoles, benzamides, boron compounds, formaldehyde donors, isothiazolones, thiocyanates, quaternary ammonium compounds, iodine derivates, phenol derivatives, phenoxyethanol and caprylyl glycol, micobicides, pyridines, dialkylthiocarbamates, nitriles, parabens, alkyl parabens and salts thereof alone or in combination.
| 1,600 |
1,246 | 15,778,693 | 1,613 |
The present invention belongs to the area of cosmetics, especially to a delivery system for actives to the skin, such as face masks and facial masks. Particularly, the present invention refers to a delivery system consisting of a basic body comprises nonwoven fibrous materials and an active-substance preparation which is an o/w emulsion or w/o emulsion, and a wetting liquid that comprises one or more actives to activate the delivery system.
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1. A delivery system comprising
(i) a basic body, (ii) an active-substance preparation, and (iii) a separate wetting liquid,
wherein (i) the basic body comprises a non-woven fibrous material, (ii) the active-substance preparation is an o/w emulsion which is printed onto the basic body (i) and (iii) the wetting liquid comprises at least one active to start liberation of an active agent of the active-substance preparation. 2. The system of claim 1, wherein the fibrous material is selected from the group consisting of natural and synthetic fibrous material and mixtures thereof. 3. The system of claim 1, wherein the o/w active-substance preparation emulsion comprises
(a) at least one active agent selected from the group consisting of whitening or brightening agents, skin cell renewal agents, anti-ageing agents, deodorant actives, anti cellulite agents, moisturizing agents, actives for sensitive skin, actives for the treatment of oily skin, antimicrobials, anti-acne drugs, antiperspirant compounds, antihistamines, anti-inflammatory agents, skin protective agents, insect repellent chemicals, sunscreens, fragrances, preservatives, actives for hair coloration, solvents and mixtures thereof, and (b) a carrier selected from the group consisting of sugars such as sucrose, glucose, lactose, levulose, trehalose, fructose, maltose, ribose, dextrose, isomalt, sorbitol, mannitol, xylitol, lactitol, maltitol, pentatol, arabinose, pentose, xylose, galactose; hydrogenated starch hydrolysates, inulin, and polysaccharides such as oligofructose; maltodextrins or dextrins (soluble fiber); hydrocolloids such as agar, gum acacia, modified gum acacia, sodium alginate, potassium alginate, ammonium alginate, calcium alginate or carrageenan; gums; polydextrose; celluloses such as sodium carboxymethylcellulose, enzymatically hydrolyzed carboxy methyl cellulose, methyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose; triglycerides such as medium-chain triglycerides (MCT) whose fatty acids have an aliphatic tail of 6-12 carbon atoms, and long-chain triglycerides (LCT) whose fatty acids have an aliphatic tail of 14-24 carbon atoms; proteins such as gelatin, pea protein, soy and whey protein isolates and hydrolyzates, and sodium caseinates and mixtures thereof. 4. The system of claim 1, wherein the o/w active-substance preparation emulsion comprises at least one polysaccharide as carrier material. 5. The system of claim 4, wherein the polysaccharide is selected from the group consisting of maltodextrin, modified starch, dextrin, gummi arabicum, mannitol and mixtures thereof. 6. The system of claim 1, wherein the o/w active-substance preparation emulsion comprises
(a) from 0.001 w.t. % to 70 w.t. % of at least one active agent, and (b) from 5 w.t. % to 50 w.t. %, of a carrier material,
each based on the total amount of the active-substance preparation. 7. The system of claim 1, wherein the delivery system is a face mask, facial sheet mask or treatment for upper legs and arms, arm pits, breast or back. 8. The system of claim 1, wherein the basic body comprises at least one layer of fibrous material. 9. A sheet-like cosmetic delivery system according to claim 6, which is obtained by printing, spraying or impregnating a non-woven fibrous material with the o/w emulsion of the active-substance preparation. 10. The system of claim 1, wherein the active agent of the active-substance preparation to be released is a whitening or brightening agent selected from the group consisting of diphenylmethanes, macrocyclic compounds or any botanical extracts that contain components that inhibit melanin production in skin such as sclareolide; Tetraselmis Suecica extract; licorice extract; pomegranate extract; hinokitiol; protocatechuic acid; NAB asafetida (Ferula Foetida) extract; resveratrol and his derivatives such as oxyresveratrol, resveratrol, resveratrol phosphate, resveratrol ferulate; ferulic acid and its derivatives such as ferulic acid phosphate; viniferol; botanical extract combinations sold by Coletica under the Phytoclar® (Saxifrage, Grape, mulberry and Scutelleria Root extracts), Phytowhite® (cucumber, apple and Scutellaria extracts) or Phytolight® (cucumber, apple and Scutellaria, and green tea extracts); Lunawhite B® (butylene glycol/water/Denothera Biennis seed extract) evening primrose extract; fatty acid esters of ascorbic acid such as ascorbyl palmitate; Euphrasia Officianalis extract, purine derivatives such as kinetin or derivatives thereof; ascorbyl glucoside; grape seed extract; vineferol, pomegranate extract, tetrahydrocurcumins, Acmella Oleracea extract, Aloesin, Tyrostat®, which are extracts of field dock, aspergillus ferment, molasses, 4-(1-Phenylethyl) 1-,3 benzenediol and mixtures thereof. 11. The system of claim 1 in an amount effective for the release of a cosmetic or pharmaceutical active agent to the skin. 12. A method for preparing the system of claim 9, comprising
printing, spraying or impregnating the o/w active-substance preparation emulsion onto non-woven fibrous material. 13. The method of claim 12, wherein the active agent of the active-substance preparation to be released is a whitening or brightening agent selected from the group consisting of diphenylmethanes, macrocyclic compounds or any botanical extracts that contain components that inhibit melanin production in skin such as sclareolide; Tetraselmis Suecica extract; licorice extract; pomegranate extract; hinokitiol; protocatechuic acid; NAB asafetida (Ferula Foetida) extract; resveratrol and his derivatives such as oxyresveratrol, resveratrol, resveratrol phosphate, resveratrol ferulate; ferulic acid and its derivatives such as ferulic acid phosphate; viniferol; botanical extract combinations sold by Coletica under the Phytoclar® (Saxifrage, Grape, mulberry and Scutelleria Root extracts), Phytowhite® (cucumber, apple and Scutellaria extracts) or Phytolight® (cucumber, apple and Scutellaria, and green tea extracts); Lunawhite B® (butylene glycol/water/Denothera Biennis seed extract) evening primrose extract; fatty acid esters of ascorbic acid such as ascorbyl palmitate; Euphrasia Officianalis extract, purine derivatives such as kinetin or derivatives thereof; ascorbyl glucoside; grape seed extract; vineferol, pomegranate extract, tetrahydrocurcumins, Acmella Oleracea extract, Aloesin, Tyrostat®, which are extracts of field dock, aspergillus ferment, molasses, 4-(1-Phenylethyl) 1-,3 benzenediol and mixtures thereof. 14. The method of claim 12, wherein the active agent of the active-substance preparation to be released is an anti-ageing active selected from the group consisting of antioxidants, matrix-metalloproteinase inhibitors, skin moisturizing agents, glycosaminoglycan stimulators, anti-inflammatory agents, TRPV1 antagonists and plant extracts and mixtures thereof. 15. A method of delivering an active agent to the skin, comprising the steps of:
(i) providing a basic body that comprises a non-woven fibrous material on which an active-substance preparation is printed in such a way that the active agent is embedded into a matrix of the basic body, to a part of the skin which is to be treated with the active agent, and (ii) bringing the basic body resulting from step (i) in contact with a wetting liquid, which comprises at least one active to start the release of the active agent of the active-substance preparation, to release the active agent to the skin part which is to be treated.
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The present invention belongs to the area of cosmetics, especially to a delivery system for actives to the skin, such as face masks and facial masks. Particularly, the present invention refers to a delivery system consisting of a basic body comprises nonwoven fibrous materials and an active-substance preparation which is an o/w emulsion or w/o emulsion, and a wetting liquid that comprises one or more actives to activate the delivery system.1. A delivery system comprising
(i) a basic body, (ii) an active-substance preparation, and (iii) a separate wetting liquid,
wherein (i) the basic body comprises a non-woven fibrous material, (ii) the active-substance preparation is an o/w emulsion which is printed onto the basic body (i) and (iii) the wetting liquid comprises at least one active to start liberation of an active agent of the active-substance preparation. 2. The system of claim 1, wherein the fibrous material is selected from the group consisting of natural and synthetic fibrous material and mixtures thereof. 3. The system of claim 1, wherein the o/w active-substance preparation emulsion comprises
(a) at least one active agent selected from the group consisting of whitening or brightening agents, skin cell renewal agents, anti-ageing agents, deodorant actives, anti cellulite agents, moisturizing agents, actives for sensitive skin, actives for the treatment of oily skin, antimicrobials, anti-acne drugs, antiperspirant compounds, antihistamines, anti-inflammatory agents, skin protective agents, insect repellent chemicals, sunscreens, fragrances, preservatives, actives for hair coloration, solvents and mixtures thereof, and (b) a carrier selected from the group consisting of sugars such as sucrose, glucose, lactose, levulose, trehalose, fructose, maltose, ribose, dextrose, isomalt, sorbitol, mannitol, xylitol, lactitol, maltitol, pentatol, arabinose, pentose, xylose, galactose; hydrogenated starch hydrolysates, inulin, and polysaccharides such as oligofructose; maltodextrins or dextrins (soluble fiber); hydrocolloids such as agar, gum acacia, modified gum acacia, sodium alginate, potassium alginate, ammonium alginate, calcium alginate or carrageenan; gums; polydextrose; celluloses such as sodium carboxymethylcellulose, enzymatically hydrolyzed carboxy methyl cellulose, methyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose; triglycerides such as medium-chain triglycerides (MCT) whose fatty acids have an aliphatic tail of 6-12 carbon atoms, and long-chain triglycerides (LCT) whose fatty acids have an aliphatic tail of 14-24 carbon atoms; proteins such as gelatin, pea protein, soy and whey protein isolates and hydrolyzates, and sodium caseinates and mixtures thereof. 4. The system of claim 1, wherein the o/w active-substance preparation emulsion comprises at least one polysaccharide as carrier material. 5. The system of claim 4, wherein the polysaccharide is selected from the group consisting of maltodextrin, modified starch, dextrin, gummi arabicum, mannitol and mixtures thereof. 6. The system of claim 1, wherein the o/w active-substance preparation emulsion comprises
(a) from 0.001 w.t. % to 70 w.t. % of at least one active agent, and (b) from 5 w.t. % to 50 w.t. %, of a carrier material,
each based on the total amount of the active-substance preparation. 7. The system of claim 1, wherein the delivery system is a face mask, facial sheet mask or treatment for upper legs and arms, arm pits, breast or back. 8. The system of claim 1, wherein the basic body comprises at least one layer of fibrous material. 9. A sheet-like cosmetic delivery system according to claim 6, which is obtained by printing, spraying or impregnating a non-woven fibrous material with the o/w emulsion of the active-substance preparation. 10. The system of claim 1, wherein the active agent of the active-substance preparation to be released is a whitening or brightening agent selected from the group consisting of diphenylmethanes, macrocyclic compounds or any botanical extracts that contain components that inhibit melanin production in skin such as sclareolide; Tetraselmis Suecica extract; licorice extract; pomegranate extract; hinokitiol; protocatechuic acid; NAB asafetida (Ferula Foetida) extract; resveratrol and his derivatives such as oxyresveratrol, resveratrol, resveratrol phosphate, resveratrol ferulate; ferulic acid and its derivatives such as ferulic acid phosphate; viniferol; botanical extract combinations sold by Coletica under the Phytoclar® (Saxifrage, Grape, mulberry and Scutelleria Root extracts), Phytowhite® (cucumber, apple and Scutellaria extracts) or Phytolight® (cucumber, apple and Scutellaria, and green tea extracts); Lunawhite B® (butylene glycol/water/Denothera Biennis seed extract) evening primrose extract; fatty acid esters of ascorbic acid such as ascorbyl palmitate; Euphrasia Officianalis extract, purine derivatives such as kinetin or derivatives thereof; ascorbyl glucoside; grape seed extract; vineferol, pomegranate extract, tetrahydrocurcumins, Acmella Oleracea extract, Aloesin, Tyrostat®, which are extracts of field dock, aspergillus ferment, molasses, 4-(1-Phenylethyl) 1-,3 benzenediol and mixtures thereof. 11. The system of claim 1 in an amount effective for the release of a cosmetic or pharmaceutical active agent to the skin. 12. A method for preparing the system of claim 9, comprising
printing, spraying or impregnating the o/w active-substance preparation emulsion onto non-woven fibrous material. 13. The method of claim 12, wherein the active agent of the active-substance preparation to be released is a whitening or brightening agent selected from the group consisting of diphenylmethanes, macrocyclic compounds or any botanical extracts that contain components that inhibit melanin production in skin such as sclareolide; Tetraselmis Suecica extract; licorice extract; pomegranate extract; hinokitiol; protocatechuic acid; NAB asafetida (Ferula Foetida) extract; resveratrol and his derivatives such as oxyresveratrol, resveratrol, resveratrol phosphate, resveratrol ferulate; ferulic acid and its derivatives such as ferulic acid phosphate; viniferol; botanical extract combinations sold by Coletica under the Phytoclar® (Saxifrage, Grape, mulberry and Scutelleria Root extracts), Phytowhite® (cucumber, apple and Scutellaria extracts) or Phytolight® (cucumber, apple and Scutellaria, and green tea extracts); Lunawhite B® (butylene glycol/water/Denothera Biennis seed extract) evening primrose extract; fatty acid esters of ascorbic acid such as ascorbyl palmitate; Euphrasia Officianalis extract, purine derivatives such as kinetin or derivatives thereof; ascorbyl glucoside; grape seed extract; vineferol, pomegranate extract, tetrahydrocurcumins, Acmella Oleracea extract, Aloesin, Tyrostat®, which are extracts of field dock, aspergillus ferment, molasses, 4-(1-Phenylethyl) 1-,3 benzenediol and mixtures thereof. 14. The method of claim 12, wherein the active agent of the active-substance preparation to be released is an anti-ageing active selected from the group consisting of antioxidants, matrix-metalloproteinase inhibitors, skin moisturizing agents, glycosaminoglycan stimulators, anti-inflammatory agents, TRPV1 antagonists and plant extracts and mixtures thereof. 15. A method of delivering an active agent to the skin, comprising the steps of:
(i) providing a basic body that comprises a non-woven fibrous material on which an active-substance preparation is printed in such a way that the active agent is embedded into a matrix of the basic body, to a part of the skin which is to be treated with the active agent, and (ii) bringing the basic body resulting from step (i) in contact with a wetting liquid, which comprises at least one active to start the release of the active agent of the active-substance preparation, to release the active agent to the skin part which is to be treated.
| 1,600 |
1,247 | 16,072,088 | 1,625 |
Disclosed herein, in part, are compounds and methods for their use in the treatment of malaria. In at least one specific embodiment, the compounds or salts thereof can include compounds of Formula (I):
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1. A compound or a salt thereof, the compound comprising a Formula (I):
wherein R1 is selected from H, F, Cl, Br, I, CN, CH3, CF3, alkyl, halogenated alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, aryloxy, arylalkoxy, heteroalkyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, alkylamino, diarylamino, dialkylamino, arylamino, alkylarylamino, acyl, acylamino, thiol, thioalkyl, alkylthio, acyloxy, nitro, oxo, carbamoyl, trifluoromethyl, phenoxy, benzyloxy, phosphonic acid, phosphate ester, sulfonic acid (—SO3H), sulfonate ester, sulfonamide, carbamate, alkyltriphenylphosphonium,
wherein R2, R3, R4, R5, R6, R7, R8, R9, R19, R11, R12, R13, R14, R15, R16, R17, and R18 are independently selected from H, F, Cl, Br, I, CN, CH3, CF3, OCH3, alkyl, halogenated alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, aryloxy, arylalkoxy, heteroalkyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, alkylamino, diarylamino, dialkylamino, arylamino, alkylarylamino, acyl, acylamino, thiol, thioalkyl, alkylthio, acyloxy, nitro, oxo, carbamoyl, trifluoromethyl, phenoxy, benzyloxy, phosphonic acid, phosphate ester, sulfonic acid (—SO3H), sulfonate ester, sulfonamide, and carbamate, alkyltriphenylphosphonium, and
wherein X is selected from NH, NR19, oxygen, sulfur, and selenium, wherein R19 is selected from the group H, F, Cl, Br, I, CN, CH3, CF3, OCH3, alkyl, halogenated alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, aryloxy, arylalkoxy, heteroalkyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, alkylamino, diarylamino, dialkylamino, arylamino, alkylarylamino, acyl, acylamino, thiol, thioalkyl, alkylthio, acyloxy, nitro, oxo, carbamoyl, trifluoromethyl, phenoxy, benzyloxy, phosphonic acid, phosphate ester, sulfonic acid (—SO3H), sulfonate ester, sulfonamide, and carbamate, alkyltriphenylphosphonium; and
wherein n is 1, 2, 3, or 4. 2. The compound of claim 1, wherein the compound comprises a formula: 3. The compound of claim 1, wherein the compound comprises a formula: 4. The compound of claim 3, wherein the compound comprises a formula: 5. The compound of claim 3, wherein the compound comprises a formula: 6. A composition comprising:
a compound or a salt thereof, the compound comprising a Formula (I):
wherein R1 is selected from H, F, Cl, Br, I, CN, CHs, CF3, alkyl, halogenated alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, aryloxy, arylalkoxy, heteroalkyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, alkylamino, diarylamino, dialkylamino, arylamino, alkylarylamino, acyl, acylamino, thiol, thioalkyl, alkylthio, acyloxy, nitro, oxo, carbamoyl, trifluoromethyl, phenoxy, benzyloxy, phosphonic acid, phosphate ester, sulfonic acid (—SO3H), sulfonate ester, sulfonamide, carbamate, alkyltriphenylphosphonium,
wherein R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18 are independently selected from H, F, Cl, Br, I, CN, CH3, CF3, OCH3, alkyl, halogenated alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, aryloxy, arylalkoxy, heteroalkyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, alkylamino, diarylamino, dialkylamino, arylamino, alkylarylamino, acyl, acylamino, thiol, thioalkyl, alkylthio, acyloxy, nitro, oxo, carbamoyl, trifluoromethyl, phenoxy, benzyloxy, phosphonic acid, phosphate ester, sulfonic acid (—SO3H), sulfonate ester, sulfonamide, and carbamate, alkyltriphenylphosphonium, and
wherein X is selected from NH, NR19, oxygen, sulfur, and selenium, wherein R19 is selected from the group H, F, Cl, Br, I, CN, CH3, CF3, OCH3, alkyl, halogenated alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, aryloxy, arylalkoxy, heteroalkyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, alkylamino, diarylamino, dialkylamino, arylamino, alkylarylamino, acyl, acylamino, thiol, thioalkyl, alkylthio, acyloxy, nitro, oxo, carbamoyl, trifluoromethyl, phenoxy, benzyloxy, phosphonic acid, phosphate ester, sulfonic acid (—SO3H), sulfonate ester, sulfonamide, and carbamate, alkyltriphenylphosphonium: and
wherein n is 1, 2, 3, or 4; and
a pharmaceutically acceptable carrier. 7.-8. (canceled) 9. The composition of claim 6, wherein the compound comprises a formula: 10. The composition of claim 6, wherein the compound comprises a formula: 11. The compound of claim 10, wherein the compound comprises a formula: 12. The composition of claim 10, wherein the compound comprises a formula: 13. A method of treating malaria in a subject in need thereof, the method comprising:
administering an amount of a compound to the subject in need thereof, the compound comprising a Formula (I):
wherein R1 is selected from H, F, Cl, Br, I, CN, CHs, CF3, alkyl, halogenated alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, aryloxy, arylalkoxy, heteroalkyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, alkylamino, diarylamino, dialkylamino, arylamino, alkylarylamino, acyl, acylamino, thiol, thioalkyl, alkylthio, acyloxy, nitro, oxo, carbamoyl, trifluoromethyl, phenoxy, benzyloxy, phosphonic acid, phosphate ester, sulfonic acid (—SO3H), sulfonate ester, sulfonamide, carbamate, alkyltriphenylphosphonium,
wherein R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18 are independently selected from H, F, Cl, Br, I, CN, CH3, CF3, OCH3, alkyl, halogenated alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, aryloxy, arylalkoxy, heteroalkyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, alkylamino, diarylamino, dialkylamino, arylamino, alkylarylamino, acyl, acylamino, thiol, thioalkyl, alkylthio, acyloxy, nitro, oxo, carbamoyl, trifluoromethyl, phenoxy, benzyloxy, phosphonic acid, phosphate ester, sulfonic acid (—SO3H), sulfonate ester, sulfonamide, and carbamate, alkyltriphenylphosphonium, and
wherein X is selected from NH, NR19, oxygen, sulfur, and selenium, wherein R19 is selected from the group H, F, Cl, Br, I, CN, CH3, CF3, OCH3, alkyl, halogenated alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, aryloxy, arylalkoxy, heteroalkyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, alkylamino, diarylamino, dialkylamino, arylamino, alkylarylamino, acyl, acylamino, thiol, thioalkyl, alkylthio, acyloxy, nitro, oxo, carbamoyl, trifluoromethyl, phenoxy, benzyloxy, phosphonic acid, phosphate ester, sulfonic acid (—SO3H), sulfonate ester, sulfonamide, and carbamate, alkyltriphenylphosphonium; and
wherein n is 1, 2, 3, or 4. 14. The method of claim 13, wherein the compound comprises a formula: 15. The method of claim 13, wherein the compound comprises a formula: 16. The method of claim 15, wherein the compound comprises a formula: 17. The method of claim 15, wherein the compound comprises a formula: 18. The method of claim 13, wherein the compound is formulated as a composition comprising the compound and a pharmaceutically acceptable carrier. 19. The method of claim 13, wherein the amount of the compound ranges from about 1 mg/kg to about 30 mg/kg.
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Disclosed herein, in part, are compounds and methods for their use in the treatment of malaria. In at least one specific embodiment, the compounds or salts thereof can include compounds of Formula (I):1. A compound or a salt thereof, the compound comprising a Formula (I):
wherein R1 is selected from H, F, Cl, Br, I, CN, CH3, CF3, alkyl, halogenated alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, aryloxy, arylalkoxy, heteroalkyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, alkylamino, diarylamino, dialkylamino, arylamino, alkylarylamino, acyl, acylamino, thiol, thioalkyl, alkylthio, acyloxy, nitro, oxo, carbamoyl, trifluoromethyl, phenoxy, benzyloxy, phosphonic acid, phosphate ester, sulfonic acid (—SO3H), sulfonate ester, sulfonamide, carbamate, alkyltriphenylphosphonium,
wherein R2, R3, R4, R5, R6, R7, R8, R9, R19, R11, R12, R13, R14, R15, R16, R17, and R18 are independently selected from H, F, Cl, Br, I, CN, CH3, CF3, OCH3, alkyl, halogenated alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, aryloxy, arylalkoxy, heteroalkyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, alkylamino, diarylamino, dialkylamino, arylamino, alkylarylamino, acyl, acylamino, thiol, thioalkyl, alkylthio, acyloxy, nitro, oxo, carbamoyl, trifluoromethyl, phenoxy, benzyloxy, phosphonic acid, phosphate ester, sulfonic acid (—SO3H), sulfonate ester, sulfonamide, and carbamate, alkyltriphenylphosphonium, and
wherein X is selected from NH, NR19, oxygen, sulfur, and selenium, wherein R19 is selected from the group H, F, Cl, Br, I, CN, CH3, CF3, OCH3, alkyl, halogenated alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, aryloxy, arylalkoxy, heteroalkyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, alkylamino, diarylamino, dialkylamino, arylamino, alkylarylamino, acyl, acylamino, thiol, thioalkyl, alkylthio, acyloxy, nitro, oxo, carbamoyl, trifluoromethyl, phenoxy, benzyloxy, phosphonic acid, phosphate ester, sulfonic acid (—SO3H), sulfonate ester, sulfonamide, and carbamate, alkyltriphenylphosphonium; and
wherein n is 1, 2, 3, or 4. 2. The compound of claim 1, wherein the compound comprises a formula: 3. The compound of claim 1, wherein the compound comprises a formula: 4. The compound of claim 3, wherein the compound comprises a formula: 5. The compound of claim 3, wherein the compound comprises a formula: 6. A composition comprising:
a compound or a salt thereof, the compound comprising a Formula (I):
wherein R1 is selected from H, F, Cl, Br, I, CN, CHs, CF3, alkyl, halogenated alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, aryloxy, arylalkoxy, heteroalkyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, alkylamino, diarylamino, dialkylamino, arylamino, alkylarylamino, acyl, acylamino, thiol, thioalkyl, alkylthio, acyloxy, nitro, oxo, carbamoyl, trifluoromethyl, phenoxy, benzyloxy, phosphonic acid, phosphate ester, sulfonic acid (—SO3H), sulfonate ester, sulfonamide, carbamate, alkyltriphenylphosphonium,
wherein R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18 are independently selected from H, F, Cl, Br, I, CN, CH3, CF3, OCH3, alkyl, halogenated alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, aryloxy, arylalkoxy, heteroalkyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, alkylamino, diarylamino, dialkylamino, arylamino, alkylarylamino, acyl, acylamino, thiol, thioalkyl, alkylthio, acyloxy, nitro, oxo, carbamoyl, trifluoromethyl, phenoxy, benzyloxy, phosphonic acid, phosphate ester, sulfonic acid (—SO3H), sulfonate ester, sulfonamide, and carbamate, alkyltriphenylphosphonium, and
wherein X is selected from NH, NR19, oxygen, sulfur, and selenium, wherein R19 is selected from the group H, F, Cl, Br, I, CN, CH3, CF3, OCH3, alkyl, halogenated alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, aryloxy, arylalkoxy, heteroalkyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, alkylamino, diarylamino, dialkylamino, arylamino, alkylarylamino, acyl, acylamino, thiol, thioalkyl, alkylthio, acyloxy, nitro, oxo, carbamoyl, trifluoromethyl, phenoxy, benzyloxy, phosphonic acid, phosphate ester, sulfonic acid (—SO3H), sulfonate ester, sulfonamide, and carbamate, alkyltriphenylphosphonium: and
wherein n is 1, 2, 3, or 4; and
a pharmaceutically acceptable carrier. 7.-8. (canceled) 9. The composition of claim 6, wherein the compound comprises a formula: 10. The composition of claim 6, wherein the compound comprises a formula: 11. The compound of claim 10, wherein the compound comprises a formula: 12. The composition of claim 10, wherein the compound comprises a formula: 13. A method of treating malaria in a subject in need thereof, the method comprising:
administering an amount of a compound to the subject in need thereof, the compound comprising a Formula (I):
wherein R1 is selected from H, F, Cl, Br, I, CN, CHs, CF3, alkyl, halogenated alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, aryloxy, arylalkoxy, heteroalkyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, alkylamino, diarylamino, dialkylamino, arylamino, alkylarylamino, acyl, acylamino, thiol, thioalkyl, alkylthio, acyloxy, nitro, oxo, carbamoyl, trifluoromethyl, phenoxy, benzyloxy, phosphonic acid, phosphate ester, sulfonic acid (—SO3H), sulfonate ester, sulfonamide, carbamate, alkyltriphenylphosphonium,
wherein R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18 are independently selected from H, F, Cl, Br, I, CN, CH3, CF3, OCH3, alkyl, halogenated alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, aryloxy, arylalkoxy, heteroalkyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, alkylamino, diarylamino, dialkylamino, arylamino, alkylarylamino, acyl, acylamino, thiol, thioalkyl, alkylthio, acyloxy, nitro, oxo, carbamoyl, trifluoromethyl, phenoxy, benzyloxy, phosphonic acid, phosphate ester, sulfonic acid (—SO3H), sulfonate ester, sulfonamide, and carbamate, alkyltriphenylphosphonium, and
wherein X is selected from NH, NR19, oxygen, sulfur, and selenium, wherein R19 is selected from the group H, F, Cl, Br, I, CN, CH3, CF3, OCH3, alkyl, halogenated alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, aryloxy, arylalkoxy, heteroalkyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, alkylamino, diarylamino, dialkylamino, arylamino, alkylarylamino, acyl, acylamino, thiol, thioalkyl, alkylthio, acyloxy, nitro, oxo, carbamoyl, trifluoromethyl, phenoxy, benzyloxy, phosphonic acid, phosphate ester, sulfonic acid (—SO3H), sulfonate ester, sulfonamide, and carbamate, alkyltriphenylphosphonium; and
wherein n is 1, 2, 3, or 4. 14. The method of claim 13, wherein the compound comprises a formula: 15. The method of claim 13, wherein the compound comprises a formula: 16. The method of claim 15, wherein the compound comprises a formula: 17. The method of claim 15, wherein the compound comprises a formula: 18. The method of claim 13, wherein the compound is formulated as a composition comprising the compound and a pharmaceutically acceptable carrier. 19. The method of claim 13, wherein the amount of the compound ranges from about 1 mg/kg to about 30 mg/kg.
| 1,600 |
1,248 | 12,689,370 | 1,634 |
A method for preserving and processing fetal nucleic acids located within maternal plasma is disclosed, wherein a sample of maternal blood containing fetal nucleic acids is treated to reduce both cell lysis of the maternal blood cells and deoxyribonuclease (DNase) and ribonuclease (RNase) activity within the fetal nucleic acids. The treatment of the sample aids in increasing the amount of fetal nucleic acids that can be identified and tested while maintaining the structure and integrity of the fetal nucleic acids.
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1. A non-invasive prenatal screening method for the identification of fetal characteristics, comprising the steps of:
a. contacting a drawn maternal blood sample that includes a plurality of blood cells with a nucleic acid protective agent in an amount and time sufficient so that the blood cells are substantially prevented from (i) releasing genomic nucleic acids into the blood sample and from (ii) experiencing nuclease activity that degrades fetal nucleic acid; b. isolating fetal nucleic acids from the maternal blood sample; and c. analyzing the isolated fetal nucleic acids to identify a fetal characteristic. 2. The method of claim 1, wherein the protective agent includes a preservative agent selected from the group consisting of: diazolidinyl urea, imidazolidinyl urea, dimethoylol-5,5-dimethylhydantoin, dimethylol urea, 2-bromo-2.-nitropropane-1,3-diol, oxazolidines, sodium hydroxymethyl glycinate, 5-hydroxymethoxymethyl-1-1aza-3,7-dioxabicyclo[3.3.0]octane, 5-hydroxymethyl-1-1 aza-3,7dioxabicyclo[3.3.0]octane, 5-hydroxypoly[methyleneoxy]methyl-1-1aza-3,7dioxabicyclo[3.3.0]octane, quaternary adamantine and any combination thereof. 3. The method of claim 2, wherein the concentration of the preservative agent prior to the contacting step is between about 0.1 g/ml and about 3 g/ml. 4. The method of claim 2, wherein the concentration of the preservative agent prior to the contacting step is between about 0.4 g/ml and about 0.8 g/ml. 5. The method of claim 2, wherein the concentration of the preservative agent prior to the contacting step is a concentration at which cross-linking of nucleic acids and proteins is observed, as indicated by agarose gel electrophoresis. 6. The method of claim 2, wherein the amount of the preservative agent is less than about 20 mg/ml of the blood sample. 7. The method of claim 1, wherein (i) either or both of the isolating or analyzing steps occurs at least 2 hours after the blood sample is drawn, (ii) either or both of the isolating or analyzing steps occurs without freezing the blood sample (e.g. to a temperature colder than about −30° C. (more preferably colder than about −70° C.)); or both (i) and (ii). 8. The method of claim 1, wherein (i) either or both of the isolating or analyzing steps occurs at least 7 days after the blood sample is drawn, (ii) either or both of the isolating or analyzing steps occurs without freezing the blood sample (e.g. to a temperature colder than about −30° C. (more preferably colder than about −70° C.)); or both (i) and (ii). 9. The method of claim 1, wherein (i) either or both of the isolating or analyzing steps occurs at least 14 days after the blood sample is drawn, (ii) either or both of the isolating or analyzing steps occurs without freezing the blood sample (e.g. to a temperature colder than about −30° C. (more preferably colder than about −70° C.)); or both (i) and (ii). 10. A non-invasive prenatal screening method for the identification of fetal characteristics, comprising the steps of:
a. contacting a drawn maternal blood sample that includes a plurality of blood cells with a nucleic acid protective agent in an amount and time sufficient so that the blood cells are substantially prevented from (i) releasing genomic nucleic acids into the blood sample and from (ii) experiencing nuclease activity that degrades fetal nucleic acid, wherein the protective agent includes a formaldehyde donor and an anitcoagulant; b. isolating fetal nucleic acids from the maternal blood sample; and c. analyzing the isolated fetal nucleic acids to identify a fetal characteristic. 11. The method of claim 10, wherein the analyzing step, the isolating step or both includes a step of contacting the fetal nucleic acid with an enzyme, an amplifier or both. 12. The method of claim 10, wherein the contacting step takes place in a blood collection tube into which the blood sample is drawn. 13. The method of claim 10, wherein the contacting step is sufficient so that after a period of at least 7 days from the time the blood sample is drawn, the amount of fetal nucleic acid is at least about 90% of the amount of fetal nucleic acid at the time the blood sample is drawn. 14. The method of claim 10, wherein the contacting step is sufficient so that after a period of at least 7 days from the time the blood sample is drawn, the amount of fetal nucleic acid present in the sample is about 100% of the amount of fetal nucleic acid present in the sample at the time the blood sample is drawn. 15. The method of claim 10, wherein the contacting step is sufficient so that after a period of at least about 14 days from the time the blood sample is drawn, the concentration of fetal nucleic acid relative to the total nucleic acid in the blood sample that is present is at least 10 times the amount of fetal nucleic acid that would be present in the absence of the contacting step. 16. The method of claim 1, wherein the contacting step is sufficient so that after a period of at least about 14 days from the time the blood sample is drawn, the concentration of fetal nucleic acid relative to the total nucleic acid in the blood sample that is present is at least about 20 to 50 times the amount of fetal nucleic acid that would be present in the absence of the contacting step. 17. The method of claim 10, wherein the anticoagulant selected from the group consisting of heparin, ethylenediamine tetraacetic acid, citrate, oxalate, and any combination thereof. 18. The method of claim 10, wherein the protective agent includes imidazolidinyl urea and ethylenediamine tetraacetic acid. 19. The method of claim 10, wherein the protective agent includes imidazolidinyl urea, ethylenediamine tetraacetic acid, and glycine. 20. A method for the preservation of fetal DNA comprising the steps of:
providing a tube having an open end and a closed end, wherein the tube is preloaded with a protective agent including imidazolidinyl urea, ethylenediamine tetraacetic acid, and glycine; drawing a maternal blood sample from a pregnant patient into the tube; inserting a closure into the open end off the tube; analyzing fetal DNA located within the maternal blood sample at least three hours post blood draw, wherein the amount of fetal DNA located within the maternal blood sample is at least about 90% of the amount of fetal nucleic acid at the time the blood sample is drawn.
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A method for preserving and processing fetal nucleic acids located within maternal plasma is disclosed, wherein a sample of maternal blood containing fetal nucleic acids is treated to reduce both cell lysis of the maternal blood cells and deoxyribonuclease (DNase) and ribonuclease (RNase) activity within the fetal nucleic acids. The treatment of the sample aids in increasing the amount of fetal nucleic acids that can be identified and tested while maintaining the structure and integrity of the fetal nucleic acids.1. A non-invasive prenatal screening method for the identification of fetal characteristics, comprising the steps of:
a. contacting a drawn maternal blood sample that includes a plurality of blood cells with a nucleic acid protective agent in an amount and time sufficient so that the blood cells are substantially prevented from (i) releasing genomic nucleic acids into the blood sample and from (ii) experiencing nuclease activity that degrades fetal nucleic acid; b. isolating fetal nucleic acids from the maternal blood sample; and c. analyzing the isolated fetal nucleic acids to identify a fetal characteristic. 2. The method of claim 1, wherein the protective agent includes a preservative agent selected from the group consisting of: diazolidinyl urea, imidazolidinyl urea, dimethoylol-5,5-dimethylhydantoin, dimethylol urea, 2-bromo-2.-nitropropane-1,3-diol, oxazolidines, sodium hydroxymethyl glycinate, 5-hydroxymethoxymethyl-1-1aza-3,7-dioxabicyclo[3.3.0]octane, 5-hydroxymethyl-1-1 aza-3,7dioxabicyclo[3.3.0]octane, 5-hydroxypoly[methyleneoxy]methyl-1-1aza-3,7dioxabicyclo[3.3.0]octane, quaternary adamantine and any combination thereof. 3. The method of claim 2, wherein the concentration of the preservative agent prior to the contacting step is between about 0.1 g/ml and about 3 g/ml. 4. The method of claim 2, wherein the concentration of the preservative agent prior to the contacting step is between about 0.4 g/ml and about 0.8 g/ml. 5. The method of claim 2, wherein the concentration of the preservative agent prior to the contacting step is a concentration at which cross-linking of nucleic acids and proteins is observed, as indicated by agarose gel electrophoresis. 6. The method of claim 2, wherein the amount of the preservative agent is less than about 20 mg/ml of the blood sample. 7. The method of claim 1, wherein (i) either or both of the isolating or analyzing steps occurs at least 2 hours after the blood sample is drawn, (ii) either or both of the isolating or analyzing steps occurs without freezing the blood sample (e.g. to a temperature colder than about −30° C. (more preferably colder than about −70° C.)); or both (i) and (ii). 8. The method of claim 1, wherein (i) either or both of the isolating or analyzing steps occurs at least 7 days after the blood sample is drawn, (ii) either or both of the isolating or analyzing steps occurs without freezing the blood sample (e.g. to a temperature colder than about −30° C. (more preferably colder than about −70° C.)); or both (i) and (ii). 9. The method of claim 1, wherein (i) either or both of the isolating or analyzing steps occurs at least 14 days after the blood sample is drawn, (ii) either or both of the isolating or analyzing steps occurs without freezing the blood sample (e.g. to a temperature colder than about −30° C. (more preferably colder than about −70° C.)); or both (i) and (ii). 10. A non-invasive prenatal screening method for the identification of fetal characteristics, comprising the steps of:
a. contacting a drawn maternal blood sample that includes a plurality of blood cells with a nucleic acid protective agent in an amount and time sufficient so that the blood cells are substantially prevented from (i) releasing genomic nucleic acids into the blood sample and from (ii) experiencing nuclease activity that degrades fetal nucleic acid, wherein the protective agent includes a formaldehyde donor and an anitcoagulant; b. isolating fetal nucleic acids from the maternal blood sample; and c. analyzing the isolated fetal nucleic acids to identify a fetal characteristic. 11. The method of claim 10, wherein the analyzing step, the isolating step or both includes a step of contacting the fetal nucleic acid with an enzyme, an amplifier or both. 12. The method of claim 10, wherein the contacting step takes place in a blood collection tube into which the blood sample is drawn. 13. The method of claim 10, wherein the contacting step is sufficient so that after a period of at least 7 days from the time the blood sample is drawn, the amount of fetal nucleic acid is at least about 90% of the amount of fetal nucleic acid at the time the blood sample is drawn. 14. The method of claim 10, wherein the contacting step is sufficient so that after a period of at least 7 days from the time the blood sample is drawn, the amount of fetal nucleic acid present in the sample is about 100% of the amount of fetal nucleic acid present in the sample at the time the blood sample is drawn. 15. The method of claim 10, wherein the contacting step is sufficient so that after a period of at least about 14 days from the time the blood sample is drawn, the concentration of fetal nucleic acid relative to the total nucleic acid in the blood sample that is present is at least 10 times the amount of fetal nucleic acid that would be present in the absence of the contacting step. 16. The method of claim 1, wherein the contacting step is sufficient so that after a period of at least about 14 days from the time the blood sample is drawn, the concentration of fetal nucleic acid relative to the total nucleic acid in the blood sample that is present is at least about 20 to 50 times the amount of fetal nucleic acid that would be present in the absence of the contacting step. 17. The method of claim 10, wherein the anticoagulant selected from the group consisting of heparin, ethylenediamine tetraacetic acid, citrate, oxalate, and any combination thereof. 18. The method of claim 10, wherein the protective agent includes imidazolidinyl urea and ethylenediamine tetraacetic acid. 19. The method of claim 10, wherein the protective agent includes imidazolidinyl urea, ethylenediamine tetraacetic acid, and glycine. 20. A method for the preservation of fetal DNA comprising the steps of:
providing a tube having an open end and a closed end, wherein the tube is preloaded with a protective agent including imidazolidinyl urea, ethylenediamine tetraacetic acid, and glycine; drawing a maternal blood sample from a pregnant patient into the tube; inserting a closure into the open end off the tube; analyzing fetal DNA located within the maternal blood sample at least three hours post blood draw, wherein the amount of fetal DNA located within the maternal blood sample is at least about 90% of the amount of fetal nucleic acid at the time the blood sample is drawn.
| 1,600 |
1,249 | 15,993,172 | 1,649 |
Provided herein are methods and compositions for treating inflammatory diseases by administering to the subject an effective dose on an anti-α 5 agent.
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1. A method for treating an inflammatory disease or condition in a patient, the method comprising:
administering to said patient a therapeutically effective dose of an anti-integrin-α5 agent. 2. The method of claim 1, wherein the patient is a human. 3. The method of claim 1, wherein the inflammatory disease is multiple sclerosis. 4. A method for treating amyotrophic lateral sclerosis in a patient, the method comprising:
administering to said patient a therapeutically effective dose of an anti-integrin-α5 agent. 5. The method of claim 1, wherein the anti-integrin-α5 agent reduces macrophage activity to enhance removal of a tattoo. 6. The method of claim 1, wherein the anti-α5 agent blocks the binding of integrin α5 to fibronectin. 7. The method of claim 6, wherein the anti-α5 agent is an antibody that specifically binds to integrin α5, integrin β1, or the heterodimer integrin α5β1. 8. The method of claim 7, wherein the antibody is a chimeric or humanized antibody specific for integrin α5, or a specific binding fragment thereof. 9. The method of claim 8, wherein the antibody comprises a human IgG4 Fc region. 10. The method of claim 3, further comprising administering an additional therapeutic agent for treatment of multiple sclerosis. 11. The method of claim 10, wherein the additional therapeutic agent is selected from a statin, a cytokine; fingolimod; and copaxone. 12. The method of claim 11, wherein the cytokine is IFNβ. 13. The method of claim 1, wherein the patient is patient is analyzed for responsiveness to cytokine therapy, and where the selection of therapeutic agent is based on such analysis. 14. A composition comprising a package comprising an anti-α5 agent and a package insert or label that indicates that the anti-α5 agent is to be administered to a patient for the treatment of a neuroinflammatory disease or ALS.
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Provided herein are methods and compositions for treating inflammatory diseases by administering to the subject an effective dose on an anti-α 5 agent.1. A method for treating an inflammatory disease or condition in a patient, the method comprising:
administering to said patient a therapeutically effective dose of an anti-integrin-α5 agent. 2. The method of claim 1, wherein the patient is a human. 3. The method of claim 1, wherein the inflammatory disease is multiple sclerosis. 4. A method for treating amyotrophic lateral sclerosis in a patient, the method comprising:
administering to said patient a therapeutically effective dose of an anti-integrin-α5 agent. 5. The method of claim 1, wherein the anti-integrin-α5 agent reduces macrophage activity to enhance removal of a tattoo. 6. The method of claim 1, wherein the anti-α5 agent blocks the binding of integrin α5 to fibronectin. 7. The method of claim 6, wherein the anti-α5 agent is an antibody that specifically binds to integrin α5, integrin β1, or the heterodimer integrin α5β1. 8. The method of claim 7, wherein the antibody is a chimeric or humanized antibody specific for integrin α5, or a specific binding fragment thereof. 9. The method of claim 8, wherein the antibody comprises a human IgG4 Fc region. 10. The method of claim 3, further comprising administering an additional therapeutic agent for treatment of multiple sclerosis. 11. The method of claim 10, wherein the additional therapeutic agent is selected from a statin, a cytokine; fingolimod; and copaxone. 12. The method of claim 11, wherein the cytokine is IFNβ. 13. The method of claim 1, wherein the patient is patient is analyzed for responsiveness to cytokine therapy, and where the selection of therapeutic agent is based on such analysis. 14. A composition comprising a package comprising an anti-α5 agent and a package insert or label that indicates that the anti-α5 agent is to be administered to a patient for the treatment of a neuroinflammatory disease or ALS.
| 1,600 |
1,250 | 15,117,896 | 1,628 |
The present invention discloses the use of paricalcitol, a synthetic Vitamin D analogue, in the treatment of inflammatory anaemia, preferably in combination with erythropoeisis-stimulating agents. The use of paricalcitol in the treatment of said pathology is associated with a reduced requirement for erythropoeisis-stimulating agents, with optimised iron absorption and with an increase in plasma erythropoietin levels in said patients. The present invention also discloses pharmaceutical compositions that comprise paricalcitol in combination with erythropoeisis-stimulating agents and pharmaceutically acceptable excipients, in addition to the use thereof as drugs in the treatment of inflammatory anaemia.
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1. A method of treating inflammatory anaemia, said method comprising administering paricalcitol to a subject in need thereof, wherein the dose of paricalcitol to be administered is between 5-10 μg/week. 2. The method of claim 1, wherein the dose of paricalcitol to be administered is 1 μg/day. 3. The method of claim 1, wherein the dose of paricalcitol to be administered is 5 μg twice a week. 4. The method of claim 1, wherein the paricalcitol is administered in combination with at least one compound selected from the group consisting of: epoetin alfa, epoetin beta, epoetin delta; epoetin zeta, Darbepoetin alfa, CERA, and combinations thereof. 5.-6. (canceled) 7. Pharmaceutical composition comprising paricalcitol in combination with at least one compound selected from the group consisting of: epoetin alfa, epoetin beta, epoetin delta; epoetin zeta, Darbepoetin alfa, CERA, and combinations thereof, and together with pharmaceutically acceptable vehicles or excipients. 8.-13. (canceled) 14. The pharmaceutical composition according to claim 7 comprising paricalcitol in combination with a compound selected from the group consisting of epoetin beta, CERA, and combinations thereof, and together with pharmaceutically acceptable vehicles or excipients. 15. A method of treating inflammatory anaemia, said method comprising administering the pharmaceutical composition of claim 7 to a subject in need thereof, wherein the dose of paricalcitol to be administered is comprised 5-10 μg/week. 16. The method of claim 15, wherein the dose of paricalcitol is 1 μg/day. 17. The method of claim 15, wherein the dose of paricalcitol is 5 μg twice a week. 18. A method of inducing an increase of endogenous erythropoietin synthesis, said method comprising administering paricalcitol to a subject, wherein the dose of paricalcitol to be administered is between 5-10 μg/week.
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The present invention discloses the use of paricalcitol, a synthetic Vitamin D analogue, in the treatment of inflammatory anaemia, preferably in combination with erythropoeisis-stimulating agents. The use of paricalcitol in the treatment of said pathology is associated with a reduced requirement for erythropoeisis-stimulating agents, with optimised iron absorption and with an increase in plasma erythropoietin levels in said patients. The present invention also discloses pharmaceutical compositions that comprise paricalcitol in combination with erythropoeisis-stimulating agents and pharmaceutically acceptable excipients, in addition to the use thereof as drugs in the treatment of inflammatory anaemia.1. A method of treating inflammatory anaemia, said method comprising administering paricalcitol to a subject in need thereof, wherein the dose of paricalcitol to be administered is between 5-10 μg/week. 2. The method of claim 1, wherein the dose of paricalcitol to be administered is 1 μg/day. 3. The method of claim 1, wherein the dose of paricalcitol to be administered is 5 μg twice a week. 4. The method of claim 1, wherein the paricalcitol is administered in combination with at least one compound selected from the group consisting of: epoetin alfa, epoetin beta, epoetin delta; epoetin zeta, Darbepoetin alfa, CERA, and combinations thereof. 5.-6. (canceled) 7. Pharmaceutical composition comprising paricalcitol in combination with at least one compound selected from the group consisting of: epoetin alfa, epoetin beta, epoetin delta; epoetin zeta, Darbepoetin alfa, CERA, and combinations thereof, and together with pharmaceutically acceptable vehicles or excipients. 8.-13. (canceled) 14. The pharmaceutical composition according to claim 7 comprising paricalcitol in combination with a compound selected from the group consisting of epoetin beta, CERA, and combinations thereof, and together with pharmaceutically acceptable vehicles or excipients. 15. A method of treating inflammatory anaemia, said method comprising administering the pharmaceutical composition of claim 7 to a subject in need thereof, wherein the dose of paricalcitol to be administered is comprised 5-10 μg/week. 16. The method of claim 15, wherein the dose of paricalcitol is 1 μg/day. 17. The method of claim 15, wherein the dose of paricalcitol is 5 μg twice a week. 18. A method of inducing an increase of endogenous erythropoietin synthesis, said method comprising administering paricalcitol to a subject, wherein the dose of paricalcitol to be administered is between 5-10 μg/week.
| 1,600 |
1,251 | 14,426,485 | 1,623 |
The present invention provides a hyaluronic acid derivative containing a disaccharide unit represented by formula (I) or formula (I) and (II), and a complex containing the hyaluronic acid derivative and a drug.
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1. A hyaluronic acid derivative comprising a repeating unit represented by formula (I):
[where R1, R2, R3, and R4 are independently selected from a hydrogen atom, C1-6 alkyl, formyl, and C1-6 alkylcarbonyl;
R5 is a hydrogen atom, formyl, or C1-6 alkylcarbonyl;
X1 is hydroxy, —O-Q+, C1-6 alkoxy, —NR7R8, or —NR9—Z1—Z2;
Q+ represents a counter cation;
R6, R7, R8, and R9 are independently selected from a hydrogen atom and C1-6 alkyl;
Ra is a hydrogen atom or C1-6 alkyl, where the alkyl may be independently substituted by one or more groups selected from hydroxy, carboxy, carbamoyl, C1-6 alkylthio, aryl, and heteroaryl, where the aryl may be substituted with one or more hydroxy groups;
Z1 is C2-30 alkylene or —(CH2CH2O)m—CH2CH2—, where into the alkylene 1 to 5 groups independently selected from —O—, —NRg—, and —S—S— may be inserted, and m is an integer selected from 1 to 100;
Z2 is selected from groups represented by the following formulas:
—NRb—Z3,
—NRb—COO—Z3,
—NRb—CO—Z3,
—NRb—CO—NRc—Z3,
—COO—Z3,
—CO—NRc—Z3,
—O—CO—NRc—Z3,
—O—COO—Z3,
—S—Z3,
—CO—Za—S—Z3,
—O—CO—Zb—S—Z3,
—NRb—CO—Zb—S—Z3, and
—S—S—Z3;
Rb and Rc are independently selected from a hydrogen atom, C1-20 alkyl, amino C2-20 alkyl, and hydroxy C2-20 alkyl, where into the alkyl moieties of the groups 1 to 3 groups independently selected from —O— and —NRf— may be inserted;
Rf is independently selected from a hydrogen atom, C1-12 alkyl, amino C2-12 alkyl, and hydroxy C2-12 alkyl, and into the alkyl moieties of the groups 1 to 2 groups independently selected from —O— and —NH— may be inserted;
Rg is independently selected from a hydrogen atom, C1-20 alkyl, amino C2-20 alkyl, or hydroxy C2-20 alkyl, and into the alkyl moieties of the groups 1 to 3 groups independently selected from —O— and —NH— may be inserted;
Z3 is a steryl group;
Za is C1-5 alkylene; and
Zb is C2-8 alkylene or C2-8 alkenylene],
wherein if the hyaluronic acid derivative comprises no repeating units represented by formula (I) in which X1 is —NR9—Z1—Z2, then the hyaluronic acid derivative further comprises a repeating unit represented by formula (II):
[where R1a, R2a, R3a, and R4a are independently selected from a hydrogen atom, C1-6 alkyl, formyl, and C1-6 alkylcarbonyl;
R5a is a hydrogen atom, formyl, or C1-6 alkylcarbonyl; and
X2 is —NR9—Z1—Z2, where R9, Z1, and Z2 are as defined above]. 2. The hyaluronic acid derivative according to claim 1, further comprising a repeating unit represented by formula (IIb):
[where R1b, R2b, R3b, and R4b are each independently selected from a hydrogen atom, C1-6 alkyl, formyl, and C1-6 alkylcarbonyl;
R5b is selected from a hydrogen atom, formyl, and C1-6 alkylcarbonyl; and
Xb is selected from hydroxy and —O-Q+, where Q+ represents a counter cation]. 3. The hyaluronic acid derivative according to claim 1, wherein X1 is —NR9—Z1—Z2 in formula (I). 4. The hyaluronic acid derivative according to claim 1, wherein a percentage of the disaccharide unit represented by formula (I) in existing disaccharide repeating units is 70 to 100%. 5. The hyaluronic acid derivative according to claim 1, wherein a percentage of the disaccharide unit comprising the group —NR9—Z1—Z2 in existing disaccharide repeating units is 3 to 50%. 6. The hyaluronic acid derivative according to claim 1, comprising no repeating units represented by formula (I) in which X1 is —NR9—Z1—Z2. 7. The hyaluronic acid derivative according to claim 1, wherein a sum of percentages of the repeating unit represented by (I) and the repeating unit represented by formula (II) in existing disaccharide repeating units is 70 to 100%. 8. The hyaluronic acid derivative according to claim 1, wherein the hyaluronic acid derivative is produced by using hyaluronic acid exclusively consisting of the disaccharide unit represented by formula (IIb)
[where R1b, R2b, R3b, and R4b are each independently selected from a hydrogen atom, C1-6 alkyl, formyl, and C1-6 alkylcarbonyl;
R5b is selected from a hydrogen atom, formyl, and C1-6 alkylcarbonyl; and
Xb is selected from hydroxy and —O-Q+, where Q+ represents a counter cation], and has a weight-average molecular weight of 3 kilo Daltons to 1,500 kilo Daltons when R1b, R2b, R3b, and R4b are all hydrogen atoms, R5b is acetyl, and Xb is —O—Na+. 9. The hyaluronic acid derivative according to claim 1, wherein Z1 is C2-10 alkylene, Z2 is —NH—COO—Z3, and Z3 is a cholesteryl group. 10. The hyaluronic acid derivative according to claim 1, wherein the hyaluronic acid derivative is obtained by reacting a hyaluronic acid derivative comprising a repeating unit represented by formula (IIb) and a repeating unit represented by formula (Ia),
[where Xa is selected from hydroxy, —O-Q+, C1-6 alkoxy, and —NR7R8 and R1, R2, R3, R4, R5, R6, R7, R8, Q+, and Ra are as defined in claim 1], with a compound represented by formula below,
HNR9—Z—Z2,
[where R9, Z1, and Z2 are as defined in claim 1]. 11. A pharmaceutical composition comprising the hyaluronic acid derivative according to claim 1 and a drug. 12. The pharmaceutical composition according to claim 11, wherein the drug is held by forming a complex with the hyaluronic acid derivative.
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The present invention provides a hyaluronic acid derivative containing a disaccharide unit represented by formula (I) or formula (I) and (II), and a complex containing the hyaluronic acid derivative and a drug.1. A hyaluronic acid derivative comprising a repeating unit represented by formula (I):
[where R1, R2, R3, and R4 are independently selected from a hydrogen atom, C1-6 alkyl, formyl, and C1-6 alkylcarbonyl;
R5 is a hydrogen atom, formyl, or C1-6 alkylcarbonyl;
X1 is hydroxy, —O-Q+, C1-6 alkoxy, —NR7R8, or —NR9—Z1—Z2;
Q+ represents a counter cation;
R6, R7, R8, and R9 are independently selected from a hydrogen atom and C1-6 alkyl;
Ra is a hydrogen atom or C1-6 alkyl, where the alkyl may be independently substituted by one or more groups selected from hydroxy, carboxy, carbamoyl, C1-6 alkylthio, aryl, and heteroaryl, where the aryl may be substituted with one or more hydroxy groups;
Z1 is C2-30 alkylene or —(CH2CH2O)m—CH2CH2—, where into the alkylene 1 to 5 groups independently selected from —O—, —NRg—, and —S—S— may be inserted, and m is an integer selected from 1 to 100;
Z2 is selected from groups represented by the following formulas:
—NRb—Z3,
—NRb—COO—Z3,
—NRb—CO—Z3,
—NRb—CO—NRc—Z3,
—COO—Z3,
—CO—NRc—Z3,
—O—CO—NRc—Z3,
—O—COO—Z3,
—S—Z3,
—CO—Za—S—Z3,
—O—CO—Zb—S—Z3,
—NRb—CO—Zb—S—Z3, and
—S—S—Z3;
Rb and Rc are independently selected from a hydrogen atom, C1-20 alkyl, amino C2-20 alkyl, and hydroxy C2-20 alkyl, where into the alkyl moieties of the groups 1 to 3 groups independently selected from —O— and —NRf— may be inserted;
Rf is independently selected from a hydrogen atom, C1-12 alkyl, amino C2-12 alkyl, and hydroxy C2-12 alkyl, and into the alkyl moieties of the groups 1 to 2 groups independently selected from —O— and —NH— may be inserted;
Rg is independently selected from a hydrogen atom, C1-20 alkyl, amino C2-20 alkyl, or hydroxy C2-20 alkyl, and into the alkyl moieties of the groups 1 to 3 groups independently selected from —O— and —NH— may be inserted;
Z3 is a steryl group;
Za is C1-5 alkylene; and
Zb is C2-8 alkylene or C2-8 alkenylene],
wherein if the hyaluronic acid derivative comprises no repeating units represented by formula (I) in which X1 is —NR9—Z1—Z2, then the hyaluronic acid derivative further comprises a repeating unit represented by formula (II):
[where R1a, R2a, R3a, and R4a are independently selected from a hydrogen atom, C1-6 alkyl, formyl, and C1-6 alkylcarbonyl;
R5a is a hydrogen atom, formyl, or C1-6 alkylcarbonyl; and
X2 is —NR9—Z1—Z2, where R9, Z1, and Z2 are as defined above]. 2. The hyaluronic acid derivative according to claim 1, further comprising a repeating unit represented by formula (IIb):
[where R1b, R2b, R3b, and R4b are each independently selected from a hydrogen atom, C1-6 alkyl, formyl, and C1-6 alkylcarbonyl;
R5b is selected from a hydrogen atom, formyl, and C1-6 alkylcarbonyl; and
Xb is selected from hydroxy and —O-Q+, where Q+ represents a counter cation]. 3. The hyaluronic acid derivative according to claim 1, wherein X1 is —NR9—Z1—Z2 in formula (I). 4. The hyaluronic acid derivative according to claim 1, wherein a percentage of the disaccharide unit represented by formula (I) in existing disaccharide repeating units is 70 to 100%. 5. The hyaluronic acid derivative according to claim 1, wherein a percentage of the disaccharide unit comprising the group —NR9—Z1—Z2 in existing disaccharide repeating units is 3 to 50%. 6. The hyaluronic acid derivative according to claim 1, comprising no repeating units represented by formula (I) in which X1 is —NR9—Z1—Z2. 7. The hyaluronic acid derivative according to claim 1, wherein a sum of percentages of the repeating unit represented by (I) and the repeating unit represented by formula (II) in existing disaccharide repeating units is 70 to 100%. 8. The hyaluronic acid derivative according to claim 1, wherein the hyaluronic acid derivative is produced by using hyaluronic acid exclusively consisting of the disaccharide unit represented by formula (IIb)
[where R1b, R2b, R3b, and R4b are each independently selected from a hydrogen atom, C1-6 alkyl, formyl, and C1-6 alkylcarbonyl;
R5b is selected from a hydrogen atom, formyl, and C1-6 alkylcarbonyl; and
Xb is selected from hydroxy and —O-Q+, where Q+ represents a counter cation], and has a weight-average molecular weight of 3 kilo Daltons to 1,500 kilo Daltons when R1b, R2b, R3b, and R4b are all hydrogen atoms, R5b is acetyl, and Xb is —O—Na+. 9. The hyaluronic acid derivative according to claim 1, wherein Z1 is C2-10 alkylene, Z2 is —NH—COO—Z3, and Z3 is a cholesteryl group. 10. The hyaluronic acid derivative according to claim 1, wherein the hyaluronic acid derivative is obtained by reacting a hyaluronic acid derivative comprising a repeating unit represented by formula (IIb) and a repeating unit represented by formula (Ia),
[where Xa is selected from hydroxy, —O-Q+, C1-6 alkoxy, and —NR7R8 and R1, R2, R3, R4, R5, R6, R7, R8, Q+, and Ra are as defined in claim 1], with a compound represented by formula below,
HNR9—Z—Z2,
[where R9, Z1, and Z2 are as defined in claim 1]. 11. A pharmaceutical composition comprising the hyaluronic acid derivative according to claim 1 and a drug. 12. The pharmaceutical composition according to claim 11, wherein the drug is held by forming a complex with the hyaluronic acid derivative.
| 1,600 |
1,252 | 16,308,050 | 1,612 |
Sunscreen composition including a combination of a linear ultraviolet radiation absorbing polyether that includes a covalently bound UV-chromophore, and at least one non-polymeric UV-screening compounds.
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1. A sunscreen composition, comprising:
a polymer composition comprising a linear, ultraviolet radiation absorbing polyether comprising a covalently bound UV-chromophore; and at least one additional UV screening compound. 2. The composition of claim 1 wherein said additional UV-screening compound is avobenzone. 3. The composition of claim 1 wherein said covalently bound UV-chromophore is a benzotriazole. 4. The composition of claim 1 wherein said additional UV screening compound is a UV blocking compound. 5. The composition of claim 4 wherein said UV blocking compound is titanium oxide or zinc oxide. 6. The composition of claim 1 wherein said additional UV screening compound is an organic UV absorbing compound. 7. The composition of claim 6 wherein said organic UV absorbing compound is selected from the group consisting of Diethylamino Hydroxybenzoyl Hexyl Benzoate, Ethylhexyl Triazone, Bis Ethylhexyloxyphenol Methoxyphenyl Triazine, Methylene Bis-Benzotriazolyl Tetramethylbutylphenol, Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine, Tris-Biphenyl Triazine, Ethylhexyl Methoxycinnamate, Octocrylene,1,1′-(1,4-piperazinediyl)bis[1-[2-[4-(diethylamino)-2-hydroxybenzoyl]phenyl]-methanone, Phenylbenzimidazole Sulfonic Acid, Ethylhexyl salicylate, Homosalate, Diethylhexyl butamido triazone, Isoamyl p-methoxycinnamate, and Polysilicone-15. 8. The composition of claim 6 wherein said organic UV absorbing compound is selected from the group consisting of Diethylamino Hydroxybenzoyl Hexyl Benzoate, Ethylhexyl Triazone, Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine, Methylene Bis-Benzotriazolyl Tetramethylbutylphenol, Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine, Tris-Biphenyl Triazine, Ethylhexyl Methoxycinnamate, Octocrylene, and 1,1′-(1,4-piperazinediyl)bis[1-[2-[4-(diethylamino)-2-hydroxybenzoyl]phenyl]-methanone. 9. The composition of claim 1 wherein said additional UV screening compound is a mixture of Ethylhexyl Triazone, Diethylamino Hydroxybenzoyl Hexyl Benzoate and Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine. 10. The composition of claim 1 wherein said additional UV screening compound is a mixture of Ethylhexyl Triazone, Butyl Methoxydibenzoylmethane, Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine, and Methylene Bis-Benzotriazolyl Tetramethylbutylphenol. 11. The composition of claim 1 wherein said additional UV-screening compound is Methylene bis-benzotriazolyl tetramethylbutylphenol and octocrylene. 12. The composition of claim 1 wherein said one additional UV-screening compound is octocrylene. 13. The composition of claim 1 further comprising acrylic/styrene copolymers. 14. The composition of claim 1 further comprising a film-forming polymer selected from natural polymers and synthetic polymers. 15. The composition of claim 14 wherein said film-forming polymer is a copolymer of vinylpyrrolidone and a long-chain alpha-olefin. 16. The composition of claim 1 further comprising silica.
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Sunscreen composition including a combination of a linear ultraviolet radiation absorbing polyether that includes a covalently bound UV-chromophore, and at least one non-polymeric UV-screening compounds.1. A sunscreen composition, comprising:
a polymer composition comprising a linear, ultraviolet radiation absorbing polyether comprising a covalently bound UV-chromophore; and at least one additional UV screening compound. 2. The composition of claim 1 wherein said additional UV-screening compound is avobenzone. 3. The composition of claim 1 wherein said covalently bound UV-chromophore is a benzotriazole. 4. The composition of claim 1 wherein said additional UV screening compound is a UV blocking compound. 5. The composition of claim 4 wherein said UV blocking compound is titanium oxide or zinc oxide. 6. The composition of claim 1 wherein said additional UV screening compound is an organic UV absorbing compound. 7. The composition of claim 6 wherein said organic UV absorbing compound is selected from the group consisting of Diethylamino Hydroxybenzoyl Hexyl Benzoate, Ethylhexyl Triazone, Bis Ethylhexyloxyphenol Methoxyphenyl Triazine, Methylene Bis-Benzotriazolyl Tetramethylbutylphenol, Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine, Tris-Biphenyl Triazine, Ethylhexyl Methoxycinnamate, Octocrylene,1,1′-(1,4-piperazinediyl)bis[1-[2-[4-(diethylamino)-2-hydroxybenzoyl]phenyl]-methanone, Phenylbenzimidazole Sulfonic Acid, Ethylhexyl salicylate, Homosalate, Diethylhexyl butamido triazone, Isoamyl p-methoxycinnamate, and Polysilicone-15. 8. The composition of claim 6 wherein said organic UV absorbing compound is selected from the group consisting of Diethylamino Hydroxybenzoyl Hexyl Benzoate, Ethylhexyl Triazone, Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine, Methylene Bis-Benzotriazolyl Tetramethylbutylphenol, Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine, Tris-Biphenyl Triazine, Ethylhexyl Methoxycinnamate, Octocrylene, and 1,1′-(1,4-piperazinediyl)bis[1-[2-[4-(diethylamino)-2-hydroxybenzoyl]phenyl]-methanone. 9. The composition of claim 1 wherein said additional UV screening compound is a mixture of Ethylhexyl Triazone, Diethylamino Hydroxybenzoyl Hexyl Benzoate and Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine. 10. The composition of claim 1 wherein said additional UV screening compound is a mixture of Ethylhexyl Triazone, Butyl Methoxydibenzoylmethane, Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine, and Methylene Bis-Benzotriazolyl Tetramethylbutylphenol. 11. The composition of claim 1 wherein said additional UV-screening compound is Methylene bis-benzotriazolyl tetramethylbutylphenol and octocrylene. 12. The composition of claim 1 wherein said one additional UV-screening compound is octocrylene. 13. The composition of claim 1 further comprising acrylic/styrene copolymers. 14. The composition of claim 1 further comprising a film-forming polymer selected from natural polymers and synthetic polymers. 15. The composition of claim 14 wherein said film-forming polymer is a copolymer of vinylpyrrolidone and a long-chain alpha-olefin. 16. The composition of claim 1 further comprising silica.
| 1,600 |
1,253 | 14,979,181 | 1,662 |
This disclosure concerns nucleic acid molecules and methods of use thereof for control of insect pests through RNA interference-mediated inhibition of target coding and transcribed non-coding sequences in insect pests, including coleopteran pests. The disclosure also concerns methods for making transgenic plants that express nucleic acid molecules useful for the control of insect pests, and the plant cells and plants obtained thereby.
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1. An isolated nucleic acid comprising at least one polynucleotide operably linked to a heterologous promoter, wherein the polynucleotide is selected from the group consisting of:
SEQ ID NO:1; the complement of SEQ ID NO:1; a fragment of at least 15 contiguous nucleotides of SEQ ID NO:1; the complement of a fragment of at least 15 contiguous nucleotides of SEQ ID NO:1; a native coding sequence of a Diabrotica organism comprising SEQ ID NO:1; the complement of a native coding sequence of a Diabrotica organism comprising SEQ ID NO:1; a fragment of at least 15 contiguous nucleotides of a native coding sequence of a Diabrotica organism comprising SEQ ID NO:1; the complement of a fragment of at least 15 contiguous nucleotides of a native coding sequence of a Diabrotica organism comprising SEQ ID NO:1; SEQ ID NO:77; the complement of SEQ ID NO:77; a fragment of at least 15 contiguous nucleotides of SEQ ID NO:77; the complement of a fragment of at least 15 contiguous nucleotides of SEQ ID NO:77; a native coding sequence of a Diabrotica organism comprising SEQ ID NO:77; the complement of a native coding sequence of a Diabrotica organism comprising SEQ ID NO:77; a fragment of at least 15 contiguous nucleotides of a native coding sequence of a Diabrotica organism comprising SEQ ID NO:77; the complement of a fragment of at least 15 contiguous nucleotides of a native coding sequence of a Diabrotica organism comprising SEQ ID NO:77; SEQ ID NO:84; the complement of SEQ ID NO:84; a fragment of at least 15 contiguous nucleotides of SEQ ID NO:84; the complement of a fragment of at least 15 contiguous nucleotides of SEQ ID NO:84; a native coding sequence of a Meligethes organism comprising SEQ ID NO:84; the complement of a native coding sequence of a Meligethes organism comprising SEQ ID NO:84; a fragment of at least 15 contiguous nucleotides of a native coding sequence of a Meligethes organism comprising SEQ ID NO:84; the complement of a fragment of at least 15 contiguous nucleotides of a native coding sequence of a Meligethes organism comprising SEQ ID NO:84; SEQ ID NO:86; the complement of SEQ ID NO:86; a fragment of at least 15 contiguous nucleotides of SEQ ID NO:86; the complement of a fragment of at least 15 contiguous nucleotides of SEQ ID NO:86; a native coding sequence of a Meligethes organism comprising SEQ ID NO:86; the complement of a native coding sequence of a Meligethes organism comprising SEQ ID NO:86; a fragment of at least 15 contiguous nucleotides of a native coding sequence of a Meligethes organism comprising SEQ ID NO:86; the complement of a fragment of at least 15 contiguous nucleotides of a native coding sequence of a Meligethes organism comprising SEQ ID NO:86; SEQ ID NO:88; the complement of SEQ ID NO:88; a fragment of at least 15 contiguous nucleotides of SEQ ID NO:88; the complement of a fragment of at least 15 contiguous nucleotides of SEQ ID NO:88; a native coding sequence of a Meligethes organism comprising SEQ ID NO:88; the complement of a native coding sequence of a Meligethes organism comprising SEQ ID NO:88; a fragment of at least 15 contiguous nucleotides of a native coding sequence of a Meligethes organism comprising SEQ ID NO:88; the complement of a fragment of at least 15 contiguous nucleotides of a native coding sequence of a Meligethes organism comprising SEQ ID NO:88; SEQ ID NO:93; the complement of SEQ ID NO:93; a fragment of at least 15 contiguous nucleotides of SEQ ID NO:93; the complement of a fragment of at least 15 contiguous nucleotides of SEQ ID NO:93; a native coding sequence of a Meligethes organism comprising SEQ ID NO:93; the complement of a native coding sequence of a Meligethes organism comprising SEQ ID NO:93; a fragment of at least 15 contiguous nucleotides of a native coding sequence of a Meligethes organism comprising SEQ ID NO:93; and the complement of a fragment of at least 15 contiguous nucleotides of a native coding sequence of a Meligethes organism comprising SEQ ID NO:93. 2. The polynucleotide of claim 1, wherein the polynucleotide is selected from the group consisting of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:17, and SEQ ID NO:77, and the complements of any of the foregoing. 3. The polynucleotide of claim 1, wherein the polynucleotide is selected from the group consisting of SEQ ID NO:84, SEQ ID NO:86, SEQ ID NO:88, SEQ ID NO:90, SEQ ID NO:93, and the complements of any of the foregoing. 4. A plant transformation vector comprising the polynucleotide of claim 1. 5. The polynucleotide of claim 1, wherein the organism is selected from the group consisting of D. v. virgifera LeConte; D. barberi Smith and Lawrence; D. u. howardi; D. v. zeae; D. balteata LeConte; D. u. tenella; D. speciosa Germar; D. u. undecimpunctata Mannerheim; and Meligethes aeneus Fabricius. 6. A ribonucleic acid (RNA) molecule transcribed from the polynucleotide of claim 1. 7. A double-stranded ribonucleic acid molecule produced from the expression of the polynucleotide of claim 1. 8. The double-stranded ribonucleic acid molecule of claim 7, wherein contacting the polynucleotide sequence with a coleopteran pest inhibits the expression of an endogenous nucleotide sequence specifically complementary to the polynucleotide. 9. The double-stranded ribonucleic acid molecule of claim 8, wherein contacting said ribonucleotide molecule with a coleopteran pest kills or inhibits the growth, and/or feeding of the pest. 10. The double stranded RNA of claim 6, comprising a first, a second and a third RNA segment, wherein the first RNA segment comprises the polynucleotide, wherein the third RNA segment is linked to the first RNA segment by the second polynucleotide sequence, and wherein the third RNA segment is substantially the reverse complement of the first RNA segment, such that the first and the third RNA segments hybridize when transcribed into a ribonucleic acid to form the double-stranded RNA. 11. The RNA of claim 6, selected from the group consisting of a double-stranded ribonucleic acid molecule and a single-stranded ribonucleic acid molecule of between about 15 and about 30 nucleotides in length. 12. A plant transformation vector comprising the polynucleotide of claim 1, wherein the heterologous promoter is functional in a plant cell. 13. A cell transformed with the polynucleotide of claim 1. 14. The cell of claim 13, wherein the cell is a prokaryotic cell. 15. The cell of claim 13, wherein the cell is a eukaryotic cell. 16. The cell of claim 15, wherein the cell is a plant cell. 17. A plant transformed with the polynucleotide of claim 1. 18. A seed of the plant of claim 17, wherein the seed comprises the polynucleotide. 19. A commodity product produced from the plant of claim 17, wherein the commodity product comprises a detectable amount of the polynucleotide. 20. The plant of claim 17, wherein the at least one polynucleotide is expressed in the plant as a double-stranded ribonucleic acid molecule. 21. The cell of claim 16, wherein the cell is a Zea mays or Brassica napus cell. 22. The plant of claim 17, wherein the plant is Zea mays or Brassica napus. 23. The plant of claim 17, wherein the at least one polynucleotide is expressed in the plant as a ribonucleic acid molecule, and the ribonucleic acid molecule inhibits the expression of an endogenous polynucleotide that is specifically complementary to the at least one polynucleotide when a coleopteran pest ingests a part of the plant. 24. The polynucleotide of claim 1, further comprising at least one additional polynucleotide that encodes an RNA molecule that inhibits the expression of an endogenous pest gene. 25. A plant transformation vector comprising the polynucleotide of claim 24, wherein the additional polynucleotide(s) are each operably linked to a heterologous promoter functional in a plant cell. 26. A method for controlling a coleopteran pest population, the method comprising providing an agent comprising a ribonucleic acid (RNA) molecule that functions upon contact with the coleopteran pest to inhibit a biological function within the coleopteran pest, wherein the RNA is specifically hybridizable with a polynucleotide selected from the group consisting of any of SEQ ID NOs:78-83; the complement of any of SEQ ID NOs:78-83; a fragment of at least 15 contiguous nucleotides of any of SEQ ID NOs:78-83; the complement of a fragment of at least 15 contiguous nucleotides of any of SEQ ID NOs:78-83; a transcript of any of SEQ ID NOs:1, 3-6, and 77; the complement of a transcript of any of SEQ ID NOs:1, 3-6, and 77; a fragment of at least 15 contiguous nucleotides of a transcript of SEQ ID NOs:1 or 77; the complement of a fragment of at least 15 contiguous nucleotides of a transcript of SEQ ID NOs:1 or 77; SEQ ID NOs:95-99; the complement of any of SEQ ID NOs:95-99; a fragment of at least 15 contiguous nucleotides of any of SEQ ID NOs:95-99; the complement of a fragment of at least 15 contiguous nucleotides of any of SEQ ID NOs:95-99; a transcript of any of SEQ ID NOs:84, 86, 88, 90, and 93; the complement of a transcript of any of SEQ ID NOs:84, 86, 88, 90, and 93; a fragment of at least 15 contiguous nucleotides of a transcript of SEQ ID NOs:84, 86, 88, 90, and 93; and the complement of a fragment of at least 15 contiguous nucleotides of a transcript of SEQ ID NOs:84, 86, 88, 90, and 93. 27. The method according to claim 26, wherein the agent is a double-stranded RNA molecule. 28. A method for controlling a coleopteran pest population, the method comprising:
providing an agent comprising a first and a second polynucleotide sequence that functions upon contact with the coleopteran pest to inhibit a biological function within the coleopteran pest, wherein the first polynucleotide sequence comprises a region that exhibits from about 90% to about 100% sequence identity to from about 15 to about 30 contiguous nucleotides of a nucleic acid selected from the group consisting of SEQ ID NO:78, SEQ ID NO:83, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, and SEQ ID NO:99, and wherein the first polynucleotide sequence is specifically hybridized to the second polynucleotide sequence. 29. A method for controlling a coleopteran pest population, the method comprising:
providing in a host plant of a coleopteran pest a transformed plant cell comprising the polynucleotide of claim 1, wherein the polynucleotide is expressed to produce a ribonucleic acid molecule that functions upon contact with a coleopteran pest belonging to the population to inhibit the expression of a target sequence within the coleopteran pest and results in decreased growth and/or survival of the coleopteran pest or pest population, relative to reproduction of the same pest species on a plant of the same host plant species that does not comprise the polynucleotide. 30. The method according to claim 29, wherein the ribonucleic acid molecule is a double-stranded ribonucleic acid molecule. 31. The method according to claim 29, wherein the coleopteran pest population is reduced relative to a population of the same pest species infesting a host plant of the same host plant species lacking the transformed plant cell. 32. A method of controlling coleopteran pest infestation in a plant, the method comprising providing in the diet of a coleopteran pest a ribonucleic acid (RNA) that is specifically hybridizable with a polynucleotide selected from the group consisting of:
SEQ ID NOs:78-83; the complement of any of SEQ ID NOs:78-83; a fragment of at least 15 contiguous nucleotides of any of SEQ ID NOs:78-83; the complement of a fragment of at least 15 contiguous nucleotides of any of SEQ ID NOs:78-83; a transcript of any of SEQ ID NOs:1, 3-6, and 77; the complement of a transcript of any of SEQ ID NOs:1, 3-6, and 77; a fragment of at least 15 contiguous nucleotides of a transcript of any of SEQ ID NOs:1, 3-6, and 77; the complement of a fragment of at least 15 contiguous nucleotides of a transcript of any of SEQ ID NOs:1, 3-6, and 77; SEQ ID NOs:95-99; the complement of any of SEQ ID NOs:95-99; a fragment of at least 15 contiguous nucleotides of any of SEQ ID NOs:95-99; the complement of a fragment of at least 15 contiguous nucleotides of any of SEQ ID NOs:95-99; a transcript of any of SEQ ID NOs:78, 80, 82, 90, and 93; the complement of a transcript of any of SEQ ID NOs:78, 80, 82, 90, and 93; a fragment of at least 15 contiguous nucleotides of a transcript of any of SEQ ID NOs:78, 80, 82, 90, and 93; and the complement of a fragment of at least 15 contiguous nucleotides of a transcript of any of SEQ ID NOs:78, 80, 82, 90, and 93. 33. The method according to claim 32, wherein the diet comprises a plant cell transformed to express the polynucleotide. 34. The method according to claim 32, wherein the specifically hybridizable RNA is comprised in a double-stranded RNA molecule. 35. A method for improving the yield of a plant crop, the method comprising:
introducing the nucleic acid of claim 1 into a plant to produce a transgenic plant; and cultivating the plant to allow the expression of the at least one polynucleotide; wherein expression of the at least one polynucleotide inhibits coleopteran pest growth and loss of yield due to coleopteran pest infection. 36. The method according to claim 35, wherein expression of the at least one polynucleotide produces an RNA molecule that suppresses at least a first target gene in a coleopteran pest that has contacted a portion of the corn plant. 37. The method according to claim 35, wherein the plant is Zea mays or Brassica napus. 38. A method for producing a transgenic plant cell, the method comprising:
transforming a plant cell with a vector comprising the nucleic acid of claim 1; culturing the transformed plant cell under conditions sufficient to allow for development of a plant cell culture comprising a plurality of transformed plant cells; selecting for transformed plant cells that have integrated the at least one polynucleotide into their genomes; screening the transformed plant cells for expression of a ribonucleic acid (RNA) molecule encoded by the at least one polynucleotide; and selecting a plant cell that expresses the RNA. 39. The method according to claim 38, wherein the RNA molecule is a double-stranded RNA molecule. 40. A method for producing a coleopteran pest-resistant transgenic plant, the method comprising:
providing the transgenic plant cell produced by the method of claim 38; and regenerating a transgenic plant from the transgenic plant cell, wherein expression of the ribonucleic acid molecule encoded by the at least one polynucleotide is sufficient to modulate the expression of a target gene in a coleopteran pest that contacts the transformed plant. 41. A method for producing a transgenic plant cell, the method comprising:
transforming a plant cell with a vector comprising a means for providing coleopteran pest resistance to a plant; culturing the transformed plant cell under conditions sufficient to allow for development of a plant cell culture comprising a plurality of transformed plant cells; selecting for transformed plant cells that have integrated the means for providing coleopteran pest resistance to a plant into their genomes; screening the transformed plant cells for expression of a means for inhibiting expression of an essential gene in a coleopteran pest; and selecting a plant cell that expresses the means for inhibiting expression of an essential gene in a coleopteran pest. 42. A method for producing a coleopteran pest-resistant transgenic plant, the method comprising:
providing the transgenic plant cell produced by the method of claim 41; and regenerating a transgenic plant from the transgenic plant cell, wherein expression of the means for inhibiting expression of an essential gene in a coleopteran pest is sufficient to modulate the expression of a target gene in a coleopteran pest that contacts the transformed plant. 43. The nucleic acid of claim 1, further comprising a polynucleotide encoding a polypeptide from Bacillus thuringiensis, Alcaligenes spp., or Pseudomonas spp. 44. The nucleic acid of claim 43, wherein the polypeptide from B. thuringiensis is selected from a group comprising Cry1B, Cry1I, Cry2A, Cry3, Cry7A, Cry8, Cry9D, Cry14, Cry18, Cry22, Cry23, Cry34, Cry35, Cry36, Cry37, Cry43, Cry55, Cyt1A, and Cyt2C. 45. The cell of claim 16, wherein the cell comprises a polynucleotide encoding a polypeptide from Bacillus thuringiensis, Alcaligenes spp., or Pseudomonas spp. 46. The cell of claim 45, wherein the polypeptide from B. thuringiensis is selected from a group comprising Cry1B, Cry1I, Cry2A, Cry3, Cry7A, Cry8, Cry9D, Cry14, Cry18, Cry22, Cry23, Cry34, Cry35, Cry36, Cry37, Cry43, Cry55, Cyt1A, and Cyt2C. 47. The plant of claim 17, wherein the plant comprises a polynucleotide encoding a polypeptide from Bacillus thuringiensis, Alcaligenes spp., or Pseudomonas spp. 48. The plant of claim 47, wherein the polypeptide from B. thuringiensis is selected from a group comprising Cry1B, Cry1I, Cry2A, Cry3, Cry7A, Cry8, Cry9D, Cry14, Cry18, Cry22, Cry23, Cry34, Cry35, Cry36, Cry37, Cry43, Cry55, Cyt1A, and Cyt2C. 49. The method according to claim 38, wherein the transformed plant cell comprises a nucleotide sequence encoding a polypeptide from Bacillus thuringiensis, Alcaligenes spp., or Pseudomonas spp. 50. The method according to claim 49, wherein the polypeptide from B. thuringiensis is selected from a group comprising Cry1B, Cry1I, Cry2A, Cry3, Cry7A, Cry8, Cry9D, Cry14, Cry18, Cry22, Cry23, Cry34, Cry35, Cry36, Cry37, Cry43, Cry55, Cyt1A, and Cyt2C. 51. A method for improving the yield of a plant crop, the method comprising:
contacting a coleopteran insect feeding on tissue of the plant with a polynucleotide selected from the group consisting of SEQ ID NOs:78-83 and 95-99, the complements of SEQ ID NOs:78-83 and 95-99, and fragments having at least 15 nucleotides of any of the foregoing; and contacting the coleopteran insect with a polynucleotide encoding an insecticidal polypeptide from Bacillus thuringiensis, or an iRNA molecule targeting an insect gene other than ncm. 52. The double stranded RNA of claim 10, wherein the second polynucleotide comprises SEQ ID NO:19.
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This disclosure concerns nucleic acid molecules and methods of use thereof for control of insect pests through RNA interference-mediated inhibition of target coding and transcribed non-coding sequences in insect pests, including coleopteran pests. The disclosure also concerns methods for making transgenic plants that express nucleic acid molecules useful for the control of insect pests, and the plant cells and plants obtained thereby.1. An isolated nucleic acid comprising at least one polynucleotide operably linked to a heterologous promoter, wherein the polynucleotide is selected from the group consisting of:
SEQ ID NO:1; the complement of SEQ ID NO:1; a fragment of at least 15 contiguous nucleotides of SEQ ID NO:1; the complement of a fragment of at least 15 contiguous nucleotides of SEQ ID NO:1; a native coding sequence of a Diabrotica organism comprising SEQ ID NO:1; the complement of a native coding sequence of a Diabrotica organism comprising SEQ ID NO:1; a fragment of at least 15 contiguous nucleotides of a native coding sequence of a Diabrotica organism comprising SEQ ID NO:1; the complement of a fragment of at least 15 contiguous nucleotides of a native coding sequence of a Diabrotica organism comprising SEQ ID NO:1; SEQ ID NO:77; the complement of SEQ ID NO:77; a fragment of at least 15 contiguous nucleotides of SEQ ID NO:77; the complement of a fragment of at least 15 contiguous nucleotides of SEQ ID NO:77; a native coding sequence of a Diabrotica organism comprising SEQ ID NO:77; the complement of a native coding sequence of a Diabrotica organism comprising SEQ ID NO:77; a fragment of at least 15 contiguous nucleotides of a native coding sequence of a Diabrotica organism comprising SEQ ID NO:77; the complement of a fragment of at least 15 contiguous nucleotides of a native coding sequence of a Diabrotica organism comprising SEQ ID NO:77; SEQ ID NO:84; the complement of SEQ ID NO:84; a fragment of at least 15 contiguous nucleotides of SEQ ID NO:84; the complement of a fragment of at least 15 contiguous nucleotides of SEQ ID NO:84; a native coding sequence of a Meligethes organism comprising SEQ ID NO:84; the complement of a native coding sequence of a Meligethes organism comprising SEQ ID NO:84; a fragment of at least 15 contiguous nucleotides of a native coding sequence of a Meligethes organism comprising SEQ ID NO:84; the complement of a fragment of at least 15 contiguous nucleotides of a native coding sequence of a Meligethes organism comprising SEQ ID NO:84; SEQ ID NO:86; the complement of SEQ ID NO:86; a fragment of at least 15 contiguous nucleotides of SEQ ID NO:86; the complement of a fragment of at least 15 contiguous nucleotides of SEQ ID NO:86; a native coding sequence of a Meligethes organism comprising SEQ ID NO:86; the complement of a native coding sequence of a Meligethes organism comprising SEQ ID NO:86; a fragment of at least 15 contiguous nucleotides of a native coding sequence of a Meligethes organism comprising SEQ ID NO:86; the complement of a fragment of at least 15 contiguous nucleotides of a native coding sequence of a Meligethes organism comprising SEQ ID NO:86; SEQ ID NO:88; the complement of SEQ ID NO:88; a fragment of at least 15 contiguous nucleotides of SEQ ID NO:88; the complement of a fragment of at least 15 contiguous nucleotides of SEQ ID NO:88; a native coding sequence of a Meligethes organism comprising SEQ ID NO:88; the complement of a native coding sequence of a Meligethes organism comprising SEQ ID NO:88; a fragment of at least 15 contiguous nucleotides of a native coding sequence of a Meligethes organism comprising SEQ ID NO:88; the complement of a fragment of at least 15 contiguous nucleotides of a native coding sequence of a Meligethes organism comprising SEQ ID NO:88; SEQ ID NO:93; the complement of SEQ ID NO:93; a fragment of at least 15 contiguous nucleotides of SEQ ID NO:93; the complement of a fragment of at least 15 contiguous nucleotides of SEQ ID NO:93; a native coding sequence of a Meligethes organism comprising SEQ ID NO:93; the complement of a native coding sequence of a Meligethes organism comprising SEQ ID NO:93; a fragment of at least 15 contiguous nucleotides of a native coding sequence of a Meligethes organism comprising SEQ ID NO:93; and the complement of a fragment of at least 15 contiguous nucleotides of a native coding sequence of a Meligethes organism comprising SEQ ID NO:93. 2. The polynucleotide of claim 1, wherein the polynucleotide is selected from the group consisting of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:17, and SEQ ID NO:77, and the complements of any of the foregoing. 3. The polynucleotide of claim 1, wherein the polynucleotide is selected from the group consisting of SEQ ID NO:84, SEQ ID NO:86, SEQ ID NO:88, SEQ ID NO:90, SEQ ID NO:93, and the complements of any of the foregoing. 4. A plant transformation vector comprising the polynucleotide of claim 1. 5. The polynucleotide of claim 1, wherein the organism is selected from the group consisting of D. v. virgifera LeConte; D. barberi Smith and Lawrence; D. u. howardi; D. v. zeae; D. balteata LeConte; D. u. tenella; D. speciosa Germar; D. u. undecimpunctata Mannerheim; and Meligethes aeneus Fabricius. 6. A ribonucleic acid (RNA) molecule transcribed from the polynucleotide of claim 1. 7. A double-stranded ribonucleic acid molecule produced from the expression of the polynucleotide of claim 1. 8. The double-stranded ribonucleic acid molecule of claim 7, wherein contacting the polynucleotide sequence with a coleopteran pest inhibits the expression of an endogenous nucleotide sequence specifically complementary to the polynucleotide. 9. The double-stranded ribonucleic acid molecule of claim 8, wherein contacting said ribonucleotide molecule with a coleopteran pest kills or inhibits the growth, and/or feeding of the pest. 10. The double stranded RNA of claim 6, comprising a first, a second and a third RNA segment, wherein the first RNA segment comprises the polynucleotide, wherein the third RNA segment is linked to the first RNA segment by the second polynucleotide sequence, and wherein the third RNA segment is substantially the reverse complement of the first RNA segment, such that the first and the third RNA segments hybridize when transcribed into a ribonucleic acid to form the double-stranded RNA. 11. The RNA of claim 6, selected from the group consisting of a double-stranded ribonucleic acid molecule and a single-stranded ribonucleic acid molecule of between about 15 and about 30 nucleotides in length. 12. A plant transformation vector comprising the polynucleotide of claim 1, wherein the heterologous promoter is functional in a plant cell. 13. A cell transformed with the polynucleotide of claim 1. 14. The cell of claim 13, wherein the cell is a prokaryotic cell. 15. The cell of claim 13, wherein the cell is a eukaryotic cell. 16. The cell of claim 15, wherein the cell is a plant cell. 17. A plant transformed with the polynucleotide of claim 1. 18. A seed of the plant of claim 17, wherein the seed comprises the polynucleotide. 19. A commodity product produced from the plant of claim 17, wherein the commodity product comprises a detectable amount of the polynucleotide. 20. The plant of claim 17, wherein the at least one polynucleotide is expressed in the plant as a double-stranded ribonucleic acid molecule. 21. The cell of claim 16, wherein the cell is a Zea mays or Brassica napus cell. 22. The plant of claim 17, wherein the plant is Zea mays or Brassica napus. 23. The plant of claim 17, wherein the at least one polynucleotide is expressed in the plant as a ribonucleic acid molecule, and the ribonucleic acid molecule inhibits the expression of an endogenous polynucleotide that is specifically complementary to the at least one polynucleotide when a coleopteran pest ingests a part of the plant. 24. The polynucleotide of claim 1, further comprising at least one additional polynucleotide that encodes an RNA molecule that inhibits the expression of an endogenous pest gene. 25. A plant transformation vector comprising the polynucleotide of claim 24, wherein the additional polynucleotide(s) are each operably linked to a heterologous promoter functional in a plant cell. 26. A method for controlling a coleopteran pest population, the method comprising providing an agent comprising a ribonucleic acid (RNA) molecule that functions upon contact with the coleopteran pest to inhibit a biological function within the coleopteran pest, wherein the RNA is specifically hybridizable with a polynucleotide selected from the group consisting of any of SEQ ID NOs:78-83; the complement of any of SEQ ID NOs:78-83; a fragment of at least 15 contiguous nucleotides of any of SEQ ID NOs:78-83; the complement of a fragment of at least 15 contiguous nucleotides of any of SEQ ID NOs:78-83; a transcript of any of SEQ ID NOs:1, 3-6, and 77; the complement of a transcript of any of SEQ ID NOs:1, 3-6, and 77; a fragment of at least 15 contiguous nucleotides of a transcript of SEQ ID NOs:1 or 77; the complement of a fragment of at least 15 contiguous nucleotides of a transcript of SEQ ID NOs:1 or 77; SEQ ID NOs:95-99; the complement of any of SEQ ID NOs:95-99; a fragment of at least 15 contiguous nucleotides of any of SEQ ID NOs:95-99; the complement of a fragment of at least 15 contiguous nucleotides of any of SEQ ID NOs:95-99; a transcript of any of SEQ ID NOs:84, 86, 88, 90, and 93; the complement of a transcript of any of SEQ ID NOs:84, 86, 88, 90, and 93; a fragment of at least 15 contiguous nucleotides of a transcript of SEQ ID NOs:84, 86, 88, 90, and 93; and the complement of a fragment of at least 15 contiguous nucleotides of a transcript of SEQ ID NOs:84, 86, 88, 90, and 93. 27. The method according to claim 26, wherein the agent is a double-stranded RNA molecule. 28. A method for controlling a coleopteran pest population, the method comprising:
providing an agent comprising a first and a second polynucleotide sequence that functions upon contact with the coleopteran pest to inhibit a biological function within the coleopteran pest, wherein the first polynucleotide sequence comprises a region that exhibits from about 90% to about 100% sequence identity to from about 15 to about 30 contiguous nucleotides of a nucleic acid selected from the group consisting of SEQ ID NO:78, SEQ ID NO:83, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, and SEQ ID NO:99, and wherein the first polynucleotide sequence is specifically hybridized to the second polynucleotide sequence. 29. A method for controlling a coleopteran pest population, the method comprising:
providing in a host plant of a coleopteran pest a transformed plant cell comprising the polynucleotide of claim 1, wherein the polynucleotide is expressed to produce a ribonucleic acid molecule that functions upon contact with a coleopteran pest belonging to the population to inhibit the expression of a target sequence within the coleopteran pest and results in decreased growth and/or survival of the coleopteran pest or pest population, relative to reproduction of the same pest species on a plant of the same host plant species that does not comprise the polynucleotide. 30. The method according to claim 29, wherein the ribonucleic acid molecule is a double-stranded ribonucleic acid molecule. 31. The method according to claim 29, wherein the coleopteran pest population is reduced relative to a population of the same pest species infesting a host plant of the same host plant species lacking the transformed plant cell. 32. A method of controlling coleopteran pest infestation in a plant, the method comprising providing in the diet of a coleopteran pest a ribonucleic acid (RNA) that is specifically hybridizable with a polynucleotide selected from the group consisting of:
SEQ ID NOs:78-83; the complement of any of SEQ ID NOs:78-83; a fragment of at least 15 contiguous nucleotides of any of SEQ ID NOs:78-83; the complement of a fragment of at least 15 contiguous nucleotides of any of SEQ ID NOs:78-83; a transcript of any of SEQ ID NOs:1, 3-6, and 77; the complement of a transcript of any of SEQ ID NOs:1, 3-6, and 77; a fragment of at least 15 contiguous nucleotides of a transcript of any of SEQ ID NOs:1, 3-6, and 77; the complement of a fragment of at least 15 contiguous nucleotides of a transcript of any of SEQ ID NOs:1, 3-6, and 77; SEQ ID NOs:95-99; the complement of any of SEQ ID NOs:95-99; a fragment of at least 15 contiguous nucleotides of any of SEQ ID NOs:95-99; the complement of a fragment of at least 15 contiguous nucleotides of any of SEQ ID NOs:95-99; a transcript of any of SEQ ID NOs:78, 80, 82, 90, and 93; the complement of a transcript of any of SEQ ID NOs:78, 80, 82, 90, and 93; a fragment of at least 15 contiguous nucleotides of a transcript of any of SEQ ID NOs:78, 80, 82, 90, and 93; and the complement of a fragment of at least 15 contiguous nucleotides of a transcript of any of SEQ ID NOs:78, 80, 82, 90, and 93. 33. The method according to claim 32, wherein the diet comprises a plant cell transformed to express the polynucleotide. 34. The method according to claim 32, wherein the specifically hybridizable RNA is comprised in a double-stranded RNA molecule. 35. A method for improving the yield of a plant crop, the method comprising:
introducing the nucleic acid of claim 1 into a plant to produce a transgenic plant; and cultivating the plant to allow the expression of the at least one polynucleotide; wherein expression of the at least one polynucleotide inhibits coleopteran pest growth and loss of yield due to coleopteran pest infection. 36. The method according to claim 35, wherein expression of the at least one polynucleotide produces an RNA molecule that suppresses at least a first target gene in a coleopteran pest that has contacted a portion of the corn plant. 37. The method according to claim 35, wherein the plant is Zea mays or Brassica napus. 38. A method for producing a transgenic plant cell, the method comprising:
transforming a plant cell with a vector comprising the nucleic acid of claim 1; culturing the transformed plant cell under conditions sufficient to allow for development of a plant cell culture comprising a plurality of transformed plant cells; selecting for transformed plant cells that have integrated the at least one polynucleotide into their genomes; screening the transformed plant cells for expression of a ribonucleic acid (RNA) molecule encoded by the at least one polynucleotide; and selecting a plant cell that expresses the RNA. 39. The method according to claim 38, wherein the RNA molecule is a double-stranded RNA molecule. 40. A method for producing a coleopteran pest-resistant transgenic plant, the method comprising:
providing the transgenic plant cell produced by the method of claim 38; and regenerating a transgenic plant from the transgenic plant cell, wherein expression of the ribonucleic acid molecule encoded by the at least one polynucleotide is sufficient to modulate the expression of a target gene in a coleopteran pest that contacts the transformed plant. 41. A method for producing a transgenic plant cell, the method comprising:
transforming a plant cell with a vector comprising a means for providing coleopteran pest resistance to a plant; culturing the transformed plant cell under conditions sufficient to allow for development of a plant cell culture comprising a plurality of transformed plant cells; selecting for transformed plant cells that have integrated the means for providing coleopteran pest resistance to a plant into their genomes; screening the transformed plant cells for expression of a means for inhibiting expression of an essential gene in a coleopteran pest; and selecting a plant cell that expresses the means for inhibiting expression of an essential gene in a coleopteran pest. 42. A method for producing a coleopteran pest-resistant transgenic plant, the method comprising:
providing the transgenic plant cell produced by the method of claim 41; and regenerating a transgenic plant from the transgenic plant cell, wherein expression of the means for inhibiting expression of an essential gene in a coleopteran pest is sufficient to modulate the expression of a target gene in a coleopteran pest that contacts the transformed plant. 43. The nucleic acid of claim 1, further comprising a polynucleotide encoding a polypeptide from Bacillus thuringiensis, Alcaligenes spp., or Pseudomonas spp. 44. The nucleic acid of claim 43, wherein the polypeptide from B. thuringiensis is selected from a group comprising Cry1B, Cry1I, Cry2A, Cry3, Cry7A, Cry8, Cry9D, Cry14, Cry18, Cry22, Cry23, Cry34, Cry35, Cry36, Cry37, Cry43, Cry55, Cyt1A, and Cyt2C. 45. The cell of claim 16, wherein the cell comprises a polynucleotide encoding a polypeptide from Bacillus thuringiensis, Alcaligenes spp., or Pseudomonas spp. 46. The cell of claim 45, wherein the polypeptide from B. thuringiensis is selected from a group comprising Cry1B, Cry1I, Cry2A, Cry3, Cry7A, Cry8, Cry9D, Cry14, Cry18, Cry22, Cry23, Cry34, Cry35, Cry36, Cry37, Cry43, Cry55, Cyt1A, and Cyt2C. 47. The plant of claim 17, wherein the plant comprises a polynucleotide encoding a polypeptide from Bacillus thuringiensis, Alcaligenes spp., or Pseudomonas spp. 48. The plant of claim 47, wherein the polypeptide from B. thuringiensis is selected from a group comprising Cry1B, Cry1I, Cry2A, Cry3, Cry7A, Cry8, Cry9D, Cry14, Cry18, Cry22, Cry23, Cry34, Cry35, Cry36, Cry37, Cry43, Cry55, Cyt1A, and Cyt2C. 49. The method according to claim 38, wherein the transformed plant cell comprises a nucleotide sequence encoding a polypeptide from Bacillus thuringiensis, Alcaligenes spp., or Pseudomonas spp. 50. The method according to claim 49, wherein the polypeptide from B. thuringiensis is selected from a group comprising Cry1B, Cry1I, Cry2A, Cry3, Cry7A, Cry8, Cry9D, Cry14, Cry18, Cry22, Cry23, Cry34, Cry35, Cry36, Cry37, Cry43, Cry55, Cyt1A, and Cyt2C. 51. A method for improving the yield of a plant crop, the method comprising:
contacting a coleopteran insect feeding on tissue of the plant with a polynucleotide selected from the group consisting of SEQ ID NOs:78-83 and 95-99, the complements of SEQ ID NOs:78-83 and 95-99, and fragments having at least 15 nucleotides of any of the foregoing; and contacting the coleopteran insect with a polynucleotide encoding an insecticidal polypeptide from Bacillus thuringiensis, or an iRNA molecule targeting an insect gene other than ncm. 52. The double stranded RNA of claim 10, wherein the second polynucleotide comprises SEQ ID NO:19.
| 1,600 |
1,254 | 15,892,078 | 1,623 |
Compositions contain citrulline and leucine or a metabolite thereof including, for example, a synergistic amount of citrulline and leucine. Such compositions may be used in methods for the treatment of pre-diabetes, metabolic syndrome, hyperglycemia, or diabetes.
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1. A method of treating a condition selected from the group consisting of pre-diabetes, metabolic syndrome, hyperglycemia, and diabetes in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of citrulline and a therapeutically effective amount of leucine or a metabolite thereof. 2. The method of claim 1, wherein the condition is selected from the group consisting of pre-diabetes and metabolic syndrome. 3. The method of claim 1, wherein the metabolite of leucine is hydroxy isocaproic acid (HICA) or beta-hydroxy-beta-methylbutyrate (HMB). 4. The method of claim 1, wherein the therapeutically effective amount of citrulline and the therapeutically effective amount of leucine or a metabolite thereof result in a synergistic effect. 5. The method of claim 1, wherein the citrulline and the leucine or metabolite thereof are administered to the subject using a regimen selected from the group consisting of weekly, daily, two times a day, and three times a day. 6. The method of claim 1, wherein the subject is administered a fixed amount of the citrulline and the leucine or metabolite thereof. 7. The method of claim 1, wherein the subject is administered a weight-based dose of the citrulline and the leucine or metabolite thereof. 8. The method of claim 7, wherein the weight-based dose is about 0.01 g/kg to about 0.3 g/kg of the citrulline and 0.01 g/kg to about 0.3 g/kg of the leucine or metabolite thereof. 9. The method of claim 7, wherein the weight-based dose is 1.0 g/kg of the citrulline and 1.0 g/kg of the leucine. 10. The method of claim 1, wherein a pharmaceutical composition is administered to the subject that comprises both the therapeutically effective amount of the citrulline and the therapeutically effective amount of the leucine or metabolite thereof. 11. The method of claim 1, wherein the therapeutically effective amount of the citrulline and the therapeutically effective amount of the leucine or metabolite thereof are administered orally. 12. The method of claim 1, wherein the method is effective to achieve at least one modification selected from the group consisting of: reduction in fasting blood sugar level, decrease in insulin resistance, reduction of hyperinsulinemia, improvement in glucose tolerance, reduction in systemic inflammation, reduction in the need for diabetes medication, decrease in serum lipids with improvement in the lipid profile, and decrease in one or more cardiovascular risk indicators. 13. The method of claim 1, wherein the therapeutically effective amount of the citrulline and the therapeutically effective amount of the leucine or metabolite thereof is administered in conjunction with at least one additional treatment method, the at least one additional treatment method comprising administering at least one pharmaceutical composition comprising an active agent selected from the group consisting of: a sulfonylurea, a meglitinide, a biguanide, an alpha-glucosidase inhibitor, a thiazolidinedione, a DPP-IV inhibitor, a glucagon-like peptide (GLP)-1 analog, and insulin. 14. The method of claim 1, wherein the subject is administered protein in conjunction with the citrulline and the leucine or metabolite thereof.
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Compositions contain citrulline and leucine or a metabolite thereof including, for example, a synergistic amount of citrulline and leucine. Such compositions may be used in methods for the treatment of pre-diabetes, metabolic syndrome, hyperglycemia, or diabetes.1. A method of treating a condition selected from the group consisting of pre-diabetes, metabolic syndrome, hyperglycemia, and diabetes in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of citrulline and a therapeutically effective amount of leucine or a metabolite thereof. 2. The method of claim 1, wherein the condition is selected from the group consisting of pre-diabetes and metabolic syndrome. 3. The method of claim 1, wherein the metabolite of leucine is hydroxy isocaproic acid (HICA) or beta-hydroxy-beta-methylbutyrate (HMB). 4. The method of claim 1, wherein the therapeutically effective amount of citrulline and the therapeutically effective amount of leucine or a metabolite thereof result in a synergistic effect. 5. The method of claim 1, wherein the citrulline and the leucine or metabolite thereof are administered to the subject using a regimen selected from the group consisting of weekly, daily, two times a day, and three times a day. 6. The method of claim 1, wherein the subject is administered a fixed amount of the citrulline and the leucine or metabolite thereof. 7. The method of claim 1, wherein the subject is administered a weight-based dose of the citrulline and the leucine or metabolite thereof. 8. The method of claim 7, wherein the weight-based dose is about 0.01 g/kg to about 0.3 g/kg of the citrulline and 0.01 g/kg to about 0.3 g/kg of the leucine or metabolite thereof. 9. The method of claim 7, wherein the weight-based dose is 1.0 g/kg of the citrulline and 1.0 g/kg of the leucine. 10. The method of claim 1, wherein a pharmaceutical composition is administered to the subject that comprises both the therapeutically effective amount of the citrulline and the therapeutically effective amount of the leucine or metabolite thereof. 11. The method of claim 1, wherein the therapeutically effective amount of the citrulline and the therapeutically effective amount of the leucine or metabolite thereof are administered orally. 12. The method of claim 1, wherein the method is effective to achieve at least one modification selected from the group consisting of: reduction in fasting blood sugar level, decrease in insulin resistance, reduction of hyperinsulinemia, improvement in glucose tolerance, reduction in systemic inflammation, reduction in the need for diabetes medication, decrease in serum lipids with improvement in the lipid profile, and decrease in one or more cardiovascular risk indicators. 13. The method of claim 1, wherein the therapeutically effective amount of the citrulline and the therapeutically effective amount of the leucine or metabolite thereof is administered in conjunction with at least one additional treatment method, the at least one additional treatment method comprising administering at least one pharmaceutical composition comprising an active agent selected from the group consisting of: a sulfonylurea, a meglitinide, a biguanide, an alpha-glucosidase inhibitor, a thiazolidinedione, a DPP-IV inhibitor, a glucagon-like peptide (GLP)-1 analog, and insulin. 14. The method of claim 1, wherein the subject is administered protein in conjunction with the citrulline and the leucine or metabolite thereof.
| 1,600 |
1,255 | 13,885,588 | 1,618 |
The present invention relates to a solid makeup and/or care cosmetic composition in the form of a compact powder, comprising, in a physiologically acceptable medium, at least: —one pulverulent phase, —one emulsifying system, —one hydrophilic gelling agent, and—one hydrophilic active agent present in a content of greater than or equal to 10% by weight relative to the total weight of the composition, the said composition comprising less than 2% by weight of water relative to the total weight of the composition. The invention also relates to an intermediate composition for the preparation of such a cosmetic composition, to a process for manufacturing this cosmetic composition, and to a process for coating the skin with the said cosmetic composition.
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1. A solid makeup composition, a care cosmetic composition, or any combination thereof, comprising, in a physiologically acceptable medium:
a pulverulent phase, an emulsifying system, a hydrophilic gelling agent, and a hydrophilic active agent in a content of greater than or equal to 10% by weight relative to a total weight of the composition, wherein the composition comprises less than 2% by weight of water relative to a total weight of the composition, and wherein the composition is a compact powder. 2. The composition according to claim 1, wherein the composition is free of water. 3. The composition according to claim 1, wherein the composition has a solids content of greater than or equal to 95%. 4. The composition according to claim 1, wherein the composition comprises a pulverulent phase in an amount of greater than or equal to 35% by weight relative to the total weight of the composition. 5. The composition according to claim 1, comprising an organic non-volatile oil in a content of greater than or equal to 1% by weight relative to the total weight of the composition. 6. The composition according to claim 1, wherein the non-volatile oil is a hydrocarbon-based or silicone non-volatile oil or any mixture thereof. 7. The composition according to claim 1, wherein the pulverulent phase comprises a filler and at least one coloring agent selected from the group consisting of a nacre, a pigment, a reflective particle, and any mixture thereof. 8. The composition according to claim 1, wherein a content of the coloring agent is from 10% to 60% by weight relative to the total weight of the composition. 9. The composition according to claim 1, wherein a content of hydrophilic active agent in the composition is between 11% and 40% by weight relative to the total weight of the composition. 10. The composition according to claim 1, wherein the hydrophilic active agent is a moisturizer, a cicatrizing agent, an anti-aging agent suitable for skin, or any mixture thereof. 11. The composition according to claim 1, wherein the emulsifying system comprises a nonionic surfactant with an HLB of less than 8 at 25° C., an anionic surfactant, a cationic surfactant an amphoteric surfactant, or any mixture thereof. 12. The composition according to claim 11, wherein the emulsifying composition comprises, as a surfactant, a saccharide ester, an ether, a fatty acid ester, an oxyalkylenated alcohol, a fatty alcohol, a silicone compound, or any combination thereof. 13. The composition according to claim 1, further comprising an organopolysiloxane elastomer. 14. The composition according to claim 1, wherein the hydrophilic gelling agent is a thickening filler, a polymeric thickener, an associate polymer, or any combination thereof. 15. The composition according to claim 1, comprising, as a chelating agent, an aminocarboxylic acid. 16. The composition according to claim 1, wherein the composition is a foundation powder or a blusher. 17. An intermediate composition, comprising:
an aqueous phase in a content ranging from 40% to 60% by weight relative to a total weight of the composition, wherein the composition is suitable for obtaining the composition of claim 1. 18. A process for manufacturing the composition according to claim 1, the process comprising:
injecting into a mold an intermediate composition, and removing an aqueous phase from the intermediate composition. 19. The process according to claim 18, further comprising:
predispersing the hydrophilic active agent in the aqueous phase and then contacting with the pulverulent phase prior to the injection. 20. A process for coating skin with the composition according to claim 1, the process comprising:
applying the composition to skin.
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The present invention relates to a solid makeup and/or care cosmetic composition in the form of a compact powder, comprising, in a physiologically acceptable medium, at least: —one pulverulent phase, —one emulsifying system, —one hydrophilic gelling agent, and—one hydrophilic active agent present in a content of greater than or equal to 10% by weight relative to the total weight of the composition, the said composition comprising less than 2% by weight of water relative to the total weight of the composition. The invention also relates to an intermediate composition for the preparation of such a cosmetic composition, to a process for manufacturing this cosmetic composition, and to a process for coating the skin with the said cosmetic composition.1. A solid makeup composition, a care cosmetic composition, or any combination thereof, comprising, in a physiologically acceptable medium:
a pulverulent phase, an emulsifying system, a hydrophilic gelling agent, and a hydrophilic active agent in a content of greater than or equal to 10% by weight relative to a total weight of the composition, wherein the composition comprises less than 2% by weight of water relative to a total weight of the composition, and wherein the composition is a compact powder. 2. The composition according to claim 1, wherein the composition is free of water. 3. The composition according to claim 1, wherein the composition has a solids content of greater than or equal to 95%. 4. The composition according to claim 1, wherein the composition comprises a pulverulent phase in an amount of greater than or equal to 35% by weight relative to the total weight of the composition. 5. The composition according to claim 1, comprising an organic non-volatile oil in a content of greater than or equal to 1% by weight relative to the total weight of the composition. 6. The composition according to claim 1, wherein the non-volatile oil is a hydrocarbon-based or silicone non-volatile oil or any mixture thereof. 7. The composition according to claim 1, wherein the pulverulent phase comprises a filler and at least one coloring agent selected from the group consisting of a nacre, a pigment, a reflective particle, and any mixture thereof. 8. The composition according to claim 1, wherein a content of the coloring agent is from 10% to 60% by weight relative to the total weight of the composition. 9. The composition according to claim 1, wherein a content of hydrophilic active agent in the composition is between 11% and 40% by weight relative to the total weight of the composition. 10. The composition according to claim 1, wherein the hydrophilic active agent is a moisturizer, a cicatrizing agent, an anti-aging agent suitable for skin, or any mixture thereof. 11. The composition according to claim 1, wherein the emulsifying system comprises a nonionic surfactant with an HLB of less than 8 at 25° C., an anionic surfactant, a cationic surfactant an amphoteric surfactant, or any mixture thereof. 12. The composition according to claim 11, wherein the emulsifying composition comprises, as a surfactant, a saccharide ester, an ether, a fatty acid ester, an oxyalkylenated alcohol, a fatty alcohol, a silicone compound, or any combination thereof. 13. The composition according to claim 1, further comprising an organopolysiloxane elastomer. 14. The composition according to claim 1, wherein the hydrophilic gelling agent is a thickening filler, a polymeric thickener, an associate polymer, or any combination thereof. 15. The composition according to claim 1, comprising, as a chelating agent, an aminocarboxylic acid. 16. The composition according to claim 1, wherein the composition is a foundation powder or a blusher. 17. An intermediate composition, comprising:
an aqueous phase in a content ranging from 40% to 60% by weight relative to a total weight of the composition, wherein the composition is suitable for obtaining the composition of claim 1. 18. A process for manufacturing the composition according to claim 1, the process comprising:
injecting into a mold an intermediate composition, and removing an aqueous phase from the intermediate composition. 19. The process according to claim 18, further comprising:
predispersing the hydrophilic active agent in the aqueous phase and then contacting with the pulverulent phase prior to the injection. 20. A process for coating skin with the composition according to claim 1, the process comprising:
applying the composition to skin.
| 1,600 |
1,256 | 15,529,680 | 1,612 |
An oral care mouth rinse composition containing at least one source of ionic tin and at least one aliphatic di- or tri-carboxylic acid in free or salt form, wherein the at least one aliphatic di- or tri-carboxylic acid in free or salt form is present in an amount of from 0.05 to 0.30 weight % based on the total weight of the oral care composition is provided.
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1. An oral care mouth rinse composition comprising
(i) at least one source of ionic tin and (ii) at least one aliphatic di- or tri-carboxylic acid in free or salt form wherein the at least one aliphatic di- or tri-carboxylic acid in free or salt form is present in an amount of from 0.05 to 0.30 weight % based on the total weight of the oral care composition. 2. The oral care mouth rinse composition of claim 1 comprising 0.10 to 0.25 weight % aliphatic di- or tri-carboxylic acid in free or salt form. 3. The oral care mouth rinse composition of claim 1 wherein the at leak one aliphatic di- or tri-carboxylic acid in free or salt form comprises a C3 to C7 aliphatic di-carboxylic acid in free or salt form. 4. The oral care mouth rinse composition of claim 1 comprising 0.10 to 0.25 weight % malic acid. 5. The oral care composition of claim 1 wherein the source of ionic tin is selected from the group comprising stannous ion sources, stannic ion sources and combinations thereof. 6. The oral care mouth rinse composition of claim 1 wherein the source of ionic tin is selected from the group comprising stannous fluoride, stannous chloride, stannic fluoride, stannic chloride, stannic acetate, stannous acetate and combinations thereof. 7. The oral care mouth rinse composition of claim 1 wherein the composition comprises at least one stannous ion source. 8. The oral care mouth rinse composition of claim 1 wherein the source of ionic tin is selected from the group comprising stannous fluoride, stannous chloride, stannous acetate and combinations thereof. 9. The oral care mouth rinse composition of claim 1 wherein the concentration of ionic tin is from 0.01 to 0.10 weight % based on the total weight of the oral care mouth rinse composition. 10. The oral care mouth rinse composition of claim 1 wherein the source of ionic tin comprises stannous fluoride. 11. The oral care mouth rinse composition of claim further comprising a non-stannous fluoride ion source. 12. The oral care mouth rinse composition of claim 1 comprising sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate, amine fluoride, ammonium fluoride and combinations thereof. 13. The oral care mouth rinse composition of claim 1 comprising sodium fluoride or amine fluoride. 14. The oral care mouth rinse composition of claim 1 comprising amine fluoride or sodium fluoride in an amount corresponding to 45 to 1500 ppm fluoride based on the total weight of the composition. 15. The oral care mouth rinse composition of claim 1 comprising 0.06 to 0.33 weight % amine fluoride or 0.01 to 0.33 weight % sodium fluoride or a combination thereof based on the total weight of the composition. 16. The oral care mouth rinse composition of claim 1 comprising 0.10 to 0.25 weight % malic acid, 0.04 to 0.08 weight % stannous fluoride and 0.10 to 0.25 weight % N,N,N′-tris(2-hydroxyethyl)-N′-octadecyl-1,3-diaminopropane dihydrofluoride. 17. A method to
(i) reduce or inhibit formation of dental caries, (ii) reduce, repair or inhibit pre-carious lesions of the enamel, (iii) reduce or inhibit demineralization and promote remineralization of the teeth, (iv) reduce hypersensitivity of the teeth, (v) reduce or inhibit gingivitis, (vi) promote healing of sores or cuts in the oral cavity, (vii) reduce levels of acid producing bacteria, (viii) reduce or inhibit microbial biofilm formation in the oral cavity, (ix) reduce or inhibit plaque formation in the oral cavity, (x) promote systemic health, or (xi) clean teeth and oral cavity,
comprising applying an effective amount of an oral care mouth rinse composition according to claim 1 to the oral cavity of a subject in need thereof. 18. An oral care mouth rinse composition according to claim 1 for use in a method to reduce or inhibit formation of dental caries,
(i) reduce, repair or inhibit pre-carious lesions of the enamel,
(ii) reduce or inhibit demineralization and promote remineralization of the teeth,
(iii) reduce hypersensitivity of the teeth,
(iv) reduce or inhibit gingivitis,
(v) promote healing of sores or cuts in the oral cavity,
(vi) reduce levels of acid producing bacteria,
(vii) reduce or inhibit microbial biofilm formation in the oral cavity,
(viii) reduce or inhibit plaque formation in the oral cavity,
(ix) promote systemic health, or
(x) clean teeth and oral cavity. 19. A method of stabilizing ionic tin in an oral care mouth rinse composition comprising at least one source of ionic tin, wherein the method comprises formulating the oral care mouth rinse composition to comprise at least one aliphatic di- or tri-carboxylic acid in free or salt form in an amount of from 0.05 to 0.30 weight % based on the total weight of the oral care composition. 20. A method of reducing staining of surfaces in the oral cavity resulting from use of an oral care mouth rinse comprising at least one source of ionic tin, wherein the method comprises formulating the oral care mouth rinse composition to comprise at least one aliphatic di- or tri-carboxylic acid in free or salt form in an amount of from 0.05 to 0.30 weight % based on the total weight of the oral care composition.
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An oral care mouth rinse composition containing at least one source of ionic tin and at least one aliphatic di- or tri-carboxylic acid in free or salt form, wherein the at least one aliphatic di- or tri-carboxylic acid in free or salt form is present in an amount of from 0.05 to 0.30 weight % based on the total weight of the oral care composition is provided.1. An oral care mouth rinse composition comprising
(i) at least one source of ionic tin and (ii) at least one aliphatic di- or tri-carboxylic acid in free or salt form wherein the at least one aliphatic di- or tri-carboxylic acid in free or salt form is present in an amount of from 0.05 to 0.30 weight % based on the total weight of the oral care composition. 2. The oral care mouth rinse composition of claim 1 comprising 0.10 to 0.25 weight % aliphatic di- or tri-carboxylic acid in free or salt form. 3. The oral care mouth rinse composition of claim 1 wherein the at leak one aliphatic di- or tri-carboxylic acid in free or salt form comprises a C3 to C7 aliphatic di-carboxylic acid in free or salt form. 4. The oral care mouth rinse composition of claim 1 comprising 0.10 to 0.25 weight % malic acid. 5. The oral care composition of claim 1 wherein the source of ionic tin is selected from the group comprising stannous ion sources, stannic ion sources and combinations thereof. 6. The oral care mouth rinse composition of claim 1 wherein the source of ionic tin is selected from the group comprising stannous fluoride, stannous chloride, stannic fluoride, stannic chloride, stannic acetate, stannous acetate and combinations thereof. 7. The oral care mouth rinse composition of claim 1 wherein the composition comprises at least one stannous ion source. 8. The oral care mouth rinse composition of claim 1 wherein the source of ionic tin is selected from the group comprising stannous fluoride, stannous chloride, stannous acetate and combinations thereof. 9. The oral care mouth rinse composition of claim 1 wherein the concentration of ionic tin is from 0.01 to 0.10 weight % based on the total weight of the oral care mouth rinse composition. 10. The oral care mouth rinse composition of claim 1 wherein the source of ionic tin comprises stannous fluoride. 11. The oral care mouth rinse composition of claim further comprising a non-stannous fluoride ion source. 12. The oral care mouth rinse composition of claim 1 comprising sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate, amine fluoride, ammonium fluoride and combinations thereof. 13. The oral care mouth rinse composition of claim 1 comprising sodium fluoride or amine fluoride. 14. The oral care mouth rinse composition of claim 1 comprising amine fluoride or sodium fluoride in an amount corresponding to 45 to 1500 ppm fluoride based on the total weight of the composition. 15. The oral care mouth rinse composition of claim 1 comprising 0.06 to 0.33 weight % amine fluoride or 0.01 to 0.33 weight % sodium fluoride or a combination thereof based on the total weight of the composition. 16. The oral care mouth rinse composition of claim 1 comprising 0.10 to 0.25 weight % malic acid, 0.04 to 0.08 weight % stannous fluoride and 0.10 to 0.25 weight % N,N,N′-tris(2-hydroxyethyl)-N′-octadecyl-1,3-diaminopropane dihydrofluoride. 17. A method to
(i) reduce or inhibit formation of dental caries, (ii) reduce, repair or inhibit pre-carious lesions of the enamel, (iii) reduce or inhibit demineralization and promote remineralization of the teeth, (iv) reduce hypersensitivity of the teeth, (v) reduce or inhibit gingivitis, (vi) promote healing of sores or cuts in the oral cavity, (vii) reduce levels of acid producing bacteria, (viii) reduce or inhibit microbial biofilm formation in the oral cavity, (ix) reduce or inhibit plaque formation in the oral cavity, (x) promote systemic health, or (xi) clean teeth and oral cavity,
comprising applying an effective amount of an oral care mouth rinse composition according to claim 1 to the oral cavity of a subject in need thereof. 18. An oral care mouth rinse composition according to claim 1 for use in a method to reduce or inhibit formation of dental caries,
(i) reduce, repair or inhibit pre-carious lesions of the enamel,
(ii) reduce or inhibit demineralization and promote remineralization of the teeth,
(iii) reduce hypersensitivity of the teeth,
(iv) reduce or inhibit gingivitis,
(v) promote healing of sores or cuts in the oral cavity,
(vi) reduce levels of acid producing bacteria,
(vii) reduce or inhibit microbial biofilm formation in the oral cavity,
(viii) reduce or inhibit plaque formation in the oral cavity,
(ix) promote systemic health, or
(x) clean teeth and oral cavity. 19. A method of stabilizing ionic tin in an oral care mouth rinse composition comprising at least one source of ionic tin, wherein the method comprises formulating the oral care mouth rinse composition to comprise at least one aliphatic di- or tri-carboxylic acid in free or salt form in an amount of from 0.05 to 0.30 weight % based on the total weight of the oral care composition. 20. A method of reducing staining of surfaces in the oral cavity resulting from use of an oral care mouth rinse comprising at least one source of ionic tin, wherein the method comprises formulating the oral care mouth rinse composition to comprise at least one aliphatic di- or tri-carboxylic acid in free or salt form in an amount of from 0.05 to 0.30 weight % based on the total weight of the oral care composition.
| 1,600 |
1,257 | 15,311,714 | 1,635 |
Described herein are aptamers capable of binding to human complement component 3 (C3) protein; compositions comprising a C3 binding aptamer with a C3-Protein; and methods of making and using the same.
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1. An aptamer that binds C3 protein, wherein the aptamer comprises the sequence 5′-KPGRMPDVD.LPAWPSVGPAYRPP-3′ (SEQ ID NO: 152)
wherein,
K is a C-5 modified pyrimidine, C, U, T, G, or a 3-carbon spacer;
each P is independently, and for each occurrence, a C-5 modified pyrimidine;
each R is independently, and for each occurrence, A or G;
M is C, U, T, a C-5 modified pyrimidine, or a 3-carbon spacer;
each D is independently, and for each occurrence, an A, C, or a 3-carbon spacer;
each V is independently, and for each occurrence, an A, G, C, or a 3-carbon spacer;
L is A, U, T or a C-5 modified pyrimidine;
W is G or a 3-carbon spacer;
S is C or a 3-carbon spacer;
Y is C, U, or T; and
n is 0 or 1. 2. The aptamer of claim 1, wherein the aptamer comprises the sequence 5′-KPGRMPDVDnLPAWPSVGPACGPP-3′ (SEQ ID NO: 131). 3. The aptamer of claim 1 or claim 2, wherein the aptamer comprises the sequence 5′-KPGRMPDVDnLPAWPSVGPACGPPM-3′ (SEQ ID NO: 135) or 5′-KPGRMPDVDnLPAWPSVGPAYRPPM-3′ (SEQ ID NO: 153) 4. An aptamer that binds C3 protein, wherein the aptamer comprises the sequence 5′-KPGRMPXPAWPSVGPAYRPP-3′ (SEQ ID NO: 154)
wherein,
K is a C-5 modified pyrimidine, C, U, T, G, or a 3-carbon spacer;
each P is independently, and for each occurrence, a C-5 modified pyrimidine;
R is A or G;
M is C, U, T a C-5 modified pyrimidine, or a 3-carbon spacer;
V is A, G, C, or a 3-carbon spacer;
W is G or a 3-carbon spacer;
S is C or a 3-carbon spacer;
Y is C, U, or T; and
X is a linker selected from a substituted or unsubstituted C2-C20 linker, an alkylene glycol, and a polyalkylene glycol. 5. The aptamer of claim 4, wherein the aptamer comprises the sequence 5′-KPGRMPXPAWP SVGPACGPP-3′ (SEQ ID NO: 136). 6. The aptamer of claim 4 or claim 5, wherein the aptamer comprises the sequence 5′-KPGRMPXPAWPSVGPACGPPM-3′ (SEQ ID NO: 137) or 5′-KPGRMPXPAWPSVGPAYRPPM-3′ (SEQ ID NO: 155). 7. The aptamer of any one of claims 1 to 6, wherein
K is a C-5 modified pyrimidine, C or G;
each M is independently, and for each occurrence, C or a C-5 modified pyrimidine; and/or
L is A or C-5 modified pyrimidine. 8. An aptamer that binds C3 protein, wherein the aptamer comprises the sequence 5′-PAWPSVGPAYRPP-3′ (SEQ ID NO: 156), wherein each P is independently, and for each occurrence, a C-5 modified pyrimidine; W is G or a 3-carbon spacer; S is C or a 3-carbon spacer; V is A, G or C; Y is C, U, or T; and R is G or A. 9. An aptamer that binds C3 protein, wherein the aptamer comprises the sequence 5′-PAWPSVGPACGPP-3′ (SEQ ID NO: 134), wherein each P is independently, and for each occurrence, a C-5 modified pyrimidine; W is G or a 3-carbon spacer; and S is C or a 3-carbon spacer; V is A, G or C. 10. An aptamer that binds C3 protein, wherein the aptamer comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% identical to a sequence selected from SEQ ID NOs: 4 to 28, 32 to 34, 37 to 75, 78 to 118, 121 to 130, and 139 to 151, wherein each P is independently, and for each occurrence, a C-5 modified pyrimidine. 11. An aptamer that binds C3 protein, wherein the aptamer comprises a first region and a second region, wherein the first region comprises the sequence 5′-PAGPC-3′ (SEQ ID NO: 132) and the second region comprises the sequence 5′-GPAYRPP-3′ (SEQ ID NO: 156), wherein each P is independently, and for each occurrence, a C-5 modified pyrimidine; Y is C, U, or T; and R is G or A. 12. An aptamer that binds C3 protein, wherein the aptamer comprises a first region and a second region, wherein the first region comprises the sequence 5′-PAGPC-3′ (SEQ ID NO: 132) and the second region comprises the sequence 5′-GPACGPP-3′ (SEQ ID NO: 133), wherein each P is independently, and for each occurrence, a C-5 modified pyrimidine. 13. The aptamer of claim 11 or claim 12, wherein the 3′-end of the first region is covalently linked to the 5′-end of the second region. 14. The aptamer of claim 13, wherein the first region and the second region are covalently linked by at least one, two, three, four or five linkers, wherein each linkers is independently selected from a nucleotide, a substituted or unsubstituted C2-C20 linker, an alkylene glycol, and a polyalkylene glycol. 15. The aptamer of claim 14, wherein each linkers is independently selected from a nucleotide, a 3-carbon spacer, and a hexaethylene glycol. 16. An aptamer that binds C3, wherein the aptamer comprises the sequence 5′-PAGPC-3′ (SEQ ID NO: 132), wherein each P is independently, and for each occurrence, a C-5 modified pyrimidine. 17. An aptamer that binds C3, wherein the aptamer comprises the sequence 5′-GPAYRPP-3′ (SEQ ID NO: 156), wherein each P is independently, and for each occurrence, a C-5 modified pyrimidine; Y is C, U, or T; and R is G or A. 18. An aptamer that binds C3, wherein the aptamer comprises the sequence 5′-GPACGPP-3′ (SEQ ID NO: 133), wherein each P is independently, and for each occurrence, a C-5 modified pyrimidine. 19. An aptamer that binds C3 protein, wherein the aptamer comprises the sequence of SEQ ID NO: 125, wherein each P is independently, and for each occurrence, a C-5 modified pyrimidine. 20. The aptamer of any one of the preceding claims, wherein each C-5 modified pyrimidine is independently selected from:
5-(N-benzylcarboxyamide)-2′-deoxyuridine (BndU), 5-(N-benzylcarboxyamide)-2′-O-methyluridine, 5-(N-benzylcarboxyamide)-2′-fluorouridine, 5-(N-phenethylcarboxyamide)-2′-deoxyuridine (PEdU), 5-(N-thiophenylmethylcarboxyamide)-2′-deoxyuridine (ThdU), 5-(N-isobutylcarboxyamide)-2′-deoxyuridine (iBudU), 5-(N-tyrosylcarboxyamide)-2′-deoxyuridine (TyrdU), 5-(N-3,4-methylenedioxybenzylcarboxyamide)-2′-deoxyuridine (MBndU), 5-(N-4-fluorobenzylcarboxyamide)-2′-deoxyuridine (FBndU), 5-(N-3-phenylpropylcarboxyamide)-2′-deoxyuridine (PPdU), 5-(N-imidizolylethylcarboxyamide)-2′-deoxyuridine (ImdU), 5-(N-isobutylcarboxyamide)-2′-O-methyluridine, 5-(N-isobutylcarboxyamide)-2′-fluorouridine, 5-(N-tryptaminocarboxyamide)-2′-deoxyuridine (TrpdU), 5-(N—R-threoninylcarboxyamide)-2′-deoxyuridine (ThrdU), 5-(N-tryptaminocarboxyamide)-2′-O-methyluridine, 5-(N-tryptaminocarboxyamide)-2′-fluorouridine, 5-(N-[1-(3-trimethylamonium) propyl]carboxyamide)-2′-deoxyuridine chloride, 5-(N-naphthylmethylcarboxyamide)-2′-deoxyuridine (NapdU), 5-(N-naphthylmethylcarboxyamide)-2′-O-methyluridine, 5-(N-naphthylmethylcarboxyamide)-2′-fluorouridine, 5-(N-[1-(2,3-dihydroxypropyl)]carboxyamide)-2′-deoxyuridine), 5-(N-2-naphthylmethylcarboxyamide)-2′-deoxyuridine (2NapdU), 5-(N-2-naphthylmethylcarboxyamide)-2′-O-methyluridine, 5-(N-2-naphthylmethylcarboxyamide)-2′-fluorouridine, 5-(N-1-naphthylethylcarboxyamide)-2′-deoxyuridine (NEdU), 5-(N-1-naphthylethylcarboxyamide)-2′-O-methyluridine, 5-(N-1-naphthylethylcarboxyamide)-2′-fluorouridine, 5-(N-2-naphthylethylcarboxyamide)-2′-deoxyuridine (2NEdU), 5-(N-2-naphthylethylcarboxyamide)-2′-O-methyluridine, 5-(N-2-naphthylethylcarboxyamide)-2′-fluorouridine, 5-(N-3-benzofuranylethylcarboxyamide)-2′-deoxyuridine (BFdU), 5-(N-3-benzofuranylethylcarboxyamide)-2′-O-methyluridine, 5-(N-3-benzofuranylethylcarboxyamide)-2′-fluorouridine, 5-(N-3-benzothiophenylethylcarboxyamide)-2′-deoxyuridine (BTdU), 5-(N-3-benzothiophenylethylcarboxyamide)-2′-O-methyluridine, and 5-(N-3-benzothiophenylethylcarboxyamide)-2′-fluorouridine. 21. The aptamer of any one of the preceding claims, wherein each C-5 modified pyrimidine is independently selected from:
5-(N-1-naphthylmethylcarboxyamide)-2′-deoxyuridine (NapdU), 5-(N-1-naphthylmethylcarboxyamide)-2′-O-methyluridine, 5-(N-1-naphthylmethylcarboxyamide)-2′-fluorouridine, 5-(N-2-naphthylmethylcarboxyamide)-2′-deoxyuridine (2NapdU), 5-(N-2-naphthylmethylcarboxyamide)-2′-O-methyluridine, 5-(N-2-naphthylmethylcarboxyamide)-2′-fluorouridine, 5-(N-1-naphthylethylcarboxyamide)-2′-deoxyuridine (NEdU), 5-(N-1-naphthylethylcarboxyamide)-2′-O-methyluridine, 5-(N-1-naphthylethylcarboxyamide)-2′-fluorouridine, 5-(N-2-naphthylethylcarboxyamide)-2′-deoxyuridine (2NEdU), 5-(N-2-naphthylethylcarboxyamide)-2′-O-methyluridine, 5-(N-2-naphthylethylcarboxyamide)-2′-fluorouridine, 5-(N-3-benzofuranylethylcarboxyamide)-2′-deoxyuridine (BFdU), 5-(N-3-benzofuranylethylcarboxyamide)-2′-O-methyluridine, 5-(N-3-benzofuranylethylcarboxyamide)-2′-fluorouridine, 5-(N-3-benzothiophenylethylcarboxyamide)-2′-deoxyuridine (BTdU), 5-(N-3-benzothiophenylethylcarboxyamide)-2′-O-methyluridine, and 5-(N-3-benzothiophenylethylcarboxyamide)-2′-fluorouridine. 22. The aptamer of any one of the preceding claims, wherein each C-5 modified pyrimidine is 5-(N-naphthylmethylcarboxyamide)-2′-deoxyuridine (NapdU). 23. The aptamer of any one of the preceding claims, wherein the aptamer comprises at least one 2′-O-methyl modified nucleotide. 24. The aptamer of any one of the preceding claims, wherein the aptamer is 24 to 100 nucleotides in length, or 30 to 60 nucleotides in length, or 28 to 60 nucleotides in length, or 28 to 50 nucleotides in length, or 28 to 40 nucleotides in length, or 40 to 50 nucleotides in length, or 28 to 32 nucleotides in length. 25. The aptamer of any one of the preceding claims, wherein the aptamer inhibits cleavage of C3 protein. 26. The aptamer of any one of the preceding claims, wherein the C3 protein is human C3 protein. 27. A composition comprising the aptamer of any one of the preceding claims and a complement component 3 (C3) protein. 28. The composition of claim 27, wherein the complement component 3 (C3) protein is a human complement component 3 (C3) protein. 29. A method for inhibiting the cleavage of a complement component 3 (C3) protein comprising contacting a C3 protein with an aptamer of any one of claims 1 to 26. 30. The method of claim 29, wherein the C3 protein is in a sample in vitro. 31. The method of claim 29, wherein the C3 protein is in a subject. 32. A method for inhibiting at least one activity of the complement system comprising contacting components of the complement system with an aptamer of any one of claims 1 to 26. 33. The method of claim 32, wherein the components of the complement system are in a sample in vitro. 34. The method of claim 32, wherein the components of the complement system are in a subject. 35. A method for inhibiting the cleavage of a complement component 3 (C3) protein in a subject comprising administering to the subject an effective amount of an aptamer of any one of claims 1 to 26. 36. A method for inhibiting at least one activity of the complement system in a subject comprising administering to the subject an effective amount of an aptamer of any one of claims 1 to 26. 37. A method of treating age-related macular degeneration, an autoimmune disease, a hematological disorder, an infectious disease, sepsis, an inflammatory disease, or a neurodegenerative disease comprising administering to a subject an effective amount of an aptamer of any one of claims 1 to 26. 38. The method of claim 37, wherein the autoimmune disease is selected from lupus erythematosus and rheumatoid arthritis. 39. The method of claim 37, wherein the hematological disorders is paroxysmal nocturnal hemoglobinuria. 40. The method of claim 37, wherein the inflammatory disease is selected from ischemia/reperfusion injury, arthritis, and nephritis. 41. The method of claim 37, wherein the neurodegenerative disease is selected from Huntington's disease and Parkinson's disease. 42. Use of an aptamer of any one of claims 1 to 26 for inhibiting cleavage of C3 protein. 43. Use of an aptamer of any one of claims 1 to 26 for inhibiting at least one activity of the complement system. 44. Use of an aptamer of any one of claims 1 to 26 for treating age-related macular degeneration, an autoimmune diseases, a hematological disorders, an infectious disease, sepsis, an inflammatory disease, or a neurodegenerative disease. 45. A method for selecting an aptamer having binding affinity for a C3 protein comprising:
(a) contacting a candidate mixture with a C3 protein, wherein the candidate mixture comprises modified nucleic acids in which one, several or all pyrimidines in at least one, or each, nucleic acid of the candidate mixture comprises a C-5 modified pyrimidine; (b) exposing the candidate mixture to a slow off-rate enrichment process, wherein nucleic acids having a slow rate of dissociation from the target molecule relative to other nucleic acids in the candidate mixture bind the C3 protein, forming nucleic acid-target molecule complexes; (c) partitioning slow off-rate nucleic acids from the candidate mixture; (d) amplifying the slow off-rate nucleic acids to yield a mixture of nucleic acids enriched in nucleic acid sequences that are capable of binding to the C3 protein with a slow off-rate, whereby a slow off-rate aptamer to the C3 protein molecule is selected. 46. The method of claim 45, wherein the candidate mixture comprises nucleic acids comprising the sequence 5′-PAGPC -3′ (SEQ ID NO: 132), wherein each P is independently, and for each occurrence, a C-5 modified pyrimidine. 47. The method of claim 45 or claim 36, wherein the candidate mixture comprises nucleic acids comprising the sequence 5′-GPAYRPP-3′ (SEQ ID NO: 156) or 5′-GPACGPP-3′ (SEQ ID NO: 133), wherein each P is independently, and for each occurrence, a C-5 modified pyrimidine; Y is C, U, or T; and R is G or A. 48. The method of any one of claims 45 to 47, wherein each nucleic acid is, independently, from about 24 to about 100 nucleotides in length, or from about 30 to about 60 nucleotides in length, or from about 28 to about 60 nucleotides in length, or from about 40 to about 50 nucleotides in length, or about 28 nucleotides in length. 49. The method of any one of claims 45 to 48, wherein each C-5 modified pyrimidine is independently selected from:5-(N-benzylcarboxyamide)-2′-deoxyuridine (BndU), 5-(N-benzylcarboxyamide)-2′-O-methyluridine, 5-(N-benzylcarboxyamide)-2′-fluorouridine, 5-(N-phenethylcarboxyamide)-2′-deoxyuridine (PEdU), 5-(N-thiophenylmethylcarboxyamide)-2′-deoxyuridine (ThdU), 5-(N-isobutylcarboxyamide)-2′-deoxyuridine (iBudU), 5-(N-tyrosylcarboxyamide)-2′-deoxyuridine (TyrdU), 5-(N-3,4-methylenedioxybenzylcarboxyamide)-2′-deoxyuridine (MBndU), 5-(N-4-fluorobenzylcarboxyamide)-2′-deoxyuridine (FBndU), 5-(N-3-phenylpropylcarboxyamide)-2′-deoxyuridine (PPdU), 5-(N-imidizolylethylcarboxyamide)-2′-deoxyuridine (ImdU), 5-(N-isobutylcarboxyamide)-2′-O-methyluridine, 5-(N-isobutylcarboxyamide)-2′-fluorouridine, 5-(N-tryptaminocarboxyamide)-2′-deoxyuridine (TrpdU), 5-(N—R-threoninylcarboxyamide)-2′-deoxyuridine (ThrdU), 5-(N-tryptaminocarboxyamide)-2′-O-methyluridine, 5-(N-tryptaminocarboxyamide)-2′-fluorouridine, 5-(N-[1-(3-trimethylamonium) propyl]carboxyamide)-2′-deoxyuridine chloride, 5-(N-naphthylmethylcarboxyamide)-2′-deoxyuridine (NapdU), 5-(N-naphthylmethylcarboxyamide)-2′-O-methyluridine, 5-(N-naphthylmethylcarboxyamide)-2′-fluorouridine, 5-(N-[1-(2,3-dihydroxypropyl)]carboxyamide)-2′-deoxyuridine), 5-(N-2-naphthylmethylcarboxyamide)-2′-deoxyuridine (2NapdU), 5-(N-2-naphthylmethylcarboxyamide)-2′-O-methyluridine, 5-(N-2-naphthylmethylcarboxyamide)-2′-fluorouridine, 5-(N-1-naphthylethylcarboxyamide)-2′-deoxyuridine (NEdU), 5-(N-1-naphthylethylcarboxyamide)-2′-O-methyluridine, 5-(N-1-naphthylethylcarboxyamide)-2′-fluorouridine, 5-(N-2-naphthylethylcarboxyamide)-2′-deoxyuridine (2NEdU), 5-(N-2-naphthylethylcarboxyamide)-2′-O-methyluridine, 5-(N-2-naphthylethylcarboxyamide)-2′-fluorouridine, 5-(N-3-benzofuranylethylcarboxyamide)-2′-deoxyuridine (BFdU), 5-(N-3-benzofuranylethylcarboxyamide)-2′-O-methyluridine, 5-(N-3-benzofuranylethylcarboxyamide)-2′-fluorouridine, 5-(N-3-benzothiophenylethylcarboxyamide)-2′-deoxyuridine (BTdU), 5-(N-3-benzothiophenylethylcarboxyamide)-2′-O-methyluridine, and 5-(N-3-benzothiophenylethylcarboxyamide)-2′-fluorouridine. 50. The method of any one of claims 45 to 49, wherein each C-5 modified pyrimidine is independently selected from: 5-(N-1-naphthylmethylcarboxyamide)-2′-deoxyuridine (NapdU), 5-(N-1-naphthylmethylcarboxyamide)-2′-O-methyluridine, 5-(N-1-naphthylmethylcarboxyamide)-2′-fluorouridine, 5-(N-2-naphthylmethylcarboxyamide)-2′-deoxyuridine (2NapdU), 5-(N-2-naphthylmethylcarboxyamide)-2′-O-methyluridine, 5-(N-2-naphthylmethylcarboxyamide)-2′-fluorouridine, 5-(N-1-naphthylethylcarboxyamide)-2′-deoxyuridine (NEdU), 5-(N-1-naphthylethylcarboxyamide)-2′-O-methyluridine, 5-(N-1-naphthylethylcarboxyamide)-2′-fluorouridine, 5-(N-2-naphthylethylcarboxyamide)-2′-deoxyuridine (2NEdU), 5-(N-2-naphthylethylcarboxyamide)-2′-O-methyluridine, 5-(N-2-naphthylethylcarboxyamide)-2′-fluorouridine, 5-(N-3-benzofuranylethylcarboxyamide)-2′-deoxyuridine (BFdU), 5-(N-3-benzofuranylethylcarboxyamide)-2′-O-methyluridine, 5-(N-3-benzofuranylethylcarboxyamide)-2′-fluorouridine, 5-(N-3-benzothiophenylethylcarboxyamide)-2′-deoxyuridine (BTdU), 5-(N-3-benzothiophenylethylcarboxyamide)-2′-O-methyluridine, and 5-(N-3-benzothiophenylethylcarboxyamide)-2′-fluorouridine. 51. The method of any one of claims 45 to 48, wherein each C-5 modified pyrimidine is 5-(N-naphthylmethylcarboxyamide)-2′-deoxyuridine (NapdU). 52. The method of any one of claims 45 to 51, wherein a plurality of nucleic acids in the mixture comprise at least one 2′-O-methyl modified nucleotide. 53. The method of any one of claims 45 to 52, wherein a plurality of nucleic acids in the mixture comprise a C3-spacer, HEG linker or PEG linker. 54. The method of any one of claims 45 to 53, wherein the C3 protein is a human C3 protein.
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Described herein are aptamers capable of binding to human complement component 3 (C3) protein; compositions comprising a C3 binding aptamer with a C3-Protein; and methods of making and using the same.1. An aptamer that binds C3 protein, wherein the aptamer comprises the sequence 5′-KPGRMPDVD.LPAWPSVGPAYRPP-3′ (SEQ ID NO: 152)
wherein,
K is a C-5 modified pyrimidine, C, U, T, G, or a 3-carbon spacer;
each P is independently, and for each occurrence, a C-5 modified pyrimidine;
each R is independently, and for each occurrence, A or G;
M is C, U, T, a C-5 modified pyrimidine, or a 3-carbon spacer;
each D is independently, and for each occurrence, an A, C, or a 3-carbon spacer;
each V is independently, and for each occurrence, an A, G, C, or a 3-carbon spacer;
L is A, U, T or a C-5 modified pyrimidine;
W is G or a 3-carbon spacer;
S is C or a 3-carbon spacer;
Y is C, U, or T; and
n is 0 or 1. 2. The aptamer of claim 1, wherein the aptamer comprises the sequence 5′-KPGRMPDVDnLPAWPSVGPACGPP-3′ (SEQ ID NO: 131). 3. The aptamer of claim 1 or claim 2, wherein the aptamer comprises the sequence 5′-KPGRMPDVDnLPAWPSVGPACGPPM-3′ (SEQ ID NO: 135) or 5′-KPGRMPDVDnLPAWPSVGPAYRPPM-3′ (SEQ ID NO: 153) 4. An aptamer that binds C3 protein, wherein the aptamer comprises the sequence 5′-KPGRMPXPAWPSVGPAYRPP-3′ (SEQ ID NO: 154)
wherein,
K is a C-5 modified pyrimidine, C, U, T, G, or a 3-carbon spacer;
each P is independently, and for each occurrence, a C-5 modified pyrimidine;
R is A or G;
M is C, U, T a C-5 modified pyrimidine, or a 3-carbon spacer;
V is A, G, C, or a 3-carbon spacer;
W is G or a 3-carbon spacer;
S is C or a 3-carbon spacer;
Y is C, U, or T; and
X is a linker selected from a substituted or unsubstituted C2-C20 linker, an alkylene glycol, and a polyalkylene glycol. 5. The aptamer of claim 4, wherein the aptamer comprises the sequence 5′-KPGRMPXPAWP SVGPACGPP-3′ (SEQ ID NO: 136). 6. The aptamer of claim 4 or claim 5, wherein the aptamer comprises the sequence 5′-KPGRMPXPAWPSVGPACGPPM-3′ (SEQ ID NO: 137) or 5′-KPGRMPXPAWPSVGPAYRPPM-3′ (SEQ ID NO: 155). 7. The aptamer of any one of claims 1 to 6, wherein
K is a C-5 modified pyrimidine, C or G;
each M is independently, and for each occurrence, C or a C-5 modified pyrimidine; and/or
L is A or C-5 modified pyrimidine. 8. An aptamer that binds C3 protein, wherein the aptamer comprises the sequence 5′-PAWPSVGPAYRPP-3′ (SEQ ID NO: 156), wherein each P is independently, and for each occurrence, a C-5 modified pyrimidine; W is G or a 3-carbon spacer; S is C or a 3-carbon spacer; V is A, G or C; Y is C, U, or T; and R is G or A. 9. An aptamer that binds C3 protein, wherein the aptamer comprises the sequence 5′-PAWPSVGPACGPP-3′ (SEQ ID NO: 134), wherein each P is independently, and for each occurrence, a C-5 modified pyrimidine; W is G or a 3-carbon spacer; and S is C or a 3-carbon spacer; V is A, G or C. 10. An aptamer that binds C3 protein, wherein the aptamer comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% identical to a sequence selected from SEQ ID NOs: 4 to 28, 32 to 34, 37 to 75, 78 to 118, 121 to 130, and 139 to 151, wherein each P is independently, and for each occurrence, a C-5 modified pyrimidine. 11. An aptamer that binds C3 protein, wherein the aptamer comprises a first region and a second region, wherein the first region comprises the sequence 5′-PAGPC-3′ (SEQ ID NO: 132) and the second region comprises the sequence 5′-GPAYRPP-3′ (SEQ ID NO: 156), wherein each P is independently, and for each occurrence, a C-5 modified pyrimidine; Y is C, U, or T; and R is G or A. 12. An aptamer that binds C3 protein, wherein the aptamer comprises a first region and a second region, wherein the first region comprises the sequence 5′-PAGPC-3′ (SEQ ID NO: 132) and the second region comprises the sequence 5′-GPACGPP-3′ (SEQ ID NO: 133), wherein each P is independently, and for each occurrence, a C-5 modified pyrimidine. 13. The aptamer of claim 11 or claim 12, wherein the 3′-end of the first region is covalently linked to the 5′-end of the second region. 14. The aptamer of claim 13, wherein the first region and the second region are covalently linked by at least one, two, three, four or five linkers, wherein each linkers is independently selected from a nucleotide, a substituted or unsubstituted C2-C20 linker, an alkylene glycol, and a polyalkylene glycol. 15. The aptamer of claim 14, wherein each linkers is independently selected from a nucleotide, a 3-carbon spacer, and a hexaethylene glycol. 16. An aptamer that binds C3, wherein the aptamer comprises the sequence 5′-PAGPC-3′ (SEQ ID NO: 132), wherein each P is independently, and for each occurrence, a C-5 modified pyrimidine. 17. An aptamer that binds C3, wherein the aptamer comprises the sequence 5′-GPAYRPP-3′ (SEQ ID NO: 156), wherein each P is independently, and for each occurrence, a C-5 modified pyrimidine; Y is C, U, or T; and R is G or A. 18. An aptamer that binds C3, wherein the aptamer comprises the sequence 5′-GPACGPP-3′ (SEQ ID NO: 133), wherein each P is independently, and for each occurrence, a C-5 modified pyrimidine. 19. An aptamer that binds C3 protein, wherein the aptamer comprises the sequence of SEQ ID NO: 125, wherein each P is independently, and for each occurrence, a C-5 modified pyrimidine. 20. The aptamer of any one of the preceding claims, wherein each C-5 modified pyrimidine is independently selected from:
5-(N-benzylcarboxyamide)-2′-deoxyuridine (BndU), 5-(N-benzylcarboxyamide)-2′-O-methyluridine, 5-(N-benzylcarboxyamide)-2′-fluorouridine, 5-(N-phenethylcarboxyamide)-2′-deoxyuridine (PEdU), 5-(N-thiophenylmethylcarboxyamide)-2′-deoxyuridine (ThdU), 5-(N-isobutylcarboxyamide)-2′-deoxyuridine (iBudU), 5-(N-tyrosylcarboxyamide)-2′-deoxyuridine (TyrdU), 5-(N-3,4-methylenedioxybenzylcarboxyamide)-2′-deoxyuridine (MBndU), 5-(N-4-fluorobenzylcarboxyamide)-2′-deoxyuridine (FBndU), 5-(N-3-phenylpropylcarboxyamide)-2′-deoxyuridine (PPdU), 5-(N-imidizolylethylcarboxyamide)-2′-deoxyuridine (ImdU), 5-(N-isobutylcarboxyamide)-2′-O-methyluridine, 5-(N-isobutylcarboxyamide)-2′-fluorouridine, 5-(N-tryptaminocarboxyamide)-2′-deoxyuridine (TrpdU), 5-(N—R-threoninylcarboxyamide)-2′-deoxyuridine (ThrdU), 5-(N-tryptaminocarboxyamide)-2′-O-methyluridine, 5-(N-tryptaminocarboxyamide)-2′-fluorouridine, 5-(N-[1-(3-trimethylamonium) propyl]carboxyamide)-2′-deoxyuridine chloride, 5-(N-naphthylmethylcarboxyamide)-2′-deoxyuridine (NapdU), 5-(N-naphthylmethylcarboxyamide)-2′-O-methyluridine, 5-(N-naphthylmethylcarboxyamide)-2′-fluorouridine, 5-(N-[1-(2,3-dihydroxypropyl)]carboxyamide)-2′-deoxyuridine), 5-(N-2-naphthylmethylcarboxyamide)-2′-deoxyuridine (2NapdU), 5-(N-2-naphthylmethylcarboxyamide)-2′-O-methyluridine, 5-(N-2-naphthylmethylcarboxyamide)-2′-fluorouridine, 5-(N-1-naphthylethylcarboxyamide)-2′-deoxyuridine (NEdU), 5-(N-1-naphthylethylcarboxyamide)-2′-O-methyluridine, 5-(N-1-naphthylethylcarboxyamide)-2′-fluorouridine, 5-(N-2-naphthylethylcarboxyamide)-2′-deoxyuridine (2NEdU), 5-(N-2-naphthylethylcarboxyamide)-2′-O-methyluridine, 5-(N-2-naphthylethylcarboxyamide)-2′-fluorouridine, 5-(N-3-benzofuranylethylcarboxyamide)-2′-deoxyuridine (BFdU), 5-(N-3-benzofuranylethylcarboxyamide)-2′-O-methyluridine, 5-(N-3-benzofuranylethylcarboxyamide)-2′-fluorouridine, 5-(N-3-benzothiophenylethylcarboxyamide)-2′-deoxyuridine (BTdU), 5-(N-3-benzothiophenylethylcarboxyamide)-2′-O-methyluridine, and 5-(N-3-benzothiophenylethylcarboxyamide)-2′-fluorouridine. 21. The aptamer of any one of the preceding claims, wherein each C-5 modified pyrimidine is independently selected from:
5-(N-1-naphthylmethylcarboxyamide)-2′-deoxyuridine (NapdU), 5-(N-1-naphthylmethylcarboxyamide)-2′-O-methyluridine, 5-(N-1-naphthylmethylcarboxyamide)-2′-fluorouridine, 5-(N-2-naphthylmethylcarboxyamide)-2′-deoxyuridine (2NapdU), 5-(N-2-naphthylmethylcarboxyamide)-2′-O-methyluridine, 5-(N-2-naphthylmethylcarboxyamide)-2′-fluorouridine, 5-(N-1-naphthylethylcarboxyamide)-2′-deoxyuridine (NEdU), 5-(N-1-naphthylethylcarboxyamide)-2′-O-methyluridine, 5-(N-1-naphthylethylcarboxyamide)-2′-fluorouridine, 5-(N-2-naphthylethylcarboxyamide)-2′-deoxyuridine (2NEdU), 5-(N-2-naphthylethylcarboxyamide)-2′-O-methyluridine, 5-(N-2-naphthylethylcarboxyamide)-2′-fluorouridine, 5-(N-3-benzofuranylethylcarboxyamide)-2′-deoxyuridine (BFdU), 5-(N-3-benzofuranylethylcarboxyamide)-2′-O-methyluridine, 5-(N-3-benzofuranylethylcarboxyamide)-2′-fluorouridine, 5-(N-3-benzothiophenylethylcarboxyamide)-2′-deoxyuridine (BTdU), 5-(N-3-benzothiophenylethylcarboxyamide)-2′-O-methyluridine, and 5-(N-3-benzothiophenylethylcarboxyamide)-2′-fluorouridine. 22. The aptamer of any one of the preceding claims, wherein each C-5 modified pyrimidine is 5-(N-naphthylmethylcarboxyamide)-2′-deoxyuridine (NapdU). 23. The aptamer of any one of the preceding claims, wherein the aptamer comprises at least one 2′-O-methyl modified nucleotide. 24. The aptamer of any one of the preceding claims, wherein the aptamer is 24 to 100 nucleotides in length, or 30 to 60 nucleotides in length, or 28 to 60 nucleotides in length, or 28 to 50 nucleotides in length, or 28 to 40 nucleotides in length, or 40 to 50 nucleotides in length, or 28 to 32 nucleotides in length. 25. The aptamer of any one of the preceding claims, wherein the aptamer inhibits cleavage of C3 protein. 26. The aptamer of any one of the preceding claims, wherein the C3 protein is human C3 protein. 27. A composition comprising the aptamer of any one of the preceding claims and a complement component 3 (C3) protein. 28. The composition of claim 27, wherein the complement component 3 (C3) protein is a human complement component 3 (C3) protein. 29. A method for inhibiting the cleavage of a complement component 3 (C3) protein comprising contacting a C3 protein with an aptamer of any one of claims 1 to 26. 30. The method of claim 29, wherein the C3 protein is in a sample in vitro. 31. The method of claim 29, wherein the C3 protein is in a subject. 32. A method for inhibiting at least one activity of the complement system comprising contacting components of the complement system with an aptamer of any one of claims 1 to 26. 33. The method of claim 32, wherein the components of the complement system are in a sample in vitro. 34. The method of claim 32, wherein the components of the complement system are in a subject. 35. A method for inhibiting the cleavage of a complement component 3 (C3) protein in a subject comprising administering to the subject an effective amount of an aptamer of any one of claims 1 to 26. 36. A method for inhibiting at least one activity of the complement system in a subject comprising administering to the subject an effective amount of an aptamer of any one of claims 1 to 26. 37. A method of treating age-related macular degeneration, an autoimmune disease, a hematological disorder, an infectious disease, sepsis, an inflammatory disease, or a neurodegenerative disease comprising administering to a subject an effective amount of an aptamer of any one of claims 1 to 26. 38. The method of claim 37, wherein the autoimmune disease is selected from lupus erythematosus and rheumatoid arthritis. 39. The method of claim 37, wherein the hematological disorders is paroxysmal nocturnal hemoglobinuria. 40. The method of claim 37, wherein the inflammatory disease is selected from ischemia/reperfusion injury, arthritis, and nephritis. 41. The method of claim 37, wherein the neurodegenerative disease is selected from Huntington's disease and Parkinson's disease. 42. Use of an aptamer of any one of claims 1 to 26 for inhibiting cleavage of C3 protein. 43. Use of an aptamer of any one of claims 1 to 26 for inhibiting at least one activity of the complement system. 44. Use of an aptamer of any one of claims 1 to 26 for treating age-related macular degeneration, an autoimmune diseases, a hematological disorders, an infectious disease, sepsis, an inflammatory disease, or a neurodegenerative disease. 45. A method for selecting an aptamer having binding affinity for a C3 protein comprising:
(a) contacting a candidate mixture with a C3 protein, wherein the candidate mixture comprises modified nucleic acids in which one, several or all pyrimidines in at least one, or each, nucleic acid of the candidate mixture comprises a C-5 modified pyrimidine; (b) exposing the candidate mixture to a slow off-rate enrichment process, wherein nucleic acids having a slow rate of dissociation from the target molecule relative to other nucleic acids in the candidate mixture bind the C3 protein, forming nucleic acid-target molecule complexes; (c) partitioning slow off-rate nucleic acids from the candidate mixture; (d) amplifying the slow off-rate nucleic acids to yield a mixture of nucleic acids enriched in nucleic acid sequences that are capable of binding to the C3 protein with a slow off-rate, whereby a slow off-rate aptamer to the C3 protein molecule is selected. 46. The method of claim 45, wherein the candidate mixture comprises nucleic acids comprising the sequence 5′-PAGPC -3′ (SEQ ID NO: 132), wherein each P is independently, and for each occurrence, a C-5 modified pyrimidine. 47. The method of claim 45 or claim 36, wherein the candidate mixture comprises nucleic acids comprising the sequence 5′-GPAYRPP-3′ (SEQ ID NO: 156) or 5′-GPACGPP-3′ (SEQ ID NO: 133), wherein each P is independently, and for each occurrence, a C-5 modified pyrimidine; Y is C, U, or T; and R is G or A. 48. The method of any one of claims 45 to 47, wherein each nucleic acid is, independently, from about 24 to about 100 nucleotides in length, or from about 30 to about 60 nucleotides in length, or from about 28 to about 60 nucleotides in length, or from about 40 to about 50 nucleotides in length, or about 28 nucleotides in length. 49. The method of any one of claims 45 to 48, wherein each C-5 modified pyrimidine is independently selected from:5-(N-benzylcarboxyamide)-2′-deoxyuridine (BndU), 5-(N-benzylcarboxyamide)-2′-O-methyluridine, 5-(N-benzylcarboxyamide)-2′-fluorouridine, 5-(N-phenethylcarboxyamide)-2′-deoxyuridine (PEdU), 5-(N-thiophenylmethylcarboxyamide)-2′-deoxyuridine (ThdU), 5-(N-isobutylcarboxyamide)-2′-deoxyuridine (iBudU), 5-(N-tyrosylcarboxyamide)-2′-deoxyuridine (TyrdU), 5-(N-3,4-methylenedioxybenzylcarboxyamide)-2′-deoxyuridine (MBndU), 5-(N-4-fluorobenzylcarboxyamide)-2′-deoxyuridine (FBndU), 5-(N-3-phenylpropylcarboxyamide)-2′-deoxyuridine (PPdU), 5-(N-imidizolylethylcarboxyamide)-2′-deoxyuridine (ImdU), 5-(N-isobutylcarboxyamide)-2′-O-methyluridine, 5-(N-isobutylcarboxyamide)-2′-fluorouridine, 5-(N-tryptaminocarboxyamide)-2′-deoxyuridine (TrpdU), 5-(N—R-threoninylcarboxyamide)-2′-deoxyuridine (ThrdU), 5-(N-tryptaminocarboxyamide)-2′-O-methyluridine, 5-(N-tryptaminocarboxyamide)-2′-fluorouridine, 5-(N-[1-(3-trimethylamonium) propyl]carboxyamide)-2′-deoxyuridine chloride, 5-(N-naphthylmethylcarboxyamide)-2′-deoxyuridine (NapdU), 5-(N-naphthylmethylcarboxyamide)-2′-O-methyluridine, 5-(N-naphthylmethylcarboxyamide)-2′-fluorouridine, 5-(N-[1-(2,3-dihydroxypropyl)]carboxyamide)-2′-deoxyuridine), 5-(N-2-naphthylmethylcarboxyamide)-2′-deoxyuridine (2NapdU), 5-(N-2-naphthylmethylcarboxyamide)-2′-O-methyluridine, 5-(N-2-naphthylmethylcarboxyamide)-2′-fluorouridine, 5-(N-1-naphthylethylcarboxyamide)-2′-deoxyuridine (NEdU), 5-(N-1-naphthylethylcarboxyamide)-2′-O-methyluridine, 5-(N-1-naphthylethylcarboxyamide)-2′-fluorouridine, 5-(N-2-naphthylethylcarboxyamide)-2′-deoxyuridine (2NEdU), 5-(N-2-naphthylethylcarboxyamide)-2′-O-methyluridine, 5-(N-2-naphthylethylcarboxyamide)-2′-fluorouridine, 5-(N-3-benzofuranylethylcarboxyamide)-2′-deoxyuridine (BFdU), 5-(N-3-benzofuranylethylcarboxyamide)-2′-O-methyluridine, 5-(N-3-benzofuranylethylcarboxyamide)-2′-fluorouridine, 5-(N-3-benzothiophenylethylcarboxyamide)-2′-deoxyuridine (BTdU), 5-(N-3-benzothiophenylethylcarboxyamide)-2′-O-methyluridine, and 5-(N-3-benzothiophenylethylcarboxyamide)-2′-fluorouridine. 50. The method of any one of claims 45 to 49, wherein each C-5 modified pyrimidine is independently selected from: 5-(N-1-naphthylmethylcarboxyamide)-2′-deoxyuridine (NapdU), 5-(N-1-naphthylmethylcarboxyamide)-2′-O-methyluridine, 5-(N-1-naphthylmethylcarboxyamide)-2′-fluorouridine, 5-(N-2-naphthylmethylcarboxyamide)-2′-deoxyuridine (2NapdU), 5-(N-2-naphthylmethylcarboxyamide)-2′-O-methyluridine, 5-(N-2-naphthylmethylcarboxyamide)-2′-fluorouridine, 5-(N-1-naphthylethylcarboxyamide)-2′-deoxyuridine (NEdU), 5-(N-1-naphthylethylcarboxyamide)-2′-O-methyluridine, 5-(N-1-naphthylethylcarboxyamide)-2′-fluorouridine, 5-(N-2-naphthylethylcarboxyamide)-2′-deoxyuridine (2NEdU), 5-(N-2-naphthylethylcarboxyamide)-2′-O-methyluridine, 5-(N-2-naphthylethylcarboxyamide)-2′-fluorouridine, 5-(N-3-benzofuranylethylcarboxyamide)-2′-deoxyuridine (BFdU), 5-(N-3-benzofuranylethylcarboxyamide)-2′-O-methyluridine, 5-(N-3-benzofuranylethylcarboxyamide)-2′-fluorouridine, 5-(N-3-benzothiophenylethylcarboxyamide)-2′-deoxyuridine (BTdU), 5-(N-3-benzothiophenylethylcarboxyamide)-2′-O-methyluridine, and 5-(N-3-benzothiophenylethylcarboxyamide)-2′-fluorouridine. 51. The method of any one of claims 45 to 48, wherein each C-5 modified pyrimidine is 5-(N-naphthylmethylcarboxyamide)-2′-deoxyuridine (NapdU). 52. The method of any one of claims 45 to 51, wherein a plurality of nucleic acids in the mixture comprise at least one 2′-O-methyl modified nucleotide. 53. The method of any one of claims 45 to 52, wherein a plurality of nucleic acids in the mixture comprise a C3-spacer, HEG linker or PEG linker. 54. The method of any one of claims 45 to 53, wherein the C3 protein is a human C3 protein.
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1,258 | 15,401,777 | 1,627 |
The present disclosure provide a combination of a chromene compound having the structure of Formula (I), or pharmaceutically acceptable salts, and a second compound that can be selected from a PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor, OX-40 agonist, CD137 agonist, LAG-3 inhibitor, IDO inhibitor, bi-specific protein, EGFR inhibitor, HER2 inhibitor, and immune stimulating therapy and a method of using the combination for treating or preventing cancer.
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1. A combination comprising:
a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof and a second compound,
wherein M is selected from the group consisting of H and alkyl;
Z is selected from the group consisting of —CF3, —CF2H and —C2F5;
each of R1, R2, R3, and R4 is independently selected from a group consisting of H, alkyl, aralkyl, deuteroalkyl, deuteroaralkyl, deuteroalkoxy, deuterocycloalkyl, deuteron, deuteriumaryloxy, deuteroaryloxy, deuteroheteroaryloxy, deuteroarylalkoxy, deuteroheteroarylalkoxy, deuterohaloalkoxy, deuterohaloalkoxy, deuteroamino, deuterosulfamidyl, sulfamidyl, cycloalkyl, cycloalkenyl, halo, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, pentafluorosulfanyl, hydroxyalkyl, trialkylsilyl, alkynyl, and alkenyl; and
wherein the second compound is selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, OX-40 agonists, CD137 agonists, LAG-3 inhibitors, IDO inhibitors, bi-specific proteins, EGFR inhibitors, HER2 inhibitors, and immune stimulating therapies. 2. The combination of claim 1, wherein at least one of R1, R2, R3, and R4 of Formula (II) is selected from the group consisting of deuteron, deuteroalkyl, and deuterocycloalkyl. 3. The combination of claim 2, wherein R2 is not H. 4. The combination of claim 3, wherein the compound of Formula (II) is selected from the group consisting of:
(S)-6,8-di-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6-bromo-8-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-8-pentadeuteroethyl-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6-chloro-8-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6-chloro-5,7-di-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6-bromo-5,7-di-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-8-chloro-6-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-8-trideuteromethyl-6-(pentafluorosulfanyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, and (S)-8-trideuteromethyl-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid. 5. The combination of claim 2, wherein the second compound is:
a PD-1 inhibitor selected from the group consisting of nivolumab, pidilizumab, pembrolizumab, AMP-224, AMP-514, STI-A1110, TSR-043, AMP-514, and AUNP-12; a PD-L1 inhibitor selected from the group consisting of RG 7446, BMS-936559, MSB0010718C, STI-A1010, avelumab, atezolizumab, and durvalumab; a CTLA-4 inhibitor selected from the group consisting of ipilimumab or tremelimumab; an OX-40 agonist selected from the group consisting of anti-OX40, TIM3 antibody, and Immutune IMP701; a CD137 agonist selected from the group consisting of urelumab and utomilumab; the LAG-3 inhibitor BMS-986016; an IDO inhibitor selected from the group consisting of GDC-0919, indoximod, 1-methyl-D-tryptophan, NLG919, epacadostat, and norharmane; an EGFR inhibitor selected from the group consisting of brigatinib, gefitinib, icotinib, neratinib, afatinib, dacomitinib, cetuximab, erlotinib, flavopiridol, zalutumumab, necitumumab, lidocaine, matuzumab, osimertinib, panitumumab, PD168393, lapatinib, vandetanib, rindopepimut, canertinib, HuMAX-EGFR, and CimaVax-EGF; an HER2 inhibitor selected from the group consisting of ado-trastuzumab emtansine, trastuzumab, and pertuzumab; and an immune stimulating therapy selected from the group consisting of vidapenant, varlilumab, monalizumab, KAHR-102, BGB324, enoblituzumab, lirilumab, bavituximab, pidilizumab, BL-8040, GDC-0919, IGN-311, elotuzumab, blinatumomab, samalizumab, plerixafor, ganitumab, pexodartinib, trabedersen, and galunisertib. 6. The combination of claim 4, wherein the second compound is:
a PD-1 inhibitor selected from the group consisting of nivolumab, pidilizumab, pembrolizumab, AMP-224, AMP-514, STI-A1110, TSR-043, AMP-514, and AUNP-12; a PD-L1 inhibitor selected from the group consisting of RG 7446, BMS-936559, MSB0010718C, and STI-A1010, avelumab, atezolizumab, and durvalumab; a CTLA-4 inhibitor selected from the group consisting of ipilimumab or tremelimumab; an OX-40 agonist selected from the group consisting of anti-OX40, TIM3 antibody, and Immutune IMP701; a CD137 agonist selected from the group consisting of urelumab and utomilumab; the LAG-3 inhibitor BMS-986016; an IDO inhibitor selected from the group consisting of GDC-0919, indoximod, 1-methyl-D-tryptophan, NLG919, epacadostat, and norharmane; a bi-specific protein selected from the group consisting of ALT-801 and MEDI-565; an EGFR inhibitor selected from the group consisting of brigatinib, gefitinib, icotinib, neratinib, afatinib, dacomitinib, cetuximab, erlotinib, flavopiridol, zalutumumab, necitumumab, lidocaine, matuzumab, osimertinib, panitumumab, PD168393, lapatinib, vandetanib, rindopepimut, canertinib, HuMAX-EGFR, and CimaVax-EGF; an HER2 inhibitor selected from the group consisting of ado-trastuzumab emtansine, trastuzumab, and pertuzumab; and an immune stimulating therapy selected from the group consisting of vidapenant, varlilumab, monalizumab, KAHR-102, BGB324, enoblituzumab, lirilumab, bavituximab, pidilizumab, BL-8040, GDC-0919, IGN-311, elotuzumab, blinatumomab, samalizumab, plerixafor, ganitumab, pexodartinib, trabedersen, and galunisertib. 7. The combination of claim 6, wherein the second compound is selected from the group consisting of erlotinib, pembrolizumab, nivolumab, atezolizumab, ipilimumab, avelumab, durvalumab, trastuzumab, cetuximab, pertuzumab, and panitumumab. 8. The combination of claim 6, wherein the compound of Formula (II) is (S)-6-bromo-8-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid and the second compound is selected from the group consisting of erlotinib, pembrolizumab, nivolumab, atezolizumab, ipilimumab, avelumab, durvalumab, trastuzumab, cetuximab, pertuzumab, and panitumumab. 9. The combination of claim 8, wherein the second compound is erlotinib, cetuximab, trastuzumab, or pertuzumab. 10. The combination of claim 8, wherein the compound of Formula (II) is (S)-6-bromo-8-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid and the second compound is pembrolizumab, nivolumab, atezolizumab, ipilimumab, durvalumab, or avelumab. 11. The combination of claim 9 wherein the second compound is erlotinib. 12. The combination of claim 10 wherein the second compound is pembrolizumab, nivolumab, or atezolizumab. 13. The combination of claim 1, wherein each of R1, R2, R3, and R4 of Formula (II) is independently selected from the group consisting of H, alkyl, aralkyl, cycloalkyl, cycloalkenyl, halo, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, pentafluorosulfanyl, hydroxyalkyl, trialkylsilyl, alkynyl, and alkenyl. 14. The combination of claim 13 of claim 1, wherein R1 is H and R2 is selected from the group consisting of halo, haloalkoxy, and pentafluorosulfanyl, and R4 is selected from H, alkyl, alkenyl, alkynyl, and halo. 15. The combination of claim 14, wherein the compound of Formula (II) is selected from the group consisting of:
(S)-6,8-dichloro-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6-chloro-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6-bromo-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6,8-dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-8-methyl-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-8-ethyl-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6-chloro-5,7-dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-7-(tert-butyl)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6-pentafluorosulfanyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6-pentafluorosulfanyl-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, and (S)-6-pentafluorosulfanyl-8-ethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid. (S)-6-pentafluorosulfanyl-8-ethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid. 16. The combination of claim 13, wherein the second compound is:
a PD-1 inhibitor selected from the group consisting of nivolumab, pidilizumab, pembrolizumab, AMP-224, AMP-514, STI-A1110, TSR-043, AMP-514, and AUNP-12; a PD-L1 inhibitor selected from the group consisting of RG 7446, BMS-936559, MSB0010718C, STI-A1010, avelumab, atezolizumab, and durvalumab; a CTLA-4 inhibitor selected from the group consisting of ipilimumab or tremelimumab; an OX-40 agonist selected from the group consisting of anti-OX40, TIM3 antibody, and Immutune IMP701; a CD137 agonist selected from the group consisting of urelumab and utomilumab; the LAG-3 inhibitor BMS-986016; an IDO inhibitor selected from the group consisting of GDC-0919, indoximod, 1-methyl-D-tryptophan, NLG919, epacadostat, and norharmane; a bi-specific protein selected from the group consisting of ALT-801 and MEDI-565; an EGFR inhibitor selected from the group consisting of brigatinib, gefitinib, icotinib, neratinib, afatinib, dacomitinib, cetuximab, erlotinib, flavopiridol, zalutumumab, necitumumab, lidocaine, matuzumab, osimertinib, panitumumab, PD168393, lapatinib, vandetanib, rindopepimut, canertinib, HuMAX-EGFR, and CimaVax-EGF; an HER2 inhibitor selected from the group consisting of ado-trastuzumab emtansine, trastuzumab, and pertuzumab; and an immune stimulating therapy selected from the group consisting of vidapenant, varlilumab, monalizumab, KAHR-102, BGB324, enoblituzumab, lirilumab, bavituximab, pidilizumab, BL-8040, GDC-0919, IGN-311, elotuzumab, blinatumomab, samalizumab, plerixafor, ganitumab, pexodartinib, trabedersen, and galunisertib. 17. The combination of claim 15, wherein the second compound is:
a PD-1 inhibitor selected from the group consisting of nivolumab, pidilizumab, pembrolizumab, AMP-224, AMP-514, STI-A1110, TSR-043, AMP-514, and AUNP-12; a PD-L1 inhibitor selected from the group consisting of RG 7446, BMS-936559, MSB0010718C, STI-A1010, avelumab, atezolizumab, and durvalumab; a CTLA-4 inhibitor selected from the group consisting of ipilimumabor tremelimumab; an OX-40 agonist selected from the group consisting of anti-OX40, TIM3 antibody, and Immutune IMP701; a CD137 agonist selected from the group consisting of urelumab and utomilumab; the LAG-3 inhibitor BMS-986016; an IDO inhibitor selected from the group consisting of GDC-0919, indoximod, 1-methyl-D-tryptophan, NLG919, epacadostat, and norharmane; a bi-specific protein selected from the group consisting of ALT-801 and MEDI-565; an EGFR inhibitor selected from the group consisting of brigatinib, gefitinib, icotinib, neratinib, afatinib, dacomitinib, cetuximab, erlotinib, flavopiridol, zalutumumab, necitumumab, lidocaine, matuzumab, osimertinib, panitumumab, PD168393, lapatinib, vandetanib, rindopepimut, canertinib, HuMAX-EGFR, and CimaVax-EGF; an HER2 inhibitor selected from the group consisting of ado-trastuzumab emtansine, trastuzumab, and pertuzumab; and an immune stimulating therapy selected from the group consisting of vidapenant, varlilumab, monalizumab, KAHR-102, BGB324, enoblituzumab, lirilumab, bavituximab, pidilizumab, BL-8040, GDC-0919, IGN-311, elotuzumab, blinatumomab, samalizumab, plerixafor, ganitumab, pexodartinib, trabedersen, and galunisertib. 18. The combination of claim 17, wherein the second compound is selected from the group consisting of erlotinib, pembrolizumab, nivolumab, atezolizumab, ipilimumab, avelumab, durvalumab, trastuzumab, cetuximab, pertuzumab, and panitumumab. 19. The combination of claim 18, wherein the second compound is erlotinib, cetuximab, trastuzumab, or pertuzumab. 20. The combination of claim 18, wherein the second compound is pembrolizumab, nivolumab, atezolizumab, ipilimumab, durvalumab, avelumab. 21. A pharmaceutical composition comprising a therapeutically effective amount of the combination of claim 1 and at least one pharmaceutically acceptable excipient. 22-24. (canceled) 25. A method for treating cancer, comprising:
administering to a subject in need thereof a therapeutically effective amount of the combination of claim 1. 26-38. (canceled)
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The present disclosure provide a combination of a chromene compound having the structure of Formula (I), or pharmaceutically acceptable salts, and a second compound that can be selected from a PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor, OX-40 agonist, CD137 agonist, LAG-3 inhibitor, IDO inhibitor, bi-specific protein, EGFR inhibitor, HER2 inhibitor, and immune stimulating therapy and a method of using the combination for treating or preventing cancer.1. A combination comprising:
a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof and a second compound,
wherein M is selected from the group consisting of H and alkyl;
Z is selected from the group consisting of —CF3, —CF2H and —C2F5;
each of R1, R2, R3, and R4 is independently selected from a group consisting of H, alkyl, aralkyl, deuteroalkyl, deuteroaralkyl, deuteroalkoxy, deuterocycloalkyl, deuteron, deuteriumaryloxy, deuteroaryloxy, deuteroheteroaryloxy, deuteroarylalkoxy, deuteroheteroarylalkoxy, deuterohaloalkoxy, deuterohaloalkoxy, deuteroamino, deuterosulfamidyl, sulfamidyl, cycloalkyl, cycloalkenyl, halo, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, pentafluorosulfanyl, hydroxyalkyl, trialkylsilyl, alkynyl, and alkenyl; and
wherein the second compound is selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, OX-40 agonists, CD137 agonists, LAG-3 inhibitors, IDO inhibitors, bi-specific proteins, EGFR inhibitors, HER2 inhibitors, and immune stimulating therapies. 2. The combination of claim 1, wherein at least one of R1, R2, R3, and R4 of Formula (II) is selected from the group consisting of deuteron, deuteroalkyl, and deuterocycloalkyl. 3. The combination of claim 2, wherein R2 is not H. 4. The combination of claim 3, wherein the compound of Formula (II) is selected from the group consisting of:
(S)-6,8-di-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6-bromo-8-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-8-pentadeuteroethyl-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6-chloro-8-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6-chloro-5,7-di-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6-bromo-5,7-di-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-8-chloro-6-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-8-trideuteromethyl-6-(pentafluorosulfanyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, and (S)-8-trideuteromethyl-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid. 5. The combination of claim 2, wherein the second compound is:
a PD-1 inhibitor selected from the group consisting of nivolumab, pidilizumab, pembrolizumab, AMP-224, AMP-514, STI-A1110, TSR-043, AMP-514, and AUNP-12; a PD-L1 inhibitor selected from the group consisting of RG 7446, BMS-936559, MSB0010718C, STI-A1010, avelumab, atezolizumab, and durvalumab; a CTLA-4 inhibitor selected from the group consisting of ipilimumab or tremelimumab; an OX-40 agonist selected from the group consisting of anti-OX40, TIM3 antibody, and Immutune IMP701; a CD137 agonist selected from the group consisting of urelumab and utomilumab; the LAG-3 inhibitor BMS-986016; an IDO inhibitor selected from the group consisting of GDC-0919, indoximod, 1-methyl-D-tryptophan, NLG919, epacadostat, and norharmane; an EGFR inhibitor selected from the group consisting of brigatinib, gefitinib, icotinib, neratinib, afatinib, dacomitinib, cetuximab, erlotinib, flavopiridol, zalutumumab, necitumumab, lidocaine, matuzumab, osimertinib, panitumumab, PD168393, lapatinib, vandetanib, rindopepimut, canertinib, HuMAX-EGFR, and CimaVax-EGF; an HER2 inhibitor selected from the group consisting of ado-trastuzumab emtansine, trastuzumab, and pertuzumab; and an immune stimulating therapy selected from the group consisting of vidapenant, varlilumab, monalizumab, KAHR-102, BGB324, enoblituzumab, lirilumab, bavituximab, pidilizumab, BL-8040, GDC-0919, IGN-311, elotuzumab, blinatumomab, samalizumab, plerixafor, ganitumab, pexodartinib, trabedersen, and galunisertib. 6. The combination of claim 4, wherein the second compound is:
a PD-1 inhibitor selected from the group consisting of nivolumab, pidilizumab, pembrolizumab, AMP-224, AMP-514, STI-A1110, TSR-043, AMP-514, and AUNP-12; a PD-L1 inhibitor selected from the group consisting of RG 7446, BMS-936559, MSB0010718C, and STI-A1010, avelumab, atezolizumab, and durvalumab; a CTLA-4 inhibitor selected from the group consisting of ipilimumab or tremelimumab; an OX-40 agonist selected from the group consisting of anti-OX40, TIM3 antibody, and Immutune IMP701; a CD137 agonist selected from the group consisting of urelumab and utomilumab; the LAG-3 inhibitor BMS-986016; an IDO inhibitor selected from the group consisting of GDC-0919, indoximod, 1-methyl-D-tryptophan, NLG919, epacadostat, and norharmane; a bi-specific protein selected from the group consisting of ALT-801 and MEDI-565; an EGFR inhibitor selected from the group consisting of brigatinib, gefitinib, icotinib, neratinib, afatinib, dacomitinib, cetuximab, erlotinib, flavopiridol, zalutumumab, necitumumab, lidocaine, matuzumab, osimertinib, panitumumab, PD168393, lapatinib, vandetanib, rindopepimut, canertinib, HuMAX-EGFR, and CimaVax-EGF; an HER2 inhibitor selected from the group consisting of ado-trastuzumab emtansine, trastuzumab, and pertuzumab; and an immune stimulating therapy selected from the group consisting of vidapenant, varlilumab, monalizumab, KAHR-102, BGB324, enoblituzumab, lirilumab, bavituximab, pidilizumab, BL-8040, GDC-0919, IGN-311, elotuzumab, blinatumomab, samalizumab, plerixafor, ganitumab, pexodartinib, trabedersen, and galunisertib. 7. The combination of claim 6, wherein the second compound is selected from the group consisting of erlotinib, pembrolizumab, nivolumab, atezolizumab, ipilimumab, avelumab, durvalumab, trastuzumab, cetuximab, pertuzumab, and panitumumab. 8. The combination of claim 6, wherein the compound of Formula (II) is (S)-6-bromo-8-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid and the second compound is selected from the group consisting of erlotinib, pembrolizumab, nivolumab, atezolizumab, ipilimumab, avelumab, durvalumab, trastuzumab, cetuximab, pertuzumab, and panitumumab. 9. The combination of claim 8, wherein the second compound is erlotinib, cetuximab, trastuzumab, or pertuzumab. 10. The combination of claim 8, wherein the compound of Formula (II) is (S)-6-bromo-8-trideuteromethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid and the second compound is pembrolizumab, nivolumab, atezolizumab, ipilimumab, durvalumab, or avelumab. 11. The combination of claim 9 wherein the second compound is erlotinib. 12. The combination of claim 10 wherein the second compound is pembrolizumab, nivolumab, or atezolizumab. 13. The combination of claim 1, wherein each of R1, R2, R3, and R4 of Formula (II) is independently selected from the group consisting of H, alkyl, aralkyl, cycloalkyl, cycloalkenyl, halo, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, pentafluorosulfanyl, hydroxyalkyl, trialkylsilyl, alkynyl, and alkenyl. 14. The combination of claim 13 of claim 1, wherein R1 is H and R2 is selected from the group consisting of halo, haloalkoxy, and pentafluorosulfanyl, and R4 is selected from H, alkyl, alkenyl, alkynyl, and halo. 15. The combination of claim 14, wherein the compound of Formula (II) is selected from the group consisting of:
(S)-6,8-dichloro-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6-chloro-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6-bromo-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6,8-dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-8-methyl-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-8-ethyl-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6-chloro-5,7-dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-7-(tert-butyl)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6-pentafluorosulfanyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6-pentafluorosulfanyl-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, and (S)-6-pentafluorosulfanyl-8-ethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid. (S)-6-pentafluorosulfanyl-8-ethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid. 16. The combination of claim 13, wherein the second compound is:
a PD-1 inhibitor selected from the group consisting of nivolumab, pidilizumab, pembrolizumab, AMP-224, AMP-514, STI-A1110, TSR-043, AMP-514, and AUNP-12; a PD-L1 inhibitor selected from the group consisting of RG 7446, BMS-936559, MSB0010718C, STI-A1010, avelumab, atezolizumab, and durvalumab; a CTLA-4 inhibitor selected from the group consisting of ipilimumab or tremelimumab; an OX-40 agonist selected from the group consisting of anti-OX40, TIM3 antibody, and Immutune IMP701; a CD137 agonist selected from the group consisting of urelumab and utomilumab; the LAG-3 inhibitor BMS-986016; an IDO inhibitor selected from the group consisting of GDC-0919, indoximod, 1-methyl-D-tryptophan, NLG919, epacadostat, and norharmane; a bi-specific protein selected from the group consisting of ALT-801 and MEDI-565; an EGFR inhibitor selected from the group consisting of brigatinib, gefitinib, icotinib, neratinib, afatinib, dacomitinib, cetuximab, erlotinib, flavopiridol, zalutumumab, necitumumab, lidocaine, matuzumab, osimertinib, panitumumab, PD168393, lapatinib, vandetanib, rindopepimut, canertinib, HuMAX-EGFR, and CimaVax-EGF; an HER2 inhibitor selected from the group consisting of ado-trastuzumab emtansine, trastuzumab, and pertuzumab; and an immune stimulating therapy selected from the group consisting of vidapenant, varlilumab, monalizumab, KAHR-102, BGB324, enoblituzumab, lirilumab, bavituximab, pidilizumab, BL-8040, GDC-0919, IGN-311, elotuzumab, blinatumomab, samalizumab, plerixafor, ganitumab, pexodartinib, trabedersen, and galunisertib. 17. The combination of claim 15, wherein the second compound is:
a PD-1 inhibitor selected from the group consisting of nivolumab, pidilizumab, pembrolizumab, AMP-224, AMP-514, STI-A1110, TSR-043, AMP-514, and AUNP-12; a PD-L1 inhibitor selected from the group consisting of RG 7446, BMS-936559, MSB0010718C, STI-A1010, avelumab, atezolizumab, and durvalumab; a CTLA-4 inhibitor selected from the group consisting of ipilimumabor tremelimumab; an OX-40 agonist selected from the group consisting of anti-OX40, TIM3 antibody, and Immutune IMP701; a CD137 agonist selected from the group consisting of urelumab and utomilumab; the LAG-3 inhibitor BMS-986016; an IDO inhibitor selected from the group consisting of GDC-0919, indoximod, 1-methyl-D-tryptophan, NLG919, epacadostat, and norharmane; a bi-specific protein selected from the group consisting of ALT-801 and MEDI-565; an EGFR inhibitor selected from the group consisting of brigatinib, gefitinib, icotinib, neratinib, afatinib, dacomitinib, cetuximab, erlotinib, flavopiridol, zalutumumab, necitumumab, lidocaine, matuzumab, osimertinib, panitumumab, PD168393, lapatinib, vandetanib, rindopepimut, canertinib, HuMAX-EGFR, and CimaVax-EGF; an HER2 inhibitor selected from the group consisting of ado-trastuzumab emtansine, trastuzumab, and pertuzumab; and an immune stimulating therapy selected from the group consisting of vidapenant, varlilumab, monalizumab, KAHR-102, BGB324, enoblituzumab, lirilumab, bavituximab, pidilizumab, BL-8040, GDC-0919, IGN-311, elotuzumab, blinatumomab, samalizumab, plerixafor, ganitumab, pexodartinib, trabedersen, and galunisertib. 18. The combination of claim 17, wherein the second compound is selected from the group consisting of erlotinib, pembrolizumab, nivolumab, atezolizumab, ipilimumab, avelumab, durvalumab, trastuzumab, cetuximab, pertuzumab, and panitumumab. 19. The combination of claim 18, wherein the second compound is erlotinib, cetuximab, trastuzumab, or pertuzumab. 20. The combination of claim 18, wherein the second compound is pembrolizumab, nivolumab, atezolizumab, ipilimumab, durvalumab, avelumab. 21. A pharmaceutical composition comprising a therapeutically effective amount of the combination of claim 1 and at least one pharmaceutically acceptable excipient. 22-24. (canceled) 25. A method for treating cancer, comprising:
administering to a subject in need thereof a therapeutically effective amount of the combination of claim 1. 26-38. (canceled)
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1,259 | 14,600,564 | 1,649 |
A method of inhibiting, reducing, and/or treating pathological apoptosis and/or protein aggregation in a subject includes administering to the subject an amount of a therapeutic polypeptide effective to inhibit, reduce, and/or treat the pathological apoptosis and/or protein aggregation. The therapeutic polypeptide including at least one of acetylated αA-crystallin, acetylated αB-crystallin, acetylated fragments thereof having molecular chaperone activity, and/or polypeptide mimetics thereof that can inhibit pathological protein aggregation and/or pathological apoptosis.
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1. A method of inhibiting, reducing, and/or treating pathological apoptosis and/or protein aggregation in a subject, the method comprising:
administering to the subject an amount of a therapeutic polypeptide effective to inhibit, reduce, and/or treat the pathological apoptosis and/or protein aggregation, the therapeutic polypeptide including at least one of acetylated αA-crystallin, acetylated αB-crystallin, acetylated fragments thereof having molecular chaperone activity, and/or polypeptide mimetics thereof that can inhibit pathological protein aggregation and/or pathological apoptosis. 2. The method of claim 1, wherein the therapeutic polypeptide has an amino acid sequence with a sequence identity of SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11 or SEQ ID NO: 12. 3. The method of claim 1 wherein the therapeutic polypeptide has an amino acid sequence with a sequence identity selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4. 4. The method of claim 1 wherein the therapeutic polypeptide has an amino acid sequence with a sequence identity selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8. 5. The method of claim 1, wherein the therapeutic polypeptide has an amino acid sequence with a sequence identity selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 7, and SEQ ID NO: 8. 6. The method of claim 1, the pathological apoptosis and/or pathological protein aggregation being associated with or resulting from an optical neuropathy, glaucoma, or cataracts. 7. The method of claim 1, the pathological apoptosis and/or pathological protein aggregation being associated with or resulting from Alzheimer's disease. 8. The method of claim 1, the pathological apoptosis and/or pathological protein aggregation being associated with or resulting from a brain injury. 9. The method of claim 1, the pathological apoptosis and/or pathological protein aggregation being associated with or resulting from an inflammatory disease. 10. The method of claim 1, the therapeutic polypeptide being administered systemically to the subject. 11. The method of claim 1, the therapeutically polypeptide being administered locally. 12. A method of inhibiting apoptosis of retinal pigment epithelial cell in a subject, the method comprising:
administering to the cell an amount of a therapeutic polypeptide effective to inhibit pathological apoptosis of the cell, the therapeutic polypeptide including at least one of acetylated αA-crystallin, acetylated αB-crystallin, acetylated fragments thereof having molecular chaperone activity, and/or polypeptide mimetics thereof. 13. The method of claim 12, wherein the therapeutic polypeptide has an amino acid sequence with a sequence identity of SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11 or SEQ ID NO: 12. 14. The method of claim 12 wherein the therapeutic polypeptide has an amino acid sequence with a sequence identity selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4. 15. The method of claim 12 wherein the therapeutic polypeptide has an amino acid sequence with a sequence identity selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8. 16. The method of claim 12, wherein the therapeutic polypeptide has an amino acid sequence with a sequence identity selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 7, and SEQ ID NO: 8. 17. The method of claim 12, the pathological apoptosis and/or pathological protein aggregation being associated with or resulting from an optical neuropathy, glaucoma, or cataracts. 18. The method of claim 12, the therapeutic polypeptide being administered systemically to the subject. 19. The method of claim 12, the therapeutically polypeptide being administered locally. 20. A method of treating a cataract in a subject, the method comprising:
administering to the subject's eye an amount of a therapeutic polypeptide effective to inhibit protein aggregation and/or epithelial cell apoptosis in the lens of the subject's eye, the therapeutic polypeptide including at least one of acetylated αA-crystallin, acetylated αB-crystallin, acetylated fragments thereof having molecular chaperone activity, and/or polypeptide mimetics thereof. 21. The method of claim 20, wherein the therapeutic polypeptide has an amino acid sequence with a sequence identity of SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11 or SEQ ID NO: 12. 22. The method of claim 20 wherein the therapeutic polypeptide has an amino acid sequence with a sequence identity selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4. 23. The method of claim 20 wherein the therapeutic polypeptide has an amino acid sequence with a sequence identity selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8. 24. The method of claim 20, wherein the therapeutic polypeptide has an amino acid sequence with a sequence identity selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 7, and SEQ ID NO: 8.
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A method of inhibiting, reducing, and/or treating pathological apoptosis and/or protein aggregation in a subject includes administering to the subject an amount of a therapeutic polypeptide effective to inhibit, reduce, and/or treat the pathological apoptosis and/or protein aggregation. The therapeutic polypeptide including at least one of acetylated αA-crystallin, acetylated αB-crystallin, acetylated fragments thereof having molecular chaperone activity, and/or polypeptide mimetics thereof that can inhibit pathological protein aggregation and/or pathological apoptosis.1. A method of inhibiting, reducing, and/or treating pathological apoptosis and/or protein aggregation in a subject, the method comprising:
administering to the subject an amount of a therapeutic polypeptide effective to inhibit, reduce, and/or treat the pathological apoptosis and/or protein aggregation, the therapeutic polypeptide including at least one of acetylated αA-crystallin, acetylated αB-crystallin, acetylated fragments thereof having molecular chaperone activity, and/or polypeptide mimetics thereof that can inhibit pathological protein aggregation and/or pathological apoptosis. 2. The method of claim 1, wherein the therapeutic polypeptide has an amino acid sequence with a sequence identity of SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11 or SEQ ID NO: 12. 3. The method of claim 1 wherein the therapeutic polypeptide has an amino acid sequence with a sequence identity selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4. 4. The method of claim 1 wherein the therapeutic polypeptide has an amino acid sequence with a sequence identity selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8. 5. The method of claim 1, wherein the therapeutic polypeptide has an amino acid sequence with a sequence identity selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 7, and SEQ ID NO: 8. 6. The method of claim 1, the pathological apoptosis and/or pathological protein aggregation being associated with or resulting from an optical neuropathy, glaucoma, or cataracts. 7. The method of claim 1, the pathological apoptosis and/or pathological protein aggregation being associated with or resulting from Alzheimer's disease. 8. The method of claim 1, the pathological apoptosis and/or pathological protein aggregation being associated with or resulting from a brain injury. 9. The method of claim 1, the pathological apoptosis and/or pathological protein aggregation being associated with or resulting from an inflammatory disease. 10. The method of claim 1, the therapeutic polypeptide being administered systemically to the subject. 11. The method of claim 1, the therapeutically polypeptide being administered locally. 12. A method of inhibiting apoptosis of retinal pigment epithelial cell in a subject, the method comprising:
administering to the cell an amount of a therapeutic polypeptide effective to inhibit pathological apoptosis of the cell, the therapeutic polypeptide including at least one of acetylated αA-crystallin, acetylated αB-crystallin, acetylated fragments thereof having molecular chaperone activity, and/or polypeptide mimetics thereof. 13. The method of claim 12, wherein the therapeutic polypeptide has an amino acid sequence with a sequence identity of SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11 or SEQ ID NO: 12. 14. The method of claim 12 wherein the therapeutic polypeptide has an amino acid sequence with a sequence identity selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4. 15. The method of claim 12 wherein the therapeutic polypeptide has an amino acid sequence with a sequence identity selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8. 16. The method of claim 12, wherein the therapeutic polypeptide has an amino acid sequence with a sequence identity selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 7, and SEQ ID NO: 8. 17. The method of claim 12, the pathological apoptosis and/or pathological protein aggregation being associated with or resulting from an optical neuropathy, glaucoma, or cataracts. 18. The method of claim 12, the therapeutic polypeptide being administered systemically to the subject. 19. The method of claim 12, the therapeutically polypeptide being administered locally. 20. A method of treating a cataract in a subject, the method comprising:
administering to the subject's eye an amount of a therapeutic polypeptide effective to inhibit protein aggregation and/or epithelial cell apoptosis in the lens of the subject's eye, the therapeutic polypeptide including at least one of acetylated αA-crystallin, acetylated αB-crystallin, acetylated fragments thereof having molecular chaperone activity, and/or polypeptide mimetics thereof. 21. The method of claim 20, wherein the therapeutic polypeptide has an amino acid sequence with a sequence identity of SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11 or SEQ ID NO: 12. 22. The method of claim 20 wherein the therapeutic polypeptide has an amino acid sequence with a sequence identity selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4. 23. The method of claim 20 wherein the therapeutic polypeptide has an amino acid sequence with a sequence identity selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8. 24. The method of claim 20, wherein the therapeutic polypeptide has an amino acid sequence with a sequence identity selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 7, and SEQ ID NO: 8.
| 1,600 |
1,260 | 15,000,504 | 1,613 |
A combination comprising as components (a) the compound 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and (b) Paracetamol or a derivative thereof, a pharmaceutical formulation and a dosage form comprising said combination as well as a method of treating pain, e.g. chronic or acute pain, characterized in that components (a) and (b) are administered simultaneously or sequentially to a mammal, wherein component (a) may be administered before or after component (b) and wherein components (a) or (b) are administered to the mammal either via the same or a different pathway of administration.
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1. A composition comprising:
(a) at least one 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I),
or a solvate or an acid addition salt thereof, and
(b) Paracetamol or a derivative thereof. 2. The composition of claim 1, wherein said compound corresponding to formula (I) is present in the form of a pure enantiomer or pure diastereoisomer. 3. The composition of claim 1, wherein said compound corresponding to formula (I) is present in the form of a mixture of stereoisomers. 4. The composition of claim 1, wherein said compound corresponding to formula (I) is present in the form of a racemic mixture. 5. The composition of claim 1, wherein said compound corresponding to formula (I) is present in the form of a solvate. 6. The composition of claim 1, wherein said compound corresponding to formula (I) is present in the form of an acid addition salt. 7. The composition of claim 1, wherein said compound corresponding to formula (I) is selected from the group consisting of:
(1R,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and any mixture of (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1R,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and (1S,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol. 8. The composition of claim 1, wherein said compound corresponding to formula (I) is selected from the group consisting of:
(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and any mixture thereof. 9. The composition of claim 1, wherein said compound corresponding to formula (I) is a (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I′),
or an acid addition salt thereof. 10. The composition of claim 9, wherein said compound corresponding to formula (I) is in the form of an acid addition salt of hydrochloride. 11. The composition of claim 1, wherein the derivative of Paracetamol is selected from the group consisting of Prop acetamol and Phenidine. 12. The composition of claim 1, wherein components (a) and (b) are present in a weight ratio such that the composition will exert a synergistic effect upon administration to a patient. 13. A composition comprising a combination of one or more auxiliary agents and a composition according to claim 1. 14. The composition of claim 13, wherein said composition of claim 13 is in the form of a pharmaceutical dosage formulation comprising a pharmaceutically effective amount of a composition according to claim 1. 15. The composition of claim 14, wherein said pharmaceutical dosage formulation is suitable for oral, intravenous, intraperitoneal, intradermal, intrathekal, intramuscular, intranasal, transmucosal, subcutaneous, or rectal administration. 16. The composition of claim 14, wherein one or both of components (a) and (b) are present in controlled-release form. 17. The composition of claim 14, further comprising caffeine. 18. A method of manufacturing a composition, said method comprising the step of combining one or more auxiliary agents with
(a) at least one 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I),
or a solvate or an acid addition salt thereof, and
(b) Paracetamol or a derivative thereof. 19. A method of treating pain in a mammal, said method comprising the step of administering to said mammal a pharmaceutically effective amount of one or more auxiliary agents and a composition comprising:
(a) at least one 3-(3-Dimethylamino-l-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I),
or a solvate or an acid addition salt thereof, and
(b) Paracetamol or a derivative thereof. 20. The method of claim 19, wherein component (a) and (b) of the combination are administered simultaneously. 21. The method of claim 19, wherein component (a) and (b) of the combination are administered sequentially and compound (a) may be administered before or after compound (b). 22. The method of claim 19, wherein compounds (a) or (b) are administered to the mammal by the same administration pathway. 23. The method of claim 19, compounds (a) or (b) are administered to the mammal by a different administration pathway. 24. The method of claim 19, wherein the pain is selected from the group consisting of inflammatory pain, neuropathic pain, acute pain, chronic pain, visceral pain, migraine pain and cancer pain.
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A combination comprising as components (a) the compound 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and (b) Paracetamol or a derivative thereof, a pharmaceutical formulation and a dosage form comprising said combination as well as a method of treating pain, e.g. chronic or acute pain, characterized in that components (a) and (b) are administered simultaneously or sequentially to a mammal, wherein component (a) may be administered before or after component (b) and wherein components (a) or (b) are administered to the mammal either via the same or a different pathway of administration.1. A composition comprising:
(a) at least one 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I),
or a solvate or an acid addition salt thereof, and
(b) Paracetamol or a derivative thereof. 2. The composition of claim 1, wherein said compound corresponding to formula (I) is present in the form of a pure enantiomer or pure diastereoisomer. 3. The composition of claim 1, wherein said compound corresponding to formula (I) is present in the form of a mixture of stereoisomers. 4. The composition of claim 1, wherein said compound corresponding to formula (I) is present in the form of a racemic mixture. 5. The composition of claim 1, wherein said compound corresponding to formula (I) is present in the form of a solvate. 6. The composition of claim 1, wherein said compound corresponding to formula (I) is present in the form of an acid addition salt. 7. The composition of claim 1, wherein said compound corresponding to formula (I) is selected from the group consisting of:
(1R,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and any mixture of (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1R,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and (1S,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol. 8. The composition of claim 1, wherein said compound corresponding to formula (I) is selected from the group consisting of:
(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and any mixture thereof. 9. The composition of claim 1, wherein said compound corresponding to formula (I) is a (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I′),
or an acid addition salt thereof. 10. The composition of claim 9, wherein said compound corresponding to formula (I) is in the form of an acid addition salt of hydrochloride. 11. The composition of claim 1, wherein the derivative of Paracetamol is selected from the group consisting of Prop acetamol and Phenidine. 12. The composition of claim 1, wherein components (a) and (b) are present in a weight ratio such that the composition will exert a synergistic effect upon administration to a patient. 13. A composition comprising a combination of one or more auxiliary agents and a composition according to claim 1. 14. The composition of claim 13, wherein said composition of claim 13 is in the form of a pharmaceutical dosage formulation comprising a pharmaceutically effective amount of a composition according to claim 1. 15. The composition of claim 14, wherein said pharmaceutical dosage formulation is suitable for oral, intravenous, intraperitoneal, intradermal, intrathekal, intramuscular, intranasal, transmucosal, subcutaneous, or rectal administration. 16. The composition of claim 14, wherein one or both of components (a) and (b) are present in controlled-release form. 17. The composition of claim 14, further comprising caffeine. 18. A method of manufacturing a composition, said method comprising the step of combining one or more auxiliary agents with
(a) at least one 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I),
or a solvate or an acid addition salt thereof, and
(b) Paracetamol or a derivative thereof. 19. A method of treating pain in a mammal, said method comprising the step of administering to said mammal a pharmaceutically effective amount of one or more auxiliary agents and a composition comprising:
(a) at least one 3-(3-Dimethylamino-l-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I),
or a solvate or an acid addition salt thereof, and
(b) Paracetamol or a derivative thereof. 20. The method of claim 19, wherein component (a) and (b) of the combination are administered simultaneously. 21. The method of claim 19, wherein component (a) and (b) of the combination are administered sequentially and compound (a) may be administered before or after compound (b). 22. The method of claim 19, wherein compounds (a) or (b) are administered to the mammal by the same administration pathway. 23. The method of claim 19, compounds (a) or (b) are administered to the mammal by a different administration pathway. 24. The method of claim 19, wherein the pain is selected from the group consisting of inflammatory pain, neuropathic pain, acute pain, chronic pain, visceral pain, migraine pain and cancer pain.
| 1,600 |
1,261 | 14,387,331 | 1,623 |
The present invention relates to a process for producing a low endotoxin alkali chitosan, and also to a process for producing low endotoxin neutral chitosan, chitosan salt and chitosan derivatives, and to the products of such processes. The process comprises contacting chitosan with an alkali solution to form a mixture and leaving the mixture for at least about 12 hours. The low endotoxin alkali chitosan may be used in the manufacture of other useful chitosan based products.
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1. A process for producing a low endotoxin alkali chitosan, the process comprising the steps of:
(a) contacting chitosan with an alkali solution to form a mixture; and (b) leaving the mixture for at least about 12 hours. 2. A process as claimed in claim 1, wherein the process further comprises a step (c) of drying the mixture, wherein the drying step is optionally performed in an oven. 3. (canceled) 4. A process as claimed in claim 1, wherein the concentration of the alkali solution is from around 0.01M to around 1M and optionally from around 0.02M to 0.2M. 5. (canceled) 6. (canceled) 7. (canceled) 8. A process as claimed claim 1, wherein the alkali solution comprises an alkali or alkaline earth component selected from the following, either alone or in combination: metal hydroxides, metal carbonates, metal bisulphites, metal persilicates, conjugate bases and ammonium hydroxide wherein the metal is optionally selected from sodium, potassium, calcium, or magnesium and wherein the alkali component is optionally selected from sodium hydroxide, potassium hydroxide or sodium carbonate. 9. (canceled) 10. (canceled) 11. A process as claimed claim 1, wherein the alkali solution is sprayed onto the chitosan or the chitosan is mixed with the alkali solution. 12. A process as claimed in claim 1, wherein the mixture is left for at least 48 hours in step (b) and optionally for around two to four weeks; and/or wherein the mixture is left in a clean container and/or under an inert atmosphere. 13. (canceled) 14. (canceled) 15. A process as claimed in claim 1, wherein the mixture further comprises a preservative optionally selected from silver ions, zinc ions, chlorohexadine, or combinations thereof. 16. (canceled) 17. (canceled) 18. A low endotoxin alkali chitosan obtainable by the process of claim 1. 19. An alkali chitosan, a neutral chitosan, a chitosan salt or a chitosan derivative comprising an endotoxin concentration of less than 100 EU/g. 20. A process for producing a low endotoxin neutral chitosan, a chitosan salt or a chitosan derivative comprising the step of contacting an alkali chitosan prepared by the process of claim 1 with an acid. 21. A process as claimed in claim 20, wherein the step of contacting the alkali chitosan with an acid is performed before the drying step (c) of claim 2; and wherein the acid is optionally sprayed onto the alkali chitosan or the alkali chitosan is mixed with the acid. 22. (canceled) 23. A process as claimed claim 20, wherein the acid is selected from the following, either alone or in combination: organic acids optionally selected from the following, either alone or in combination: acetic acid, tartaric acid, citric acid, ascorbic acid, acetylsalicylic acid, gluconic acid and lactic acid; carboxylic acids; fatty acids optionally selected from the following, either alone or in combination: myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid linoelaidic acid, α-Linolenic acid, arachidonic acid, eicosapentaenoic acid, eurcic acid, docosahexeenoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid; amino acids optionally selected from the following, either alone or in combination; histidine, lysine, aspartic acid, glutamic acid, glutamine, glycine, proline, taurine; lewis acids; monoprotic acids; diprotic acids; polyprotic acids; nucleic acids; and mineral acids optionally selected from the following, either alone or in combination: hydrochloric acid, sulphuric acid and nitric acid. 24. (canceled) 25. (canceled) 26. (canceled) 27. (canceled) 28. A process as claimed in claim 20, wherein the acid has a concentration of about 1M. 29. A process as claimed in claim 20, wherein the acid is present as an acid liquor comprising the acid and a non-solvent optionally selected from ethyl lactate, ethyl acetate, meth acetate, ethanol, acetone, 80:20 mixture of ethanol:water or mixtures thereof. 30. (canceled) 31. A process as claimed in claim 29, wherein the ratio of chitosan to acid liquor is from about 5:1 to about 1:5; and/or wherein the alkali chitosan is mixed with the acid for around 5 minutes. 32. (canceled) 33. A process as claimed in claim 20, further comprising the step of drying the reaction product, wherein the drying step is optionally performed in an oven or by filtration of the product through an air dryer. 34. (canceled) 35. (canceled) 36. (canceled) 37. Use of a low endotoxin chitosan salt of claim 18 for stemming blood flow. 38. A low endotoxin chitosan salt of claim 18 for use as a haemostat for stemming blood flow or for use in a wound dressing for superficial non-life threatening bleeding or life threatening bleeding. 39. (canceled) 40. A haemostatic wound dressing comprising a low endotoxin chitosan salt of claim 18. 41. A method of stemming blood flow comprising the steps of: optionally cleaning a wound area where possible; applying to said wound area a haemostatic wound dressing comprising a low endotoxin chitosan salt of claim 18; and applying constant pressure to the wound area until a gel clot forms. 42. (canceled) 43. A low endotoxin neutral chitosan, a chitosan salt or a chitosan derivative obtainable by the process of claim 1.
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The present invention relates to a process for producing a low endotoxin alkali chitosan, and also to a process for producing low endotoxin neutral chitosan, chitosan salt and chitosan derivatives, and to the products of such processes. The process comprises contacting chitosan with an alkali solution to form a mixture and leaving the mixture for at least about 12 hours. The low endotoxin alkali chitosan may be used in the manufacture of other useful chitosan based products.1. A process for producing a low endotoxin alkali chitosan, the process comprising the steps of:
(a) contacting chitosan with an alkali solution to form a mixture; and (b) leaving the mixture for at least about 12 hours. 2. A process as claimed in claim 1, wherein the process further comprises a step (c) of drying the mixture, wherein the drying step is optionally performed in an oven. 3. (canceled) 4. A process as claimed in claim 1, wherein the concentration of the alkali solution is from around 0.01M to around 1M and optionally from around 0.02M to 0.2M. 5. (canceled) 6. (canceled) 7. (canceled) 8. A process as claimed claim 1, wherein the alkali solution comprises an alkali or alkaline earth component selected from the following, either alone or in combination: metal hydroxides, metal carbonates, metal bisulphites, metal persilicates, conjugate bases and ammonium hydroxide wherein the metal is optionally selected from sodium, potassium, calcium, or magnesium and wherein the alkali component is optionally selected from sodium hydroxide, potassium hydroxide or sodium carbonate. 9. (canceled) 10. (canceled) 11. A process as claimed claim 1, wherein the alkali solution is sprayed onto the chitosan or the chitosan is mixed with the alkali solution. 12. A process as claimed in claim 1, wherein the mixture is left for at least 48 hours in step (b) and optionally for around two to four weeks; and/or wherein the mixture is left in a clean container and/or under an inert atmosphere. 13. (canceled) 14. (canceled) 15. A process as claimed in claim 1, wherein the mixture further comprises a preservative optionally selected from silver ions, zinc ions, chlorohexadine, or combinations thereof. 16. (canceled) 17. (canceled) 18. A low endotoxin alkali chitosan obtainable by the process of claim 1. 19. An alkali chitosan, a neutral chitosan, a chitosan salt or a chitosan derivative comprising an endotoxin concentration of less than 100 EU/g. 20. A process for producing a low endotoxin neutral chitosan, a chitosan salt or a chitosan derivative comprising the step of contacting an alkali chitosan prepared by the process of claim 1 with an acid. 21. A process as claimed in claim 20, wherein the step of contacting the alkali chitosan with an acid is performed before the drying step (c) of claim 2; and wherein the acid is optionally sprayed onto the alkali chitosan or the alkali chitosan is mixed with the acid. 22. (canceled) 23. A process as claimed claim 20, wherein the acid is selected from the following, either alone or in combination: organic acids optionally selected from the following, either alone or in combination: acetic acid, tartaric acid, citric acid, ascorbic acid, acetylsalicylic acid, gluconic acid and lactic acid; carboxylic acids; fatty acids optionally selected from the following, either alone or in combination: myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid linoelaidic acid, α-Linolenic acid, arachidonic acid, eicosapentaenoic acid, eurcic acid, docosahexeenoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid; amino acids optionally selected from the following, either alone or in combination; histidine, lysine, aspartic acid, glutamic acid, glutamine, glycine, proline, taurine; lewis acids; monoprotic acids; diprotic acids; polyprotic acids; nucleic acids; and mineral acids optionally selected from the following, either alone or in combination: hydrochloric acid, sulphuric acid and nitric acid. 24. (canceled) 25. (canceled) 26. (canceled) 27. (canceled) 28. A process as claimed in claim 20, wherein the acid has a concentration of about 1M. 29. A process as claimed in claim 20, wherein the acid is present as an acid liquor comprising the acid and a non-solvent optionally selected from ethyl lactate, ethyl acetate, meth acetate, ethanol, acetone, 80:20 mixture of ethanol:water or mixtures thereof. 30. (canceled) 31. A process as claimed in claim 29, wherein the ratio of chitosan to acid liquor is from about 5:1 to about 1:5; and/or wherein the alkali chitosan is mixed with the acid for around 5 minutes. 32. (canceled) 33. A process as claimed in claim 20, further comprising the step of drying the reaction product, wherein the drying step is optionally performed in an oven or by filtration of the product through an air dryer. 34. (canceled) 35. (canceled) 36. (canceled) 37. Use of a low endotoxin chitosan salt of claim 18 for stemming blood flow. 38. A low endotoxin chitosan salt of claim 18 for use as a haemostat for stemming blood flow or for use in a wound dressing for superficial non-life threatening bleeding or life threatening bleeding. 39. (canceled) 40. A haemostatic wound dressing comprising a low endotoxin chitosan salt of claim 18. 41. A method of stemming blood flow comprising the steps of: optionally cleaning a wound area where possible; applying to said wound area a haemostatic wound dressing comprising a low endotoxin chitosan salt of claim 18; and applying constant pressure to the wound area until a gel clot forms. 42. (canceled) 43. A low endotoxin neutral chitosan, a chitosan salt or a chitosan derivative obtainable by the process of claim 1.
| 1,600 |
1,262 | 13,814,963 | 1,613 |
The present disclosure relates to silicone based cosmetic compositions comprising at least at least one silicone amine, at least one anionic silicone and a cosmetically acceptable carrier such as water and other components. The compositions are useful for treating keratinous substrates such as hair, for example, for styling, conditioning and/or improving the manageability of hair. The present disclosure also relates to silicone based hair coloring compositions comprising at least one silicone amine, at least one anionic silicone, at least one colorant, a cosmetically acceptable carrier; and optionally, at least one oxidizing agent. The compositions are useful for coloring hair.
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1. A cosmetic composition comprising:
(a) at least one silicone amine; (b) at least one anionic silicone; and (c) a cosmetically acceptable carrier. 2. The cosmetic composition of claim 1, wherein the at least one silicone amine (a) is chosen from amodimethicone, trimethylsilylamodimethicone, aminopropyl phenyltrimethicone, PEG-7 amodimethicone, aminopropyl triethyoxysilane, alkyl modified amino silicone, amino silanes, PEG-8 amodimethicone, bis-isobutyl PEG-14/amodimethicone copolymer, bis-isobutyl PEG-15/amodimethicone copolymer, bis-isobutyl PEG/PPG-20/35/amodimethicone copolymer and mixtures thereof. 3. The cosmetic composition of claim 1, wherein the at least one silicone amine (a) includes amodimethicone. 4. The cosmetic composition of claim 1, wherein the at least one silicone amine (a) is present in an amount of from greater than 0 to about 90% by weight, based on the total weight of the cosmetic composition. 5. The cosmetic composition of claim 1, wherein the at least one silicone amine (a) is present in an amount of from about 1% to about 15% by weight, based on the total weight of the cosmetic composition. 6. The cosmetic composition of claim 1, wherein the at least one anionic silicone (b) is chosen from silicone carboxylates, silicone phosphates, silicone sulfates, silicone sulfosuccinates, silicone sulfonates, and mixtures thereof. 7. The cosmetic composition of claim 1, wherein the at least one anionic silicone (b) includes a silicone carboxylate. 8. The cosmetic composition of claim 1, wherein the silicone carboxylate is chosen from dimethicone PEG-7 phthalate and dimethicone PEG-7 succinate. 9. The cosmetic composition of claim 1, wherein the at least one anionic silicone (b) includes a silicone phosphate. 10. The cosmetic composition of claim 1, wherein the silicone phosphate is chosen from dimethicone PEG-7 phosphate, dimethicone PEG-8 phosphate, dimethicone PEG-10 phosphate, potassium dimethicone PEG-7 panthenyl phosphate, dimethicone PEG/PPG-7/4 phosphate, dimethicone PEG/PPG-12/4 phosphate, Trideceth-9 PG-Amodimethicone and mixtures thereof. 11. The cosmetic composition of claim 1, wherein the silicone phosphate includes dimethicone PEG-8 phosphate. 12. The cosmetic composition of claim 1, wherein the at least one anionic silicone (b) is present in an amount of from greater than 0 to about 90% by weight, based on the total weight of the cosmetic composition. 13. The cosmetic composition of claim 1, wherein the at least one anionic silicone (b) is present in an amount of from about 1% to about 15% by weight, based on the total weight of the composition. 14. The cosmetic composition of claim 1, wherein the cosmetically acceptable carrier (c) is chosen from water, alcohol, organic solvents, hydrocarbons, esters, silicones, and mixtures thereof. 15. The cosmetic composition of claim 1, wherein the cosmetically acceptable carrier (c) is present in an amount of from about 1% to about 90% by weight, based on the total weight of the cosmetic composition. 16. The cosmetic composition of claim 1, wherein the cosmetic composition further comprises at least one auxiliary ingredient (d) selected from the group consisting of film forming agents, surfactants, conditioning agents, skin active agents and mixtures thereof. 17. The cosmetic composition of claim 16 comprising at least one film forming agent, wherein the at least one film forming agent is selected from the group consisting of polysilicone 8, polydimethylsiloxane, dimethylsiloxane/3-thiopropyl methyl siloxane copolymer, vinylpyyrolidone/vinylacetate copolymer, polyvinyacetate, starch, polyquaternium-4, polyquaternium-11, acrylates/steareth-2 methacrylate crosspolymer, vinylacetate/vinyl neodecanoate copolymer, polyester-5, cetyl ethylhexanoate, vinyl acetate, crotonate/vinyl neodecanoate copolymer, 2-acryamido-2-methyl propane sulfonic acid (AMPS)/acrylic acid (AA) copolymer, AMPS/AA/acryl methacrylate copolymer, polyacrylamide, C13-C14 isoparaffin, laureth-7, octylacrylamide, acrylate/butylaminoethylmethacrylate copolymer and mixtures thereof. 18. The cosmetic composition of claim 16 comprising at least one surfactant, wherein the at least one surfactant is selected from the group consisting of anionic surfactants, cationic surfactants, nonionic surfactants, amphoteric surfactants, zwitterionic surfactants and mixtures thereof. 19. The cosmetic composition of claim 16 comprising at least one auxiliary ingredient, wherein the at least one auxiliary ingredient is a conditioning agent is selected from the group consisting of polyalkyl siloxane, a polyaryl siloxane, a polyalkylaryl siloxane, a polyether siloxane copolymer, amino acids, proteins, extracts, fats, oils, esters, hydrocarbons, quats, polyquats, polyols, humectants, alkanolamides, fatty acids, ketones and mixtures thereof. 20. The cosmetic composition of claim 16 comprising at least one skin active agent, wherein the at least one skin active agent is selected from the group consisting of photoprotective agents, self-tanning agents, desquamating agents, depigmenting agents, moisturizing agents, skin lightening agents, anti-aging ingredients, anti-wrinkle agents, anti-dandruff agents and mixtures thereof. 21. The cosmetic composition of claim 16, wherein the at least one auxiliary ingredient (d) is present in an amount of from about 0.05 to about 75% by weight, based on the total weight of the cosmetic composition. 22. A cosmetic composition comprising:
(a) at least one silicone amine chosen from amodimethicone, trimethylsilylamodimethicone, aminopropyl phenyltrimethicone, PEG-7 amodimethicone, aminopropyl triethyoxysilane, alkyl modified amino silicone, amino silanes, and mixtures thereof; (b) at least one anionic silicone chosen from silicone carboxylates, silicone phosphates, silicone sulfates, silicone sulfosuccinates, silicone sulfonates, and mixtures thereof; and (c) a cosmetically acceptable carrier. 23. The cosmetic composition of claim 22, further comprising at least one auxiliary ingredient (d) is chosen from film forming agents, surfactants, conditioning agents, skin active agents and mixtures thereof. 24. The cosmetic composition of claim 22, wherein
(a) the at least one silicone amine is amodimethicone; (b) the at least one anionic silicone is chosen from silicone carboxylates, silicone phosphates, and mixtures thereof; and (c) the cosmetically acceptable carrier comprises water. 25. The cosmetic composition of claim 22, wherein the at least one anionic silicone is dimethicone PEG-8 phosphate. 26. A method for beneficially coating a keratinous substrate comprising applying a composition according to claim 1 to the keratinous substrate. 27. A method for preserving artificial color on a keratinous substrate comprising applying a composition according to claim 1 to an artificially-colored keratinous substrate. 28. A hair coloring composition comprising:
(a) at least one silicone amine; (b) at least one anionic silicone; (c) at least one colorant; (d) a cosmetically acceptable carrier; and (e) optionally, at least one oxidizing agent. 29-59. (canceled) 60. A method for artificially coloring a keratinous substrate comprising applying a composition according to claim 28 to hair. 61. A method for simultaneously washing and depositing color onto hair comprising:
(a) applying a composition according to claim 29 to hair; and (b) rinsing the composition from the hair.
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The present disclosure relates to silicone based cosmetic compositions comprising at least at least one silicone amine, at least one anionic silicone and a cosmetically acceptable carrier such as water and other components. The compositions are useful for treating keratinous substrates such as hair, for example, for styling, conditioning and/or improving the manageability of hair. The present disclosure also relates to silicone based hair coloring compositions comprising at least one silicone amine, at least one anionic silicone, at least one colorant, a cosmetically acceptable carrier; and optionally, at least one oxidizing agent. The compositions are useful for coloring hair.1. A cosmetic composition comprising:
(a) at least one silicone amine; (b) at least one anionic silicone; and (c) a cosmetically acceptable carrier. 2. The cosmetic composition of claim 1, wherein the at least one silicone amine (a) is chosen from amodimethicone, trimethylsilylamodimethicone, aminopropyl phenyltrimethicone, PEG-7 amodimethicone, aminopropyl triethyoxysilane, alkyl modified amino silicone, amino silanes, PEG-8 amodimethicone, bis-isobutyl PEG-14/amodimethicone copolymer, bis-isobutyl PEG-15/amodimethicone copolymer, bis-isobutyl PEG/PPG-20/35/amodimethicone copolymer and mixtures thereof. 3. The cosmetic composition of claim 1, wherein the at least one silicone amine (a) includes amodimethicone. 4. The cosmetic composition of claim 1, wherein the at least one silicone amine (a) is present in an amount of from greater than 0 to about 90% by weight, based on the total weight of the cosmetic composition. 5. The cosmetic composition of claim 1, wherein the at least one silicone amine (a) is present in an amount of from about 1% to about 15% by weight, based on the total weight of the cosmetic composition. 6. The cosmetic composition of claim 1, wherein the at least one anionic silicone (b) is chosen from silicone carboxylates, silicone phosphates, silicone sulfates, silicone sulfosuccinates, silicone sulfonates, and mixtures thereof. 7. The cosmetic composition of claim 1, wherein the at least one anionic silicone (b) includes a silicone carboxylate. 8. The cosmetic composition of claim 1, wherein the silicone carboxylate is chosen from dimethicone PEG-7 phthalate and dimethicone PEG-7 succinate. 9. The cosmetic composition of claim 1, wherein the at least one anionic silicone (b) includes a silicone phosphate. 10. The cosmetic composition of claim 1, wherein the silicone phosphate is chosen from dimethicone PEG-7 phosphate, dimethicone PEG-8 phosphate, dimethicone PEG-10 phosphate, potassium dimethicone PEG-7 panthenyl phosphate, dimethicone PEG/PPG-7/4 phosphate, dimethicone PEG/PPG-12/4 phosphate, Trideceth-9 PG-Amodimethicone and mixtures thereof. 11. The cosmetic composition of claim 1, wherein the silicone phosphate includes dimethicone PEG-8 phosphate. 12. The cosmetic composition of claim 1, wherein the at least one anionic silicone (b) is present in an amount of from greater than 0 to about 90% by weight, based on the total weight of the cosmetic composition. 13. The cosmetic composition of claim 1, wherein the at least one anionic silicone (b) is present in an amount of from about 1% to about 15% by weight, based on the total weight of the composition. 14. The cosmetic composition of claim 1, wherein the cosmetically acceptable carrier (c) is chosen from water, alcohol, organic solvents, hydrocarbons, esters, silicones, and mixtures thereof. 15. The cosmetic composition of claim 1, wherein the cosmetically acceptable carrier (c) is present in an amount of from about 1% to about 90% by weight, based on the total weight of the cosmetic composition. 16. The cosmetic composition of claim 1, wherein the cosmetic composition further comprises at least one auxiliary ingredient (d) selected from the group consisting of film forming agents, surfactants, conditioning agents, skin active agents and mixtures thereof. 17. The cosmetic composition of claim 16 comprising at least one film forming agent, wherein the at least one film forming agent is selected from the group consisting of polysilicone 8, polydimethylsiloxane, dimethylsiloxane/3-thiopropyl methyl siloxane copolymer, vinylpyyrolidone/vinylacetate copolymer, polyvinyacetate, starch, polyquaternium-4, polyquaternium-11, acrylates/steareth-2 methacrylate crosspolymer, vinylacetate/vinyl neodecanoate copolymer, polyester-5, cetyl ethylhexanoate, vinyl acetate, crotonate/vinyl neodecanoate copolymer, 2-acryamido-2-methyl propane sulfonic acid (AMPS)/acrylic acid (AA) copolymer, AMPS/AA/acryl methacrylate copolymer, polyacrylamide, C13-C14 isoparaffin, laureth-7, octylacrylamide, acrylate/butylaminoethylmethacrylate copolymer and mixtures thereof. 18. The cosmetic composition of claim 16 comprising at least one surfactant, wherein the at least one surfactant is selected from the group consisting of anionic surfactants, cationic surfactants, nonionic surfactants, amphoteric surfactants, zwitterionic surfactants and mixtures thereof. 19. The cosmetic composition of claim 16 comprising at least one auxiliary ingredient, wherein the at least one auxiliary ingredient is a conditioning agent is selected from the group consisting of polyalkyl siloxane, a polyaryl siloxane, a polyalkylaryl siloxane, a polyether siloxane copolymer, amino acids, proteins, extracts, fats, oils, esters, hydrocarbons, quats, polyquats, polyols, humectants, alkanolamides, fatty acids, ketones and mixtures thereof. 20. The cosmetic composition of claim 16 comprising at least one skin active agent, wherein the at least one skin active agent is selected from the group consisting of photoprotective agents, self-tanning agents, desquamating agents, depigmenting agents, moisturizing agents, skin lightening agents, anti-aging ingredients, anti-wrinkle agents, anti-dandruff agents and mixtures thereof. 21. The cosmetic composition of claim 16, wherein the at least one auxiliary ingredient (d) is present in an amount of from about 0.05 to about 75% by weight, based on the total weight of the cosmetic composition. 22. A cosmetic composition comprising:
(a) at least one silicone amine chosen from amodimethicone, trimethylsilylamodimethicone, aminopropyl phenyltrimethicone, PEG-7 amodimethicone, aminopropyl triethyoxysilane, alkyl modified amino silicone, amino silanes, and mixtures thereof; (b) at least one anionic silicone chosen from silicone carboxylates, silicone phosphates, silicone sulfates, silicone sulfosuccinates, silicone sulfonates, and mixtures thereof; and (c) a cosmetically acceptable carrier. 23. The cosmetic composition of claim 22, further comprising at least one auxiliary ingredient (d) is chosen from film forming agents, surfactants, conditioning agents, skin active agents and mixtures thereof. 24. The cosmetic composition of claim 22, wherein
(a) the at least one silicone amine is amodimethicone; (b) the at least one anionic silicone is chosen from silicone carboxylates, silicone phosphates, and mixtures thereof; and (c) the cosmetically acceptable carrier comprises water. 25. The cosmetic composition of claim 22, wherein the at least one anionic silicone is dimethicone PEG-8 phosphate. 26. A method for beneficially coating a keratinous substrate comprising applying a composition according to claim 1 to the keratinous substrate. 27. A method for preserving artificial color on a keratinous substrate comprising applying a composition according to claim 1 to an artificially-colored keratinous substrate. 28. A hair coloring composition comprising:
(a) at least one silicone amine; (b) at least one anionic silicone; (c) at least one colorant; (d) a cosmetically acceptable carrier; and (e) optionally, at least one oxidizing agent. 29-59. (canceled) 60. A method for artificially coloring a keratinous substrate comprising applying a composition according to claim 28 to hair. 61. A method for simultaneously washing and depositing color onto hair comprising:
(a) applying a composition according to claim 29 to hair; and (b) rinsing the composition from the hair.
| 1,600 |
1,263 | 15,277,877 | 1,618 |
Injectable hydrogels in the form of crosslinked nano beads or particle in the size range 5 nm to 10 μm, comprising PAMAM dendrimer with asymmetrical peripheral end groups such that one of the terminal groups is involved in formation of hydrogel and the other in involved in the conjugation of drugs or imaging agents are formed by reaction of the PAMAM dendrimer with asymmetrical end groups with linear, branched, hyperbranched or star shaped polymers with functionalized terminal groups. The PAMAM dendrimer with asymmetrical terminal groups consists of a Generation 2 and above PAMAM dendrimer with symmetrical end groups modified using the amino acids or their modified forms. The gel is formed as small crosslinked particles in the size range 25 nm to 10 μm and is suitable for injectable delivery of hydrogel or ocular delivery for the purpose of therapeutic treatment and imaging.
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1-35. (canceled) 36. A composition comprising a poly(amidoamine) (PAMAM) dendrimer covalently conjugated via a terminal functional group to an amino acid linker,
wherein the amino acid linker after conjugation to the dendrimer comprises at least two different chemical reactive groups. 37. The composition of claim 36, wherein each of the chemical reactive groups is conjugated to a functional moiety, optionally via one or more spacers, and wherein the functional moiety is selected from the group consisting of a polymer, a drug, an imaging agent, and a targeting moiety. 38. The composition of claim 36, wherein the terminal functional group of the dendrimer is selected from the group consisting of amine, carboxylic acid, and hydroxyl. 39. The composition of claim 36, wherein the amino acid linker comprises an amino acid selected from the group consisting of serine, aspartic acid, cysteine, glutamic acid, threonine, tyrosine, and derivatives thereof. 40. The composition of claim 39, wherein the amino acid linker is in a protected form selected from the group consisting of tert-butylcarbonyl-serine-hydroxysuccinimide (Boc-Ser-NHS), tert-butylcarbonyl-aspartic acid (Boc-Asp-OH), tertbutylcarbonyl-glutamic acid (Boc-Glu-OH), fluorenylmethoxycarbonyl-serine (Fmoc-Ser), fluorenylmethoxycarbonyl-aspartic acid (Fmoc-Asp-OH), fluorenylmethoxycarbonyl-glutamic acid (Fmoc-Glu-OH), tert-butylcarbonylcysteine-hydroxysuccinimide (Boc-Cys-NHS), serine-methylester (H-ser-OMe), cysteine-methylester (H-Cys-OMe), aspartic acid-methylester (H-Asp-OMe), glutamic acid-methyl ester (H-Glu-OMe), tert-butylcarbonyl-threoninehydroxysuccinimide (Boc-Thr-NHS), threonine-methylester (H-Thr-OMe), fluorenylmethoxycarbonyl-threonine (Fmoc-Thr), tert-butylcarbonyl-tyrosinehydroxysuccinimide (Boc-Tyr-NHS), tert-butylcarbonyl-tyrosine (Boc-Tyr-OH), tyrosine-methylester (H-Tyr-OMe), cysteine-dithiopyridine (Cys-S-STP), and tertbutylcarbonyl-cysteine-dithiopyridine (Boc-Cys-S-STP) when it is covalently bound to the PAMAM dendrimer prior to attachment of the two different agents. 41. The composition of claim 37, wherein the polymer is selected from the group consisting of a linear polymer, a branched polymer, and a star shaped polymer. 42. The composition of claim 41, wherein the polymer is a functionalized polyethylene glycol (PEG) polymer. 43. The composition of claim 42, wherein the functionalized polyethylene glycol (PEG) polymer is between 5 kDa and 80 kDa in size, inclusive, preferably between 20 kDa and 40 kDa in size, inclusive. 44. The composition of claim 42, wherein the functionalized polyethylene glycol (PEG) polymer is selected from the group consisting of 8-arm-polyethylene glycol with thiol terminations, methoxy-polyethylene glycol with thiol termination, and pyridyldithio-propionate polyethylene glycol-pyridyldithio-propionate. 45. The composition of claim 36, wherein the PAMAM dendrimer is a Generation 2 or greater PAMAM dendrimer, preferably a G4 PAMAM dendrimer. 46. The composition of claim 37, wherein the one or more spacers are selected from the group consisting of maleimide-poly(ethyleneglycol)-maleimide, Succinimidyl-carboxyl-methyl ester-poly(ethyleneglycol)-succinimidyl-carboxyl-methyl ester, acrylate-poly(ethyleneglycol)-acrylate, ortho-pyridyldisulfide-poly(ethyleneglycol)-ortho-pyridyldisulfide, thiol-poly(ethyleneglycol)-thiol, nitrophenyl carbonate-poly(ethyleneglycol)-nitrophenyl carbonate, isocyanate-poly(ethyleneglycol)-isocyanate, and 1,6-hexane-bis-vinylsulfone. 47. The composition of claim 37, comprising drug selected from the group consisting of macrolide antibiotics, tetracyclines, fluoroquinolones, cephalosporins, non-steroidal anti-inflammatory, analgesic drugs, corticosteroids antibodies, vitamins, growth factors, neurostimulants, neuroprotectants and a pharmaceutically acceptable salts thereof. 48. The composition of claim 47, wherein the drug is selected from the group consisting of erythromycin, azithromycin, rapamycin, clarithromycin, minocycline, doxycycline, ciprofloxacin, enrofloxacin, ofloxacin, gatifloxacin, levofloxacin, norfloxacin, cefuroxime, cefaclor, cephalexin, cephadroxil, cepfodoxime proxetil, N-acetyl cysteine, ibuprofen, aspirin, resolvins, acetaminophen, diclofenac sodium, fluocinolone acetonide, methylprednisolone, and ranibizumab. 49. The composition of claim 37, comprising imaging agent selected from the group consisting of fluorescent dyes, radiolabeled dyes, and magnetic resonance imaging agents. 50. The composition of claim 36 further comprises a pharmaceutically acceptable excipient suitable for intravenous, topical, intravitreal, intramuscular, or subcutaneous administration. 51. A hydrogel nanoparticle comprising the composition of claim 36. 52. A method of reducing, or preventing inflammation comprises administering an effective amount of composition according to claim 36. 53. The method of claim 52, wherein the method of reducing, or preventing neuroinflammation and/or inflammation comprises administering an effective amount of composition according to claim 36 via intraocular injection into the eye. 54. The method of claim 52, wherein the inflammation is neuroinflammation, or inflammation of the eye. 55. A method of reducing, or preventing microbial growth in a subject in need thereof comprises administering an effective amount of composition according to claim 36. 56. The method of claim 55, wherein the method of reducing, or preventing microbial growth comprises administering via a route selected from the group consisting of vaginal, cervical, and rectal routes.
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Injectable hydrogels in the form of crosslinked nano beads or particle in the size range 5 nm to 10 μm, comprising PAMAM dendrimer with asymmetrical peripheral end groups such that one of the terminal groups is involved in formation of hydrogel and the other in involved in the conjugation of drugs or imaging agents are formed by reaction of the PAMAM dendrimer with asymmetrical end groups with linear, branched, hyperbranched or star shaped polymers with functionalized terminal groups. The PAMAM dendrimer with asymmetrical terminal groups consists of a Generation 2 and above PAMAM dendrimer with symmetrical end groups modified using the amino acids or their modified forms. The gel is formed as small crosslinked particles in the size range 25 nm to 10 μm and is suitable for injectable delivery of hydrogel or ocular delivery for the purpose of therapeutic treatment and imaging.1-35. (canceled) 36. A composition comprising a poly(amidoamine) (PAMAM) dendrimer covalently conjugated via a terminal functional group to an amino acid linker,
wherein the amino acid linker after conjugation to the dendrimer comprises at least two different chemical reactive groups. 37. The composition of claim 36, wherein each of the chemical reactive groups is conjugated to a functional moiety, optionally via one or more spacers, and wherein the functional moiety is selected from the group consisting of a polymer, a drug, an imaging agent, and a targeting moiety. 38. The composition of claim 36, wherein the terminal functional group of the dendrimer is selected from the group consisting of amine, carboxylic acid, and hydroxyl. 39. The composition of claim 36, wherein the amino acid linker comprises an amino acid selected from the group consisting of serine, aspartic acid, cysteine, glutamic acid, threonine, tyrosine, and derivatives thereof. 40. The composition of claim 39, wherein the amino acid linker is in a protected form selected from the group consisting of tert-butylcarbonyl-serine-hydroxysuccinimide (Boc-Ser-NHS), tert-butylcarbonyl-aspartic acid (Boc-Asp-OH), tertbutylcarbonyl-glutamic acid (Boc-Glu-OH), fluorenylmethoxycarbonyl-serine (Fmoc-Ser), fluorenylmethoxycarbonyl-aspartic acid (Fmoc-Asp-OH), fluorenylmethoxycarbonyl-glutamic acid (Fmoc-Glu-OH), tert-butylcarbonylcysteine-hydroxysuccinimide (Boc-Cys-NHS), serine-methylester (H-ser-OMe), cysteine-methylester (H-Cys-OMe), aspartic acid-methylester (H-Asp-OMe), glutamic acid-methyl ester (H-Glu-OMe), tert-butylcarbonyl-threoninehydroxysuccinimide (Boc-Thr-NHS), threonine-methylester (H-Thr-OMe), fluorenylmethoxycarbonyl-threonine (Fmoc-Thr), tert-butylcarbonyl-tyrosinehydroxysuccinimide (Boc-Tyr-NHS), tert-butylcarbonyl-tyrosine (Boc-Tyr-OH), tyrosine-methylester (H-Tyr-OMe), cysteine-dithiopyridine (Cys-S-STP), and tertbutylcarbonyl-cysteine-dithiopyridine (Boc-Cys-S-STP) when it is covalently bound to the PAMAM dendrimer prior to attachment of the two different agents. 41. The composition of claim 37, wherein the polymer is selected from the group consisting of a linear polymer, a branched polymer, and a star shaped polymer. 42. The composition of claim 41, wherein the polymer is a functionalized polyethylene glycol (PEG) polymer. 43. The composition of claim 42, wherein the functionalized polyethylene glycol (PEG) polymer is between 5 kDa and 80 kDa in size, inclusive, preferably between 20 kDa and 40 kDa in size, inclusive. 44. The composition of claim 42, wherein the functionalized polyethylene glycol (PEG) polymer is selected from the group consisting of 8-arm-polyethylene glycol with thiol terminations, methoxy-polyethylene glycol with thiol termination, and pyridyldithio-propionate polyethylene glycol-pyridyldithio-propionate. 45. The composition of claim 36, wherein the PAMAM dendrimer is a Generation 2 or greater PAMAM dendrimer, preferably a G4 PAMAM dendrimer. 46. The composition of claim 37, wherein the one or more spacers are selected from the group consisting of maleimide-poly(ethyleneglycol)-maleimide, Succinimidyl-carboxyl-methyl ester-poly(ethyleneglycol)-succinimidyl-carboxyl-methyl ester, acrylate-poly(ethyleneglycol)-acrylate, ortho-pyridyldisulfide-poly(ethyleneglycol)-ortho-pyridyldisulfide, thiol-poly(ethyleneglycol)-thiol, nitrophenyl carbonate-poly(ethyleneglycol)-nitrophenyl carbonate, isocyanate-poly(ethyleneglycol)-isocyanate, and 1,6-hexane-bis-vinylsulfone. 47. The composition of claim 37, comprising drug selected from the group consisting of macrolide antibiotics, tetracyclines, fluoroquinolones, cephalosporins, non-steroidal anti-inflammatory, analgesic drugs, corticosteroids antibodies, vitamins, growth factors, neurostimulants, neuroprotectants and a pharmaceutically acceptable salts thereof. 48. The composition of claim 47, wherein the drug is selected from the group consisting of erythromycin, azithromycin, rapamycin, clarithromycin, minocycline, doxycycline, ciprofloxacin, enrofloxacin, ofloxacin, gatifloxacin, levofloxacin, norfloxacin, cefuroxime, cefaclor, cephalexin, cephadroxil, cepfodoxime proxetil, N-acetyl cysteine, ibuprofen, aspirin, resolvins, acetaminophen, diclofenac sodium, fluocinolone acetonide, methylprednisolone, and ranibizumab. 49. The composition of claim 37, comprising imaging agent selected from the group consisting of fluorescent dyes, radiolabeled dyes, and magnetic resonance imaging agents. 50. The composition of claim 36 further comprises a pharmaceutically acceptable excipient suitable for intravenous, topical, intravitreal, intramuscular, or subcutaneous administration. 51. A hydrogel nanoparticle comprising the composition of claim 36. 52. A method of reducing, or preventing inflammation comprises administering an effective amount of composition according to claim 36. 53. The method of claim 52, wherein the method of reducing, or preventing neuroinflammation and/or inflammation comprises administering an effective amount of composition according to claim 36 via intraocular injection into the eye. 54. The method of claim 52, wherein the inflammation is neuroinflammation, or inflammation of the eye. 55. A method of reducing, or preventing microbial growth in a subject in need thereof comprises administering an effective amount of composition according to claim 36. 56. The method of claim 55, wherein the method of reducing, or preventing microbial growth comprises administering via a route selected from the group consisting of vaginal, cervical, and rectal routes.
| 1,600 |
1,264 | 14,973,765 | 1,615 |
The present invention relates to an anhydrous cosmetic composition for topical application to skin in the intimate area. The compositions can be used following shaving or trimming hair in the intimate area. The compositions can also be used in the intimate skin area for consumers that wear absorbent articles against the intimate skin area for long periods of time.
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1. An anhydrous cosmetic composition for topical application comprising:
one or more complexed or encapsulated compounds having a thiol vapor pressure suppression index (TVPS) of more than 20 when measured according to the test methodology described herein, wherein the anhydrous cosmetic composition is in the form of a solid stick comprising a product hardness of at least 600 gram-force; and wherein the anhydrous cosmetic composition is devoid of an antiperspirant active. 2. The anhydrous cosmetic composition according to claim 1, wherein said one or more compounds are starch encapsulated. 3. The anhydrous cosmetic composition according to claim 1, wherein said one or more compounds are encapsulated in reservoir type capsules and can be released by a mechanical action breaking the shell of the capsule. 4. The anhydrous cosmetic composition according to claim 1, wherein the one or more compounds are comprised as cyclodextrin complexes. 5. The anhydrous cosmetic composition according to claim 1 wherein said one or more compounds are comprised in at least two or three forms selected from (i) encapsulated in reservoir type capsules which can be released by a mechanical action breaking the shell of the capsule, (ii) cyclodextrin complexes, or (iii) starch capsules. 6. The anhydrous cosmetic composition according to claim 1, further comprising a cosmetic active, wherein the cosmetic active is zinc oxide. 7. The anhydrous cosmetic composition according to claim 1, further comprising a cosmetic active, wherein the cosmetic active is panthenyl triacetate. 8. An anhydrous cosmetic composition comprising:
a. a volatile solvent comprising a siloxane; b. a thickening agent; and c. a cosmetic active selected from the group consisting of zinc oxide and an oil-soluble Vitamin B5 derivative; d. wherein the anhydrous cosmetic composition is in the form of a solid stick comprising a product hardness of at least 600 gram-force; and e. wherein the anhydrous cosmetic composition is devoid of an antiperspirant active. 9. The anhydrous cosmetic composition according to claim 8, wherein the cosmetic active is zinc oxide. 10. The anhydrous cosmetic composition according to claim 8, wherein the cosmetic active is panthenyl triacetate. 11. A method for grooming hair in the intimate skin area, the method comprising the steps of:
(i) cutting or removing hair from skin in the intimate skin area by at least one of the following methods, shaving, trimming, laser hair removal, epilation, waxing, chemical methods, and the like; (ii) thereafter, prepping the skin in the intimate skin area for application of a cosmetic composition; and (iii) thereafter, rubbing an anhydrous cosmetic composition onto the skin in the intimate skin area, the anhydrous cosmetic composition comprising: a volatile solvent; and a product hardness of at least 600 gram-force. 12. The method according to claim 11, wherein the product hardness is from about 800 gram-force to about 1,400 gram-force. 13. The method according to claim 11, wherein the anhydrous cosmetic composition further comprises a Vitamin B5 derivative. 14. The method according to claim 13, wherein the Vitamin B5 derivative comprises panthenyl triacetate. 15. A method according to claim 11, wherein the anhydrous cosmetic composition is devoid of an antiperspirant active. 16. A method according to claim 11, wherein the anhydrous cosmetic composition comprises less than 1 weight percent of propylene glycol and dipropylene glycol. 17. A method according to claim 11, wherein the anhydrous cosmetic composition leaves a translucent residue upon application to the intimate skin. 18. A method according to claim 11, wherein the anhydrous cosmetic composition provides a substantive protective film upon application to the skin in the intimate area. 19. A method for managing incontinence, the method comprising the steps of:
(i) rubbing an anhydrous cosmetic composition onto skin and/or hair in an intimate skin area to apply the anhydrous cosmetic composition to the same, the anhydrous cosmetic composition comprising:
a product hardness of at least 600 gram-force; and
a volatile solvent; and
(ii) applying an incontinence absorbent article against the skin and/or hair in the intimate skin area comprising the anhydrous cosmetic composition, the incontinence absorbent article comprising a liner, a pad, or a pant. 20. A method according to claim 19, wherein the product hardness is from about 800 gram-force to about 1,400 gram-force. 21. A method according to claim 19, wherein the anhydrous cosmetic composition further comprises a cosmetic active. 22. A method according to claim 21, wherein the cosmetic active comprises zinc oxide. 23. A method according to claim 19, wherein the anhydrous cosmetic composition is devoid of an antiperspirant active. 24. A method according to claim 19, wherein the anhydrous cosmetic composition comprises less than 1 weight percent of propylene glycol and dipropylene glycol. 25. A method according to claim 19, wherein the anhydrous cosmetic composition provides an opaque residue upon application to the skin in the intimate area. 26. A method according to claim 19, wherein the anhydrous cosmetic composition provides a substantive protective film upon application to the skin in the intimate area.
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The present invention relates to an anhydrous cosmetic composition for topical application to skin in the intimate area. The compositions can be used following shaving or trimming hair in the intimate area. The compositions can also be used in the intimate skin area for consumers that wear absorbent articles against the intimate skin area for long periods of time.1. An anhydrous cosmetic composition for topical application comprising:
one or more complexed or encapsulated compounds having a thiol vapor pressure suppression index (TVPS) of more than 20 when measured according to the test methodology described herein, wherein the anhydrous cosmetic composition is in the form of a solid stick comprising a product hardness of at least 600 gram-force; and wherein the anhydrous cosmetic composition is devoid of an antiperspirant active. 2. The anhydrous cosmetic composition according to claim 1, wherein said one or more compounds are starch encapsulated. 3. The anhydrous cosmetic composition according to claim 1, wherein said one or more compounds are encapsulated in reservoir type capsules and can be released by a mechanical action breaking the shell of the capsule. 4. The anhydrous cosmetic composition according to claim 1, wherein the one or more compounds are comprised as cyclodextrin complexes. 5. The anhydrous cosmetic composition according to claim 1 wherein said one or more compounds are comprised in at least two or three forms selected from (i) encapsulated in reservoir type capsules which can be released by a mechanical action breaking the shell of the capsule, (ii) cyclodextrin complexes, or (iii) starch capsules. 6. The anhydrous cosmetic composition according to claim 1, further comprising a cosmetic active, wherein the cosmetic active is zinc oxide. 7. The anhydrous cosmetic composition according to claim 1, further comprising a cosmetic active, wherein the cosmetic active is panthenyl triacetate. 8. An anhydrous cosmetic composition comprising:
a. a volatile solvent comprising a siloxane; b. a thickening agent; and c. a cosmetic active selected from the group consisting of zinc oxide and an oil-soluble Vitamin B5 derivative; d. wherein the anhydrous cosmetic composition is in the form of a solid stick comprising a product hardness of at least 600 gram-force; and e. wherein the anhydrous cosmetic composition is devoid of an antiperspirant active. 9. The anhydrous cosmetic composition according to claim 8, wherein the cosmetic active is zinc oxide. 10. The anhydrous cosmetic composition according to claim 8, wherein the cosmetic active is panthenyl triacetate. 11. A method for grooming hair in the intimate skin area, the method comprising the steps of:
(i) cutting or removing hair from skin in the intimate skin area by at least one of the following methods, shaving, trimming, laser hair removal, epilation, waxing, chemical methods, and the like; (ii) thereafter, prepping the skin in the intimate skin area for application of a cosmetic composition; and (iii) thereafter, rubbing an anhydrous cosmetic composition onto the skin in the intimate skin area, the anhydrous cosmetic composition comprising: a volatile solvent; and a product hardness of at least 600 gram-force. 12. The method according to claim 11, wherein the product hardness is from about 800 gram-force to about 1,400 gram-force. 13. The method according to claim 11, wherein the anhydrous cosmetic composition further comprises a Vitamin B5 derivative. 14. The method according to claim 13, wherein the Vitamin B5 derivative comprises panthenyl triacetate. 15. A method according to claim 11, wherein the anhydrous cosmetic composition is devoid of an antiperspirant active. 16. A method according to claim 11, wherein the anhydrous cosmetic composition comprises less than 1 weight percent of propylene glycol and dipropylene glycol. 17. A method according to claim 11, wherein the anhydrous cosmetic composition leaves a translucent residue upon application to the intimate skin. 18. A method according to claim 11, wherein the anhydrous cosmetic composition provides a substantive protective film upon application to the skin in the intimate area. 19. A method for managing incontinence, the method comprising the steps of:
(i) rubbing an anhydrous cosmetic composition onto skin and/or hair in an intimate skin area to apply the anhydrous cosmetic composition to the same, the anhydrous cosmetic composition comprising:
a product hardness of at least 600 gram-force; and
a volatile solvent; and
(ii) applying an incontinence absorbent article against the skin and/or hair in the intimate skin area comprising the anhydrous cosmetic composition, the incontinence absorbent article comprising a liner, a pad, or a pant. 20. A method according to claim 19, wherein the product hardness is from about 800 gram-force to about 1,400 gram-force. 21. A method according to claim 19, wherein the anhydrous cosmetic composition further comprises a cosmetic active. 22. A method according to claim 21, wherein the cosmetic active comprises zinc oxide. 23. A method according to claim 19, wherein the anhydrous cosmetic composition is devoid of an antiperspirant active. 24. A method according to claim 19, wherein the anhydrous cosmetic composition comprises less than 1 weight percent of propylene glycol and dipropylene glycol. 25. A method according to claim 19, wherein the anhydrous cosmetic composition provides an opaque residue upon application to the skin in the intimate area. 26. A method according to claim 19, wherein the anhydrous cosmetic composition provides a substantive protective film upon application to the skin in the intimate area.
| 1,600 |
1,265 | 14,409,066 | 1,616 |
One subject of the present invention is a translucent cosmetic composition in the form of an oil-in-water emulsion comprising: (1) a dispersed fatty phase comprising at least one oil; (2) a continuous aqueous phase comprising at least one hydrophilic thickening polymer; and (3) hydrophobic silica aerogel particles; the ratio of the amount by weight of silica aerogel particles to the amount by weight of oil(s) being greater than 0.06; the composition being free of surfactant(s). The composition in accordance with the invention is in the form of an emulsified gel of translucent appearance which makes it possible to obtain good cosmetic properties such as a sensation of freshness on application and a satisfactory nutritive efficacy.
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1. A translucent cosmetic composition in the form of an oil-in-water emulsion comprising:
(1) a dispersed fatty phase comprising at least one oil; (2) a continuous aqueous phase comprising at least one hydrophilic thickening polymer; and (3) hydrophobic silica aerogel particles; the ratio of the amount by weight of silica aerogel particles to the amount by weight of oil(s) being greater than 0.06; the composition being free of surfactant(s). 2. The composition as claimed in claim 1, wherein the hydrophilic thickening polymer(s) is (are) not amphiphilic. 3. The composition as claimed in claim 1, wherein the hydrophilic thickening polymer(s) is (are) selected from:
1) acrylic acid homopolymers or copolymers and salts thereof; 2) polyacrylate salts; 3) 2-acrylamido-2-methylpropanesulfonic acid (AMPS®) polymers and copolymers, which are optionally crosslinked and/or neutralized, selected from:
a) poly(2-acrylamido-2-methylpropanesulfonic acid) polymers which are crosslinked and neutralized to at least 90%;
b) copolymers of acrylamide and of AMPS®; 4) polysaccharides; 5) glyceryl acrylate polymers. 4. The composition as claimed in claim 3, wherein the hydrophilic thickening polymer(s) is (are) selected from:
1) acrylic acid homopolymers or copolymers and salts thereof; 2) polyacrylate salts; 3) 2-acrylamido-2-methylpropanesulfonic acid (AMPS®) polymers and copolymers, which are optionally crosslinked and/or neutralized, selected from:
a) poly(2-acrylamido-2-methylpropanesulfonic acid) polymers which are crosslinked and neutralized to at least 90%;
b) copolymers of acrylamide and of AMPS®;
4) polysaccharides. 5. The composition as claimed in claim 4, wherein the hydrophilic thickening polymer(s) is (are) selected from: acrylic acid homopolymers or copolymers, which are preferably crosslinked, and salts thereof; 2-acrylamido-2-methylpropanesulfonic acid (AMPS®) polymers and copolymers, which are optionally crosslinked and/or neutralized, selected from poly(2-acrylamido-2-methylpropanesulfonic acid) polymers which are crosslinked and neutralized to at least 90%, and copolymers of acrylamide and of AMPS. 6. The composition as claimed in claim 1, wherein the hydrophobic silica aerogel particles have a specific surface area per unit of mass SM ranging from 200 to 1500 m2/g. 7. The composition as claimed in claim 1, wherein the hydrophobic silica aerogel particles have a size, expressed as the volume-average diameter (D[0.5]), of less than 1500 μm. 8. The composition as claimed in claim 1, wherein the hydrophobic silica aerogel particles have a tapped density ranging from 0.02 g/cm3 to 0.10 g/cm3. 9. The composition as claimed in claim 1, wherein the hydrophobic silica aerogel particles have a specific surface area per unit of volume Sv ranging from 5 to 60 m2/cm3, preferably from 10 to 50 m2/cm3. 10. The composition as claimed in claim 1, wherein the hydrophobic silica aerogel particles have an oil absorption capacity, measured at the wet point, ranging from 5 to 18 ml/g. 11. The composition as claimed in claim 1, wherein the hydrophobic silica aerogel particles are organic, inorganic or hybrid organic-inorganic particles. 12. The composition as claimed in claim 1, wherein the hydrophobic silica aerogel particles are surface-modified with trimethylsilyl groups. 13. The composition as claimed in claim 1, wherein the hydrophobic silica aerogel particles are present in a content ranging from 0.001% to 10% by weight relative to the total weight of the composition. 14. The composition as claimed in claim 1, wherein the oil(s) is (are) selected from silicone oils and fatty acid esters. 15. The composition as claimed in claim 1, wherein the proportion of the fatty phase is less than or equal to 25% by weight relative to the total weight of the composition. 16. A method for the cosmetic treatment of a keratin material, wherein a composition as defined in claim 1 is applied to the keratin material. 17. The composition as claimed in claim 1, wherein the hydrophilic thickening polymer(s) is (are) selected from:
1) acrylic acid homopolymers or copolymers and salts thereof; 2) polyacrylate salts; 3) 2-acrylamido-2-methylpropanesulfonic acid (AMPS®) polymers and copolymers, which are optionally crosslinked and/or neutralized, selected from:
a) poly(2-acrylamido-2-methylpropanesulfonic acid) polymers which are crosslinked and neutralized to at least 90%;
b) copolymers of acrylamide and of AMPS®;
4) polysaccharides; 5) glyceryl acrylate polymers. 18. The composition as claimed claim 2, wherein the hydrophobic silica aerogel particles have a specific surface area per unit of mass SM ranging from 200 to 1500 m2/g. 19. The composition as claimed claim 3, wherein the hydrophobic silica aerogel particles have a specific surface area per unit of mass SM ranging from 200 to 1500 m2/g. 20. The composition as claimed claim 4, wherein the hydrophobic silica aerogel particles have a specific surface area per unit of mass SM ranging from 200 to 1500 m2/g.
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One subject of the present invention is a translucent cosmetic composition in the form of an oil-in-water emulsion comprising: (1) a dispersed fatty phase comprising at least one oil; (2) a continuous aqueous phase comprising at least one hydrophilic thickening polymer; and (3) hydrophobic silica aerogel particles; the ratio of the amount by weight of silica aerogel particles to the amount by weight of oil(s) being greater than 0.06; the composition being free of surfactant(s). The composition in accordance with the invention is in the form of an emulsified gel of translucent appearance which makes it possible to obtain good cosmetic properties such as a sensation of freshness on application and a satisfactory nutritive efficacy.1. A translucent cosmetic composition in the form of an oil-in-water emulsion comprising:
(1) a dispersed fatty phase comprising at least one oil; (2) a continuous aqueous phase comprising at least one hydrophilic thickening polymer; and (3) hydrophobic silica aerogel particles; the ratio of the amount by weight of silica aerogel particles to the amount by weight of oil(s) being greater than 0.06; the composition being free of surfactant(s). 2. The composition as claimed in claim 1, wherein the hydrophilic thickening polymer(s) is (are) not amphiphilic. 3. The composition as claimed in claim 1, wherein the hydrophilic thickening polymer(s) is (are) selected from:
1) acrylic acid homopolymers or copolymers and salts thereof; 2) polyacrylate salts; 3) 2-acrylamido-2-methylpropanesulfonic acid (AMPS®) polymers and copolymers, which are optionally crosslinked and/or neutralized, selected from:
a) poly(2-acrylamido-2-methylpropanesulfonic acid) polymers which are crosslinked and neutralized to at least 90%;
b) copolymers of acrylamide and of AMPS®; 4) polysaccharides; 5) glyceryl acrylate polymers. 4. The composition as claimed in claim 3, wherein the hydrophilic thickening polymer(s) is (are) selected from:
1) acrylic acid homopolymers or copolymers and salts thereof; 2) polyacrylate salts; 3) 2-acrylamido-2-methylpropanesulfonic acid (AMPS®) polymers and copolymers, which are optionally crosslinked and/or neutralized, selected from:
a) poly(2-acrylamido-2-methylpropanesulfonic acid) polymers which are crosslinked and neutralized to at least 90%;
b) copolymers of acrylamide and of AMPS®;
4) polysaccharides. 5. The composition as claimed in claim 4, wherein the hydrophilic thickening polymer(s) is (are) selected from: acrylic acid homopolymers or copolymers, which are preferably crosslinked, and salts thereof; 2-acrylamido-2-methylpropanesulfonic acid (AMPS®) polymers and copolymers, which are optionally crosslinked and/or neutralized, selected from poly(2-acrylamido-2-methylpropanesulfonic acid) polymers which are crosslinked and neutralized to at least 90%, and copolymers of acrylamide and of AMPS. 6. The composition as claimed in claim 1, wherein the hydrophobic silica aerogel particles have a specific surface area per unit of mass SM ranging from 200 to 1500 m2/g. 7. The composition as claimed in claim 1, wherein the hydrophobic silica aerogel particles have a size, expressed as the volume-average diameter (D[0.5]), of less than 1500 μm. 8. The composition as claimed in claim 1, wherein the hydrophobic silica aerogel particles have a tapped density ranging from 0.02 g/cm3 to 0.10 g/cm3. 9. The composition as claimed in claim 1, wherein the hydrophobic silica aerogel particles have a specific surface area per unit of volume Sv ranging from 5 to 60 m2/cm3, preferably from 10 to 50 m2/cm3. 10. The composition as claimed in claim 1, wherein the hydrophobic silica aerogel particles have an oil absorption capacity, measured at the wet point, ranging from 5 to 18 ml/g. 11. The composition as claimed in claim 1, wherein the hydrophobic silica aerogel particles are organic, inorganic or hybrid organic-inorganic particles. 12. The composition as claimed in claim 1, wherein the hydrophobic silica aerogel particles are surface-modified with trimethylsilyl groups. 13. The composition as claimed in claim 1, wherein the hydrophobic silica aerogel particles are present in a content ranging from 0.001% to 10% by weight relative to the total weight of the composition. 14. The composition as claimed in claim 1, wherein the oil(s) is (are) selected from silicone oils and fatty acid esters. 15. The composition as claimed in claim 1, wherein the proportion of the fatty phase is less than or equal to 25% by weight relative to the total weight of the composition. 16. A method for the cosmetic treatment of a keratin material, wherein a composition as defined in claim 1 is applied to the keratin material. 17. The composition as claimed in claim 1, wherein the hydrophilic thickening polymer(s) is (are) selected from:
1) acrylic acid homopolymers or copolymers and salts thereof; 2) polyacrylate salts; 3) 2-acrylamido-2-methylpropanesulfonic acid (AMPS®) polymers and copolymers, which are optionally crosslinked and/or neutralized, selected from:
a) poly(2-acrylamido-2-methylpropanesulfonic acid) polymers which are crosslinked and neutralized to at least 90%;
b) copolymers of acrylamide and of AMPS®;
4) polysaccharides; 5) glyceryl acrylate polymers. 18. The composition as claimed claim 2, wherein the hydrophobic silica aerogel particles have a specific surface area per unit of mass SM ranging from 200 to 1500 m2/g. 19. The composition as claimed claim 3, wherein the hydrophobic silica aerogel particles have a specific surface area per unit of mass SM ranging from 200 to 1500 m2/g. 20. The composition as claimed claim 4, wherein the hydrophobic silica aerogel particles have a specific surface area per unit of mass SM ranging from 200 to 1500 m2/g.
| 1,600 |
1,266 | 15,571,575 | 1,628 |
The present invention relates to methods for controlling and/or preventing infestation of stinkbugs, comprising applying to a crop of plants, the locus thereof, or propagation material thereof, a compound of formula I wherein R 1 , R 6a , R 6b Q, W, A 1 , A 2 , A 3 , A 4 , Z 1 , Z 2 and Z 3 are as defined in the description.
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1. A method of controlling and/or preventing infestation of stinkbugs comprising applying to a crop of plants, the locus thereof, or propagation material thereof, a compound of formula (I)
wherein
R1 is selected from H, C1-C6-alkyl, C3-C6 alkenyl, C3-C6 alkinyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C3-alkyl, C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonyl, aryl(C1-C3)-alkyl and heteroaryl(C1-C3)-alkyl, wherein each of C1-C6-alkyl, C3-C6 alkenyl, C3-C6 alkinyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C3-alkyl, C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonyl, aryl(C1-C3)-alkyl and heteroaryl(C1-C3)-alkyl is unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, cyano, C1-C6-alkoxy and C1-C6-alkoxycarbonyl;
Q is selected from H, hydroxy, HC(═O)—, C1-C6-alkyl, C1-C6-alkoxy, C3-C6 alkenyl, C3-C6 alkinyl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, C3-C7 cycloalkyl-C1-C3-alkyl, C1-C3-alkyl-C3-C7 cycloalkyl, aryl(C1-C3)-alkyl, heteroaryl(C1-C3)-alkyl, N—C1-C6-alkylamino, N—C1-C6-alkylcarbonylamino and N,N-di (C1-C6-alkyl)amino, wherein each of C1-C6-alkyl, C1-C6-alkoxy, C3-C6 alkenyl, C3-C6 alkinyl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, C3-C7 cycloalkyl-C1-C3-alkyl, C1-C3-alkyl-C3-C7 cycloalkyl, aryl(C1-C3)-alkyl, heteroaryl(C1-C3)-alkyl, N—C1-C6-alkylamino, N—C1-C6-alkylcarbonylamino and N,N-di (C1-C6-alkyl)amino is unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, nitro, amino, cyano, C1-C6-alkoxy, C1-C6-alkoxycarbonyl, hydroxycarbonyl, C1-C6-alkylcarbamoyl, C3-C6-cycloalkylcarbamoyl and phenyl; A1 is CR2 or N;
A2 is CR3 or N;
A3 is CR4 or N;
A4 is CR5 or N;
with the proviso that no more than 3 of A1, A2, A3 and A4 are N;
R2, R3, R4 and R5 are independently selected from H, halogen, cyano, nitro, C1-C6-alkyl, C1-C6-alkoxy, N—C1-C6-alkoxy-imino-C1-C3-alkyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, N—C1-C6-alkylamino and N,N-di-C1-C6-alkylamino, wherein each of C1-C6-alkyl, C1-C6-alkoxy, N—C1-C6-alkoxy-imino-C1-C3-alkyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, N—C1-C6-alkylamino and N,N-di-C1-C6-alkylamino is unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, hydroxy, nitro, amino, cyano, C1-C6-alkoxy, C1-C6-alkoxycarbonyl, hydroxycarbonyl, C1-C6-alkylcarbamoyl, C3-C6-cycloalkylcarbamoyl and phenyl;
W is O or S;
R6a and R6b are independently selected from H, halogen, cyano, nitro, amino, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylcarbonyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, wherein each of C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylcarbonyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl is unsubstituted or substituted with 1 to 5 halogen;
Z1 is selected from C1-C6-halogenalkyl, C3-C6-cycloalkyl and C3-C6-halogencycloalkyl, wherein each of C1-C6-halogenalkyl, C3-C6-cycloalkyl and C3-C6-halogencycloalkyl is unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, hydroxy, nitro, amino, cyano, C1-C6-alkoxy, C1-C6-alkoxycarbonyl, hydroxycarbonyl, C1-C6-alkylcarbamoyl, C3-C6-cycloalkylcarbamoyl and phenyl;
Z2 is selected from H, halogen, cyano, nitro, amino, C1-C6-alkyl, C1-C6-alkylcarbonyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl and C1-C6-alkylsulfonyl, wherein each of C1-C6-alkyl, C1-C6-alkylcarbonyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl and C1-C6-alkylsulfonyl is unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, hydroxy, nitro, amino, cyano, C1-C6-alkoxy, C1-C6-alkoxycarbonyl, hydroxycarbonyl, C1-C6-alkylcarbamoyl, C3-C6-cycloalkylcarbamoyl and phenyl;
Z3 is selected from C1-C6-alkyl, C1-C6-cycloalkyl, C1-C6-alkenyl, C1-C6-alkinyl, aryl and heteroaryl, wherein each of C1-C6-alkyl, C1-C6-cycloalkyl, C1-C6-alkenyl, C1-C6-alkinyl, aryl and heteroaryl is unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, hydroxy, nitro, amino, cyano, C1-C6-alkoxy, C1-C6-alkoxycarbonyl, hydroxycarbonyl, C1-C6-alkylcarbamoyl, C3-C6-cycloalkylcarbamoyl and phenyl;
or an agrochemically acceptable salt or N-oxide thereof. 2. The method according to claim 1, wherein
R1 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, methoxymethyl, ethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, s-butylcarbonyl, t-butylcarbonyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, cyanomethyl, 2-cyanoethyl, benzyl, 4-methoxybenzyl, pyrid-2-yl-methyl, pyrid-3-yl-methyl, pyrid-4-yl-methyl and 4-chlor-pyrid-3-yl-methyl; Q is selected from H, methyl, ethyl, n-propyl, 1-methylethyl, 1,1-dimethylethyl, 1-methylpropyl, n-butyl, 2-methylpropyl, 2-methylbutyl, hydroxyethyl, 2-hydroxypropyl, cyanomethyl, 2-cyanoethyl, 2-fluorethyl, 2,2-difluorethyl, 2,2,2-trifluorethyl, 1-trifluormethylethyl, 2,2-difluorpropyl, 3,3,3-trifluorpropyl, 2,2-dimethyl-3-fluorpropyl, cyclopropyl, 1-cyano-cyclopropyl, 1-methoxycarbonyl-cyclopropyl, 1-(N-methylcarbamoyl)cyclopropyl, 1-carbamoyl-cyclopropyl, 1-carbamothioyl-cyclopropyl, 1-(N-cyclopropylcarbamoyl)cyclopropyl, cyclopropyl-methyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclopropylethyl, bis(cyclopropyl)methyl, 2,2-dimethylcyclopropyl-methyl, 2-phenylcyclopropyl, 2,2-dichlorcyclopropyl, trans-2-chlorcyclopropyl, cis-2-chlorcyclopropyl, 2,2-difluorcyclopropyl, trans-2-fluorcyclopropyl, cis-2-fluorcyclopropyl, trans-4-hydroxycyclohexyl, 4-trifluormethylcyclohexyl, prop-2-enyl, 2-methylprop-2-enyl, prop-2-inyl, 1,1-dimethylbut-2-inyl, 3-chlor-prop-2-enyl, 3-fluor-prop-2-enyl, 3,3-dichlor-prop-2-enyl, 3,3-dichlor-1,1-dimethylprop-2-enyl, oxetan-3-yl, thietan-3-yl, l-oxido-thietan-3-yl, l,l-dioxido-thietan-3-yl, isoxazol-3-ylmethyl, l,2,4-triazol-3-ylmethyl, 3-methyloxetan-3-ylmethyl, benzyl, 2,6-difluorphenylmethyl, 3-fluorphenylmethyl, 2-fluorphenylmethyl, 2,5-difluorphenylmethyl, 1-phenylethyl, 4-chlorphenylethyl, 2-trifluormethylphenylethyl, 1-pyridin-2-ylethyl, pyridin-2-ylmethyl, 5-fluorpyridin-2-ylmethyl, (6-chlor-pyridin-3-yl)methyl, pyrimidin-2-ylmethyl, methoxy, 2-ethoxyethyl, 2-methoxyethyl, 2-(methylsulfanyl)ethyl, l-methyl-2-(ethylsulfanyl)ethyl, 2-methyl-1-(methylsulfanyl)propan-2-yl, methoxycarbonyl, methoxycarbonylmethyl, NH2, N-ethylamino, N-allylamino, N,N-dimethylamino and N,N-diethylamino; or Q is selected from phenyl, naphthyl, pyridazin, pyrazin, pyrimidin, triazin, pyridin, pyrazol, thiazol, isothiazol, oxazol, isoxazol, triazol, imidazol, furan, thiophen, pyrrol, oxadiazol, and thiadiazol, each of which is unsubstituted or substituted with 1 to 4 substituents independently selected from V; V is selected from fluoro, chloro, bromo, iodo, Cyano, nitro, methyl, ethyl, difluormethyl, trichloromethyl, chlordifluoromethyl, dichlorofluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,2,2,2-tetrafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2,2,2-trichloroethyl, 2-chloro-2,2-difluoroethyl, 1,1-dilfluoroethyl, pentafluoroethyl heptafluoro-n-propyl, heptafluoro-isopropyl, nonafluoro-n-butyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, n-propoxy, 1-methylethoxy, fluormethoxy, difluormethoxy, chloro-difluormethoxy, dichloro-fluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluorethoxy, pentafluorethoxy, N-methoxyiminomethyl, l-(N-methoxyimino)-ethyl, methylsulfanyl, methylsulfonyl, methylsulfinyl, trifluormethylsulfonyl, trifluormethylsulfinyl, trifluormethylsulfanyl and N,N-dimethylamino; W is O or S; A1 is CR2 or N; A2 is CR3 or N; A3 is CR4 or N; A4 is CR5 or N; with the proviso that no more than 3 of A1, A2, A3 and A4 are N; R2 and R5 are independently selected from H, methyl, fluoro and chloro; R3 and R4 are independently selected from H, fluoro, chloro, bromo, iodo, cyano, nitro, methyl, ethyl, fluoromethyl, difluoromethyl, chlordifluormethyl, trifluormethyl, 2,2,2-trilfluoroethyl, methoxy, ethoxy, n-propoxy, 1-methylethoxy, fluoromethoxy, difluoromethoxy, chloro-difluoromethoxy, dichloro-fluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluorethoxy, pentafluoroethoxy, N-methoxyiminomethyl, l-(N-methoxyimino)-ethyl, methylsulfanyl, trifluoromethylsulfanyl, methylsulfonyl, methylsulfinyl, trifluormethylsulfonyl and trifluormethylsulfinyl; R6a and R6b are independently selected from halogen, cyano, nitro, amino, methyl, ethyl, propyl, 1-methylethyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, methylcarbonyl, ethylcarbonyl, trifluoromethylcarbonyl, methylsulfanyl, methylsulfinyl, methylsulfonyl, trifluoromethylsulfonyl, trifluoromethylsulfanyl and trilfluoromethylsulfinyl; Z1 is selected from methyl, ethyl, 1,1-dimethylethyl, difluoromethyl, trichloromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trifluoromethyl, bromodichloromethyl, 1-fluoroethyl, 1-fluoro-1-methylethyl, 2-fluoroethyl, 2,2-difluorethyl, 2,2,2-trifluoroethyl, 1,2,2,2-tetrafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2,2,2-trichloroethyl, 2-chloro-2,2-difluoroethyl, 1,1-difluoroethyl, pentafluoroethyl heptafluor-n-propyl, heptafluor-isopropyl, nonafluoro-n-butyl, cyclopropyl, 1-chlorocyclopropyl, 1-fluorocyclopropyl, 1-bromocyclopropyl, 1-cyano-cyclopropyl, 1-trifluoromehtyl-cyclopropyl, cyclobutyl and 2,2-Difluor-l-methyl-cyclopropyl; Z2 is selected from H, halogen, cyano, nitro, amino, methyl, ethyl, 1,1-dimethylethyl, difluoromethyl, trichloromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trifluoromethyl, bromodichloromethyl, 1-fluoroethyl, 1-fluoro-1 methylethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,2,2,2-tetrafluoroethyl, 1-chlor-1,2,2,2-tetrafluoroethyl, 2,2,2-trichloroethyl, 2-chloro-2,2-difluoroethyl, 1,1-difluoroethyl, pentafluoroethyl heptafluoro-n-propyl, heptafluoro-isopropyl, nonafluoro-n-butyl, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylthio, ethylsulfinyl, ethylsulfonyl, trifluoromethylsulfanyl, trifluoromethylsulfinyl, trifluoromethylsulfonyl, chloro-difluoromethylsulfanyl, chloro-difluoromethylsulfinyl, chloro-difluoromethylsulfonyl, dichloro-fluoromethylsulfanyl, dichloro-fluoromethylsulfinyl, dichloro-fluoromethylsulfonyl; and Z3 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, ethenyl, 1-propenyl, 1-propinyl, 1-butinyl, difluoromethyl, trichloromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trifluoromethyl, 1-fluoroethyl, 1 fluoro-1-methylethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,6-dichlorophenyl 2,6-dichloro-4-trifluoromethylphenyl and 3-chlor-5-trifluormethylpyridin-2-yl. 3. The method according to claim 1, wherein R1 is H, methyl, ethyl, n-propyl, n-propylcarbonyl and propenyl;
Q is selected from 1-cyano-cyclopropyl, benzyl, cyclopropyl, 2-thienylmethyl, carbamothioylcyclopropyl, pyrid-4-yl, 2,2,2-trifluorethyl, methylsulfonyl, thietan-3-yl and 1-carbamoylcyclopropyl; W is O; A1 and A4 are CH; A2 is CH or CF; A3 is CH or CCl; R6a is H or methyl; R6b is H, methyl or CF3; Z1 is CF2CF3; Z2 is CF3; Z3 is selected from methyl, ethyl, phenyl, 4-NO2-phenyl and 3-chlorpyridin-2-yl. 4. The method according to claim 1, wherein
R1 is H or methyl; Q is selected from 1-cyano-cyclopropyl, benzyl, cyclopropyl, 2-thienylmethyl, carbamothioylcyclopropyl, pyrid-4-yl, 2,2,2-trifluorethyl, methylsulfonyl, thietan-3-yl and 1-carbamoylcyclopropyl; W is O; A1 and A4 are CH; A2 is N; A3 is CH or CCl; R6a is H or methyl; R6b is H, methyl or CF3; Z1 is CF2CF3; Z2 is CF3; Z3 is methyl, ethyl, phenyl, 4-NO2-phenyl, 3-chloropyridin-2-yl. 5. The method according to claim 1, wherein the compound is selected from a compound of formula (I)
wherein Z1, Z2, Z3, R6a, R6b, A1, A2, A3, A4, W, Q and R1 are as defined in the table below
Ex no
Z1
Z2
Z3
R1
R6a
R6b
A4
A3
A2
A1
W
Q
Ic-2
CF2CF3
CF3
CH3
H
H
H
C—H
C—Cl
C—H
C—H
O
1-Cyano-cyclopropyl
Ic-3
CF2CF3
CF3
CH3
H
H
H
C—H
C—Cl
C—H
C—H
O
Benzyl
Ic-4
CF2CF3
CF3
CH3
H
H
CF3
C—H
C—Cl
C—H
C—H
O
Cyclopropyl
Ic-5
CF2CF3
CF3
CH3
H
CH3
CF3
C—H
C—Cl
C—H
C—H
O
Cyclopropyl
Ic-6
CF2CF3
CF3
Phenyl
H
H
H
C—H
C—Cl
C—H
C—H
O
Cyclopropyl
Ic-7
CF2CF3
CF3
Phenyl
H
H
H
C—H
C—Cl
C—H
C—H
O
1-Cyano-cyclopropyl
Ic-8
CF2CF3
CF3
4-N02-
H
H
H
C—H
C—Cl
C—H
C—H
O
Cyclopropyl
Phenyl
Ic-9
CF2CF3
CF3
CH3
H
CH3
CH3
C—H
C—Cl
C—H
C—H
O
Cyclopropyl
Ic-10
CF2CF3
CF3
CH3
H
H
H
C—H
C—Cl
C—H
C—H
O
2-Thienylmethyl
Ic-11
CF2CF3
CF3
CH3
H
H
H
C—H
C—Cl
C—H
C—H
O
1-
Carbamothioylcyclopropyl
Ic-12
CF2CF3
CF3
CH3
H
H
CH3
C—H
C—Cl
C—H
C—H
O
Cyclopropyl
Ic-13
CF2CF3
CF3
CH3
H
CH3
H
C—H
C—Cl
C—H
C—H
O
Cyclopropyl
Ic-14
CF2CF3
CF3
3-Chlorpyridin-2-yl
H
H
H
C—H
C—Cl
C—H
C—H
O
Cyclopropyl
Ic-15
CF2CF3
CF3
3-
H
H
H
C—H
C—Cl
C—H
C—H
O
1-Cyano-cyclopropyl
Chlorpyridin-2-yl
Ic-16
CF2CF3
CF3
CH2CH3
H
H
H
C—H
C—Cl
C—H
C—H
O
Cyclopropyl
Ic-17
CF2CF3
CF3
CH3
H
H
H
C—H
C—H
C—H
C—H
O
Benzyl
Ic-18
CF2CF3
CF3
CH3
H
H
H
C—H
C—H
C—H
C—H
O
Cyclopropyl
Ic-19
CF2CF3
CF3
CH3
H
H
H
C—H
C—H
C—H
C—H
O
1-Cyano-cyclopropyl
Ic-20
CF2CF3
CF3
CH3
H
H
H
C—H
C—H
C—H
C—H
O
2-Thienylmethyl
Ic-21
CF2CF3
CF3
CH2CH3
H
H
H
C—H
C—Cl
C—H
C—H
O
1-Cyano-cyclopropyl
Ic-22
CF2CF3
CF3
CH3
H
H
H
C—H
C—Cl
C—H
C—H
O
Pyrid-4-yl
Ic-23
CF2CF3
CF3
CH3
H
H
H
C—H
C—Cl
C—H
C—H
O
2,2,2-Trifluorethyl
Ic-24
CF2CF3
CF3
CH3
H
H
H
C—H
C—Cl
C—F
C—H
O
Cyclopropyl
Ic-25
CF2CF3
CF3
CH3
H
H
H
C—H
C—Cl
C—H
C—H
O
4-Chlorphenyl
Ic-26
CF2CF3
CF3
CH3
H
H
H
C—H
C—Cl
C—H
C—H
O
Methylsulfonyl
Ic-27
CF2CF3
CF3
CH3
H
H
H
C—H
C—Cl
C—F
C—H
O
1-Cyano-cyclopropyl
Ic-28
CF2CF3
CF3
CH3
H
H
H
C—H
C—Cl
C—H
C—H
O
Thietan-3-yl
Ic-29
CF2CF3
CF3
CH3
H
H
H
C—H
C—Cl
C—H
C—H
O
1-Carbamoylcyclopropyl
Ic-30
CF3
CN
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropyl
Ic-31
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-oxo-2-[(2,2,2-
trifluoroethyl)amino]ethyl
Ic-32
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-(CF3)cyclopropyl
Ic-33
CF2CF3
CF3
Me
H
H
H
C—F
C—H
C—H
C—H
O
cyclopropyl
Ic-34
CF2CF3
CF3
Me
H
H
H
C—H
C—Br
C—H
C—H
O
1-cyanocyclopropyl
Ic-35
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—H
C—H
O
H
Ic-36
CF2CF3
CF3
Me
H
H
H
C—H
C—F
C—H
C—H
O
1-cyanocyclopropyl
Ic-37
CF2CF3
CF3
Me
H
H
H
C—H
C—F
C—H
C—H
O
cyclopropyl
Ic-38
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—F
C—H
O
1-cyanocyclopropyl
Ic-39
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—F
C—H
O
cyclopropyl
Ic-40
CF2CF3
CF3
Me
H
H
H
C—F
C—H
C—H
C—H
O
1-cyanocyclopropyl
Ic-41
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—H
C—F
O
cyclopropyl
Ic-42
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—H
C—F
O
1-cyanocyclopropyl
Ic-43
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—Cl
C—H
O
1-cyanocyclopropyl
Ic-44
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—Cl
C—H
O
cyclopropyl
Ic-45
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—H
C—Cl
O
1-cyanocyclopropyl
Ic-46
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—H
C—Cl
O
cyclopropyl
Ic-47
CF2CF3
CF3
Me
H
H
H
C—H
C—F
C—F
C—H
O
1-cyanocyclopropyl
Ic-48
CF2CF3
CF3
Me
H
H
H
C—H
C—F
C—H
C—Cl
O
1-cyanocyclopropyl
Ic-49
CF2CF3
CF3
Me
H
H
H
C—H
C—F
C—H
C—Cl
O
cyclopropyl
Ic-50
CF3
(E/Z) (hydroxyimino)methyl
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropyl
Ic-51
CF3
(E/Z)
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropyl
(methoxyimino)methyl
Ic-52
CF3
formyl
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropyl
Ic-53
CF3
CN
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-54
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—Me
C—H
O
cyclopropyl
Ic-55
CF2CF3
CF3
Me
H
H
H
C—H
C—F
C—F
C—H
O
cyclopropyl
Ic-56
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—Me
C—H
O
1-cyanocyclopropyl
Ic-57
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—H
C—Me
O
cyclopropyl
Ic-58
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—H
C—Me
O
1-cyanocyclopropyl
Ic-59
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—CF3
C—H
O
cyclopropyl
Ic-60
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—CF3
C—H
O
1-cyanocyclopropyl
Ic-61
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—F
C—F
O
cyclopropyl
Ic-62
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—
C—H
O
cyclopropyl
Ic-63
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—OMe
C—H
O
1-cyanocyclopropyl
Ic-64
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—F
C—F
O
1-cyanocyclopropyl
Ic-65
CF2CF3
CF3
Me
H
H
H
C—H
C—N02
C—H
C—H
O
1-cyanocyclopropyl
Ic-66
CF2CF3
CF3
Me
H
H
H
C—H
C—N02
C—H
C—H
O
cyclopropyl
Ic-67
CF2CF3
CF3
Me
H
H
H
C—H
C—OMe
C—H
C—H
O
1-cyanocyclopropyl
Ic-68
CF2CF3
CF3
Me
H
H
H
C—H
C—OMe
C—H
C—H
O
cyclopropyl
Ic-69
CF3
CH2OH
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropyl
Ic-70
CF2CF3
CF3
Me
H
H
H
C—H
C—H
N
C—H
O
cyclopropyl
Ic-71
CF2CF3
CF3
Me
H
H
H
C—H
C—H
N
C—H
O
1-cyanocyclopropyl
Ic-72
CF2CF3
CF3
Me
H
H
H
C—H
N
C—H
C—F
O
cyclopropyl
Ic-73
CF2CF3
CF3
Me
H
H
H
C—H
N
C—H
C—F
O
1-cyanocyclopropyl
Ic-74
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—OCF3
C—H
O
cyclopropyl
Ic-75
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—OCF3
C—H
O
1-cyanocyclopropyl
Ic-76
CF2CF3
CF3
Me
H
H
H
C—H
N
C—H
C—H
O
1-cyanocyclopropyl
Ic-77
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-fluoroethyl
Ic-78
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2,2-difluoroethyl
Ic-79
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-methylcyclopropyl
Ic-80
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2,2-difluoropropyl
Ic-81
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-fluorocyclopropyl
Ic-83
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
N
C—H
O
1-cyanocyclopropyl
Ic-84
CF2CF3
CF3
Me
H
H
H
C—H
C—Me
N
C—H
O
cyclopropyl
Ic-85
CF2CF3
CF3
Me
H
H
H
C—H
C—Me
N
C—H
O
1-cyanocyclopropyl
Ic-86
CF2CF3
CF3
Me
H
H
H
C—H
C—OMe
N
C—H
O
cyclopropyl
Ic-87
CF2CF3
CF3
Me
H
H
H
C—H
C—OMe
N
C—H
O
1-cyanocyclopropyl
Ic-88
CF2CF3
CF3
Me
H
H
H
C—H
N
C—Cl
C—H
O
cyclopropyl
Ic-89
CF2CF3
CF3
Me
H
H
H
C—H
N
C—Cl
C—H
O
1-cyanocyclopropyl
Ic-90
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—Me
C—H
O
cyclopropyl
Ic-91
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—Me
C—H
O
1-cyanocyclopropyl
Ic-92
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—F
O
cyclopropyl
Ic-93
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—F
O
1-cyanocyclopropyl
Ic-94
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—Cl
C—H
O
cyclopropyl
Ic-95
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—Cl
C—H
O
1-cyanocyclopropyl
Ic-96
CF2CF3
CF3
Me
Me
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-97
CF2CF3
CF3
Me
Me
H
H
C—H
C—Cl
C—H
C—H
O
1-
Ic-98
CF3
(E/Z)
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
(hydroxyimino)methyl
Ic-99
CF3
(E/Z)
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
(methoxyimino)methyl
Ic-100
CF3
cyclopropylcarbamoyl
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropyl
Ic-101
CF3
cyclopropylcarbamoyl
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-102
CF3
formyl
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-103
CF3
CH2F
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropyl
Ic-104
CF3
CH2OH
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-105
CF2CF3
CF3
Me
H
H
H
N
C—H
C—H
C—H
O
1-cyanocyclopropyl
Ic-106
CF2CF3
CF3
Me
H
H
H
C—F
C—Cl
C—H
C—H
O
cyclopropyl
Ic-107
CF2CF3
CF3
Me
H
H
H
C—F
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-108
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
3-
(methylsulfanyl)cyclobutyl
Ic-109
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
prop-2-yn-1-yl
Ic-110
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1,1,1-trifluoropropan-2-yl
Ic-111
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
buta-2,3-dien-1-yl
Ic-112
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
3-chloroprop-2-en-1-yl
Ic-113
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
isopropyl
Ic-114
CF3
CH2Cl
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropyl
Ic-115
CF3
CH2F
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-116
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-oxidothietan-3-yl
Ic-117
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1,1-dioxidothietan-3-yl
Ic-118
CF2CF3
CF3
Me
H
H
H
C—H
C-(E/Z)-
C—H
C—H
O
cyclopropyl
(methoxyimino)met
Ic-119
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-
(methylsulfanyl)cyclobutyl
Ic-120
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-
[(methylsulfanyl)methyl]cyclobutyl
Ic-121
CF2CF3
formyl
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-122
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
3-
(methylsulfonyl)cyclobutyl
Ic-123
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-
[(methylsulfinyl)methyl]cyclobutyl
Ic-124
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
(1S,2R)-2-
(methylsulfonyl)cyclobutyl
Ic-125
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-
(methylsulfinyl)cyclobutyl
Ic-126
CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropyl
Ic-127
CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-128
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
3-cyanothietan-3-yl
Ic-129
CF2CF3
CF3
Me
H
H
H
C—H
C—Me
C—H
C—H
O
1-cyanocyclopropyl
Ic-130
CF2CF3
CF3
Me
H
H
H
C—H
C—Me
C—H
C—H
O
cyclopropyl
Ic-131
CF2CF3
CF3
Me
H
H
H
C—H
C—Me
C—H
C—H
O
4-fluorophenyl
Ic-132
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
S
cyclopropyl
Ic-133
CF3
CHF2
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropyl
Ic-134
CF3
S(O)Me
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-135
CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
phenyl
Ic-136
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
phenyl
Ic-137
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
3-methylbutan-2-yl
Ic-138
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-(dimethylamino)ethyl
Ic-139
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-methoxyethyl
Ic-140
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
pyridin-2-yl
Ic-141
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclopentyl
Ic-142
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
isobutyl
Ic-143
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclobutyl
Ic-144
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1H-tetrazol-5-yl
Ic-145
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1,2-oxazol-3-yl
Ic-146
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1H-imidazol-2-ylmethyl
Ic-147
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyanomethyl
Ic-148
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
5-methyl-1,2-oxazol-3-yl
Ic-149
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
pyridin-3-yl
Ic-150
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1H-pyrazol-3-yl
Ic-151
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
3-chloropropyl
Ic-152
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
methyl
Ic-153
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropylmethyl
Ic-154
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-amino-1-oxopropan-2-yl
Ic-155
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
methoxy
Ic-156
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-amino-2-oxoethyl
Ic-157
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1H-pyrazol-3-ylmethyl
Ic-158
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
5-methyl-1,3,4-oxadiazol-
2-yl
Ic-159
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-methyl-1H-pyrazol-3-yl
Ic-160
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
4-methyl-1,3-oxazol-2-yl
Ic-161
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyclopropylpropan-2-yl
Ic-162
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
5-hydroxy-1H-pyrazol-3-
Ic-163
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-methyl-1H-pyrazol-5-yl
Ic-164
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
(3R)-tetrahydrofuran-3-yl
Ic-165
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-methoxypropan-2-yl
Ic-166
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-methyl-1H-pyrazol-4-yl
Ic-167
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-(methylsulfanyl)ethyl
Ic-168
CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-fluoroethyl
Ic-169
CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2,2,2-trifluoroethyl
Ic-170
CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2,2-difluoroethyl
Ic-171
CF2CF3
CF3
Me
H
H
H
C—H
C—H
H
C-0-
O
cyclopropyl
CF2-0-C
Ic-172
CF2CF3
CF3
Me
H
H
H
C—H
C—H
H
C-0-
O
1-cyanocyclopropyl
CF2-0-C
Ic-173
CF2CF3
CF3
Me
H
H
H
C—H
C—F
C-
C—H
O
cyclopropyl
sulfamoyl
Ic-174
CF2CF3
CF3
Me
H
H
H
C—F
C—F
C—H
C—H
O
cyclopropyl
Ic-175
CF2CF3
CF3
Me
H
H
H
C—F
C—F
C—H
C—H
O
1-cyanocyclopropyl
Ic-176
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-ethoxycyclopropyl
Ic-177
CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-fluorocyclopropyl
Ic-178
CF2CF3
CF3
Me
H
H
H
N
C—H
N
C—H
O
cyclopropyl
Ic-179
CF2CF3
CF3
Me
H
H
H
N
C—H
N
C—H
O
1-cyanocyclopropyl
Ic-180
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
(1R,2R)-2-
ethoxycyclopropyl
Ic-181
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-(CF3)cyclopropyl
Ic-182
CF2CF3
CF3
Me
H
H
H
C—H
C—SMe
C—H
C—H
O
cyclopropyl
Ic-183
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
(1S,2S,3S)-2-ethoxy-3-
methylcyclopropyl
Ic-184
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2,2-dichlorocyclopropyl
Ic-185
CF2CF3
CF3
Me
H
H
H
C—H
C-
C—H
C—H
O
cyclopropyl
diethylsulfamoyl
Ic-186
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
(1S,28)-2-
ethoxycyclopropyl
Ic-187
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-methoxycyclopropyl
Ic-188
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1,1′-bi(cyclopropyl)-1-yl
Ic-189
CF2CF3
CF3
Me
H
H
H
C—H
C—S(O)Me
C—H
C—H
O
cyclopropyl
Ic-190
CF2CF3
CF3
Me
H
H
H
C—H
C—S(0)2Me
C—H
C—H
O
cyclopropyl
Ic-191
CF2CF3
CF3
Me
H
H
amino
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-192
CF2CF3
CF3
Me
H
H
amino
C—H
C—Cl
C—H
C—H
O
cyclopropyl
Ic-193
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
but-3-yn-2-yl
Ic-194
CF2CF3
SMe
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-195
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C-
C—H
O
cyclopropyl
sulfamoyl
Ic-196
CF2CF3
CF3
Me
H
H
H
C—H
C—CF3
C—H
C—H
O
cyclopropyl
Ic-197
CF2CF3
CF3
Me
Et
H
H
C—H
C-
C—H
C—H
O
ethyl
cyclopropylsulfamoyl
Ic-198
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
pent-3-yn-2-yl
Ic-199
CF2CF3
CF3
Me
Me
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropyl
Ic-200
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-methylcyclopropyl
Ic-201
CF2CF3
CF3
Me
H
H
H
C—H
C—F
C—F
C—F
O
cyclopropyl
Ic-202
CF2CF3
CF3
Me
H
H
H
C—H
C—F
C—F
C—F
O
1-cyanocyclopropyl
Ic-203
CF2CF3
CF3
Me
H
H
H
C—H
C—CF3
C—H
C—H
O
1-cyanocyclopropyl
Ic-204
CF2CF3
CF3
Me
nPr
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-205
CF2CF3
CF3
Me
propionyl
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-206
CF2CF3
CF3
Me
allyl
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-207
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyclopropylethyl
Ic-208
CF2CF3
CF3
Me
Et
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-209
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
4-fluorophenyl
Ic-210
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyclobutylcyclopropyl
Ic-211
CF2CF3
CF3
Me
Et
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropyl
Ic-212
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
N
O
cyclopropyl
Ic-213
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
N
O
1-cyanocyclopropyl
Ic-214
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
pyrazin-2-yl
or an agrochemically acceptable salt or N-oxide thereof. 6. The method according to claim 1, wherein the compound is selected from 7. A method according to claim 1, wherein the stinkbug is selected from Nezara spp. (e.g. Nezara viridula, Nezara antennata, Nezara hilare), Piezodorus spp. (e.g. Piezodorus guildinii), Acrosternum spp. (e.g. Acrosternum hilare), Euchistus spp. (e.g. Euchistus heros, Euschistus servus), Halymorpha spp. (e.g. Halyomorpha halys), Plautia crossota, Riptortus clavatus, Rhopalus msculatus, Antestiopsis spp. (e.g. Antestiopsis orbitalus), Dichelops spp. (e.g. Dichelops furcatus, Dichelops melacanthus), Edessa spp. (e.g. Edessa meditabunda), Eurygaster spp. (e.g. Eurygaster intergriceps, Eurygaster maura), Murgantia spp., Oebalus spp. (e.g. Oebalus mexicana, Oebalus poecilus, Oebalus pugnase, Oebalus pugnax), Thianta spp., Pentatomidae, Lygus spp. (e.g. Lygus lineolaris, Lygus hesperus, Lygus elisus), Thyanta spp., Tibraca spp. and Scotinophara spp. (e.g. Scotinophara lurida, Scotinophara coarctata). 8. A method according to claim 1, wherein the stinkbug is from the genus Euschistus. 9. The method according to claim 1, wherein the stinkbug is Euschistus heros. 10. (canceled) 11. (canceled) 12. (canceled) 13. (canceled) 14. A method for obtaining regulatory approval for the use of a compound as defined in claim 1 for controlling and/or preventing infestation of stinkbugs, particularly Euschistus spp., comprising at least one step of referring to, submitting or relying on biological data showing that said active ingredient reduces stinkbug pressure. 15. The method according to claim 1, wherein the plant is selected from soybean, sorghum, sunflower, sugarbeet, cereals, coffee, cocoa, corn, cotton, citrus fruits, grapes, potato, rice, sugarcane and vegetables. 16. The method according claim 1, wherein the plant is selected from soybean and sunflower, in particular soybean. 17. A method for growing soybean comprising applying or treating soybean or a seed thereof with a compound as defined in claim 1.
|
The present invention relates to methods for controlling and/or preventing infestation of stinkbugs, comprising applying to a crop of plants, the locus thereof, or propagation material thereof, a compound of formula I wherein R 1 , R 6a , R 6b Q, W, A 1 , A 2 , A 3 , A 4 , Z 1 , Z 2 and Z 3 are as defined in the description.1. A method of controlling and/or preventing infestation of stinkbugs comprising applying to a crop of plants, the locus thereof, or propagation material thereof, a compound of formula (I)
wherein
R1 is selected from H, C1-C6-alkyl, C3-C6 alkenyl, C3-C6 alkinyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C3-alkyl, C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonyl, aryl(C1-C3)-alkyl and heteroaryl(C1-C3)-alkyl, wherein each of C1-C6-alkyl, C3-C6 alkenyl, C3-C6 alkinyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C3-alkyl, C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonyl, aryl(C1-C3)-alkyl and heteroaryl(C1-C3)-alkyl is unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, cyano, C1-C6-alkoxy and C1-C6-alkoxycarbonyl;
Q is selected from H, hydroxy, HC(═O)—, C1-C6-alkyl, C1-C6-alkoxy, C3-C6 alkenyl, C3-C6 alkinyl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, C3-C7 cycloalkyl-C1-C3-alkyl, C1-C3-alkyl-C3-C7 cycloalkyl, aryl(C1-C3)-alkyl, heteroaryl(C1-C3)-alkyl, N—C1-C6-alkylamino, N—C1-C6-alkylcarbonylamino and N,N-di (C1-C6-alkyl)amino, wherein each of C1-C6-alkyl, C1-C6-alkoxy, C3-C6 alkenyl, C3-C6 alkinyl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, C3-C7 cycloalkyl-C1-C3-alkyl, C1-C3-alkyl-C3-C7 cycloalkyl, aryl(C1-C3)-alkyl, heteroaryl(C1-C3)-alkyl, N—C1-C6-alkylamino, N—C1-C6-alkylcarbonylamino and N,N-di (C1-C6-alkyl)amino is unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, nitro, amino, cyano, C1-C6-alkoxy, C1-C6-alkoxycarbonyl, hydroxycarbonyl, C1-C6-alkylcarbamoyl, C3-C6-cycloalkylcarbamoyl and phenyl; A1 is CR2 or N;
A2 is CR3 or N;
A3 is CR4 or N;
A4 is CR5 or N;
with the proviso that no more than 3 of A1, A2, A3 and A4 are N;
R2, R3, R4 and R5 are independently selected from H, halogen, cyano, nitro, C1-C6-alkyl, C1-C6-alkoxy, N—C1-C6-alkoxy-imino-C1-C3-alkyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, N—C1-C6-alkylamino and N,N-di-C1-C6-alkylamino, wherein each of C1-C6-alkyl, C1-C6-alkoxy, N—C1-C6-alkoxy-imino-C1-C3-alkyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, N—C1-C6-alkylamino and N,N-di-C1-C6-alkylamino is unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, hydroxy, nitro, amino, cyano, C1-C6-alkoxy, C1-C6-alkoxycarbonyl, hydroxycarbonyl, C1-C6-alkylcarbamoyl, C3-C6-cycloalkylcarbamoyl and phenyl;
W is O or S;
R6a and R6b are independently selected from H, halogen, cyano, nitro, amino, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylcarbonyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, wherein each of C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylcarbonyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl is unsubstituted or substituted with 1 to 5 halogen;
Z1 is selected from C1-C6-halogenalkyl, C3-C6-cycloalkyl and C3-C6-halogencycloalkyl, wherein each of C1-C6-halogenalkyl, C3-C6-cycloalkyl and C3-C6-halogencycloalkyl is unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, hydroxy, nitro, amino, cyano, C1-C6-alkoxy, C1-C6-alkoxycarbonyl, hydroxycarbonyl, C1-C6-alkylcarbamoyl, C3-C6-cycloalkylcarbamoyl and phenyl;
Z2 is selected from H, halogen, cyano, nitro, amino, C1-C6-alkyl, C1-C6-alkylcarbonyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl and C1-C6-alkylsulfonyl, wherein each of C1-C6-alkyl, C1-C6-alkylcarbonyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl and C1-C6-alkylsulfonyl is unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, hydroxy, nitro, amino, cyano, C1-C6-alkoxy, C1-C6-alkoxycarbonyl, hydroxycarbonyl, C1-C6-alkylcarbamoyl, C3-C6-cycloalkylcarbamoyl and phenyl;
Z3 is selected from C1-C6-alkyl, C1-C6-cycloalkyl, C1-C6-alkenyl, C1-C6-alkinyl, aryl and heteroaryl, wherein each of C1-C6-alkyl, C1-C6-cycloalkyl, C1-C6-alkenyl, C1-C6-alkinyl, aryl and heteroaryl is unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, hydroxy, nitro, amino, cyano, C1-C6-alkoxy, C1-C6-alkoxycarbonyl, hydroxycarbonyl, C1-C6-alkylcarbamoyl, C3-C6-cycloalkylcarbamoyl and phenyl;
or an agrochemically acceptable salt or N-oxide thereof. 2. The method according to claim 1, wherein
R1 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, methoxymethyl, ethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, s-butylcarbonyl, t-butylcarbonyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, cyanomethyl, 2-cyanoethyl, benzyl, 4-methoxybenzyl, pyrid-2-yl-methyl, pyrid-3-yl-methyl, pyrid-4-yl-methyl and 4-chlor-pyrid-3-yl-methyl; Q is selected from H, methyl, ethyl, n-propyl, 1-methylethyl, 1,1-dimethylethyl, 1-methylpropyl, n-butyl, 2-methylpropyl, 2-methylbutyl, hydroxyethyl, 2-hydroxypropyl, cyanomethyl, 2-cyanoethyl, 2-fluorethyl, 2,2-difluorethyl, 2,2,2-trifluorethyl, 1-trifluormethylethyl, 2,2-difluorpropyl, 3,3,3-trifluorpropyl, 2,2-dimethyl-3-fluorpropyl, cyclopropyl, 1-cyano-cyclopropyl, 1-methoxycarbonyl-cyclopropyl, 1-(N-methylcarbamoyl)cyclopropyl, 1-carbamoyl-cyclopropyl, 1-carbamothioyl-cyclopropyl, 1-(N-cyclopropylcarbamoyl)cyclopropyl, cyclopropyl-methyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclopropylethyl, bis(cyclopropyl)methyl, 2,2-dimethylcyclopropyl-methyl, 2-phenylcyclopropyl, 2,2-dichlorcyclopropyl, trans-2-chlorcyclopropyl, cis-2-chlorcyclopropyl, 2,2-difluorcyclopropyl, trans-2-fluorcyclopropyl, cis-2-fluorcyclopropyl, trans-4-hydroxycyclohexyl, 4-trifluormethylcyclohexyl, prop-2-enyl, 2-methylprop-2-enyl, prop-2-inyl, 1,1-dimethylbut-2-inyl, 3-chlor-prop-2-enyl, 3-fluor-prop-2-enyl, 3,3-dichlor-prop-2-enyl, 3,3-dichlor-1,1-dimethylprop-2-enyl, oxetan-3-yl, thietan-3-yl, l-oxido-thietan-3-yl, l,l-dioxido-thietan-3-yl, isoxazol-3-ylmethyl, l,2,4-triazol-3-ylmethyl, 3-methyloxetan-3-ylmethyl, benzyl, 2,6-difluorphenylmethyl, 3-fluorphenylmethyl, 2-fluorphenylmethyl, 2,5-difluorphenylmethyl, 1-phenylethyl, 4-chlorphenylethyl, 2-trifluormethylphenylethyl, 1-pyridin-2-ylethyl, pyridin-2-ylmethyl, 5-fluorpyridin-2-ylmethyl, (6-chlor-pyridin-3-yl)methyl, pyrimidin-2-ylmethyl, methoxy, 2-ethoxyethyl, 2-methoxyethyl, 2-(methylsulfanyl)ethyl, l-methyl-2-(ethylsulfanyl)ethyl, 2-methyl-1-(methylsulfanyl)propan-2-yl, methoxycarbonyl, methoxycarbonylmethyl, NH2, N-ethylamino, N-allylamino, N,N-dimethylamino and N,N-diethylamino; or Q is selected from phenyl, naphthyl, pyridazin, pyrazin, pyrimidin, triazin, pyridin, pyrazol, thiazol, isothiazol, oxazol, isoxazol, triazol, imidazol, furan, thiophen, pyrrol, oxadiazol, and thiadiazol, each of which is unsubstituted or substituted with 1 to 4 substituents independently selected from V; V is selected from fluoro, chloro, bromo, iodo, Cyano, nitro, methyl, ethyl, difluormethyl, trichloromethyl, chlordifluoromethyl, dichlorofluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,2,2,2-tetrafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2,2,2-trichloroethyl, 2-chloro-2,2-difluoroethyl, 1,1-dilfluoroethyl, pentafluoroethyl heptafluoro-n-propyl, heptafluoro-isopropyl, nonafluoro-n-butyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, n-propoxy, 1-methylethoxy, fluormethoxy, difluormethoxy, chloro-difluormethoxy, dichloro-fluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluorethoxy, pentafluorethoxy, N-methoxyiminomethyl, l-(N-methoxyimino)-ethyl, methylsulfanyl, methylsulfonyl, methylsulfinyl, trifluormethylsulfonyl, trifluormethylsulfinyl, trifluormethylsulfanyl and N,N-dimethylamino; W is O or S; A1 is CR2 or N; A2 is CR3 or N; A3 is CR4 or N; A4 is CR5 or N; with the proviso that no more than 3 of A1, A2, A3 and A4 are N; R2 and R5 are independently selected from H, methyl, fluoro and chloro; R3 and R4 are independently selected from H, fluoro, chloro, bromo, iodo, cyano, nitro, methyl, ethyl, fluoromethyl, difluoromethyl, chlordifluormethyl, trifluormethyl, 2,2,2-trilfluoroethyl, methoxy, ethoxy, n-propoxy, 1-methylethoxy, fluoromethoxy, difluoromethoxy, chloro-difluoromethoxy, dichloro-fluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluorethoxy, pentafluoroethoxy, N-methoxyiminomethyl, l-(N-methoxyimino)-ethyl, methylsulfanyl, trifluoromethylsulfanyl, methylsulfonyl, methylsulfinyl, trifluormethylsulfonyl and trifluormethylsulfinyl; R6a and R6b are independently selected from halogen, cyano, nitro, amino, methyl, ethyl, propyl, 1-methylethyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, methylcarbonyl, ethylcarbonyl, trifluoromethylcarbonyl, methylsulfanyl, methylsulfinyl, methylsulfonyl, trifluoromethylsulfonyl, trifluoromethylsulfanyl and trilfluoromethylsulfinyl; Z1 is selected from methyl, ethyl, 1,1-dimethylethyl, difluoromethyl, trichloromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trifluoromethyl, bromodichloromethyl, 1-fluoroethyl, 1-fluoro-1-methylethyl, 2-fluoroethyl, 2,2-difluorethyl, 2,2,2-trifluoroethyl, 1,2,2,2-tetrafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2,2,2-trichloroethyl, 2-chloro-2,2-difluoroethyl, 1,1-difluoroethyl, pentafluoroethyl heptafluor-n-propyl, heptafluor-isopropyl, nonafluoro-n-butyl, cyclopropyl, 1-chlorocyclopropyl, 1-fluorocyclopropyl, 1-bromocyclopropyl, 1-cyano-cyclopropyl, 1-trifluoromehtyl-cyclopropyl, cyclobutyl and 2,2-Difluor-l-methyl-cyclopropyl; Z2 is selected from H, halogen, cyano, nitro, amino, methyl, ethyl, 1,1-dimethylethyl, difluoromethyl, trichloromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trifluoromethyl, bromodichloromethyl, 1-fluoroethyl, 1-fluoro-1 methylethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,2,2,2-tetrafluoroethyl, 1-chlor-1,2,2,2-tetrafluoroethyl, 2,2,2-trichloroethyl, 2-chloro-2,2-difluoroethyl, 1,1-difluoroethyl, pentafluoroethyl heptafluoro-n-propyl, heptafluoro-isopropyl, nonafluoro-n-butyl, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylthio, ethylsulfinyl, ethylsulfonyl, trifluoromethylsulfanyl, trifluoromethylsulfinyl, trifluoromethylsulfonyl, chloro-difluoromethylsulfanyl, chloro-difluoromethylsulfinyl, chloro-difluoromethylsulfonyl, dichloro-fluoromethylsulfanyl, dichloro-fluoromethylsulfinyl, dichloro-fluoromethylsulfonyl; and Z3 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, ethenyl, 1-propenyl, 1-propinyl, 1-butinyl, difluoromethyl, trichloromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trifluoromethyl, 1-fluoroethyl, 1 fluoro-1-methylethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,6-dichlorophenyl 2,6-dichloro-4-trifluoromethylphenyl and 3-chlor-5-trifluormethylpyridin-2-yl. 3. The method according to claim 1, wherein R1 is H, methyl, ethyl, n-propyl, n-propylcarbonyl and propenyl;
Q is selected from 1-cyano-cyclopropyl, benzyl, cyclopropyl, 2-thienylmethyl, carbamothioylcyclopropyl, pyrid-4-yl, 2,2,2-trifluorethyl, methylsulfonyl, thietan-3-yl and 1-carbamoylcyclopropyl; W is O; A1 and A4 are CH; A2 is CH or CF; A3 is CH or CCl; R6a is H or methyl; R6b is H, methyl or CF3; Z1 is CF2CF3; Z2 is CF3; Z3 is selected from methyl, ethyl, phenyl, 4-NO2-phenyl and 3-chlorpyridin-2-yl. 4. The method according to claim 1, wherein
R1 is H or methyl; Q is selected from 1-cyano-cyclopropyl, benzyl, cyclopropyl, 2-thienylmethyl, carbamothioylcyclopropyl, pyrid-4-yl, 2,2,2-trifluorethyl, methylsulfonyl, thietan-3-yl and 1-carbamoylcyclopropyl; W is O; A1 and A4 are CH; A2 is N; A3 is CH or CCl; R6a is H or methyl; R6b is H, methyl or CF3; Z1 is CF2CF3; Z2 is CF3; Z3 is methyl, ethyl, phenyl, 4-NO2-phenyl, 3-chloropyridin-2-yl. 5. The method according to claim 1, wherein the compound is selected from a compound of formula (I)
wherein Z1, Z2, Z3, R6a, R6b, A1, A2, A3, A4, W, Q and R1 are as defined in the table below
Ex no
Z1
Z2
Z3
R1
R6a
R6b
A4
A3
A2
A1
W
Q
Ic-2
CF2CF3
CF3
CH3
H
H
H
C—H
C—Cl
C—H
C—H
O
1-Cyano-cyclopropyl
Ic-3
CF2CF3
CF3
CH3
H
H
H
C—H
C—Cl
C—H
C—H
O
Benzyl
Ic-4
CF2CF3
CF3
CH3
H
H
CF3
C—H
C—Cl
C—H
C—H
O
Cyclopropyl
Ic-5
CF2CF3
CF3
CH3
H
CH3
CF3
C—H
C—Cl
C—H
C—H
O
Cyclopropyl
Ic-6
CF2CF3
CF3
Phenyl
H
H
H
C—H
C—Cl
C—H
C—H
O
Cyclopropyl
Ic-7
CF2CF3
CF3
Phenyl
H
H
H
C—H
C—Cl
C—H
C—H
O
1-Cyano-cyclopropyl
Ic-8
CF2CF3
CF3
4-N02-
H
H
H
C—H
C—Cl
C—H
C—H
O
Cyclopropyl
Phenyl
Ic-9
CF2CF3
CF3
CH3
H
CH3
CH3
C—H
C—Cl
C—H
C—H
O
Cyclopropyl
Ic-10
CF2CF3
CF3
CH3
H
H
H
C—H
C—Cl
C—H
C—H
O
2-Thienylmethyl
Ic-11
CF2CF3
CF3
CH3
H
H
H
C—H
C—Cl
C—H
C—H
O
1-
Carbamothioylcyclopropyl
Ic-12
CF2CF3
CF3
CH3
H
H
CH3
C—H
C—Cl
C—H
C—H
O
Cyclopropyl
Ic-13
CF2CF3
CF3
CH3
H
CH3
H
C—H
C—Cl
C—H
C—H
O
Cyclopropyl
Ic-14
CF2CF3
CF3
3-Chlorpyridin-2-yl
H
H
H
C—H
C—Cl
C—H
C—H
O
Cyclopropyl
Ic-15
CF2CF3
CF3
3-
H
H
H
C—H
C—Cl
C—H
C—H
O
1-Cyano-cyclopropyl
Chlorpyridin-2-yl
Ic-16
CF2CF3
CF3
CH2CH3
H
H
H
C—H
C—Cl
C—H
C—H
O
Cyclopropyl
Ic-17
CF2CF3
CF3
CH3
H
H
H
C—H
C—H
C—H
C—H
O
Benzyl
Ic-18
CF2CF3
CF3
CH3
H
H
H
C—H
C—H
C—H
C—H
O
Cyclopropyl
Ic-19
CF2CF3
CF3
CH3
H
H
H
C—H
C—H
C—H
C—H
O
1-Cyano-cyclopropyl
Ic-20
CF2CF3
CF3
CH3
H
H
H
C—H
C—H
C—H
C—H
O
2-Thienylmethyl
Ic-21
CF2CF3
CF3
CH2CH3
H
H
H
C—H
C—Cl
C—H
C—H
O
1-Cyano-cyclopropyl
Ic-22
CF2CF3
CF3
CH3
H
H
H
C—H
C—Cl
C—H
C—H
O
Pyrid-4-yl
Ic-23
CF2CF3
CF3
CH3
H
H
H
C—H
C—Cl
C—H
C—H
O
2,2,2-Trifluorethyl
Ic-24
CF2CF3
CF3
CH3
H
H
H
C—H
C—Cl
C—F
C—H
O
Cyclopropyl
Ic-25
CF2CF3
CF3
CH3
H
H
H
C—H
C—Cl
C—H
C—H
O
4-Chlorphenyl
Ic-26
CF2CF3
CF3
CH3
H
H
H
C—H
C—Cl
C—H
C—H
O
Methylsulfonyl
Ic-27
CF2CF3
CF3
CH3
H
H
H
C—H
C—Cl
C—F
C—H
O
1-Cyano-cyclopropyl
Ic-28
CF2CF3
CF3
CH3
H
H
H
C—H
C—Cl
C—H
C—H
O
Thietan-3-yl
Ic-29
CF2CF3
CF3
CH3
H
H
H
C—H
C—Cl
C—H
C—H
O
1-Carbamoylcyclopropyl
Ic-30
CF3
CN
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropyl
Ic-31
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-oxo-2-[(2,2,2-
trifluoroethyl)amino]ethyl
Ic-32
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-(CF3)cyclopropyl
Ic-33
CF2CF3
CF3
Me
H
H
H
C—F
C—H
C—H
C—H
O
cyclopropyl
Ic-34
CF2CF3
CF3
Me
H
H
H
C—H
C—Br
C—H
C—H
O
1-cyanocyclopropyl
Ic-35
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—H
C—H
O
H
Ic-36
CF2CF3
CF3
Me
H
H
H
C—H
C—F
C—H
C—H
O
1-cyanocyclopropyl
Ic-37
CF2CF3
CF3
Me
H
H
H
C—H
C—F
C—H
C—H
O
cyclopropyl
Ic-38
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—F
C—H
O
1-cyanocyclopropyl
Ic-39
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—F
C—H
O
cyclopropyl
Ic-40
CF2CF3
CF3
Me
H
H
H
C—F
C—H
C—H
C—H
O
1-cyanocyclopropyl
Ic-41
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—H
C—F
O
cyclopropyl
Ic-42
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—H
C—F
O
1-cyanocyclopropyl
Ic-43
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—Cl
C—H
O
1-cyanocyclopropyl
Ic-44
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—Cl
C—H
O
cyclopropyl
Ic-45
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—H
C—Cl
O
1-cyanocyclopropyl
Ic-46
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—H
C—Cl
O
cyclopropyl
Ic-47
CF2CF3
CF3
Me
H
H
H
C—H
C—F
C—F
C—H
O
1-cyanocyclopropyl
Ic-48
CF2CF3
CF3
Me
H
H
H
C—H
C—F
C—H
C—Cl
O
1-cyanocyclopropyl
Ic-49
CF2CF3
CF3
Me
H
H
H
C—H
C—F
C—H
C—Cl
O
cyclopropyl
Ic-50
CF3
(E/Z) (hydroxyimino)methyl
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropyl
Ic-51
CF3
(E/Z)
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropyl
(methoxyimino)methyl
Ic-52
CF3
formyl
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropyl
Ic-53
CF3
CN
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-54
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—Me
C—H
O
cyclopropyl
Ic-55
CF2CF3
CF3
Me
H
H
H
C—H
C—F
C—F
C—H
O
cyclopropyl
Ic-56
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—Me
C—H
O
1-cyanocyclopropyl
Ic-57
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—H
C—Me
O
cyclopropyl
Ic-58
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—H
C—Me
O
1-cyanocyclopropyl
Ic-59
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—CF3
C—H
O
cyclopropyl
Ic-60
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—CF3
C—H
O
1-cyanocyclopropyl
Ic-61
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—F
C—F
O
cyclopropyl
Ic-62
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—
C—H
O
cyclopropyl
Ic-63
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—OMe
C—H
O
1-cyanocyclopropyl
Ic-64
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—F
C—F
O
1-cyanocyclopropyl
Ic-65
CF2CF3
CF3
Me
H
H
H
C—H
C—N02
C—H
C—H
O
1-cyanocyclopropyl
Ic-66
CF2CF3
CF3
Me
H
H
H
C—H
C—N02
C—H
C—H
O
cyclopropyl
Ic-67
CF2CF3
CF3
Me
H
H
H
C—H
C—OMe
C—H
C—H
O
1-cyanocyclopropyl
Ic-68
CF2CF3
CF3
Me
H
H
H
C—H
C—OMe
C—H
C—H
O
cyclopropyl
Ic-69
CF3
CH2OH
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropyl
Ic-70
CF2CF3
CF3
Me
H
H
H
C—H
C—H
N
C—H
O
cyclopropyl
Ic-71
CF2CF3
CF3
Me
H
H
H
C—H
C—H
N
C—H
O
1-cyanocyclopropyl
Ic-72
CF2CF3
CF3
Me
H
H
H
C—H
N
C—H
C—F
O
cyclopropyl
Ic-73
CF2CF3
CF3
Me
H
H
H
C—H
N
C—H
C—F
O
1-cyanocyclopropyl
Ic-74
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—OCF3
C—H
O
cyclopropyl
Ic-75
CF2CF3
CF3
Me
H
H
H
C—H
C—H
C—OCF3
C—H
O
1-cyanocyclopropyl
Ic-76
CF2CF3
CF3
Me
H
H
H
C—H
N
C—H
C—H
O
1-cyanocyclopropyl
Ic-77
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-fluoroethyl
Ic-78
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2,2-difluoroethyl
Ic-79
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-methylcyclopropyl
Ic-80
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2,2-difluoropropyl
Ic-81
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-fluorocyclopropyl
Ic-83
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
N
C—H
O
1-cyanocyclopropyl
Ic-84
CF2CF3
CF3
Me
H
H
H
C—H
C—Me
N
C—H
O
cyclopropyl
Ic-85
CF2CF3
CF3
Me
H
H
H
C—H
C—Me
N
C—H
O
1-cyanocyclopropyl
Ic-86
CF2CF3
CF3
Me
H
H
H
C—H
C—OMe
N
C—H
O
cyclopropyl
Ic-87
CF2CF3
CF3
Me
H
H
H
C—H
C—OMe
N
C—H
O
1-cyanocyclopropyl
Ic-88
CF2CF3
CF3
Me
H
H
H
C—H
N
C—Cl
C—H
O
cyclopropyl
Ic-89
CF2CF3
CF3
Me
H
H
H
C—H
N
C—Cl
C—H
O
1-cyanocyclopropyl
Ic-90
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—Me
C—H
O
cyclopropyl
Ic-91
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—Me
C—H
O
1-cyanocyclopropyl
Ic-92
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—F
O
cyclopropyl
Ic-93
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—F
O
1-cyanocyclopropyl
Ic-94
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—Cl
C—H
O
cyclopropyl
Ic-95
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—Cl
C—H
O
1-cyanocyclopropyl
Ic-96
CF2CF3
CF3
Me
Me
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-97
CF2CF3
CF3
Me
Me
H
H
C—H
C—Cl
C—H
C—H
O
1-
Ic-98
CF3
(E/Z)
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
(hydroxyimino)methyl
Ic-99
CF3
(E/Z)
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
(methoxyimino)methyl
Ic-100
CF3
cyclopropylcarbamoyl
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropyl
Ic-101
CF3
cyclopropylcarbamoyl
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-102
CF3
formyl
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-103
CF3
CH2F
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropyl
Ic-104
CF3
CH2OH
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-105
CF2CF3
CF3
Me
H
H
H
N
C—H
C—H
C—H
O
1-cyanocyclopropyl
Ic-106
CF2CF3
CF3
Me
H
H
H
C—F
C—Cl
C—H
C—H
O
cyclopropyl
Ic-107
CF2CF3
CF3
Me
H
H
H
C—F
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-108
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
3-
(methylsulfanyl)cyclobutyl
Ic-109
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
prop-2-yn-1-yl
Ic-110
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1,1,1-trifluoropropan-2-yl
Ic-111
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
buta-2,3-dien-1-yl
Ic-112
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
3-chloroprop-2-en-1-yl
Ic-113
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
isopropyl
Ic-114
CF3
CH2Cl
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropyl
Ic-115
CF3
CH2F
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-116
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-oxidothietan-3-yl
Ic-117
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1,1-dioxidothietan-3-yl
Ic-118
CF2CF3
CF3
Me
H
H
H
C—H
C-(E/Z)-
C—H
C—H
O
cyclopropyl
(methoxyimino)met
Ic-119
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-
(methylsulfanyl)cyclobutyl
Ic-120
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-
[(methylsulfanyl)methyl]cyclobutyl
Ic-121
CF2CF3
formyl
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-122
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
3-
(methylsulfonyl)cyclobutyl
Ic-123
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-
[(methylsulfinyl)methyl]cyclobutyl
Ic-124
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
(1S,2R)-2-
(methylsulfonyl)cyclobutyl
Ic-125
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-
(methylsulfinyl)cyclobutyl
Ic-126
CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropyl
Ic-127
CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-128
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
3-cyanothietan-3-yl
Ic-129
CF2CF3
CF3
Me
H
H
H
C—H
C—Me
C—H
C—H
O
1-cyanocyclopropyl
Ic-130
CF2CF3
CF3
Me
H
H
H
C—H
C—Me
C—H
C—H
O
cyclopropyl
Ic-131
CF2CF3
CF3
Me
H
H
H
C—H
C—Me
C—H
C—H
O
4-fluorophenyl
Ic-132
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
S
cyclopropyl
Ic-133
CF3
CHF2
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropyl
Ic-134
CF3
S(O)Me
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-135
CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
phenyl
Ic-136
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
phenyl
Ic-137
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
3-methylbutan-2-yl
Ic-138
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-(dimethylamino)ethyl
Ic-139
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-methoxyethyl
Ic-140
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
pyridin-2-yl
Ic-141
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclopentyl
Ic-142
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
isobutyl
Ic-143
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclobutyl
Ic-144
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1H-tetrazol-5-yl
Ic-145
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1,2-oxazol-3-yl
Ic-146
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1H-imidazol-2-ylmethyl
Ic-147
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyanomethyl
Ic-148
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
5-methyl-1,2-oxazol-3-yl
Ic-149
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
pyridin-3-yl
Ic-150
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1H-pyrazol-3-yl
Ic-151
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
3-chloropropyl
Ic-152
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
methyl
Ic-153
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropylmethyl
Ic-154
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-amino-1-oxopropan-2-yl
Ic-155
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
methoxy
Ic-156
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-amino-2-oxoethyl
Ic-157
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1H-pyrazol-3-ylmethyl
Ic-158
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
5-methyl-1,3,4-oxadiazol-
2-yl
Ic-159
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-methyl-1H-pyrazol-3-yl
Ic-160
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
4-methyl-1,3-oxazol-2-yl
Ic-161
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyclopropylpropan-2-yl
Ic-162
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
5-hydroxy-1H-pyrazol-3-
Ic-163
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-methyl-1H-pyrazol-5-yl
Ic-164
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
(3R)-tetrahydrofuran-3-yl
Ic-165
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-methoxypropan-2-yl
Ic-166
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-methyl-1H-pyrazol-4-yl
Ic-167
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-(methylsulfanyl)ethyl
Ic-168
CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-fluoroethyl
Ic-169
CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2,2,2-trifluoroethyl
Ic-170
CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2,2-difluoroethyl
Ic-171
CF2CF3
CF3
Me
H
H
H
C—H
C—H
H
C-0-
O
cyclopropyl
CF2-0-C
Ic-172
CF2CF3
CF3
Me
H
H
H
C—H
C—H
H
C-0-
O
1-cyanocyclopropyl
CF2-0-C
Ic-173
CF2CF3
CF3
Me
H
H
H
C—H
C—F
C-
C—H
O
cyclopropyl
sulfamoyl
Ic-174
CF2CF3
CF3
Me
H
H
H
C—F
C—F
C—H
C—H
O
cyclopropyl
Ic-175
CF2CF3
CF3
Me
H
H
H
C—F
C—F
C—H
C—H
O
1-cyanocyclopropyl
Ic-176
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-ethoxycyclopropyl
Ic-177
CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-fluorocyclopropyl
Ic-178
CF2CF3
CF3
Me
H
H
H
N
C—H
N
C—H
O
cyclopropyl
Ic-179
CF2CF3
CF3
Me
H
H
H
N
C—H
N
C—H
O
1-cyanocyclopropyl
Ic-180
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
(1R,2R)-2-
ethoxycyclopropyl
Ic-181
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2-(CF3)cyclopropyl
Ic-182
CF2CF3
CF3
Me
H
H
H
C—H
C—SMe
C—H
C—H
O
cyclopropyl
Ic-183
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
(1S,2S,3S)-2-ethoxy-3-
methylcyclopropyl
Ic-184
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
2,2-dichlorocyclopropyl
Ic-185
CF2CF3
CF3
Me
H
H
H
C—H
C-
C—H
C—H
O
cyclopropyl
diethylsulfamoyl
Ic-186
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
(1S,28)-2-
ethoxycyclopropyl
Ic-187
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-methoxycyclopropyl
Ic-188
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1,1′-bi(cyclopropyl)-1-yl
Ic-189
CF2CF3
CF3
Me
H
H
H
C—H
C—S(O)Me
C—H
C—H
O
cyclopropyl
Ic-190
CF2CF3
CF3
Me
H
H
H
C—H
C—S(0)2Me
C—H
C—H
O
cyclopropyl
Ic-191
CF2CF3
CF3
Me
H
H
amino
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-192
CF2CF3
CF3
Me
H
H
amino
C—H
C—Cl
C—H
C—H
O
cyclopropyl
Ic-193
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
but-3-yn-2-yl
Ic-194
CF2CF3
SMe
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-195
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C-
C—H
O
cyclopropyl
sulfamoyl
Ic-196
CF2CF3
CF3
Me
H
H
H
C—H
C—CF3
C—H
C—H
O
cyclopropyl
Ic-197
CF2CF3
CF3
Me
Et
H
H
C—H
C-
C—H
C—H
O
ethyl
cyclopropylsulfamoyl
Ic-198
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
pent-3-yn-2-yl
Ic-199
CF2CF3
CF3
Me
Me
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropyl
Ic-200
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-methylcyclopropyl
Ic-201
CF2CF3
CF3
Me
H
H
H
C—H
C—F
C—F
C—F
O
cyclopropyl
Ic-202
CF2CF3
CF3
Me
H
H
H
C—H
C—F
C—F
C—F
O
1-cyanocyclopropyl
Ic-203
CF2CF3
CF3
Me
H
H
H
C—H
C—CF3
C—H
C—H
O
1-cyanocyclopropyl
Ic-204
CF2CF3
CF3
Me
nPr
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-205
CF2CF3
CF3
Me
propionyl
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-206
CF2CF3
CF3
Me
allyl
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-207
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyclopropylethyl
Ic-208
CF2CF3
CF3
Me
Et
H
H
C—H
C—Cl
C—H
C—H
O
1-cyanocyclopropyl
Ic-209
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
4-fluorophenyl
Ic-210
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
1-cyclobutylcyclopropyl
Ic-211
CF2CF3
CF3
Me
Et
H
H
C—H
C—Cl
C—H
C—H
O
cyclopropyl
Ic-212
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
N
O
cyclopropyl
Ic-213
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
N
O
1-cyanocyclopropyl
Ic-214
CF2CF3
CF3
Me
H
H
H
C—H
C—Cl
C—H
C—H
O
pyrazin-2-yl
or an agrochemically acceptable salt or N-oxide thereof. 6. The method according to claim 1, wherein the compound is selected from 7. A method according to claim 1, wherein the stinkbug is selected from Nezara spp. (e.g. Nezara viridula, Nezara antennata, Nezara hilare), Piezodorus spp. (e.g. Piezodorus guildinii), Acrosternum spp. (e.g. Acrosternum hilare), Euchistus spp. (e.g. Euchistus heros, Euschistus servus), Halymorpha spp. (e.g. Halyomorpha halys), Plautia crossota, Riptortus clavatus, Rhopalus msculatus, Antestiopsis spp. (e.g. Antestiopsis orbitalus), Dichelops spp. (e.g. Dichelops furcatus, Dichelops melacanthus), Edessa spp. (e.g. Edessa meditabunda), Eurygaster spp. (e.g. Eurygaster intergriceps, Eurygaster maura), Murgantia spp., Oebalus spp. (e.g. Oebalus mexicana, Oebalus poecilus, Oebalus pugnase, Oebalus pugnax), Thianta spp., Pentatomidae, Lygus spp. (e.g. Lygus lineolaris, Lygus hesperus, Lygus elisus), Thyanta spp., Tibraca spp. and Scotinophara spp. (e.g. Scotinophara lurida, Scotinophara coarctata). 8. A method according to claim 1, wherein the stinkbug is from the genus Euschistus. 9. The method according to claim 1, wherein the stinkbug is Euschistus heros. 10. (canceled) 11. (canceled) 12. (canceled) 13. (canceled) 14. A method for obtaining regulatory approval for the use of a compound as defined in claim 1 for controlling and/or preventing infestation of stinkbugs, particularly Euschistus spp., comprising at least one step of referring to, submitting or relying on biological data showing that said active ingredient reduces stinkbug pressure. 15. The method according to claim 1, wherein the plant is selected from soybean, sorghum, sunflower, sugarbeet, cereals, coffee, cocoa, corn, cotton, citrus fruits, grapes, potato, rice, sugarcane and vegetables. 16. The method according claim 1, wherein the plant is selected from soybean and sunflower, in particular soybean. 17. A method for growing soybean comprising applying or treating soybean or a seed thereof with a compound as defined in claim 1.
| 1,600 |
1,267 | 15,245,855 | 1,627 |
A combination comprising as components (a) the compound 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and (b) one or more non-steroidal anti-inflammatory drugs (NSAIDs); a pharmaceutical salt comprising said components; a compound derived from said components; a pharmaceutical formulation and a dosage form comprising said combination, salt, or compound; as well as a method of treating pain, e.g. chronic or acute pain, in a mammal characterized in that components (a) and (b) are administered simultaneously or sequentially to a mammal, wherein component (a) may be administered before or after component (b) and wherein components (a) or (b) are administered to the mammal either via the same or a different pathway of administration.
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1. A composition comprising:
(a) at least one 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I),
or a solvate or an acid addition salt thereof, and
(b) one or more non-steroidal anti-inflammatory drugs (NSAIDs). 2. The composition of claim 1, wherein said compound corresponding to formula (I) is present in the form of a pure enantiomer or pure diastereoisomer. 3. The composition of claim 1, wherein said compound corresponding to formula (I) is present in the form of a mixture of stereoisomers. 4. The composition of claim 1, wherein said compound corresponding to formula (I) is present in the form of a racemic mixture. 5. The composition of claim 1, wherein said compound corresponding to formula (I) is present in the form of a solvate. 6. The composition of claim 1, wherein said compound corresponding to formula (I) is present in the form of an acid addition salt. 7. The composition of claim 1, wherein said compound corresponding to formula (I) is selected from the group consisting of:
(1R,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and any mixture of (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1R,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and (1S,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol. 8. The composition of claim 1, wherein said compound corresponding to formula (I) is selected from the group consisting of:
(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and any mixture thereof. 9. The composition of claim 1, wherein said compound corresponding to formula (I) is a (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I′),
or an acid addition salt thereof. 10. The composition of claim 9, wherein said compound corresponding to formula (I) is in the form of an acid addition salt of hydrochloride. 11. The composition of claim 1, wherein said one or more non-steroidal anti-inflammatory drugs (NSAIDs) are selected from the group consisting of Acemetacin, Acetylsalicylic Acid, Bufexamac, Diclofenac, Diclofenac-Sodium, Diflunisal, Dipyrone (Metamizol), Metamizol-Sodium, Ethenzamide, Etofenamate, Flufenamic Acid, Flurbiprofen, Ibuprofen, Indomethacin, Isoxicam, Kebuzone, Ketoprofen, Ketorolac, Lonazolac, Lornoxicam, Meclofenamic Acid, Mefenamic acid, Mofebutazone, Nabumetone, Naproxen, (+)-Ibuprofen, (−)-Ibuprofen, (+)-Naproxen, Niflumic Acid, Oxaprozine, Oxyphenbutazone, Phenylbutazone, Piroxicam, Propyphenazone, Salicylamide, Sulindac, Tenoxicam, Tiaprofenic Acid, SC560; Sulphasalazine and Tolmetin. 12. The composition of claim 1, wherein said one or more non-steroidal anti-inflammatory drugs (NSAIDs) are selected from the group consisting of Acetylsalicylic Acid, Diclofenac, Diclofenac-Sodium, Dipyrone (Metamizol), Metamizol-Sodium, Flurbiprofen, Ibuprofen, Isoxicam, Ketoprofen, Naproxen, (+)-Ibuprofen, (−)-Ibuprofen, (+)-Naproxen, Phenylbutazone and Piroxicam. 13. The composition of claim 1, wherein said one or more non-steroidal anti-inflammatory drugs (NSAIDs) are selected from the group consisting of Acetylsalicylic Acid, Diclofenac, Diclofenac-Sodium, Flurbiprofen, Ibuprofen, Isoxicam, Ketoprofen, Naproxen, (+)-Ibuprofen, (−)-Ibuprofen, (+)-Naproxen, Phenylbutazone and Piroxicam. 14. The composition of claim 1, wherein said one or more non-steroidal anti-inflammatory drugs (NSAIDs) are selected from the group consisting of Diclofenac, Diclofenac-Sodium, Ibuprofen, Metamizol, Metamizol-Sodium, (+)-Naproxen and Ketoprofen. 15. The composition of claim 1, wherein said one or more non-steroidal anti-inflammatory drugs (NSAIDs) are selected from the group consisting of Diclofenac, Diclofenac-Sodium and Ibuprofen. 16. The composition of claim 1, wherein components (a) and (b) are present as a salt formed from these two components. 17. The composition of claim 1, wherein components (a) and (b) are present in a weight ratio such that the composition will exert a synergistic effect upon administration to a patient. 18. A salt comprising:
(a) at least one 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I),
or a solvate thereof, and
(b) one or more non-steroidal anti-inflammatory drugs (NSAIDs) having a group that is capable of forming a salt with component (a). 19. The salt of claim 18, wherein said compound corresponding to formula (I) is present in the form of a pure enantiomer or pure diastereoisomer. 20. The salt of claim 18, wherein said compound corresponding to formula (I) is present in the form of a mixture of stereoisomers. 21. The salt of claim 18, wherein said compound corresponding to formula (I) is present in the form of a racemic mixture. 22. The salt of claim 18, wherein said compound corresponding to formula (I) is present in the form of a solvate. 23. The salt claim 18, wherein the 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound forms a cationic salt component and the non-steroidal anti-inflammatory drug is acidic and forms an anionic salt component. 24. The salt of claim 18, wherein said compound corresponding to formula (I) is selected from the group consisting of:
(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1R,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol and a mixture of any of the foregoing. 25. The salt of claim 18, wherein said compound corresponding to formula (I) is selected from the group consisting of:
(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and a mixture thereof. 26. The salt of claim 18, wherein said compound corresponding to formula (I) is a (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I′) 27. The salt of claim 18, wherein the non-steroidal anti-inflammatory drug is selected from the group consisting of: Acetylsalicylic Acid, Diclofenac, Dipyrone (Metamizol), Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, (+)-Ibuprofen, (−)-Ibuprofen and (+)-Naproxen. 28. The salt of claim 18, wherein the non-steroidal anti-inflammatory drug is selected from the group consisting of: Diclofenac, Dipyrone (Metamizol), Ibuprofen, Ketoprofen, (+)-Naproxen and Naproxen. 29. A compound corresponding to formula (I″)
wherein R is an active fragment of a non-steroidal anti-inflammatory drug (NSAID) that is attached to the oxygen atom via a covalent bond,
or a solvate or an acid addition salt thereof. 30. The compound of claim 29, wherein said compound corresponding to formula (I″) is present in the form of a pure enantiomer or pure diastereoisomer. 31. The compound of claim 29, wherein said compound corresponding to formula (I″) is present in the form of a mixture of stereoisomers. 32. The compound of claim 29, wherein said compound corresponding to formula (I″) is present in the form of a racemic mixture. 33. The compound of claim 29, wherein said compound corresponding to formula (I″) is present in the form of a solvate. 34. The compound of claim 29, wherein said compound corresponding to formula (I″) is present in the form of an acid addition salt. 35. The compound of claim 29, wherein the portion of said compound attached to R is a dehydrogenate residue of
(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or any mixture thereof. 36. The compound of claim 29, wherein the portion of said compound attached to R is a dehydrogenated residue of:
(1R,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol or any mixture of dehydrogenated residues of (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1R,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and (1S,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol. 37. The compound of claim 29, wherein the portion of said compound attached to R is a dehydrogenated residue of a (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to of formula (I′) 38. The compound of claim 29, wherein said non-steroidal anti-inflammatory drug is selected from Acetylsalicylic Acid, Diclofenac, Dipyrone (Metamizol), Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, (+)-Ibuprofen, (−)-Ibuprofen and (+)-Naproxen. 39. The compound of claim 29, wherein said non-steroidal anti-inflammatory drug is selected from Diclofenac, Dipyrone (Metamizol), Ibuprofen, Ketoprofen, Naproxen and (+)-Naproxen. 40. A composition comprising a combination of at least two of (i), (ii) and (iii), wherein
(i) is a composition comprising (a) at least one 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I),
or a solvate or an acid addition salt thereof, and
(b) one or more non-steroidal anti-inflammatory drugs (NSAIDs).
(ii) is a salt comprising:
(c) at least one 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I),
or a solvate thereof, and
(d) one or more non-steroidal anti-inflammatory drugs (NSAIDs) having a group that is capable of forming a salt with component (c), and
(iii) is a compound corresponding to formula (I″)
wherein R is an active fragment of a non-steroidal anti-inflammatory drug (NSAID) that is attached to the oxygen atom via a covalent bond,
or a solvate or an acid addition salt thereof,
and one or more auxiliary agents. 41. The composition of claim 40, wherein said composition is in the form of a pharmaceutical dosage formulation and said composition comprises a pharmaceutically effective amount of at least two of (i), (ii) and (iii). 42. The composition of claim 41, wherein said pharmaceutical dosage formulation is suitable for oral, intravenous, intraperitoneal, intradermal, intrathekal, intramuscular, intranasal, transmucosal, subcutaneous, or rectal administration. 43. The composition of claim 41, wherein at least one of (a), (b), (ii) and (iii) are present in a controlled-release form. 44. The composition of claim 40, further comprising caffeine. 45. A method of manufacturing a composition, said method comprising the step of combining at least two of (i), (ii) and (iii), wherein
(i) is a composition comprising (a) at least one 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I),
or a solvate or an acid addition salt thereof, and
(b) one or more non-steroidal anti-inflammatory drugs (NSAIDs).
(ii) is a salt comprising:
(c) at least one 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I),
or a solvate thereof, and
(d) one or more non-steroidal anti-inflammatory drugs (NSAIDs) having a group that is capable of forming a salt with component (c), and
(iii) is a compound corresponding to formula (I″)
wherein R is an active fragment of a non-steroidal anti-inflammatory drug (NSAID) that is attached to the oxygen atom via a covalent bond,
or a solvate or an acid addition salt thereof. 46. A method of treating pain in a mammal, said method comprising the step of administering to said mammal a pharmaceutically effective amount of one or more auxiliary agents and a combination of at least two of (i), (ii) and (iii), wherein
(i) is a composition comprising (a) at least one 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I),
or a solvate or an acid addition salt thereof, and
(b) one or more non-steroidal anti-inflammatory drugs (NSAIDs).
(ii) is a salt comprising:
(c) at least one 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I),
or a solvate thereof, and
(d) one or more non-steroidal anti-inflammatory drugs (NSAIDs) having a group that is capable of forming a salt with component (c), and
(iii) is a compound corresponding to formula (I″)
wherein R is an active fragment of a non-steroidal anti-inflammatory drug (NSAID) that is attached to the oxygen atom via a covalent bond,
or a solvate or an acid addition salt thereof. 47. The method of claim 46, wherein components (a) and (b) are administered sequentially to the mammal and compound (a) may be administered before or after compound (b). 48. The method of claim 47, wherein components (a) and (b) are administered to the mammal simultaneously. 49. The method of claim 47, wherein components (a) and (b) are administered to the mammal by different administration pathways. 50. The method of claim 47, wherein components (a) and (b) are administered to the mammal by the same administration pathway. 51. The method of claim 46, wherein the pain is selected from inflammatory pain, neuropathic pain, acute pain, chronic pain, visceral pain, migraine pain and cancer pain.
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A combination comprising as components (a) the compound 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and (b) one or more non-steroidal anti-inflammatory drugs (NSAIDs); a pharmaceutical salt comprising said components; a compound derived from said components; a pharmaceutical formulation and a dosage form comprising said combination, salt, or compound; as well as a method of treating pain, e.g. chronic or acute pain, in a mammal characterized in that components (a) and (b) are administered simultaneously or sequentially to a mammal, wherein component (a) may be administered before or after component (b) and wherein components (a) or (b) are administered to the mammal either via the same or a different pathway of administration.1. A composition comprising:
(a) at least one 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I),
or a solvate or an acid addition salt thereof, and
(b) one or more non-steroidal anti-inflammatory drugs (NSAIDs). 2. The composition of claim 1, wherein said compound corresponding to formula (I) is present in the form of a pure enantiomer or pure diastereoisomer. 3. The composition of claim 1, wherein said compound corresponding to formula (I) is present in the form of a mixture of stereoisomers. 4. The composition of claim 1, wherein said compound corresponding to formula (I) is present in the form of a racemic mixture. 5. The composition of claim 1, wherein said compound corresponding to formula (I) is present in the form of a solvate. 6. The composition of claim 1, wherein said compound corresponding to formula (I) is present in the form of an acid addition salt. 7. The composition of claim 1, wherein said compound corresponding to formula (I) is selected from the group consisting of:
(1R,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and any mixture of (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1R,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and (1S,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol. 8. The composition of claim 1, wherein said compound corresponding to formula (I) is selected from the group consisting of:
(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and any mixture thereof. 9. The composition of claim 1, wherein said compound corresponding to formula (I) is a (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I′),
or an acid addition salt thereof. 10. The composition of claim 9, wherein said compound corresponding to formula (I) is in the form of an acid addition salt of hydrochloride. 11. The composition of claim 1, wherein said one or more non-steroidal anti-inflammatory drugs (NSAIDs) are selected from the group consisting of Acemetacin, Acetylsalicylic Acid, Bufexamac, Diclofenac, Diclofenac-Sodium, Diflunisal, Dipyrone (Metamizol), Metamizol-Sodium, Ethenzamide, Etofenamate, Flufenamic Acid, Flurbiprofen, Ibuprofen, Indomethacin, Isoxicam, Kebuzone, Ketoprofen, Ketorolac, Lonazolac, Lornoxicam, Meclofenamic Acid, Mefenamic acid, Mofebutazone, Nabumetone, Naproxen, (+)-Ibuprofen, (−)-Ibuprofen, (+)-Naproxen, Niflumic Acid, Oxaprozine, Oxyphenbutazone, Phenylbutazone, Piroxicam, Propyphenazone, Salicylamide, Sulindac, Tenoxicam, Tiaprofenic Acid, SC560; Sulphasalazine and Tolmetin. 12. The composition of claim 1, wherein said one or more non-steroidal anti-inflammatory drugs (NSAIDs) are selected from the group consisting of Acetylsalicylic Acid, Diclofenac, Diclofenac-Sodium, Dipyrone (Metamizol), Metamizol-Sodium, Flurbiprofen, Ibuprofen, Isoxicam, Ketoprofen, Naproxen, (+)-Ibuprofen, (−)-Ibuprofen, (+)-Naproxen, Phenylbutazone and Piroxicam. 13. The composition of claim 1, wherein said one or more non-steroidal anti-inflammatory drugs (NSAIDs) are selected from the group consisting of Acetylsalicylic Acid, Diclofenac, Diclofenac-Sodium, Flurbiprofen, Ibuprofen, Isoxicam, Ketoprofen, Naproxen, (+)-Ibuprofen, (−)-Ibuprofen, (+)-Naproxen, Phenylbutazone and Piroxicam. 14. The composition of claim 1, wherein said one or more non-steroidal anti-inflammatory drugs (NSAIDs) are selected from the group consisting of Diclofenac, Diclofenac-Sodium, Ibuprofen, Metamizol, Metamizol-Sodium, (+)-Naproxen and Ketoprofen. 15. The composition of claim 1, wherein said one or more non-steroidal anti-inflammatory drugs (NSAIDs) are selected from the group consisting of Diclofenac, Diclofenac-Sodium and Ibuprofen. 16. The composition of claim 1, wherein components (a) and (b) are present as a salt formed from these two components. 17. The composition of claim 1, wherein components (a) and (b) are present in a weight ratio such that the composition will exert a synergistic effect upon administration to a patient. 18. A salt comprising:
(a) at least one 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I),
or a solvate thereof, and
(b) one or more non-steroidal anti-inflammatory drugs (NSAIDs) having a group that is capable of forming a salt with component (a). 19. The salt of claim 18, wherein said compound corresponding to formula (I) is present in the form of a pure enantiomer or pure diastereoisomer. 20. The salt of claim 18, wherein said compound corresponding to formula (I) is present in the form of a mixture of stereoisomers. 21. The salt of claim 18, wherein said compound corresponding to formula (I) is present in the form of a racemic mixture. 22. The salt of claim 18, wherein said compound corresponding to formula (I) is present in the form of a solvate. 23. The salt claim 18, wherein the 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound forms a cationic salt component and the non-steroidal anti-inflammatory drug is acidic and forms an anionic salt component. 24. The salt of claim 18, wherein said compound corresponding to formula (I) is selected from the group consisting of:
(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1R,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol and a mixture of any of the foregoing. 25. The salt of claim 18, wherein said compound corresponding to formula (I) is selected from the group consisting of:
(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and a mixture thereof. 26. The salt of claim 18, wherein said compound corresponding to formula (I) is a (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I′) 27. The salt of claim 18, wherein the non-steroidal anti-inflammatory drug is selected from the group consisting of: Acetylsalicylic Acid, Diclofenac, Dipyrone (Metamizol), Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, (+)-Ibuprofen, (−)-Ibuprofen and (+)-Naproxen. 28. The salt of claim 18, wherein the non-steroidal anti-inflammatory drug is selected from the group consisting of: Diclofenac, Dipyrone (Metamizol), Ibuprofen, Ketoprofen, (+)-Naproxen and Naproxen. 29. A compound corresponding to formula (I″)
wherein R is an active fragment of a non-steroidal anti-inflammatory drug (NSAID) that is attached to the oxygen atom via a covalent bond,
or a solvate or an acid addition salt thereof. 30. The compound of claim 29, wherein said compound corresponding to formula (I″) is present in the form of a pure enantiomer or pure diastereoisomer. 31. The compound of claim 29, wherein said compound corresponding to formula (I″) is present in the form of a mixture of stereoisomers. 32. The compound of claim 29, wherein said compound corresponding to formula (I″) is present in the form of a racemic mixture. 33. The compound of claim 29, wherein said compound corresponding to formula (I″) is present in the form of a solvate. 34. The compound of claim 29, wherein said compound corresponding to formula (I″) is present in the form of an acid addition salt. 35. The compound of claim 29, wherein the portion of said compound attached to R is a dehydrogenate residue of
(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or any mixture thereof. 36. The compound of claim 29, wherein the portion of said compound attached to R is a dehydrogenated residue of:
(1R,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol or any mixture of dehydrogenated residues of (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1R,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and (1S,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol. 37. The compound of claim 29, wherein the portion of said compound attached to R is a dehydrogenated residue of a (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to of formula (I′) 38. The compound of claim 29, wherein said non-steroidal anti-inflammatory drug is selected from Acetylsalicylic Acid, Diclofenac, Dipyrone (Metamizol), Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, (+)-Ibuprofen, (−)-Ibuprofen and (+)-Naproxen. 39. The compound of claim 29, wherein said non-steroidal anti-inflammatory drug is selected from Diclofenac, Dipyrone (Metamizol), Ibuprofen, Ketoprofen, Naproxen and (+)-Naproxen. 40. A composition comprising a combination of at least two of (i), (ii) and (iii), wherein
(i) is a composition comprising (a) at least one 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I),
or a solvate or an acid addition salt thereof, and
(b) one or more non-steroidal anti-inflammatory drugs (NSAIDs).
(ii) is a salt comprising:
(c) at least one 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I),
or a solvate thereof, and
(d) one or more non-steroidal anti-inflammatory drugs (NSAIDs) having a group that is capable of forming a salt with component (c), and
(iii) is a compound corresponding to formula (I″)
wherein R is an active fragment of a non-steroidal anti-inflammatory drug (NSAID) that is attached to the oxygen atom via a covalent bond,
or a solvate or an acid addition salt thereof,
and one or more auxiliary agents. 41. The composition of claim 40, wherein said composition is in the form of a pharmaceutical dosage formulation and said composition comprises a pharmaceutically effective amount of at least two of (i), (ii) and (iii). 42. The composition of claim 41, wherein said pharmaceutical dosage formulation is suitable for oral, intravenous, intraperitoneal, intradermal, intrathekal, intramuscular, intranasal, transmucosal, subcutaneous, or rectal administration. 43. The composition of claim 41, wherein at least one of (a), (b), (ii) and (iii) are present in a controlled-release form. 44. The composition of claim 40, further comprising caffeine. 45. A method of manufacturing a composition, said method comprising the step of combining at least two of (i), (ii) and (iii), wherein
(i) is a composition comprising (a) at least one 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I),
or a solvate or an acid addition salt thereof, and
(b) one or more non-steroidal anti-inflammatory drugs (NSAIDs).
(ii) is a salt comprising:
(c) at least one 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I),
or a solvate thereof, and
(d) one or more non-steroidal anti-inflammatory drugs (NSAIDs) having a group that is capable of forming a salt with component (c), and
(iii) is a compound corresponding to formula (I″)
wherein R is an active fragment of a non-steroidal anti-inflammatory drug (NSAID) that is attached to the oxygen atom via a covalent bond,
or a solvate or an acid addition salt thereof. 46. A method of treating pain in a mammal, said method comprising the step of administering to said mammal a pharmaceutically effective amount of one or more auxiliary agents and a combination of at least two of (i), (ii) and (iii), wherein
(i) is a composition comprising (a) at least one 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I),
or a solvate or an acid addition salt thereof, and
(b) one or more non-steroidal anti-inflammatory drugs (NSAIDs).
(ii) is a salt comprising:
(c) at least one 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I),
or a solvate thereof, and
(d) one or more non-steroidal anti-inflammatory drugs (NSAIDs) having a group that is capable of forming a salt with component (c), and
(iii) is a compound corresponding to formula (I″)
wherein R is an active fragment of a non-steroidal anti-inflammatory drug (NSAID) that is attached to the oxygen atom via a covalent bond,
or a solvate or an acid addition salt thereof. 47. The method of claim 46, wherein components (a) and (b) are administered sequentially to the mammal and compound (a) may be administered before or after compound (b). 48. The method of claim 47, wherein components (a) and (b) are administered to the mammal simultaneously. 49. The method of claim 47, wherein components (a) and (b) are administered to the mammal by different administration pathways. 50. The method of claim 47, wherein components (a) and (b) are administered to the mammal by the same administration pathway. 51. The method of claim 46, wherein the pain is selected from inflammatory pain, neuropathic pain, acute pain, chronic pain, visceral pain, migraine pain and cancer pain.
| 1,600 |
1,268 | 13,520,689 | 1,619 |
A constitution in which at least 5 to 30% by mass of titanium oxide, an acid dye or an organic pigment, an alkali-soluble type acryl resin and water are contained is employed in order to provide aqueous cosmetics having the respective compositions in an acid dye aqueous cosmetic containing titanium oxide and an acid dye or an organic pigment aqueous cosmetic containing titanium oxide and an organic pigment which is excellent in an aging settling stability of titanium oxide to make a hard cake less liable to be produced even when titanium oxide settles down and can readily be redispersed by stirring and which is excellent in usability and a coating performance and suited to manicure compositions for a nail art, cosmetics for skin coloring and the like.
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1. An aqueous cosmetic containing at least 5 to 30% by mass of titanium oxide, an acid dye, an alkali-soluble type acryl resin and water. 2. An aqueous cosmetic containing at least 5 to 30% by mass of titanium oxide, an organic pigment, an alkali-soluble type acryl resin and water. 3. The aqueous cosmetic as described in claim 1, wherein titanium oxide coated on a surface with alumina is contained. 4. The aqueous cosmetic as described in claim 1, wherein a mass ratio of the alkali-soluble type acryl resin to titanium oxide is 0.01 to 1. 5. The aqueous cosmetic as described in claim 1, wherein the alkali-soluble type acryl resin is an (alkyl acrylate/octylacrylamide) copolymer. 6. The aqueous cosmetic as described in claim 1, wherein in measuring a viscosity of the aqueous cosmetic at 25° C. by means of a cone plate type viscometer, a viscosity thereof at a shear rate of 3.83 s−1 is 150 mPa·s or less, and a viscosity thereof at a shear rate of 383 s−1 is 20 mPa·s or less. 7. The aqueous cosmetic as described in claim 1, wherein in an applicator which is equipped with at least a liquid storing part and an applying member and in which a liquid is transported from the liquid storing part to the applying member by virtue of a capillary force, the aqueous cosmetic is loaded in the liquid storing part described above. 8. The aqueous cosmetic as described in claim 2, wherein titanium oxide coated on a surface with alumina is contained. 9. The aqueous cosmetic as described in claim 2, wherein a mass ratio of the alkali-soluble type acryl resin to titanium oxide is 0.01 to 1. 10. The aqueous cosmetic as described in claim 2, wherein the alkali-soluble type acryl resin is an (alkyl acrylate/octylacrylamide) copolymer. 11. The aqueous cosmetic as described in claim 2, wherein in measuring a viscosity of the aqueous cosmetic at 25° C. by means of a cone plate type viscometer, a viscosity thereof at a shear rate of 3.83 s−1 is 150 mPa·s or less, and a viscosity thereof at a shear rate of 383 s−1 is 20 mPa·s or less. 12. The aqueous cosmetic as described in claim 1, wherein in an applicator which is equipped with at least a liquid storing part and an applying member and in which a liquid is transported from the liquid storing part to the applying member by virtue of a capillary force, the aqueous cosmetic is loaded in the liquid storing part described above.
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A constitution in which at least 5 to 30% by mass of titanium oxide, an acid dye or an organic pigment, an alkali-soluble type acryl resin and water are contained is employed in order to provide aqueous cosmetics having the respective compositions in an acid dye aqueous cosmetic containing titanium oxide and an acid dye or an organic pigment aqueous cosmetic containing titanium oxide and an organic pigment which is excellent in an aging settling stability of titanium oxide to make a hard cake less liable to be produced even when titanium oxide settles down and can readily be redispersed by stirring and which is excellent in usability and a coating performance and suited to manicure compositions for a nail art, cosmetics for skin coloring and the like.1. An aqueous cosmetic containing at least 5 to 30% by mass of titanium oxide, an acid dye, an alkali-soluble type acryl resin and water. 2. An aqueous cosmetic containing at least 5 to 30% by mass of titanium oxide, an organic pigment, an alkali-soluble type acryl resin and water. 3. The aqueous cosmetic as described in claim 1, wherein titanium oxide coated on a surface with alumina is contained. 4. The aqueous cosmetic as described in claim 1, wherein a mass ratio of the alkali-soluble type acryl resin to titanium oxide is 0.01 to 1. 5. The aqueous cosmetic as described in claim 1, wherein the alkali-soluble type acryl resin is an (alkyl acrylate/octylacrylamide) copolymer. 6. The aqueous cosmetic as described in claim 1, wherein in measuring a viscosity of the aqueous cosmetic at 25° C. by means of a cone plate type viscometer, a viscosity thereof at a shear rate of 3.83 s−1 is 150 mPa·s or less, and a viscosity thereof at a shear rate of 383 s−1 is 20 mPa·s or less. 7. The aqueous cosmetic as described in claim 1, wherein in an applicator which is equipped with at least a liquid storing part and an applying member and in which a liquid is transported from the liquid storing part to the applying member by virtue of a capillary force, the aqueous cosmetic is loaded in the liquid storing part described above. 8. The aqueous cosmetic as described in claim 2, wherein titanium oxide coated on a surface with alumina is contained. 9. The aqueous cosmetic as described in claim 2, wherein a mass ratio of the alkali-soluble type acryl resin to titanium oxide is 0.01 to 1. 10. The aqueous cosmetic as described in claim 2, wherein the alkali-soluble type acryl resin is an (alkyl acrylate/octylacrylamide) copolymer. 11. The aqueous cosmetic as described in claim 2, wherein in measuring a viscosity of the aqueous cosmetic at 25° C. by means of a cone plate type viscometer, a viscosity thereof at a shear rate of 3.83 s−1 is 150 mPa·s or less, and a viscosity thereof at a shear rate of 383 s−1 is 20 mPa·s or less. 12. The aqueous cosmetic as described in claim 1, wherein in an applicator which is equipped with at least a liquid storing part and an applying member and in which a liquid is transported from the liquid storing part to the applying member by virtue of a capillary force, the aqueous cosmetic is loaded in the liquid storing part described above.
| 1,600 |
1,269 | 15,581,993 | 1,613 |
The instant disclosure relates to essentially anhydrous hair-treatment compositions. The anhydrous hair-treatment compositions typically include: one or more polyurethane latex polymers; one or more bis-urea derivatives; and one or more solvents. Additional components such as silicones, auxiliary agents, etc., can also be included. The instant disclosure also relates to kits that include the essentially anhydrous hair-treatment compositions and to methods for treating hair with the essentially anhydrous hair-treatment compositions.
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1. An essentially anhydrous hair-treatment composition comprising:
one or more polyurethane latex polymers; one or more bis-urea derivatives of formula (I):
wherein R is a C3-C18 linear, branched, or cyclic moiety; and
R′ and R″ may be the same or different and are selected from the group consisting of C1-C36 linear or branched alkanes or aryl alkanes, α-methyl branched C2-C36 alkanes, α-methyl branched C2-C36 ethers, β-methyl branched C2-C36 alkanes, and β-methyl branched C2-C36 ethers;
wherein if R′ and R″ are the same, then both of said groups is selected from the group consisting of α-methyl branched C2-C18 ethers and β-methyl branched C2-C18 ethers;
wherein L and L′ may be same or different and are selected from the group consisting of ethylene oxide chains, propylene oxide chains, and mixtures thereof, and the chains may comprise one or a plurality of repeat units; and
one or more solvents. 2. An essentially anhydrous hair-treatment composition of claim 1, wherein the one or more polyurethane latex polymer are film-forming polymer and are dispersed as particles in an aqueous dispersion medium. 3. An essentially anhydrous hair-treatment composition of claim 1, wherein the one or more polyurethane latex polymers are selected from the group consisting of polyurethane-32, polyurethane-34, polyurethane-35, polyurethane-48, and a mixture thereof. 4. An essentially anhydrous hair-treatment composition of claim 1, wherein the total amount of the one or more polyurethane latex polymers is about 0.01 to about 10 wt. %, based on the total weight of the hair-treatment composition. 5. An essentially anhydrous hair-treatment composition of claim 1, wherein one of the one or more bis-urea derivatives is BIS-(C12-14 alkyl PPG-4) hexamethylenediurea. 6. An essentially anhydrous hair-treatment composition of claim 1, wherein the total amount of the one or more bis-urea derivatives is about 0.1 to about 20 wt. %, based on the total weight of the hair-treatment composition. 7. An essentially anhydrous hair-treatment composition of claim 1, wherein the one or more solvents are selected from the group consisting of oils, waxes, butters, alkanes, fatty alcohols, fatty acids, fatty alcohol derivatives, fatty acid derivatives (such as alkoxylated fatty acids or polyethylene glycol esters of fatty acids or propylene glycol esters of fatty acids or butylene glycol esters of fatty acids or esters of neopentyl glycol and fatty acids or polyglycerol/glycerol esters of fatty acids or glycol diesters or diesters of ethylene glycol and fatty acids or esters of fatty acids and fatty alcohols, esters of short chain alcohols and fatty acids), esters of fatty alcohols, hydroxy-substituted fatty acids, waxes, triglyceride compounds, lanolin, ceramide, and a mixture thereof. 8. An essentially anhydrous hair-treatment composition of claim 1, wherein the total amount of the one or more solvents is about 50 to about 98 wt. %, based on the total weight of the hair-treatment composition. 9. An essentially anhydrous hair-treatment composition of claim 1, further comprising:
one or more silicones. 10. An essentially anhydrous hair-treatment composition of claim 9, wherein the one or more silicones are selected from the group consisting of polyorganosiloxanes, polyalkylsiloxanes, polyarylsiloxanes, polyalkarylsiloxanes, polyestersiloxanes, alkylmethylsilicone polyether copolymers, and a mixture thereof. 11. An essentially anhydrous hair-treatment composition of claim 9, wherein the total amount of the one or more silicones is about 0.01 to about 40 wt. %, based on the total weight of the hair-treatment composition. 12. An essentially anhydrous hair-treatment composition of claim 1, further comprising:
one or more auxiliary agents. 13. An essentially anhydrous hair-treatment composition of claim 12, wherein the one or more auxiliary agents are selected from the group consisting of silica silicate, fumed silica, amorphous silica, clays, ceramic beads, calcium carbonate, titanium oxides, magnesium oxides, aluminium silicates and derivatives thereof, mixed silicates of natural or synthetic origin, which are optionally hydrated, natural hydrated aluminium silicates, bentonite, kaolin, Nylon, microspheres based on a copolymer of vinylidene chloride/acrylonitrile/methacrylonitrile containing isobutane, micronized or non-micronized vegetable powders, rice grain husk powders, and a mixture thereof. 14. An essentially anhydrous hair-treatment composition of claim 12, wherein the total amount of the one or more auxiliary agents is about 0.01 to about 10 wt. %, based on the total weight of the hair-treatment composition. 15. An essentially anhydrous hair-treatment composition comprising:
about 0.01 to about 10 wt. % of polyurethane-34; about 0.1 to about 10 wt. % of BIS-(C12-14 alkyl PPG-4) hexamethylenediurea; and about 70 to about 98 wt. % of one or more solvents selected from the group consisting of oils, alkanes, fatty alcohols, fatty acids, fatty alcohol derivatives, fatty acid derivatives, esters of fatty alcohols, hydroxy-substituted fatty acids, waxes, and a mixture thereof. 16. An essentially anhydrous hair-treatment composition comprising:
about 0.01 to about 10 wt. % of polyurethane-34; about 0.1 to about 10 wt. % of BIS-(C12-14 alkyl PPG-4) hexamethylenediurea; about 60 to about 98 wt. % of one or more solvents selected from the group consisting of oils, alkanes, fatty alcohols, fatty acids, fatty alcohol derivatives, fatty acid derivatives, esters of fatty alcohols, hydroxy-substituted fatty acids, waxes, and a mixture thereof about 0.01 to about 40 wt. % of one or more silicones selected from the group consisting of ; and about 0.01 to about 10 wt. % of one or more auxiliary agents. 17. A kit comprising:
(A) at least one essentially anhydrous hair-treatment composition of claim 1; and (B) at least one additional hair-treatment composition that is different than the essentially anhydrous hair-treatment composition of (A);
wherein the at least one hair-treatment composition of (A) and the at least one additional hair-treatment composition of (B) are separately contained. 18. The kit of claim 17, wherein the at least one additional hair-treatment composition that is different than (A) is a shampoo, a conditioner, or a conditioning shampoo (all-in-one shampoo/conditioner). 19. The kit of claim 17 comprising at least two additional hair-treatment compositions of (B), wherein at least one of the at least two additional hair-treatment compositions is a shampoo and at least one or the at least two additional hair-treatment compositions is a conditioner. 20. A method for treating hair comprising applying a hair-treatment composition of claim 1 to the hair. 21. A method of claim 20, wherein the hair-treatment composition is:
mixed with a shampoo prior to application to hair; layered onto hair with a shampoo; applied to wet hair after a shampoo has been rinsed from the hair; layered onto hair with a conditioner; mixed with a conditioner prior to application to hair; and/or applied to wet hair after a conditioner has been rinsed from the hair. 22. A method of claim 20, wherein treating the hair comprises:
conditioning the hair; providing curl definition to the hair; providing frizz control to the hair; improving ease of combability and detangling; protecting the hair from damage; and increasing the appearance of hair volume.
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The instant disclosure relates to essentially anhydrous hair-treatment compositions. The anhydrous hair-treatment compositions typically include: one or more polyurethane latex polymers; one or more bis-urea derivatives; and one or more solvents. Additional components such as silicones, auxiliary agents, etc., can also be included. The instant disclosure also relates to kits that include the essentially anhydrous hair-treatment compositions and to methods for treating hair with the essentially anhydrous hair-treatment compositions.1. An essentially anhydrous hair-treatment composition comprising:
one or more polyurethane latex polymers; one or more bis-urea derivatives of formula (I):
wherein R is a C3-C18 linear, branched, or cyclic moiety; and
R′ and R″ may be the same or different and are selected from the group consisting of C1-C36 linear or branched alkanes or aryl alkanes, α-methyl branched C2-C36 alkanes, α-methyl branched C2-C36 ethers, β-methyl branched C2-C36 alkanes, and β-methyl branched C2-C36 ethers;
wherein if R′ and R″ are the same, then both of said groups is selected from the group consisting of α-methyl branched C2-C18 ethers and β-methyl branched C2-C18 ethers;
wherein L and L′ may be same or different and are selected from the group consisting of ethylene oxide chains, propylene oxide chains, and mixtures thereof, and the chains may comprise one or a plurality of repeat units; and
one or more solvents. 2. An essentially anhydrous hair-treatment composition of claim 1, wherein the one or more polyurethane latex polymer are film-forming polymer and are dispersed as particles in an aqueous dispersion medium. 3. An essentially anhydrous hair-treatment composition of claim 1, wherein the one or more polyurethane latex polymers are selected from the group consisting of polyurethane-32, polyurethane-34, polyurethane-35, polyurethane-48, and a mixture thereof. 4. An essentially anhydrous hair-treatment composition of claim 1, wherein the total amount of the one or more polyurethane latex polymers is about 0.01 to about 10 wt. %, based on the total weight of the hair-treatment composition. 5. An essentially anhydrous hair-treatment composition of claim 1, wherein one of the one or more bis-urea derivatives is BIS-(C12-14 alkyl PPG-4) hexamethylenediurea. 6. An essentially anhydrous hair-treatment composition of claim 1, wherein the total amount of the one or more bis-urea derivatives is about 0.1 to about 20 wt. %, based on the total weight of the hair-treatment composition. 7. An essentially anhydrous hair-treatment composition of claim 1, wherein the one or more solvents are selected from the group consisting of oils, waxes, butters, alkanes, fatty alcohols, fatty acids, fatty alcohol derivatives, fatty acid derivatives (such as alkoxylated fatty acids or polyethylene glycol esters of fatty acids or propylene glycol esters of fatty acids or butylene glycol esters of fatty acids or esters of neopentyl glycol and fatty acids or polyglycerol/glycerol esters of fatty acids or glycol diesters or diesters of ethylene glycol and fatty acids or esters of fatty acids and fatty alcohols, esters of short chain alcohols and fatty acids), esters of fatty alcohols, hydroxy-substituted fatty acids, waxes, triglyceride compounds, lanolin, ceramide, and a mixture thereof. 8. An essentially anhydrous hair-treatment composition of claim 1, wherein the total amount of the one or more solvents is about 50 to about 98 wt. %, based on the total weight of the hair-treatment composition. 9. An essentially anhydrous hair-treatment composition of claim 1, further comprising:
one or more silicones. 10. An essentially anhydrous hair-treatment composition of claim 9, wherein the one or more silicones are selected from the group consisting of polyorganosiloxanes, polyalkylsiloxanes, polyarylsiloxanes, polyalkarylsiloxanes, polyestersiloxanes, alkylmethylsilicone polyether copolymers, and a mixture thereof. 11. An essentially anhydrous hair-treatment composition of claim 9, wherein the total amount of the one or more silicones is about 0.01 to about 40 wt. %, based on the total weight of the hair-treatment composition. 12. An essentially anhydrous hair-treatment composition of claim 1, further comprising:
one or more auxiliary agents. 13. An essentially anhydrous hair-treatment composition of claim 12, wherein the one or more auxiliary agents are selected from the group consisting of silica silicate, fumed silica, amorphous silica, clays, ceramic beads, calcium carbonate, titanium oxides, magnesium oxides, aluminium silicates and derivatives thereof, mixed silicates of natural or synthetic origin, which are optionally hydrated, natural hydrated aluminium silicates, bentonite, kaolin, Nylon, microspheres based on a copolymer of vinylidene chloride/acrylonitrile/methacrylonitrile containing isobutane, micronized or non-micronized vegetable powders, rice grain husk powders, and a mixture thereof. 14. An essentially anhydrous hair-treatment composition of claim 12, wherein the total amount of the one or more auxiliary agents is about 0.01 to about 10 wt. %, based on the total weight of the hair-treatment composition. 15. An essentially anhydrous hair-treatment composition comprising:
about 0.01 to about 10 wt. % of polyurethane-34; about 0.1 to about 10 wt. % of BIS-(C12-14 alkyl PPG-4) hexamethylenediurea; and about 70 to about 98 wt. % of one or more solvents selected from the group consisting of oils, alkanes, fatty alcohols, fatty acids, fatty alcohol derivatives, fatty acid derivatives, esters of fatty alcohols, hydroxy-substituted fatty acids, waxes, and a mixture thereof. 16. An essentially anhydrous hair-treatment composition comprising:
about 0.01 to about 10 wt. % of polyurethane-34; about 0.1 to about 10 wt. % of BIS-(C12-14 alkyl PPG-4) hexamethylenediurea; about 60 to about 98 wt. % of one or more solvents selected from the group consisting of oils, alkanes, fatty alcohols, fatty acids, fatty alcohol derivatives, fatty acid derivatives, esters of fatty alcohols, hydroxy-substituted fatty acids, waxes, and a mixture thereof about 0.01 to about 40 wt. % of one or more silicones selected from the group consisting of ; and about 0.01 to about 10 wt. % of one or more auxiliary agents. 17. A kit comprising:
(A) at least one essentially anhydrous hair-treatment composition of claim 1; and (B) at least one additional hair-treatment composition that is different than the essentially anhydrous hair-treatment composition of (A);
wherein the at least one hair-treatment composition of (A) and the at least one additional hair-treatment composition of (B) are separately contained. 18. The kit of claim 17, wherein the at least one additional hair-treatment composition that is different than (A) is a shampoo, a conditioner, or a conditioning shampoo (all-in-one shampoo/conditioner). 19. The kit of claim 17 comprising at least two additional hair-treatment compositions of (B), wherein at least one of the at least two additional hair-treatment compositions is a shampoo and at least one or the at least two additional hair-treatment compositions is a conditioner. 20. A method for treating hair comprising applying a hair-treatment composition of claim 1 to the hair. 21. A method of claim 20, wherein the hair-treatment composition is:
mixed with a shampoo prior to application to hair; layered onto hair with a shampoo; applied to wet hair after a shampoo has been rinsed from the hair; layered onto hair with a conditioner; mixed with a conditioner prior to application to hair; and/or applied to wet hair after a conditioner has been rinsed from the hair. 22. A method of claim 20, wherein treating the hair comprises:
conditioning the hair; providing curl definition to the hair; providing frizz control to the hair; improving ease of combability and detangling; protecting the hair from damage; and increasing the appearance of hair volume.
| 1,600 |
1,270 | 15,569,320 | 1,617 |
The present invention relates to a multi-step process for the production of nitrogen monoxide (NO) from a pH-labile NO donor in the presence of at least one antioxidant. The invention also relates to a device for implementation of said process and the use of said device for the treatment of diseases. Moreover, the invention relates to a cosmetic process using said process or said device.
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1. A process for the production of nitrogen monoxide (NO), comprising:
(a) providing a carrier medium comprising at least one pH-labile NO donor; (b) adjusting a pH value of the carrier medium to a pH value that induces degradation of the at least one pH-labile NO donor while producing NO; (c) maintaining the pH value that induces the production of NO for a period of time from 15 seconds to 60 minutes to permit production of an amount of 0.01 to 2 mM of NO; and (d) increasing the pH value of the carrier medium by at least one pH level; wherein at least one antioxidant is contained in the carrier medium in step (a) or at least one antioxidant is added in step (b), and wherein the process optionally further comprises an addition of at least another antioxidant. 2. The process according to claim 1, wherein the carrier medium is selected from a group consisting of foam, gel, cream, and liquid. 3. The process according to claim 1, wherein the at least one pH-labile NO donor is selected from a group consisting of inorganic nitrite salts, alkyl nitrites, diazeniumdiolate derivatives, trans[RuCl([15]aneN4)NO]2+, 6-nitrobenzo[a]pyrrol, S-nitroso-glutathione, S-nitroso-thiol, S-nitroso-N-acetyl-D-penicillamine (SNAP), nitroaniline derivatives, 2-methyl-2-nitrosopropane, imidazolyl derivatives, nitrate esters, hydroxylnitrosamine, hydroxylamine, hydroxy urea, and sodium nitroprusside. 4. The process according to claims 1, wherein the at least one pH-labile NO donor is selected from a group consisting of LiNO2, NaNO2, KNO2, RbNO2, CsNO2, FrNO2, Be(NO2)2, Mg(NO2)2, Ca(NO2)2, Sr(NO2)2, Ba(NO2)2. 5. The process according to claim 1 , wherein the at least one antioxidant contained in the carrier medium in step (a) and/or the at least another antioxidant added is selected from a group consisting of ascorbate and derivatives thereof, tocopherol, tocotrienol, tocomonoenol and derivatives thereof, butylhydroxyanisol (BHA), butylhydroxytoluene (BHT), glutathione, cysteine, thiolactic acid, alpha-lipoic acid, p-cumaric acid, ferulic acid, sinapinic acid, caffeic acid, gallic acid, protocatechuic acid, syringic acid, vanillic acid, polyphenolic anthocyanin compounds, flavonoids, and phytooestrogens. 6. The process according to claim 1, wherein the at least one antioxidant is contained in the carrier medium in step (a) and is:
a mixture of ascorbate and (RS)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), or a mixture of alpha-tocopherol and at least one of ascorbyl palmitate and ascorbyl stearate. 7. The process according to claim 1, wherein the carrier medium in step (b) contains nitrite, ascorbate, and Trolox at a molar ratio of 1:2-20:4-100, and wherein the molar ratio: is nitrite<ascorbate<Trolox. 8. The process according to claim 1, wherein the pH value adjusted in step (b) is between 0.0 and 6.9. 9. The process according to claim 1, wherein the pH adjustment in step (b) is effectuated by an addition of an acid or by photolytic cleavage of a photo-latent acid producer. 10. The process according to claim 1, wherein the period of time in step (c) is between 1 and 30 minutes. 11. The process according to claim 1, wherein the amount of NO produced in step (c) is between 0.05 to 1 mM. 12. The process according to claim 1, wherein the pH increase in step (d):
(i) is an increase of the pH value to pH 7 or more; and/or (ii) is an increase of the pH value to a pH value that is associated with a reduced generation of NO such that an amount of newly generated NO is equivalent to a decreasing amount of NO in the carrier medium. 13. The process according to claim 1, wherein the increase in pH in step (d) is effectuated by use of a base or a basic buffer selected from a group consisting of NaOH, KOH, NH4OH, Ca(OH)2, NH4OH, sodium hydrogen carbonate, phosphate buffer, barbital-acetate buffer, 4-(2-hydroxyethyl)-1-piperazinethanesulfonic add (HEPES) buffer, tris(hydroxymethyl)-aminomethane (TRIS) buffer, 4-(2-hydroxyethyl)piperazin-1-propansulfonic acid (HEPPS) buffer, barbital-acetate buffer, acetic acid-acetate buffer, carbonic acid-silicate buffer, 2-(N-morpholino)ethansulfonic acid (MES) buffer, carbonic acid-bicarbonate buffer, citric acid buffer and citrate buffer. 14. The process according to claim 1, wherein the pH increase in step (d) is to a pH that is between 7.0 and 12.0. 15. The process according to claim 1, wherein the process further comprises addition of the at least another antioxidant, and wherein the at least another antioxidant is selected from a group consisting of glutathione, cysteine, N-acetylcysteine, dimercapto succinic acid, dimercapto propansulfonic acid, ethanthiol (ethylmercaptan), dithiothreitol (DTT), dithioerythritol (DTE), captopril, coenzym A, penicillamine, 1-propanthiol, 2-propanthiol, homocysteine, Mesna, methanthiol (methylmercaptan), and thiophenol. 16. The process according to claim 1, wherein the carrier medium is irradiated with light for photolytic degradation of the NO and simultaneous production of NO after step (d) or after addition of the at least another antioxidant. 17. A cosmetic process comprising contacting skin of a human with NO produced by a process according to claim 1.
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The present invention relates to a multi-step process for the production of nitrogen monoxide (NO) from a pH-labile NO donor in the presence of at least one antioxidant. The invention also relates to a device for implementation of said process and the use of said device for the treatment of diseases. Moreover, the invention relates to a cosmetic process using said process or said device.1. A process for the production of nitrogen monoxide (NO), comprising:
(a) providing a carrier medium comprising at least one pH-labile NO donor; (b) adjusting a pH value of the carrier medium to a pH value that induces degradation of the at least one pH-labile NO donor while producing NO; (c) maintaining the pH value that induces the production of NO for a period of time from 15 seconds to 60 minutes to permit production of an amount of 0.01 to 2 mM of NO; and (d) increasing the pH value of the carrier medium by at least one pH level; wherein at least one antioxidant is contained in the carrier medium in step (a) or at least one antioxidant is added in step (b), and wherein the process optionally further comprises an addition of at least another antioxidant. 2. The process according to claim 1, wherein the carrier medium is selected from a group consisting of foam, gel, cream, and liquid. 3. The process according to claim 1, wherein the at least one pH-labile NO donor is selected from a group consisting of inorganic nitrite salts, alkyl nitrites, diazeniumdiolate derivatives, trans[RuCl([15]aneN4)NO]2+, 6-nitrobenzo[a]pyrrol, S-nitroso-glutathione, S-nitroso-thiol, S-nitroso-N-acetyl-D-penicillamine (SNAP), nitroaniline derivatives, 2-methyl-2-nitrosopropane, imidazolyl derivatives, nitrate esters, hydroxylnitrosamine, hydroxylamine, hydroxy urea, and sodium nitroprusside. 4. The process according to claims 1, wherein the at least one pH-labile NO donor is selected from a group consisting of LiNO2, NaNO2, KNO2, RbNO2, CsNO2, FrNO2, Be(NO2)2, Mg(NO2)2, Ca(NO2)2, Sr(NO2)2, Ba(NO2)2. 5. The process according to claim 1 , wherein the at least one antioxidant contained in the carrier medium in step (a) and/or the at least another antioxidant added is selected from a group consisting of ascorbate and derivatives thereof, tocopherol, tocotrienol, tocomonoenol and derivatives thereof, butylhydroxyanisol (BHA), butylhydroxytoluene (BHT), glutathione, cysteine, thiolactic acid, alpha-lipoic acid, p-cumaric acid, ferulic acid, sinapinic acid, caffeic acid, gallic acid, protocatechuic acid, syringic acid, vanillic acid, polyphenolic anthocyanin compounds, flavonoids, and phytooestrogens. 6. The process according to claim 1, wherein the at least one antioxidant is contained in the carrier medium in step (a) and is:
a mixture of ascorbate and (RS)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), or a mixture of alpha-tocopherol and at least one of ascorbyl palmitate and ascorbyl stearate. 7. The process according to claim 1, wherein the carrier medium in step (b) contains nitrite, ascorbate, and Trolox at a molar ratio of 1:2-20:4-100, and wherein the molar ratio: is nitrite<ascorbate<Trolox. 8. The process according to claim 1, wherein the pH value adjusted in step (b) is between 0.0 and 6.9. 9. The process according to claim 1, wherein the pH adjustment in step (b) is effectuated by an addition of an acid or by photolytic cleavage of a photo-latent acid producer. 10. The process according to claim 1, wherein the period of time in step (c) is between 1 and 30 minutes. 11. The process according to claim 1, wherein the amount of NO produced in step (c) is between 0.05 to 1 mM. 12. The process according to claim 1, wherein the pH increase in step (d):
(i) is an increase of the pH value to pH 7 or more; and/or (ii) is an increase of the pH value to a pH value that is associated with a reduced generation of NO such that an amount of newly generated NO is equivalent to a decreasing amount of NO in the carrier medium. 13. The process according to claim 1, wherein the increase in pH in step (d) is effectuated by use of a base or a basic buffer selected from a group consisting of NaOH, KOH, NH4OH, Ca(OH)2, NH4OH, sodium hydrogen carbonate, phosphate buffer, barbital-acetate buffer, 4-(2-hydroxyethyl)-1-piperazinethanesulfonic add (HEPES) buffer, tris(hydroxymethyl)-aminomethane (TRIS) buffer, 4-(2-hydroxyethyl)piperazin-1-propansulfonic acid (HEPPS) buffer, barbital-acetate buffer, acetic acid-acetate buffer, carbonic acid-silicate buffer, 2-(N-morpholino)ethansulfonic acid (MES) buffer, carbonic acid-bicarbonate buffer, citric acid buffer and citrate buffer. 14. The process according to claim 1, wherein the pH increase in step (d) is to a pH that is between 7.0 and 12.0. 15. The process according to claim 1, wherein the process further comprises addition of the at least another antioxidant, and wherein the at least another antioxidant is selected from a group consisting of glutathione, cysteine, N-acetylcysteine, dimercapto succinic acid, dimercapto propansulfonic acid, ethanthiol (ethylmercaptan), dithiothreitol (DTT), dithioerythritol (DTE), captopril, coenzym A, penicillamine, 1-propanthiol, 2-propanthiol, homocysteine, Mesna, methanthiol (methylmercaptan), and thiophenol. 16. The process according to claim 1, wherein the carrier medium is irradiated with light for photolytic degradation of the NO and simultaneous production of NO after step (d) or after addition of the at least another antioxidant. 17. A cosmetic process comprising contacting skin of a human with NO produced by a process according to claim 1.
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1,271 | 15,039,134 | 1,617 |
A composition for wound healing and/or skin treatment comprises honey and a carbonate and/or bicarbonate salt. The salt is preferably capable of releasing CO 2 . The composition may optionally comprise thickeners and/or organic acids. Wound dressings, kits and treatment methods are also provided.
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1. A topical desloughing, debriding, wound treating, exfoliating or cosmetic composition comprising:
honey and/or a honey substitute; and, a pharmaceutically acceptable carbonate (CO3 −2) and/or bicarbonate (HCO3 −1) salt. 2. The composition according to claim 1, wherein said honey is produced by bees that have fed exclusively on Leptospermum plant species. 3. The composition according to claim 2 wherein said honey is Manuka honey produced from Leptospermum scoparium. 4. The composition according to claim 3 wherein said Manuka honey has a pH 3.2 to 4.5 and a minimum methylglyoxal concentration of 150 mg/kg. 5. The composition according to any one of claims 1 to 4, wherein said composition is in the form of a foam or mousse, and further comprises cells or bubbles comprising carbon dioxide. 6. The composition according to claim 5, wherein said composition further comprises cells or bubbles comprising carbon dioxide. 7. The composition according to any one of claims 1 to 4, wherein said composition is a gel, lotion, cream, ointment or balm. 8. The composition according to any one of claims 1 to 7, wherein said pharmaceutically acceptable salt is sodium carbonate (Na2CO3), potassium carbonate (K2CO3), ammonium carbonate ((NH4)2CO3), sodium bicarbonate (NaHCO3), potassium bicarbonate (KHCO3), ammonium bicarbonate ((NH4)HCO3) or any combination thereof. 9. The composition according to claim 8, wherein said salt is sodium bicarbonate (NaHCO3). 10. The composition according to claim 9, wherein the sodium bicarbonate is present at 2.5 to 20% w/v of said composition. 11. The composition according to claim 9, wherein the sodium bicarbonate is present at 5 to 15% w/v of said composition. 12. The composition according to claim 9, wherein the sodium bicarbonate is present at 7.5 to 12.5% w/v of said composition. 13. The composition according to any one of claims 1 to 12, wherein the pH of the composition is between about 5 to 7.4. 14. The composition according to any one of claims 1 to 13, further comprising one or more organic acids, wherein said one or more organic acids are additional to organic acids naturally occurring in said honey. 15. The composition according to claim 14, wherein the organic acid is: gluconic acid, lactic acid, acetic acid, butyric acid, citric acid, malic acid, pyroglutamic acid, succinic acid, ascorbic acid, glycolic acid, lactic acid, citric acid, mandelic acid, or any combination thereof. 16. The composition according to claim 15, wherein said organic acid is ascorbic acid. 17. The composition according to claim 16, wherein the ascorbic acid is present at a concentration of 0.2 to 10% w/v of said composition. 18. The composition according to claim 16, wherein the ascorbic acid is present at a concentration of 1 to 5% w/v of said composition. 19. The composition according to any one of claims 1 to 18, further comprising one or more thickening agents. 20. The composition according to claim 19, wherein the thickening agents is/are polysaccharides, starches, agar, alginic acid and salts thereof, carrageenan, pectin, beta glucan, xanthan gum, gum arabic, gum ghatti, guar gum, locust bean gum, and any combination thereof. 21. The composition according to claim 20, wherein said thickening agent is xanthan gum. 22. The composition according to claim 21, wherein said xanthan gum is present at a concentration of 0.2 to 6% w/v. 23. The composition according to claim 21, wherein said xanthan gum is present at a concentration of 1 to 5% w/v. 24. The composition according to claim 21, wherein said xanthan gum is present at a concentration of 2 to 5% w/v. 25. The composition according to any one of claims 1 to 24, further comprising sodium lauryl sulfate. 26. The composition according to claim 25 wherein said sodium lauryl sulfate is present at a concentration of 0.0001 to 0.1% w/v. 27. The composition according to any one of claims 1 to 26, further comprising one or more proteolytic enzymes selected from the group consisting of: papain, actinidin, bromelain, ficain, cucumisin and bacteria-derived proteolytic enzymes. 28. The composition according to claim 27, wherein said proteolytic enzyme is actinidin. 29. The composition according to claim 28, wherein said actinidin is provided in kiwi fruit or an extract thereof. 30. The composition according to any one of claims 1 to 29, further comprising one or more preservatives selected from the group consisting of: methyl paraben, propyl paraben, butyl paraben, imidazolidinyl urea, tetradecyl-trimethyl ammonium bromide (Cetrimide®), sodium benzoate, potassium sorbate, thymol and polyaminopropyl biguanide. 31. The composition according to any one of claims 1 to 30, wherein said composition has an osmotic concentration at least 14.5 times the osmotic concentration of human blood. 32. The composition according to claim 1 comprising:
honey;
7.5 to 12.5% w/v sodium bicarbonate;
2 to 4% w/v xanthan gum; and
1 to 5% w/v ascorbic acid. 33. The composition according to claim 32, wherein said honey is produced by bees that have fed exclusively on Leptospermum plant species. 34. The composition according to claim 33 wherein said honey is Manuka honey produced from Leptospermum scoparium. 35. The composition according to claim 34 wherein said Manuka honey has a pH 3.2 to 4.5 and a minimum methylglyoxal concentration of 150 mg/kg. 36. The composition according to any one of claims 32 to 35, wherein said composition has an osmotic concentration at least 14.5 times the osmotic concentration of human blood. 37. The composition according to any one of claims 32 to 36, further comprising one or more proteolytic enzymes selected from the group consisting of: papain, actinidin, bromelain, ficain, cucumisin and bacteria-derived proteolytic enzymes. 38. The composition according to claim 37, wherein said proteolytic enzyme is actinidin. 39. The composition according to claim 38, wherein said actinidin is provided in kiwi fruit or an extract thereof. 40. Use of the composition according to any one of claims 1 to 39 as a desloughing agent, a debriding agent, an exfoliating agent, or a wound treatment agent. 41. Use of the composition according to any one of claims 1 to 39, for treatment of a chronic skin disorder, wherein the disorder is ichthyosis, psoriasis, seborrheic dermatitis, atopic dermatitis, or eczema. 42. A skin treatment system comprising a composition according to any one of claims 1 to 39, and a carrier or applicator. 43. A system of wound treatment comprising:
(a) the composition according to any one of claims 1 to 39; (b) an isotonic diluent solution of around pH 7, comprising: 0.015 M ascorbic acid; 0.015 M sodium bicarbonate; 0.12 sodium chloride; wherein said isotonic diluent solution is used to dilute said composition at a minimum ratio of 1 part said composition to 2 parts said diluent solution (1:2), thereby forming a wound irrigation solution; and wherein said wound irrigation solution is used to irrigate a site of treatment on a patient before application of said composition. 44. A wound dressing comprising at least a first layer and a second layer, wherein:
the first layer comprises honey; and, the second layer comprises a pharmaceutically acceptable carbonate (CO3 −2) and/or bicarbonate (HCO3 −1) salt. 45. The wound dressing of claim 44, wherein the honey is provided in the form of dry granules. 46. The wound dressing of claim 45, wherein the honey granules are encapsulated in a dissolvable coating. 47. The wound dressing of claim 46, wherein the encapsulated honey granules are adhered to the first layer. 48. The wound dressing of claim 47, wherein the honey granules are combined with granules of ascorbic acid. 49. The wound dressing according to any one of claims 44 to 48, wherein said honey is Manuka honey produced from Leptospermum scoparium. 50. The wound dressing according to any one of claims 44 to 49, wherein said pharmaceutically acceptable salt is sodium carbonate (Na2CO3), potassium carbonate (K2CO3), ammonium carbonate ((NH4)2CO3), sodium bicarbonate (NaHCO3), potassium bicarbonate (KHCO3), ammonium bicarbonate ((NH4)HCO3) or any combination thereof. 51. A treatment kit for desloughing, debriding, exfoliating, or treating a wound, the kit comprising:
honey and/or a honey substitute, wherein the honey and/or honey substitute is in the form of dry granules; and, a pharmaceutically acceptable carbonate (CO3 −2) and/or bicarbonate (HCO3 −1) salt. 52. The treatment kit of claim 51, wherein the honey and/or honey substitute granules are encapsulated. 53. The treatment kit of claim 51 or 52, wherein the honey and the carbonate and/or bicarbonate salt are combined in a single container. 54. The treatment kit according to any one of claims 51 to 53 further comprising a mixing container for combining the honey and the carbonate and/or bicarbonate salt to form an aqueous slurry. 55. The treatment kit according to any one of claims 51 to 54, wherein said honey is Manuka honey produced from Leptospermum scoparium. 56. The treatment kit according to any one of claims 51 to 55, wherein said pharmaceutically acceptable salt is sodium carbonate (Na2CO3), potassium carbonate (K2CO3), ammonium carbonate ((NH4)2CO3), sodium bicarbonate (NaHCO3), potassium bicarbonate (KHCO3), ammonium bicarbonate ((NH4)HCO3) or any combination thereof. 57. A method of desloughing, debriding or exfoliating a region of skin of a mammal or treating a wound on a mammal, the method comprising applying to the region or the wound a topical composition comprising:
honey and/or a honey substitute; and, a pharmaceutically acceptable carbonate (CO3 −2) and/or bicarbonate (HCO3 −1) salt. 58. The method of claim 57, wherein the composition is in the form of a foam or mousse. 59. The method according to claim 57 or 58, wherein said honey is Manuka honey produced from Leptospermum scoparium. 60. The method according to any one of claims 57 to 59, wherein said pharmaceutically acceptable salt is sodium carbonate (Na2CO3), potassium carbonate (K2CO3), ammonium carbonate ((NH4)2CO3), sodium bicarbonate (NaHCO3), potassium bicarbonate (KHCO3), ammonium bicarbonate ((NH4)HCO3) or any combination thereof.
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A composition for wound healing and/or skin treatment comprises honey and a carbonate and/or bicarbonate salt. The salt is preferably capable of releasing CO 2 . The composition may optionally comprise thickeners and/or organic acids. Wound dressings, kits and treatment methods are also provided.1. A topical desloughing, debriding, wound treating, exfoliating or cosmetic composition comprising:
honey and/or a honey substitute; and, a pharmaceutically acceptable carbonate (CO3 −2) and/or bicarbonate (HCO3 −1) salt. 2. The composition according to claim 1, wherein said honey is produced by bees that have fed exclusively on Leptospermum plant species. 3. The composition according to claim 2 wherein said honey is Manuka honey produced from Leptospermum scoparium. 4. The composition according to claim 3 wherein said Manuka honey has a pH 3.2 to 4.5 and a minimum methylglyoxal concentration of 150 mg/kg. 5. The composition according to any one of claims 1 to 4, wherein said composition is in the form of a foam or mousse, and further comprises cells or bubbles comprising carbon dioxide. 6. The composition according to claim 5, wherein said composition further comprises cells or bubbles comprising carbon dioxide. 7. The composition according to any one of claims 1 to 4, wherein said composition is a gel, lotion, cream, ointment or balm. 8. The composition according to any one of claims 1 to 7, wherein said pharmaceutically acceptable salt is sodium carbonate (Na2CO3), potassium carbonate (K2CO3), ammonium carbonate ((NH4)2CO3), sodium bicarbonate (NaHCO3), potassium bicarbonate (KHCO3), ammonium bicarbonate ((NH4)HCO3) or any combination thereof. 9. The composition according to claim 8, wherein said salt is sodium bicarbonate (NaHCO3). 10. The composition according to claim 9, wherein the sodium bicarbonate is present at 2.5 to 20% w/v of said composition. 11. The composition according to claim 9, wherein the sodium bicarbonate is present at 5 to 15% w/v of said composition. 12. The composition according to claim 9, wherein the sodium bicarbonate is present at 7.5 to 12.5% w/v of said composition. 13. The composition according to any one of claims 1 to 12, wherein the pH of the composition is between about 5 to 7.4. 14. The composition according to any one of claims 1 to 13, further comprising one or more organic acids, wherein said one or more organic acids are additional to organic acids naturally occurring in said honey. 15. The composition according to claim 14, wherein the organic acid is: gluconic acid, lactic acid, acetic acid, butyric acid, citric acid, malic acid, pyroglutamic acid, succinic acid, ascorbic acid, glycolic acid, lactic acid, citric acid, mandelic acid, or any combination thereof. 16. The composition according to claim 15, wherein said organic acid is ascorbic acid. 17. The composition according to claim 16, wherein the ascorbic acid is present at a concentration of 0.2 to 10% w/v of said composition. 18. The composition according to claim 16, wherein the ascorbic acid is present at a concentration of 1 to 5% w/v of said composition. 19. The composition according to any one of claims 1 to 18, further comprising one or more thickening agents. 20. The composition according to claim 19, wherein the thickening agents is/are polysaccharides, starches, agar, alginic acid and salts thereof, carrageenan, pectin, beta glucan, xanthan gum, gum arabic, gum ghatti, guar gum, locust bean gum, and any combination thereof. 21. The composition according to claim 20, wherein said thickening agent is xanthan gum. 22. The composition according to claim 21, wherein said xanthan gum is present at a concentration of 0.2 to 6% w/v. 23. The composition according to claim 21, wherein said xanthan gum is present at a concentration of 1 to 5% w/v. 24. The composition according to claim 21, wherein said xanthan gum is present at a concentration of 2 to 5% w/v. 25. The composition according to any one of claims 1 to 24, further comprising sodium lauryl sulfate. 26. The composition according to claim 25 wherein said sodium lauryl sulfate is present at a concentration of 0.0001 to 0.1% w/v. 27. The composition according to any one of claims 1 to 26, further comprising one or more proteolytic enzymes selected from the group consisting of: papain, actinidin, bromelain, ficain, cucumisin and bacteria-derived proteolytic enzymes. 28. The composition according to claim 27, wherein said proteolytic enzyme is actinidin. 29. The composition according to claim 28, wherein said actinidin is provided in kiwi fruit or an extract thereof. 30. The composition according to any one of claims 1 to 29, further comprising one or more preservatives selected from the group consisting of: methyl paraben, propyl paraben, butyl paraben, imidazolidinyl urea, tetradecyl-trimethyl ammonium bromide (Cetrimide®), sodium benzoate, potassium sorbate, thymol and polyaminopropyl biguanide. 31. The composition according to any one of claims 1 to 30, wherein said composition has an osmotic concentration at least 14.5 times the osmotic concentration of human blood. 32. The composition according to claim 1 comprising:
honey;
7.5 to 12.5% w/v sodium bicarbonate;
2 to 4% w/v xanthan gum; and
1 to 5% w/v ascorbic acid. 33. The composition according to claim 32, wherein said honey is produced by bees that have fed exclusively on Leptospermum plant species. 34. The composition according to claim 33 wherein said honey is Manuka honey produced from Leptospermum scoparium. 35. The composition according to claim 34 wherein said Manuka honey has a pH 3.2 to 4.5 and a minimum methylglyoxal concentration of 150 mg/kg. 36. The composition according to any one of claims 32 to 35, wherein said composition has an osmotic concentration at least 14.5 times the osmotic concentration of human blood. 37. The composition according to any one of claims 32 to 36, further comprising one or more proteolytic enzymes selected from the group consisting of: papain, actinidin, bromelain, ficain, cucumisin and bacteria-derived proteolytic enzymes. 38. The composition according to claim 37, wherein said proteolytic enzyme is actinidin. 39. The composition according to claim 38, wherein said actinidin is provided in kiwi fruit or an extract thereof. 40. Use of the composition according to any one of claims 1 to 39 as a desloughing agent, a debriding agent, an exfoliating agent, or a wound treatment agent. 41. Use of the composition according to any one of claims 1 to 39, for treatment of a chronic skin disorder, wherein the disorder is ichthyosis, psoriasis, seborrheic dermatitis, atopic dermatitis, or eczema. 42. A skin treatment system comprising a composition according to any one of claims 1 to 39, and a carrier or applicator. 43. A system of wound treatment comprising:
(a) the composition according to any one of claims 1 to 39; (b) an isotonic diluent solution of around pH 7, comprising: 0.015 M ascorbic acid; 0.015 M sodium bicarbonate; 0.12 sodium chloride; wherein said isotonic diluent solution is used to dilute said composition at a minimum ratio of 1 part said composition to 2 parts said diluent solution (1:2), thereby forming a wound irrigation solution; and wherein said wound irrigation solution is used to irrigate a site of treatment on a patient before application of said composition. 44. A wound dressing comprising at least a first layer and a second layer, wherein:
the first layer comprises honey; and, the second layer comprises a pharmaceutically acceptable carbonate (CO3 −2) and/or bicarbonate (HCO3 −1) salt. 45. The wound dressing of claim 44, wherein the honey is provided in the form of dry granules. 46. The wound dressing of claim 45, wherein the honey granules are encapsulated in a dissolvable coating. 47. The wound dressing of claim 46, wherein the encapsulated honey granules are adhered to the first layer. 48. The wound dressing of claim 47, wherein the honey granules are combined with granules of ascorbic acid. 49. The wound dressing according to any one of claims 44 to 48, wherein said honey is Manuka honey produced from Leptospermum scoparium. 50. The wound dressing according to any one of claims 44 to 49, wherein said pharmaceutically acceptable salt is sodium carbonate (Na2CO3), potassium carbonate (K2CO3), ammonium carbonate ((NH4)2CO3), sodium bicarbonate (NaHCO3), potassium bicarbonate (KHCO3), ammonium bicarbonate ((NH4)HCO3) or any combination thereof. 51. A treatment kit for desloughing, debriding, exfoliating, or treating a wound, the kit comprising:
honey and/or a honey substitute, wherein the honey and/or honey substitute is in the form of dry granules; and, a pharmaceutically acceptable carbonate (CO3 −2) and/or bicarbonate (HCO3 −1) salt. 52. The treatment kit of claim 51, wherein the honey and/or honey substitute granules are encapsulated. 53. The treatment kit of claim 51 or 52, wherein the honey and the carbonate and/or bicarbonate salt are combined in a single container. 54. The treatment kit according to any one of claims 51 to 53 further comprising a mixing container for combining the honey and the carbonate and/or bicarbonate salt to form an aqueous slurry. 55. The treatment kit according to any one of claims 51 to 54, wherein said honey is Manuka honey produced from Leptospermum scoparium. 56. The treatment kit according to any one of claims 51 to 55, wherein said pharmaceutically acceptable salt is sodium carbonate (Na2CO3), potassium carbonate (K2CO3), ammonium carbonate ((NH4)2CO3), sodium bicarbonate (NaHCO3), potassium bicarbonate (KHCO3), ammonium bicarbonate ((NH4)HCO3) or any combination thereof. 57. A method of desloughing, debriding or exfoliating a region of skin of a mammal or treating a wound on a mammal, the method comprising applying to the region or the wound a topical composition comprising:
honey and/or a honey substitute; and, a pharmaceutically acceptable carbonate (CO3 −2) and/or bicarbonate (HCO3 −1) salt. 58. The method of claim 57, wherein the composition is in the form of a foam or mousse. 59. The method according to claim 57 or 58, wherein said honey is Manuka honey produced from Leptospermum scoparium. 60. The method according to any one of claims 57 to 59, wherein said pharmaceutically acceptable salt is sodium carbonate (Na2CO3), potassium carbonate (K2CO3), ammonium carbonate ((NH4)2CO3), sodium bicarbonate (NaHCO3), potassium bicarbonate (KHCO3), ammonium bicarbonate ((NH4)HCO3) or any combination thereof.
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1,272 | 14,317,392 | 1,616 |
Described is an intra-mammary teat sealant and a corresponding method of forming a physical barrier in the teat canal of a non-human animal for prophylactic treatment of mammary disorders during the animal's dry period. The method includes the step of infusing a bismuth-free teat seal formulation into the teat canal of the animal. The method also prevents the formation of black spot defect in dairy products, especially cheddar cheese, made from the milk of animals so treated.
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1. A method of forming a physical barrier in the teat canal of a non-human animal for prophylactic treatment of mammary disorders during the animal's dry period wherein the physical barrier does not cause black spot defect in dairy products made with milk from the animal, the method comprising:
infusing an amount of a teat seal formulation into the teat canal of the animal, wherein the teat seal formulation comprises a bismuth-free, non-toxic, metal salt, and wherein the amount is sufficient to form a physical barrier to entry of microorganisms into the teat canal, and wherein the teat seal formulation does not cause black spot defect in aged cheese made with milk from the animal. 2. The method of claim 1, wherein the teat seal formulation is devoid of anti-infective agents. 3. The method of claim 1, wherein the teat seal formulation comprises a bismuth-free, non-toxic metal salt in a gel base. 4. The method of claim 1, wherein the teat seal formulation comprises at least about 30% by weight of the bismuth-free, non-toxic metal salt. 5. The method of claim 1, wherein the teat seal formulation comprises about 50% to about 75% by weight of the bismuth-free, non-toxic metal salt. 6. The method of claim 1, wherein the teat seal formulation comprises about 65% by weight of the bismuth-free, non-toxic metal salt. 7. The method of claim 1, wherein the non-toxic metal salt is selected from the group consisting of titanium dioxide, zinc oxide, barium sulfate and combinations thereof. 8. The method of claim 3, wherein the gel base comprises aluminum stearate. 9. The method of claim 3, wherein the gel base comprises liquid paraffin. 10. An intra-mammary teat sealant comprising, in combination:
a gel base; and a non-toxic metal salt dispersed in the gel base, wherein the metal salt is devoid of bismuth, and comprises at least about 30% by weight of the metal salt. 11. The intra-mammary teat sealant of claim 10, wherein the sealant is devoid of anti-infective agents. 12. (canceled) 13. The intra-mammary teat sealant of claim 10, comprising about 50% to about 75% by weight of the metal salt. 14. The intra-mammary teat sealant of claim 10, comprising about 65% by weight of the metal salt. 15. An intra-mammary teat sealant comprising, in combination:
a gel base; and a non-toxic metal salt dispersed in the gel base, wherein the metal salt is devoid of bismuth, wherein the metal salt is selected from the group consisting of titanium dioxide, zinc oxide, barium sulfate, and combinations thereof, and wherein the composition comprises at least about 30% by weight of the metal salt. 16. The intra-mammary teat sealant of claim 10, wherein the gel base comprises aluminum stearate. 17. The intra-mammary teat sealant of claim 10, wherein the gel base comprises liquid paraffin. 18. In a method of forming a physical barrier in the teat canal of a non-human animal for prophylactic treatment of mammary disorders during the animal's dry period, the method comprising the step of infusing a seal formulation into the teat canal of the animal, an improvement comprising:
infusing a teat seal formulation comprising a bismuth-free, non-toxic metal salt in a gel base, wherein the teat seal formulation comprises at least about 30% by weight of the metal salt and is devoid of anti-infective agents. 19. The improvement of claim 18, comprising infusing a teat seal formulation comprising at least about 30% by weight of the bismuth-free, non-toxic metal. 20. The improvement of claim 18, comprising infusing a teat seal formulation comprising about 50% to about 75% by weight of the bismuth-free, non-toxic metal. 21. The improvement of claim 18, comprising infusing a teat seal formulation comprising about 65% by weight of the bismuth-free, non-toxic metal salt. 22. The improvement of claim 18, wherein the metal salt is selected from the group consisting of titanium dioxide, zinc oxide, barium sulfate, and combinations thereof. 23. The intra-mammary teat sealant of claim 15, comprising about 50% to about 75% by weight of the metal salt. 24. The intra-mammary teat sealant of claim 15, comprising about 65% by weight of the metal salt. 25. The intra-mammary teat sealant of claim 15, wherein the gel base comprises aluminum stearate. 26. The intra-mammary teat sealant of claim 15, wherein the gel base comprises liquid paraffin.
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Described is an intra-mammary teat sealant and a corresponding method of forming a physical barrier in the teat canal of a non-human animal for prophylactic treatment of mammary disorders during the animal's dry period. The method includes the step of infusing a bismuth-free teat seal formulation into the teat canal of the animal. The method also prevents the formation of black spot defect in dairy products, especially cheddar cheese, made from the milk of animals so treated.1. A method of forming a physical barrier in the teat canal of a non-human animal for prophylactic treatment of mammary disorders during the animal's dry period wherein the physical barrier does not cause black spot defect in dairy products made with milk from the animal, the method comprising:
infusing an amount of a teat seal formulation into the teat canal of the animal, wherein the teat seal formulation comprises a bismuth-free, non-toxic, metal salt, and wherein the amount is sufficient to form a physical barrier to entry of microorganisms into the teat canal, and wherein the teat seal formulation does not cause black spot defect in aged cheese made with milk from the animal. 2. The method of claim 1, wherein the teat seal formulation is devoid of anti-infective agents. 3. The method of claim 1, wherein the teat seal formulation comprises a bismuth-free, non-toxic metal salt in a gel base. 4. The method of claim 1, wherein the teat seal formulation comprises at least about 30% by weight of the bismuth-free, non-toxic metal salt. 5. The method of claim 1, wherein the teat seal formulation comprises about 50% to about 75% by weight of the bismuth-free, non-toxic metal salt. 6. The method of claim 1, wherein the teat seal formulation comprises about 65% by weight of the bismuth-free, non-toxic metal salt. 7. The method of claim 1, wherein the non-toxic metal salt is selected from the group consisting of titanium dioxide, zinc oxide, barium sulfate and combinations thereof. 8. The method of claim 3, wherein the gel base comprises aluminum stearate. 9. The method of claim 3, wherein the gel base comprises liquid paraffin. 10. An intra-mammary teat sealant comprising, in combination:
a gel base; and a non-toxic metal salt dispersed in the gel base, wherein the metal salt is devoid of bismuth, and comprises at least about 30% by weight of the metal salt. 11. The intra-mammary teat sealant of claim 10, wherein the sealant is devoid of anti-infective agents. 12. (canceled) 13. The intra-mammary teat sealant of claim 10, comprising about 50% to about 75% by weight of the metal salt. 14. The intra-mammary teat sealant of claim 10, comprising about 65% by weight of the metal salt. 15. An intra-mammary teat sealant comprising, in combination:
a gel base; and a non-toxic metal salt dispersed in the gel base, wherein the metal salt is devoid of bismuth, wherein the metal salt is selected from the group consisting of titanium dioxide, zinc oxide, barium sulfate, and combinations thereof, and wherein the composition comprises at least about 30% by weight of the metal salt. 16. The intra-mammary teat sealant of claim 10, wherein the gel base comprises aluminum stearate. 17. The intra-mammary teat sealant of claim 10, wherein the gel base comprises liquid paraffin. 18. In a method of forming a physical barrier in the teat canal of a non-human animal for prophylactic treatment of mammary disorders during the animal's dry period, the method comprising the step of infusing a seal formulation into the teat canal of the animal, an improvement comprising:
infusing a teat seal formulation comprising a bismuth-free, non-toxic metal salt in a gel base, wherein the teat seal formulation comprises at least about 30% by weight of the metal salt and is devoid of anti-infective agents. 19. The improvement of claim 18, comprising infusing a teat seal formulation comprising at least about 30% by weight of the bismuth-free, non-toxic metal. 20. The improvement of claim 18, comprising infusing a teat seal formulation comprising about 50% to about 75% by weight of the bismuth-free, non-toxic metal. 21. The improvement of claim 18, comprising infusing a teat seal formulation comprising about 65% by weight of the bismuth-free, non-toxic metal salt. 22. The improvement of claim 18, wherein the metal salt is selected from the group consisting of titanium dioxide, zinc oxide, barium sulfate, and combinations thereof. 23. The intra-mammary teat sealant of claim 15, comprising about 50% to about 75% by weight of the metal salt. 24. The intra-mammary teat sealant of claim 15, comprising about 65% by weight of the metal salt. 25. The intra-mammary teat sealant of claim 15, wherein the gel base comprises aluminum stearate. 26. The intra-mammary teat sealant of claim 15, wherein the gel base comprises liquid paraffin.
| 1,600 |
1,273 | 14,916,439 | 1,619 |
This invention provides methods for producing a polymer particle which contains unusually high negative charges on the surface of the particle. Preferably, the polymer is pharmaceutically acceptable. The negative charges can be conferred by chemical groups such as carboxyl, sulfonate, nitrate, fluorate, chloride, iodide, persulfate, and many others, with carboxyl group being preferred. The invention also provides polymer particle produced by the methods of the invention.
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1. A method for the preparation of a composition comprising microparticles or nanoparticles having negative surface charges, said method comprising producing said microparticles or nanoparticles with a pharmaceutically acceptable polymer using either an emulsion process or a precipitation process:
(a) wherein said emulsion process or said precipitation process is carried out in an aqueous solution having a pH that promotes ionization of said pharmaceutically acceptable polymer; (b) wherein said pharmaceutically acceptable polymer has an average molecular weight of from about 500 to about 1,000,000 Da, preferably from about 1,000 to about 50,000 Da; and/or, (c) wherein said pharmaceutically acceptable polymer contains multiple negatively charged terminal groups. 2. The method of claim 1, wherein said emulsion process comprises:
(1) dissolving the pharmaceutically acceptable polymer in a first solvent to form a polymer solution; (2) emulsifying the polymer solution in a solution of a second solvent to form an emulsion, wherein the first solvent is not miscible or partially miscible the second solvent, and wherein the solution of the second solvent optionally comprises a pharmaceutically acceptable negatively charged agent; and, (3) removing the first solvent to form said microparticles or nanoparticles having negative surface charges;
wherein said solution of the second solvent is optionally said aqueous solution. 3. The method of claim 1, said precipitation process comprises:
(1) dissolving the pharmaceutically acceptable polymer in a first solvent to form a polymer solution; (2) preparing a solution of a second solvent, wherein the first solvent is miscible with the second solvent, and wherein the solution of the second solvent optionally comprises a pharmaceutically acceptable negatively charged agent and optionally comprises a surfactant; and, (3) combining the polymer solution to the solution of the second solvent while mixing, thus forming said microparticles or nanoparticles having negative surface charges;
wherein said solution of the second solvent is optionally said aqueous solution. 4. The method of claim 1, wherein said emulsion process is a double emulsion process comprising:
(1) dissolving the pharmaceutically acceptable polymer in a first solvent to form a polymer solution; (2) adding a small amount of a solution of a second solvent to the polymer solution to form a mixture, wherein the first solvent is not miscible or partially miscible with the second solvent, and wherein the solution of the second solvent optionally comprises an active pharmaceutical ingredient (API); (3) emulsifying the mixture to form a first emulsion; (4) emulsifying the first emulsion in the solution of the second solvent to form a second emulsion, wherein the solution of the second solvent optionally comprises a pharmaceutically acceptable negatively charged agent, and optionally further comprises a surfactant; and, (5) removing the first solvent to form said microparticles or nanoparticles having negative surface charges;
wherein said solution of the second solvent is optionally said aqueous solution. 5. The method of claim 2, wherein the pharmaceutically acceptable negatively charged agent is incorporated onto said microparticles or nanoparticles to increase negative surface charges on said microparticles or nanoparticles. 6. The method of claim 2, wherein the pharmaceutically acceptable negatively charged agent is incorporated onto said microparticles or nanoparticles to increase negative surface charge density on (e.g., the number of COOH groups on the surface of) said microparticles or nanoparticles. 7-10. (canceled) 11. The method of claim 1, wherein the microparticles or nanoparticles have a zeta potential of from about −5 mV to about −200 mV, preferably from about −15 mV to about −100 mV, most preferably from −35 mV to −85 mV. 12. The method of claim 2, wherein the first solvent is a volatile solvent. 13. The method of claim 12, wherein the polymer is a PLGA polymer, and the volatile solvent is methylene chloride, ethyl acetate, or chloroform. 14. The method of claim 2, wherein the solution of the second solvent comprises a surfactant. 15. (canceled) 16. The method of claim 14, wherein the polymer is a PLGA polymer, and the surfactant is/comprises polyvinyl alcohol, polyvinylpyrrolidone, a Tween series surfactant, Pluronic series, Poloxamer series, or Triton X-100 or a salt, derivative, copolymer, or mixture thereof. 17. The method of claim 1, wherein the emulsifying step comprises homogenization, mechanical stirring, and/or microfluidization. 18. The method of claim 1, wherein the first solvent is removed through solvent exchange and/or evaporation. 19. The method of claim 2, wherein the pharmaceutically acceptable negatively charged agent is a carboxyl-containing agent. 20. The method of claim 19, wherein the carboxyl-containing agent comprises hyaluronic acid; gelatin; polysaccharide; polyacrylic acid; polymethacrylic acid;
poly(hydroxyethylmethacrylic acid); amino acid; or a salt, derivative, copolymer, or mixture thereof. 21. The method of claim 1, wherein said pH that promotes ionization of said pharmaceutically acceptable polymer is between about 4-14, 6-14, 6-10, or about 8-12. 22. (canceled) 23. The method of claim 3, wherein the second solvent is water, and the first solvent miscible with water is acetone, tetrahydrofuron (THF), acetonitrile, dimethyl sulfoxide (DMSO), or dimethylformamide (DMF). 24. The method of claim 1, wherein the multiple negatively charged terminal groups are carboxyl terminal groups. 25. The method of claim 24, wherein the polymer containing multiple negatively charged carboxyl terminal groups is produced by using a carboxyl-functional initiator in the preparation of the polymer. 26. The method of claim 25, wherein the carboxyl-functional initiator is an a-hydroxyl acid, preferably lactic acid or glycolic acid. 27. The method of claim 24, wherein the polymer containing multiple negatively charged carboxyl terminal groups is produced by grafting a carboxyl-containing entity to the polymer. 28. The method of claim 27, wherein the carboxyl-containing entity is polyacrylic acid, polymethacrylic acid, poly(hydroxyethyl methacrylic acid), poly(maleic acid), polyanhydrides, or a salt, derivative, copolymer, or mixture thereof. 29. The method of claim 24, wherein the polymer containing multiple negatively charged carboxyl terminal groups is produced by converting a functional group on the polymer to carboxyl group. 30. The method of claim 29, wherein the functional group is a hydroxyl group, and wherein the hydroxyl group is converted to the carboxyl group by reacting with an anhydride (e.g., dihydrofuran-2,5-dione). 31. The method of claim 24, wherein the polymer containing multiple negatively charged carboxyl terminal groups is produced by using an initiator that contains multiple carboxyl groups for generating hyperbranched polymer containing multiple negatively charged carboxyl terminal groups. 32. The method of claim 1, wherein the microparticles or nanoparticles have average particle sizes of from about 1 nm to about 1000 μm, preferably from about 10 nm to about 100 μm, and most preferably from about 20 nm to about 5 μm. 33. The method of claim 1, wherein the pharmaceutically acceptable polymer is PLGA, and wherein the microparticles or nanoparticles are PEGylated. 34-37. (canceled) 38. The method of claim 2, wherein an API (active pharmaceutical ingredient) is covalently attached to the surface of the microparticles or nanoparticles via covalent bonds. 39. The method of claim 2, wherein said solution of the second solvent is a mixture of the first solvent and the second solvent, and the volume ratio of the first solvent to the second solvent in said solution of the second solvent is about 0.1:99.9, about 1:99, about 5:95, about 7.5:92.5; about 7.8:92.2; about 8:92, or about 10:90. 40. The method of claim 1, further comprising chemically conjugating a biomolecule (e.g., a peptide or a protein) to the surface of the microparticles or nanoparticles. 41-43. (canceled)
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This invention provides methods for producing a polymer particle which contains unusually high negative charges on the surface of the particle. Preferably, the polymer is pharmaceutically acceptable. The negative charges can be conferred by chemical groups such as carboxyl, sulfonate, nitrate, fluorate, chloride, iodide, persulfate, and many others, with carboxyl group being preferred. The invention also provides polymer particle produced by the methods of the invention.1. A method for the preparation of a composition comprising microparticles or nanoparticles having negative surface charges, said method comprising producing said microparticles or nanoparticles with a pharmaceutically acceptable polymer using either an emulsion process or a precipitation process:
(a) wherein said emulsion process or said precipitation process is carried out in an aqueous solution having a pH that promotes ionization of said pharmaceutically acceptable polymer; (b) wherein said pharmaceutically acceptable polymer has an average molecular weight of from about 500 to about 1,000,000 Da, preferably from about 1,000 to about 50,000 Da; and/or, (c) wherein said pharmaceutically acceptable polymer contains multiple negatively charged terminal groups. 2. The method of claim 1, wherein said emulsion process comprises:
(1) dissolving the pharmaceutically acceptable polymer in a first solvent to form a polymer solution; (2) emulsifying the polymer solution in a solution of a second solvent to form an emulsion, wherein the first solvent is not miscible or partially miscible the second solvent, and wherein the solution of the second solvent optionally comprises a pharmaceutically acceptable negatively charged agent; and, (3) removing the first solvent to form said microparticles or nanoparticles having negative surface charges;
wherein said solution of the second solvent is optionally said aqueous solution. 3. The method of claim 1, said precipitation process comprises:
(1) dissolving the pharmaceutically acceptable polymer in a first solvent to form a polymer solution; (2) preparing a solution of a second solvent, wherein the first solvent is miscible with the second solvent, and wherein the solution of the second solvent optionally comprises a pharmaceutically acceptable negatively charged agent and optionally comprises a surfactant; and, (3) combining the polymer solution to the solution of the second solvent while mixing, thus forming said microparticles or nanoparticles having negative surface charges;
wherein said solution of the second solvent is optionally said aqueous solution. 4. The method of claim 1, wherein said emulsion process is a double emulsion process comprising:
(1) dissolving the pharmaceutically acceptable polymer in a first solvent to form a polymer solution; (2) adding a small amount of a solution of a second solvent to the polymer solution to form a mixture, wherein the first solvent is not miscible or partially miscible with the second solvent, and wherein the solution of the second solvent optionally comprises an active pharmaceutical ingredient (API); (3) emulsifying the mixture to form a first emulsion; (4) emulsifying the first emulsion in the solution of the second solvent to form a second emulsion, wherein the solution of the second solvent optionally comprises a pharmaceutically acceptable negatively charged agent, and optionally further comprises a surfactant; and, (5) removing the first solvent to form said microparticles or nanoparticles having negative surface charges;
wherein said solution of the second solvent is optionally said aqueous solution. 5. The method of claim 2, wherein the pharmaceutically acceptable negatively charged agent is incorporated onto said microparticles or nanoparticles to increase negative surface charges on said microparticles or nanoparticles. 6. The method of claim 2, wherein the pharmaceutically acceptable negatively charged agent is incorporated onto said microparticles or nanoparticles to increase negative surface charge density on (e.g., the number of COOH groups on the surface of) said microparticles or nanoparticles. 7-10. (canceled) 11. The method of claim 1, wherein the microparticles or nanoparticles have a zeta potential of from about −5 mV to about −200 mV, preferably from about −15 mV to about −100 mV, most preferably from −35 mV to −85 mV. 12. The method of claim 2, wherein the first solvent is a volatile solvent. 13. The method of claim 12, wherein the polymer is a PLGA polymer, and the volatile solvent is methylene chloride, ethyl acetate, or chloroform. 14. The method of claim 2, wherein the solution of the second solvent comprises a surfactant. 15. (canceled) 16. The method of claim 14, wherein the polymer is a PLGA polymer, and the surfactant is/comprises polyvinyl alcohol, polyvinylpyrrolidone, a Tween series surfactant, Pluronic series, Poloxamer series, or Triton X-100 or a salt, derivative, copolymer, or mixture thereof. 17. The method of claim 1, wherein the emulsifying step comprises homogenization, mechanical stirring, and/or microfluidization. 18. The method of claim 1, wherein the first solvent is removed through solvent exchange and/or evaporation. 19. The method of claim 2, wherein the pharmaceutically acceptable negatively charged agent is a carboxyl-containing agent. 20. The method of claim 19, wherein the carboxyl-containing agent comprises hyaluronic acid; gelatin; polysaccharide; polyacrylic acid; polymethacrylic acid;
poly(hydroxyethylmethacrylic acid); amino acid; or a salt, derivative, copolymer, or mixture thereof. 21. The method of claim 1, wherein said pH that promotes ionization of said pharmaceutically acceptable polymer is between about 4-14, 6-14, 6-10, or about 8-12. 22. (canceled) 23. The method of claim 3, wherein the second solvent is water, and the first solvent miscible with water is acetone, tetrahydrofuron (THF), acetonitrile, dimethyl sulfoxide (DMSO), or dimethylformamide (DMF). 24. The method of claim 1, wherein the multiple negatively charged terminal groups are carboxyl terminal groups. 25. The method of claim 24, wherein the polymer containing multiple negatively charged carboxyl terminal groups is produced by using a carboxyl-functional initiator in the preparation of the polymer. 26. The method of claim 25, wherein the carboxyl-functional initiator is an a-hydroxyl acid, preferably lactic acid or glycolic acid. 27. The method of claim 24, wherein the polymer containing multiple negatively charged carboxyl terminal groups is produced by grafting a carboxyl-containing entity to the polymer. 28. The method of claim 27, wherein the carboxyl-containing entity is polyacrylic acid, polymethacrylic acid, poly(hydroxyethyl methacrylic acid), poly(maleic acid), polyanhydrides, or a salt, derivative, copolymer, or mixture thereof. 29. The method of claim 24, wherein the polymer containing multiple negatively charged carboxyl terminal groups is produced by converting a functional group on the polymer to carboxyl group. 30. The method of claim 29, wherein the functional group is a hydroxyl group, and wherein the hydroxyl group is converted to the carboxyl group by reacting with an anhydride (e.g., dihydrofuran-2,5-dione). 31. The method of claim 24, wherein the polymer containing multiple negatively charged carboxyl terminal groups is produced by using an initiator that contains multiple carboxyl groups for generating hyperbranched polymer containing multiple negatively charged carboxyl terminal groups. 32. The method of claim 1, wherein the microparticles or nanoparticles have average particle sizes of from about 1 nm to about 1000 μm, preferably from about 10 nm to about 100 μm, and most preferably from about 20 nm to about 5 μm. 33. The method of claim 1, wherein the pharmaceutically acceptable polymer is PLGA, and wherein the microparticles or nanoparticles are PEGylated. 34-37. (canceled) 38. The method of claim 2, wherein an API (active pharmaceutical ingredient) is covalently attached to the surface of the microparticles or nanoparticles via covalent bonds. 39. The method of claim 2, wherein said solution of the second solvent is a mixture of the first solvent and the second solvent, and the volume ratio of the first solvent to the second solvent in said solution of the second solvent is about 0.1:99.9, about 1:99, about 5:95, about 7.5:92.5; about 7.8:92.2; about 8:92, or about 10:90. 40. The method of claim 1, further comprising chemically conjugating a biomolecule (e.g., a peptide or a protein) to the surface of the microparticles or nanoparticles. 41-43. (canceled)
| 1,600 |
1,274 | 15,850,364 | 1,647 |
Methods for increasing the patency of biodegradable, synthetic vascular grafts are provided. The methods include administering one or more cytokines and/or chemokines that promote outward tissue remodeling of the vascular grafts and vascular neotissue formation. The disclosed methods do not require cell seeding of the vascular grafts, thus avoiding many problems associated with cell seeding. Biodegradable, polymeric vascular grafts which provide controlled release of cytokines and/or chemokines at the site of vascular graft implantation are also provided.
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1-10. (canceled) 11. A biodegradable polymeric vascular graft or conduit comprising monocyte chemoattractant protein 1 (MCP-1), wherein the MCP-1 is locally released from the graft in an effective amount following graft implantation to recruit an effective amount of host monocytes to the graft within one week of graft implantation to prevent, inhibit or reduce stenosis, and promote neotissue formation and increase the patency of the graft in the host over time relative to the patency of the graft in the absence of MCP 1. 12. (canceled) 13. The polymeric vascular graft or conduit of claim 1, wherein the biodegradable or bioabsorbable polymers are selected from the group consisting of poly(lactic acid), poly(glycolic acid), polyanhydrides, poly(ortho)esters, polyesters, polyurethanes, poly(butic acid), poly(valeric acid), poly(caprolactone), poly(hydroxyalkanoates), and poly(lactide-co-caprolactone), or combinations, blends or co-polymers thereof. 14. The polymeric vascular graft or conduit of claim 13, wherein the biodegradable or bioabsorbable polymers are formed into a fiber-based mesh. 15. The polymeric vascular graft or conduit of claim 14, wherein the fiber-based mesh is a non-woven mesh. 16. The polymeric vascular graft or conduit of claim 15, wherein the vascular graft further comprises a polymeric sealant. 17. The polymeric vascular graft or conduit of claim 16, wherein the polymeric sealant comprises a co-polymer of ε-caprolactone and L-lactide. 18. The polymeric vascular graft or conduit of claim 11, further comprising a cytokine or chemokine selected from the group consisting interleukin (IL) 1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12(p40), IL-12(p70), IL-13, IL-15, IL-17, IP-10, eotaxin, interferon γ (IFNγ), granulocyte colony-stimulating factor (G-CSF), granulocyte/macrophage colony-stimulating factor (GM-CSF), macrophage inflammatory protein 1α (MIP-1α), RANTES, tumor necrosis factor (TNF)-α, platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB, TGF-beta, VEGF, and combinations thereof. 19. (canceled) 20. The polymeric vascular graft or conduit of claim 11, wherein the vascular graft or conduit further comprises an active agent selected from the group consisting of anti-thrombogenic agents, anti-proliferative agents, anti-inflammatory agents, antiproliferative agents, anesthetic agents, anti-coagulants, cholesterol-lowering agents, vasodilating agents, and agents which interfere with endogenous vasoactive mechanisms. 21. The polymeric vascular graft or conduit of claim 11, wherein the MCP-1 or other cytokine or chemokine is dispersed throughout the vascular graft or conduit. 22. The polymeric vascular graft or conduit of claim 21, wherein the cytokine or chemokine is encapsulated in the form of microspheres, nanospheres, microparticles and/or microcapsules that are seeded into the vascular graft or conduit. 23. The polymeric vascular graft or conduit of claim 11, wherein the effective amount of MCP-1 is released from microparticles in the graft over a period of 1 to 3 days after the graft is implanted into the host. 24. The polymeric vascular graft or conduit of claim 11, wherein the MCP-1 is incorporated into or onto the graft by seeding the graft with microparticles comprising MCP-1 before implantation of the graft into the host. 25. The polymeric vascular graft or conduit of claim 11, wherein the graft or conduit is seeded with human bone marrow mononuclear cells. 26. The polymeric vascular graft or conduit of claim 11, wherein the MCP-1 is provided in microparticles between 1 μm and 20 μm in diameter incorporated into the graft. 27. The polymeric vascular graft or conduit of claim 11, wherein the internal diameter of the graft or conduit is larger relative to the internal diameter of the graft or conduit in the absence of MCP-1 ten weeks after implantation of the graft into the host. 28. The polymeric vascular graft or conduit of claim 11, wherein the wall thickness of the graft or conduit is thinner relative to the wall thickness of the graft or conduit in the absence of MCP-1 ten weeks after implantation of the graft or conduit into the host. 29. The polymeric vascular graft or conduit of claim 11, for implantation into a pediatric patient. 30. The polymeric vascular graft or conduit of claim 14 wherein the graft or conduit is formed of knitted or braided fibers. 31. The polymeric vascular graft or conduit of claim 14 wherein the graft or conduit is formed of a woven mesh
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Methods for increasing the patency of biodegradable, synthetic vascular grafts are provided. The methods include administering one or more cytokines and/or chemokines that promote outward tissue remodeling of the vascular grafts and vascular neotissue formation. The disclosed methods do not require cell seeding of the vascular grafts, thus avoiding many problems associated with cell seeding. Biodegradable, polymeric vascular grafts which provide controlled release of cytokines and/or chemokines at the site of vascular graft implantation are also provided.1-10. (canceled) 11. A biodegradable polymeric vascular graft or conduit comprising monocyte chemoattractant protein 1 (MCP-1), wherein the MCP-1 is locally released from the graft in an effective amount following graft implantation to recruit an effective amount of host monocytes to the graft within one week of graft implantation to prevent, inhibit or reduce stenosis, and promote neotissue formation and increase the patency of the graft in the host over time relative to the patency of the graft in the absence of MCP 1. 12. (canceled) 13. The polymeric vascular graft or conduit of claim 1, wherein the biodegradable or bioabsorbable polymers are selected from the group consisting of poly(lactic acid), poly(glycolic acid), polyanhydrides, poly(ortho)esters, polyesters, polyurethanes, poly(butic acid), poly(valeric acid), poly(caprolactone), poly(hydroxyalkanoates), and poly(lactide-co-caprolactone), or combinations, blends or co-polymers thereof. 14. The polymeric vascular graft or conduit of claim 13, wherein the biodegradable or bioabsorbable polymers are formed into a fiber-based mesh. 15. The polymeric vascular graft or conduit of claim 14, wherein the fiber-based mesh is a non-woven mesh. 16. The polymeric vascular graft or conduit of claim 15, wherein the vascular graft further comprises a polymeric sealant. 17. The polymeric vascular graft or conduit of claim 16, wherein the polymeric sealant comprises a co-polymer of ε-caprolactone and L-lactide. 18. The polymeric vascular graft or conduit of claim 11, further comprising a cytokine or chemokine selected from the group consisting interleukin (IL) 1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12(p40), IL-12(p70), IL-13, IL-15, IL-17, IP-10, eotaxin, interferon γ (IFNγ), granulocyte colony-stimulating factor (G-CSF), granulocyte/macrophage colony-stimulating factor (GM-CSF), macrophage inflammatory protein 1α (MIP-1α), RANTES, tumor necrosis factor (TNF)-α, platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB, TGF-beta, VEGF, and combinations thereof. 19. (canceled) 20. The polymeric vascular graft or conduit of claim 11, wherein the vascular graft or conduit further comprises an active agent selected from the group consisting of anti-thrombogenic agents, anti-proliferative agents, anti-inflammatory agents, antiproliferative agents, anesthetic agents, anti-coagulants, cholesterol-lowering agents, vasodilating agents, and agents which interfere with endogenous vasoactive mechanisms. 21. The polymeric vascular graft or conduit of claim 11, wherein the MCP-1 or other cytokine or chemokine is dispersed throughout the vascular graft or conduit. 22. The polymeric vascular graft or conduit of claim 21, wherein the cytokine or chemokine is encapsulated in the form of microspheres, nanospheres, microparticles and/or microcapsules that are seeded into the vascular graft or conduit. 23. The polymeric vascular graft or conduit of claim 11, wherein the effective amount of MCP-1 is released from microparticles in the graft over a period of 1 to 3 days after the graft is implanted into the host. 24. The polymeric vascular graft or conduit of claim 11, wherein the MCP-1 is incorporated into or onto the graft by seeding the graft with microparticles comprising MCP-1 before implantation of the graft into the host. 25. The polymeric vascular graft or conduit of claim 11, wherein the graft or conduit is seeded with human bone marrow mononuclear cells. 26. The polymeric vascular graft or conduit of claim 11, wherein the MCP-1 is provided in microparticles between 1 μm and 20 μm in diameter incorporated into the graft. 27. The polymeric vascular graft or conduit of claim 11, wherein the internal diameter of the graft or conduit is larger relative to the internal diameter of the graft or conduit in the absence of MCP-1 ten weeks after implantation of the graft into the host. 28. The polymeric vascular graft or conduit of claim 11, wherein the wall thickness of the graft or conduit is thinner relative to the wall thickness of the graft or conduit in the absence of MCP-1 ten weeks after implantation of the graft or conduit into the host. 29. The polymeric vascular graft or conduit of claim 11, for implantation into a pediatric patient. 30. The polymeric vascular graft or conduit of claim 14 wherein the graft or conduit is formed of knitted or braided fibers. 31. The polymeric vascular graft or conduit of claim 14 wherein the graft or conduit is formed of a woven mesh
| 1,600 |
1,275 | 14,912,657 | 1,617 |
A method of providing anesthesia and organ-protection to a subject in need thereof comprises co-administering to the subject a non-anesthetic protective gas in an amount effect to provide organ protection, and a liquid anesthetic agent in an amount effective to provide anesthesia, at normobaric conditions.
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1. A method of providing anesthesia and organ-protection to a subject in need thereof, comprising co-administering to the subject a non-anesthetic protective gas in an amount effect to provide organ protection, and a liquid anesthetic agent in an amount effective to provide anesthesia, at normobaric conditions. 2. The method according to claim 1 wherein the non-anesthetic protective gas is helium, neon, argon, krypton, or radon. 3. The method according to claim 2 wherein the non-anesthetic protective gas is argon. 4. The method according to claim 2, wherein the argon is administered at a concentration of between 1% and 79%. 5. The method according to claim 1 wherein the non-anesthetic protective gas is hydrogen sulfide. 6. The method according to claim 5 wherein hydrogen sulfide is administered at a level of less than 1000 ppm. 7. The method according to claim 1 wherein the liquid anesthetic agent is administered in liquid form. 8. The method according to claim 7 wherein the liquid anesthetic agent is thiopental, propofol, ketamine, hypnomidate, barbiturate, buprenorphine, or dexmedetomidine. 9. The method according to claim 7 wherein the liquid anesthetic agent is administered intravenously. 10. The method according to claim 1 wherein the liquid anesthetic agent is administered in a vapor state. 11. The method according to claim 10 wherein the liquid anesthetic agent is sevoflurane, isoflurane or desflurane. 12. The method according to claim 11 wherein the liquid anesthetic agent is sevoflurane. 13. The method according to claim 10 wherein the non-anesthetic protective gas and the liquid anesthetic agent are administered to the subject by a membrane-based device. 14. The method according to claim 10, wherein the non-anesthetic protective gas and the liquid anesthetic agent are administered to the subject by a ventilator. 15. The method according to claim 14 wherein the ventilator comprises one or more gas separation membranes that selectively retains, sequesters or exhausts the non-anesthetic protective gas from the air exhaled by the subject, and optionally i) when the non-anesthetic protective gas is retained it is available for further use on the patient and ii) when the non-anesthetic protective gas is sequestered or exhausted, it is subsequently recaptured for future use. 16. The method according claim 1 wherein administration of the non-anesthetic protective gas in combination with the liquid anesthetic agent reduces damage to the brain, the spinal cord, the kidney, the liver and/or the heart. 17. The method according to claim 1 wherein administration of the non-anesthetic protective gas in combination with the liquid anesthetic agent reduces damage resulting from hypoglycemia, hypoxemia, hypoxia, ischemia, cerebral edema or axotomy. 18. The method according to claim 1 wherein the non-anesthetic protective gas and the liquid anesthetic agent are administered concurrently or sequentially. 19. The method according to claim 1 wherein the liquid anesthetic agent and non-anesthetic protective gas are administered to a patient that is intubated and ventilated for stroke, is undergoing surgery, including cardiac surgery, neurosurgery optionally general surgery or trauma surgery, optionally trauma surgery to treat impact trauma, such as traumatic CNS injury (brain injury or spinal cord injury) or traumatic injury to organs in the torso. 20. The method according to claim 1, wherein the non-anesthetic protective gas and the liquid anesthetic agent are administered in the absence of xenon. 21. The method according to claim 1, wherein the non-anesthetic protective gas and the liquid anesthetic agent are administered in the absence of nitrous oxide. 22. The method according to claim 1, wherein the non-anesthetic protective gas and liquid anesthetic agent are administered under normothermic conditions. 23. A use of a non-anesthetic protective gas in combination with a liquid anesthetic agent in an amount effective to provide anesthesia, at normobaric conditions, for providing anesthesia and organ-protection to a subject in need thereof, optionally wherein the non-anesthetic protective gas is argon, optionally wherein the liquid anesthetic agent is sevoflurane, isoflurane or desflurane. 24. A method of providing organ-protection to a subject in need thereof, comprising co-administering to the subject a non-anesthetic protective gas and a liquid anesthetic agent, in amounts effective to provide organ protection, at normobaric conditions.
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A method of providing anesthesia and organ-protection to a subject in need thereof comprises co-administering to the subject a non-anesthetic protective gas in an amount effect to provide organ protection, and a liquid anesthetic agent in an amount effective to provide anesthesia, at normobaric conditions.1. A method of providing anesthesia and organ-protection to a subject in need thereof, comprising co-administering to the subject a non-anesthetic protective gas in an amount effect to provide organ protection, and a liquid anesthetic agent in an amount effective to provide anesthesia, at normobaric conditions. 2. The method according to claim 1 wherein the non-anesthetic protective gas is helium, neon, argon, krypton, or radon. 3. The method according to claim 2 wherein the non-anesthetic protective gas is argon. 4. The method according to claim 2, wherein the argon is administered at a concentration of between 1% and 79%. 5. The method according to claim 1 wherein the non-anesthetic protective gas is hydrogen sulfide. 6. The method according to claim 5 wherein hydrogen sulfide is administered at a level of less than 1000 ppm. 7. The method according to claim 1 wherein the liquid anesthetic agent is administered in liquid form. 8. The method according to claim 7 wherein the liquid anesthetic agent is thiopental, propofol, ketamine, hypnomidate, barbiturate, buprenorphine, or dexmedetomidine. 9. The method according to claim 7 wherein the liquid anesthetic agent is administered intravenously. 10. The method according to claim 1 wherein the liquid anesthetic agent is administered in a vapor state. 11. The method according to claim 10 wherein the liquid anesthetic agent is sevoflurane, isoflurane or desflurane. 12. The method according to claim 11 wherein the liquid anesthetic agent is sevoflurane. 13. The method according to claim 10 wherein the non-anesthetic protective gas and the liquid anesthetic agent are administered to the subject by a membrane-based device. 14. The method according to claim 10, wherein the non-anesthetic protective gas and the liquid anesthetic agent are administered to the subject by a ventilator. 15. The method according to claim 14 wherein the ventilator comprises one or more gas separation membranes that selectively retains, sequesters or exhausts the non-anesthetic protective gas from the air exhaled by the subject, and optionally i) when the non-anesthetic protective gas is retained it is available for further use on the patient and ii) when the non-anesthetic protective gas is sequestered or exhausted, it is subsequently recaptured for future use. 16. The method according claim 1 wherein administration of the non-anesthetic protective gas in combination with the liquid anesthetic agent reduces damage to the brain, the spinal cord, the kidney, the liver and/or the heart. 17. The method according to claim 1 wherein administration of the non-anesthetic protective gas in combination with the liquid anesthetic agent reduces damage resulting from hypoglycemia, hypoxemia, hypoxia, ischemia, cerebral edema or axotomy. 18. The method according to claim 1 wherein the non-anesthetic protective gas and the liquid anesthetic agent are administered concurrently or sequentially. 19. The method according to claim 1 wherein the liquid anesthetic agent and non-anesthetic protective gas are administered to a patient that is intubated and ventilated for stroke, is undergoing surgery, including cardiac surgery, neurosurgery optionally general surgery or trauma surgery, optionally trauma surgery to treat impact trauma, such as traumatic CNS injury (brain injury or spinal cord injury) or traumatic injury to organs in the torso. 20. The method according to claim 1, wherein the non-anesthetic protective gas and the liquid anesthetic agent are administered in the absence of xenon. 21. The method according to claim 1, wherein the non-anesthetic protective gas and the liquid anesthetic agent are administered in the absence of nitrous oxide. 22. The method according to claim 1, wherein the non-anesthetic protective gas and liquid anesthetic agent are administered under normothermic conditions. 23. A use of a non-anesthetic protective gas in combination with a liquid anesthetic agent in an amount effective to provide anesthesia, at normobaric conditions, for providing anesthesia and organ-protection to a subject in need thereof, optionally wherein the non-anesthetic protective gas is argon, optionally wherein the liquid anesthetic agent is sevoflurane, isoflurane or desflurane. 24. A method of providing organ-protection to a subject in need thereof, comprising co-administering to the subject a non-anesthetic protective gas and a liquid anesthetic agent, in amounts effective to provide organ protection, at normobaric conditions.
| 1,600 |
1,276 | 16,576,485 | 1,617 |
The present application discloses a sustained release composition in pellet form, wherein the core of the pellet comprises:
(a) a therapeutically effective amount of a medicament; (b) 0.5 to 50% by weight of a water-soluble polymer; and (c) 1 to 25% by weight of a water-insoluble polymer applied as an aqueous latex dispersion and subsequently the water is removed, wherein the sum of the percentages of the medicament, the water-insoluble polymer and the water-soluble polymer is equal to or less than 100%. It also discloses methods of making this composition.
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1. A unit dosage form, in the form of an oral capsule comprising a plurality of pellets, said pellets comprising:
(a) a therapeutically effective amount of carbamazepine; (b) a sustained release water-soluble polymer; and (c) a water-insoluble polymer that is substantially water-insoluble in aqueous medium independent of the pH;
wherein the ratio of said water-soluble polymer to said water insoluble-polymer ranges from about 5:95 to about 50:50; and
wherein all of said plurality of pellets are free of an enteric coating. 2. The unit dosage form according to claim 1, wherein each of said pellets comprise a core, wherein said core comprises from about 0.5 to about 50% said water-soluble polymer by weight of said core. 3. The unit dosage form according to claim 1, wherein each of said pellets comprise a core, wherein said core comprises from about 1 to about 25% said water-insoluble polymer by weight of said core. 4. The unit dosage form according to claim 1, wherein each of said pellets comprise a core, wherein said core comprises from about 0.5 to about 50% said water-soluble polymer by weight of said core and from about 1 to about 25% said water-insoluble polymer by weight of said core. 5. The unit dosage form according to claim 1, wherein each of said pellets comprise a core, wherein any section of said core has approximately the same composition as any other section of said core. 6. The unit dosage form according to claim 1, wherein each of said plurality of pellets further comprise a diluent. 7. The unit dosage form according to claim 1, wherein each of said plurality of pellets are spheres. 8. The unit dosage form according to claim 7, wherein said spheres have a diameter from 0.2 mm to 2.5 mm. 9. The unit dosage form according to claim 1, wherein said water-soluble polymer is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, hydrocolloid, polyvinyl alcohol, and polyvinylpyrrolidone. 10. The unit dosage form according to claim 1, wherein said water-insoluble polymer is selected from ethyl cellulose, cellulose acetate, and methylmethacrylate copolymers. 11. A unit dosage form, in the form of an oral capsule comprising a plurality of pellets, said pellets comprising:
(a) a therapeutically effective amount of carbamazepine; (b) a sustained release water-soluble polymer; and (c) a water-insoluble polymer that is substantially water-insoluble in aqueous medium independent of the pH;
wherein the ratio of said water-soluble polymer to said water insoluble-polymer ranges from about 5:95 to about 50:50; and
wherein all of said plurality of pellets have a coating. 12. The unit dosage form according to claim 11, wherein each of said pellets comprise a core, wherein said core comprises from about 0.5 to about 50% said water-soluble polymer by weight of said core. 13. The unit dosage form according to claim 11, wherein each of said pellets comprise a core, wherein said core comprises from about 1 to about 25% said water-insoluble polymer by weight of said core. 14. The unit dosage form according to claim 11, wherein each of said pellets comprise a core, wherein said core comprises from about 0.5 to about 50% said water-soluble polymer by weight of said core and from about 1 to about 25% said water-insoluble polymer by weight of said core. 15. The unit dosage form according to claim 11, wherein each of said pellets comprise a core, wherein any section of said core has approximately the same composition as any other section of said core. 16. The unit dosage form according to claim 11, wherein each of said plurality of pellets further comprise a diluent. 17. The unit dosage form according to claim 11, wherein each of said plurality of pellets are spheres. 18. The unit dosage form according to claim 17, wherein said spheres have a diameter from 0.2 mm to 2.5 mm. 19. The unit dosage form according to claim 11, wherein said water-soluble polymer is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, hydrocolloid, polyvinyl alcohol, and polyvinylpyrrolidone. 20. The unit dosage form according to claim 11, wherein said water-insoluble polymer is selected from ethyl cellulose, cellulose acetate, and methylmethacrylate copolymers.
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The present application discloses a sustained release composition in pellet form, wherein the core of the pellet comprises:
(a) a therapeutically effective amount of a medicament; (b) 0.5 to 50% by weight of a water-soluble polymer; and (c) 1 to 25% by weight of a water-insoluble polymer applied as an aqueous latex dispersion and subsequently the water is removed, wherein the sum of the percentages of the medicament, the water-insoluble polymer and the water-soluble polymer is equal to or less than 100%. It also discloses methods of making this composition.1. A unit dosage form, in the form of an oral capsule comprising a plurality of pellets, said pellets comprising:
(a) a therapeutically effective amount of carbamazepine; (b) a sustained release water-soluble polymer; and (c) a water-insoluble polymer that is substantially water-insoluble in aqueous medium independent of the pH;
wherein the ratio of said water-soluble polymer to said water insoluble-polymer ranges from about 5:95 to about 50:50; and
wherein all of said plurality of pellets are free of an enteric coating. 2. The unit dosage form according to claim 1, wherein each of said pellets comprise a core, wherein said core comprises from about 0.5 to about 50% said water-soluble polymer by weight of said core. 3. The unit dosage form according to claim 1, wherein each of said pellets comprise a core, wherein said core comprises from about 1 to about 25% said water-insoluble polymer by weight of said core. 4. The unit dosage form according to claim 1, wherein each of said pellets comprise a core, wherein said core comprises from about 0.5 to about 50% said water-soluble polymer by weight of said core and from about 1 to about 25% said water-insoluble polymer by weight of said core. 5. The unit dosage form according to claim 1, wherein each of said pellets comprise a core, wherein any section of said core has approximately the same composition as any other section of said core. 6. The unit dosage form according to claim 1, wherein each of said plurality of pellets further comprise a diluent. 7. The unit dosage form according to claim 1, wherein each of said plurality of pellets are spheres. 8. The unit dosage form according to claim 7, wherein said spheres have a diameter from 0.2 mm to 2.5 mm. 9. The unit dosage form according to claim 1, wherein said water-soluble polymer is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, hydrocolloid, polyvinyl alcohol, and polyvinylpyrrolidone. 10. The unit dosage form according to claim 1, wherein said water-insoluble polymer is selected from ethyl cellulose, cellulose acetate, and methylmethacrylate copolymers. 11. A unit dosage form, in the form of an oral capsule comprising a plurality of pellets, said pellets comprising:
(a) a therapeutically effective amount of carbamazepine; (b) a sustained release water-soluble polymer; and (c) a water-insoluble polymer that is substantially water-insoluble in aqueous medium independent of the pH;
wherein the ratio of said water-soluble polymer to said water insoluble-polymer ranges from about 5:95 to about 50:50; and
wherein all of said plurality of pellets have a coating. 12. The unit dosage form according to claim 11, wherein each of said pellets comprise a core, wherein said core comprises from about 0.5 to about 50% said water-soluble polymer by weight of said core. 13. The unit dosage form according to claim 11, wherein each of said pellets comprise a core, wherein said core comprises from about 1 to about 25% said water-insoluble polymer by weight of said core. 14. The unit dosage form according to claim 11, wherein each of said pellets comprise a core, wherein said core comprises from about 0.5 to about 50% said water-soluble polymer by weight of said core and from about 1 to about 25% said water-insoluble polymer by weight of said core. 15. The unit dosage form according to claim 11, wherein each of said pellets comprise a core, wherein any section of said core has approximately the same composition as any other section of said core. 16. The unit dosage form according to claim 11, wherein each of said plurality of pellets further comprise a diluent. 17. The unit dosage form according to claim 11, wherein each of said plurality of pellets are spheres. 18. The unit dosage form according to claim 17, wherein said spheres have a diameter from 0.2 mm to 2.5 mm. 19. The unit dosage form according to claim 11, wherein said water-soluble polymer is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, hydrocolloid, polyvinyl alcohol, and polyvinylpyrrolidone. 20. The unit dosage form according to claim 11, wherein said water-insoluble polymer is selected from ethyl cellulose, cellulose acetate, and methylmethacrylate copolymers.
| 1,600 |
1,277 | 15,752,936 | 1,658 |
The present invention relates to lysobactin for use in the treatment of bovine mastitis.
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1. Lysobactin for use in the treatment of bovine mastitis. 2. Lysobactin for use in the treatment of bovine mastitis according to claim 1, wherein lysobactin is administered intramammarily. 3. Lysobactin for use in the treatment of bovine mastitis according to claim 1 or 2, wherein the bovine mastitis is a clinically manifest bovine mastitis. 4. Lysobactin for use in the treatment of bovine mastitis according to claim 1 or 2, wherein the bovine mastitis is a subclinical bovine mastitis. 5. Lysobactin for use in the treatment of bovine mastitis according to one of claims 1 to 4, wherein the lysobactin is provided at a dose of 25 to 1000 mg per udder quarter. 6. Lysobactin for use in the treatment of bovine mastitis according to one of claims 1 to 5, wherein the bovine mastitis is caused by Staphylococcus bacteria, Streptococcus bacteria, Trueperella bacteria and/or Corynebacterium bacteria. 7. Lysobactin for use in the treatment of bovine mastitis according to claim 6, wherein the bovine mastitis is caused by Staphylococcus aureus, coagulase-negative staphylococci, Streptococcus uberis, Streptococcus dysgalacticae and/or Streptococcus agalacticae. 8. Lysobactin for use in the treatment of bovine mastitis according to claim 6, wherein the bovine mastitis is caused by Trueperella pyogenes. 9. Lysobactin for use in the treatment of bovine mastitis according to claim 6, wherein the bovine mastitis is caused by Corynebacterium bovis. 10. Pharmaceutical composition formulated for intramammary administration into bovine mammaries, characterized in that the composition comprises lysobactin. 11. Use of lysobactin for the preparation of pharmaceuticals for the treatment of bovine mastitis. 12. Use according to claim 11, wherein the bovine mastitis is a clinically manifest bovine mastitis. 13. Use according to claim 11, wherein the bovine mastitis is a subclinical bovine mastitis. 14. Use according to one of claims 11 to 13, wherein the bovine mastitis is caused by Staphylococcus bacteria, Streptococcus bacteria, Trueperella bacteria and/or Corynebacterium bacteria. 15. A method of treating bovine mastitis, the method comprising the step of administering to a cow in need thereof a therapeutically effective amount of lysobactin.
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The present invention relates to lysobactin for use in the treatment of bovine mastitis.1. Lysobactin for use in the treatment of bovine mastitis. 2. Lysobactin for use in the treatment of bovine mastitis according to claim 1, wherein lysobactin is administered intramammarily. 3. Lysobactin for use in the treatment of bovine mastitis according to claim 1 or 2, wherein the bovine mastitis is a clinically manifest bovine mastitis. 4. Lysobactin for use in the treatment of bovine mastitis according to claim 1 or 2, wherein the bovine mastitis is a subclinical bovine mastitis. 5. Lysobactin for use in the treatment of bovine mastitis according to one of claims 1 to 4, wherein the lysobactin is provided at a dose of 25 to 1000 mg per udder quarter. 6. Lysobactin for use in the treatment of bovine mastitis according to one of claims 1 to 5, wherein the bovine mastitis is caused by Staphylococcus bacteria, Streptococcus bacteria, Trueperella bacteria and/or Corynebacterium bacteria. 7. Lysobactin for use in the treatment of bovine mastitis according to claim 6, wherein the bovine mastitis is caused by Staphylococcus aureus, coagulase-negative staphylococci, Streptococcus uberis, Streptococcus dysgalacticae and/or Streptococcus agalacticae. 8. Lysobactin for use in the treatment of bovine mastitis according to claim 6, wherein the bovine mastitis is caused by Trueperella pyogenes. 9. Lysobactin for use in the treatment of bovine mastitis according to claim 6, wherein the bovine mastitis is caused by Corynebacterium bovis. 10. Pharmaceutical composition formulated for intramammary administration into bovine mammaries, characterized in that the composition comprises lysobactin. 11. Use of lysobactin for the preparation of pharmaceuticals for the treatment of bovine mastitis. 12. Use according to claim 11, wherein the bovine mastitis is a clinically manifest bovine mastitis. 13. Use according to claim 11, wherein the bovine mastitis is a subclinical bovine mastitis. 14. Use according to one of claims 11 to 13, wherein the bovine mastitis is caused by Staphylococcus bacteria, Streptococcus bacteria, Trueperella bacteria and/or Corynebacterium bacteria. 15. A method of treating bovine mastitis, the method comprising the step of administering to a cow in need thereof a therapeutically effective amount of lysobactin.
| 1,600 |
1,278 | 15,750,318 | 1,628 |
Pharmaceutical compositions for the treatment of cancer are provided. In one embodiment the composition comprises Gamitrinib and a MAPK inhibitor selected from the MAPK inhibitor is selected from RAF265, AZD6244, PLX4720, PD0325901, LGX818, MEK162, vemurafenib, trametinib and dabrafenib. Methods of treating cancer are also provided.
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1. A pharmaceutical composition comprising a MAPK inhibitor and a reagent that downregulates or reduces TFAM, TRAP-1, PPRC1, or ESSRA. 2-3. (canceled) 4. The composition according to claim 1, wherein the MAPK inhibitor is selected from RAF265, AZD6244, PLX4720, PD0325901, LGX818, MEK162, vemurafenib, trametinib and dabrafenib. 5. The composition according to claim 1, wherein the reagent that downregulates or reduces TFAM, TRAP-1, PPRC1, or ESSRA is a Gamitrinib, phenformin, an siRNA or antibody. 6. A method of treating cancer comprising administering the composition of claim 5. 7. The method according to claim 6, wherein the Gamitrinib is administered at a dosage of 0.1-50 mg/kg. 8-11. (canceled) 12. The method according to claim 6, wherein the cancer is a drug-resistant cancer. 13-14. (canceled) 15. The method according to claim 12, wherein the cancer is BRAFV600 mutant melanoma. 16. A method of treating BRAF inhibitor resistant cancer or a combination therapy resistant cancer or immunotherapy resistant cancer comprising administering Gamitrinib. 17. A composition comprising:
(a) a ligand selected from a nucleic acid sequence, polynucleotide or oligonucleotide capable of specifically complexing with, hybridizing to, or identifying a gene transcript or expression product of a gene of Table 1 from a mammalian biological sample; and (b) an optional additional ligand selected from a nucleic acid sequence, polynucleotide or oligonucleotide capable of specifically complexing with, hybridizing to, or identifying a gene transcript or expression product of an additional gene of Table 1 from a mammalian biological sample; wherein each ligand and additional ligand binds to a different gene transcript or expression product selected from Table 1. 18. The composition according to claim 17, wherein each said ligand is an amplification nucleic acid primer or primer pair that amplifies and detects a nucleic acid sequence of said gene transcript or, a polynucleotide probe that hybridizes to the gene's mRNA nucleic acid sequence, or an antibody or fragment of an antibody, each ligand being specific for at least gene of Table 1. 19-22. (canceled) 23. The composition according to claim 17, wherein one or more polynucleotide or oligonucleotide or ligand is associated with a detectable label. 24. The composition according to claim 17, wherein the cancer is a melanoma. 25. The composition according to claim 17, wherein said composition enables detection of changes in expression in the same selected genes in the blood of a subject from that of a reference or control, wherein said changes correlate with a diagnosis or evaluation of a cancer. 26. The composition according to claim 17, wherein said diagnosis or evaluation comprise one or more of a diagnosis of a cancer, a diagnosis of a stage of cancer, a diagnosis of a type or classification of a cancer, a diagnosis or detection of a recurrence of a cancer, a diagnosis or detection of a regression of a cancer, a prognosis of a cancer, or an evaluation of the response of a cancer to a surgical or non-surgical therapy. 27. The composition according to claim 17, wherein the ligand is an RNA primer. 28. The composition according to claim 17, comprising 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 ligands. 29. A method for diagnosing the existence or evaluating a cancer in a mammalian subject comprising identifying in the biological fluid of a mammalian subject changes in the expression of a gene product of a gene selected from Table 1 using the composition of claim 17, and comparing said subject's expression levels with the levels of the same gene product in the same biological sample from a reference or control, wherein changes in expression of the subject's gene product from those of the reference correlates with a diagnosis or evaluation of a disease or cancer. 30. The method according to claim 29, wherein an increase in expression levels correlates with an evaluation that the cancer is drug resistant. 31-39. (canceled) 40. A method of treating cancer, comprising
(i) measuring the level of expression of one or more mitobiogenesis biomarker listed in Table 1 using the composition of claim 17; (ii) comparing levels with the level of the same biomarker in a control sample, and (iii)(a) where the level of expression of one or more mitobiogenesis biomarkers is higher than the control level, decreasing the amount of MAPK inhibitor as compared to normal regimen; or (iii)(b) where the level of expression of one or more mitobiogenesis biomarkers is lower than the control level, increasing the amount of MAPK inhibitor as compared to normal regimen. 41. The method according to claim 40, wherein the control level is derived from a BRAFV600 melanoma cell line.
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Pharmaceutical compositions for the treatment of cancer are provided. In one embodiment the composition comprises Gamitrinib and a MAPK inhibitor selected from the MAPK inhibitor is selected from RAF265, AZD6244, PLX4720, PD0325901, LGX818, MEK162, vemurafenib, trametinib and dabrafenib. Methods of treating cancer are also provided.1. A pharmaceutical composition comprising a MAPK inhibitor and a reagent that downregulates or reduces TFAM, TRAP-1, PPRC1, or ESSRA. 2-3. (canceled) 4. The composition according to claim 1, wherein the MAPK inhibitor is selected from RAF265, AZD6244, PLX4720, PD0325901, LGX818, MEK162, vemurafenib, trametinib and dabrafenib. 5. The composition according to claim 1, wherein the reagent that downregulates or reduces TFAM, TRAP-1, PPRC1, or ESSRA is a Gamitrinib, phenformin, an siRNA or antibody. 6. A method of treating cancer comprising administering the composition of claim 5. 7. The method according to claim 6, wherein the Gamitrinib is administered at a dosage of 0.1-50 mg/kg. 8-11. (canceled) 12. The method according to claim 6, wherein the cancer is a drug-resistant cancer. 13-14. (canceled) 15. The method according to claim 12, wherein the cancer is BRAFV600 mutant melanoma. 16. A method of treating BRAF inhibitor resistant cancer or a combination therapy resistant cancer or immunotherapy resistant cancer comprising administering Gamitrinib. 17. A composition comprising:
(a) a ligand selected from a nucleic acid sequence, polynucleotide or oligonucleotide capable of specifically complexing with, hybridizing to, or identifying a gene transcript or expression product of a gene of Table 1 from a mammalian biological sample; and (b) an optional additional ligand selected from a nucleic acid sequence, polynucleotide or oligonucleotide capable of specifically complexing with, hybridizing to, or identifying a gene transcript or expression product of an additional gene of Table 1 from a mammalian biological sample; wherein each ligand and additional ligand binds to a different gene transcript or expression product selected from Table 1. 18. The composition according to claim 17, wherein each said ligand is an amplification nucleic acid primer or primer pair that amplifies and detects a nucleic acid sequence of said gene transcript or, a polynucleotide probe that hybridizes to the gene's mRNA nucleic acid sequence, or an antibody or fragment of an antibody, each ligand being specific for at least gene of Table 1. 19-22. (canceled) 23. The composition according to claim 17, wherein one or more polynucleotide or oligonucleotide or ligand is associated with a detectable label. 24. The composition according to claim 17, wherein the cancer is a melanoma. 25. The composition according to claim 17, wherein said composition enables detection of changes in expression in the same selected genes in the blood of a subject from that of a reference or control, wherein said changes correlate with a diagnosis or evaluation of a cancer. 26. The composition according to claim 17, wherein said diagnosis or evaluation comprise one or more of a diagnosis of a cancer, a diagnosis of a stage of cancer, a diagnosis of a type or classification of a cancer, a diagnosis or detection of a recurrence of a cancer, a diagnosis or detection of a regression of a cancer, a prognosis of a cancer, or an evaluation of the response of a cancer to a surgical or non-surgical therapy. 27. The composition according to claim 17, wherein the ligand is an RNA primer. 28. The composition according to claim 17, comprising 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 ligands. 29. A method for diagnosing the existence or evaluating a cancer in a mammalian subject comprising identifying in the biological fluid of a mammalian subject changes in the expression of a gene product of a gene selected from Table 1 using the composition of claim 17, and comparing said subject's expression levels with the levels of the same gene product in the same biological sample from a reference or control, wherein changes in expression of the subject's gene product from those of the reference correlates with a diagnosis or evaluation of a disease or cancer. 30. The method according to claim 29, wherein an increase in expression levels correlates with an evaluation that the cancer is drug resistant. 31-39. (canceled) 40. A method of treating cancer, comprising
(i) measuring the level of expression of one or more mitobiogenesis biomarker listed in Table 1 using the composition of claim 17; (ii) comparing levels with the level of the same biomarker in a control sample, and (iii)(a) where the level of expression of one or more mitobiogenesis biomarkers is higher than the control level, decreasing the amount of MAPK inhibitor as compared to normal regimen; or (iii)(b) where the level of expression of one or more mitobiogenesis biomarkers is lower than the control level, increasing the amount of MAPK inhibitor as compared to normal regimen. 41. The method according to claim 40, wherein the control level is derived from a BRAFV600 melanoma cell line.
| 1,600 |
1,279 | 16,401,725 | 1,615 |
A sunscreen composition includes a silicone phase that includes at least one silicone film former, a blend of silicones that includes at least one of each of a low viscosity silicone fluid, a silicone co-emulsifier and a self-emulsifying silicone elastomer. The composition includes a UV filter system that includes one or more UV filters. The silicone film former and blend of silicones are present in quantities sufficient to provide an SPF that is boosted by at least 100% as compared to a composition that lacks silicone film former, and the cosmetic composition has a unique texture that provides low friction and high glide.
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1. A sunscreen composition, comprising:
a) a silicone phase that comprises:
1) at least one silicone film former present from about 0.1% to about 5.0% by weight, based on the total weight of the composition;
2) a blend of silicones present from about 20% to about 35% by weight, based on the total weight of the composition, the blend of silicones comprising at least one of each of
i. a low viscosity silicone fluid;
ii. at least one silicone co-emulsifier; and,
iii. at least one self-emulsifying silicone elastomer; and
a UV filter system that comprises one or more UV filters, the UV filter system present from about 20% to about 30% by weight, based on the total weight of the composition wherein the silicone film former and blend of silicones are present in quantities sufficient such that the composition has an SPF that is boosted by at least 100% as compared to a composition that lacks silicone film former. 2. The sunscreen composition according to claim 1, wherein
a) the at least one silicone fluid is present from about 5% to about 20% by weight; b) the at least one silicone co-emulsifier is present from about 0.1% to about 2.0% by weight; and, c) the at least one self-emulsifying silicone elastomer is present from about 2% to about 15% by weight,
each based on the total weight of the composition. 3. The sunscreen composition according to claim 1, wherein the UV filter system comprises at least one or a combination of inorganic UV filters, or at least one or a combination of organic UV filters. 4. The sunscreen composition according to claim 1, wherein the UV filter system comprises one or more of:
a) inorganic UV filters selected from
1) titanium dioxide;
2) Zinc oxide; and
3) titanium dioxide (and) silica; and
b) organic UV filter selected from
1) butyl methoxydibenzoylmethane;
2) ethylhexyl salicylate;
3) triethoxycaprylylsilane;
4) octocrylene; and
5) homosalate. 5. The sunscreen composition according to claim 1, wherein the at least one silicone film former comprises a silicone acrylate co-polymer. 6. The sunscreen composition according to claim 1, wherein the silicone film former comprises one or a combination of
a) dimethicone (and) dimethiconol present from about 0.5% to about 2.0% by weight based on the total weight of the composition, and b) dimethicone (and) acrylates/dimethicone copolymer present from about 2.0% to about 2.5% by weight based on the total weight of the composition. 7. The sunscreen composition according to claim 1, comprising two or more silicone film formers. 8. The sunscreen composition according to claim 1, wherein the at least one low viscosity silicone fluid in the blend of silicones comprises one or more volatile and nonvolatile silicone oils. 9. The sunscreen composition according to claim 1, wherein the at least one silicone fluid in the blend of silicones comprises dimethicone present from about 5% to about 18% by weight based on the total weight of the composition. 10. The sunscreen composition according to claim 1, wherein the at least one silicone co-emulsifier is selected from polyether-modified silicones. 11. The sunscreen composition according to claim 1, wherein the at least one silicone co-emulsifier in the blend of silicones comprises lauryl PEG-9 polydimethylsiloxyethyl dimethicone present from about 0.2% to about 0.7% by weight based on the total weight of the composition. 12. The sunscreen composition according to claim 1, wherein the at least one self-emulsifying silicone elastomer in the blend of silicones comprises a substituted or unsubstituted dimethicone crosspolymer. 13. The sunscreen composition according to claim 1, wherein the at least one self-emulsifying silicone elastomer in the blend of silicones comprises one or more of
a) dimethicone (and) dimethicone/vinyl dimethicone crosspolymer present from about 2% to about 15% by weight based on the total weight of the composition, b) dimethicone (and) dimethicone/polyglycerin-3 crosspolymer present from about 4% to about 10% by weight based on the total weight of the composition, c) dimethicone (and) dimethicone/PEG-10/15 crosspolymer present from about 3% to about 7% by weight based on the total weight of the composition, and d) dimethicone (and) dimethicone crosspolymer present from about 4% to about 8% by weight based on the total weight of the composition. 14. The sunscreen composition according to claim 1, wherein the composition is a water-in-silicone emulsion that comprises an aqueous phase. 15. The sunscreen composition according to claim 14, the aqueous phase comprising: a hydrating agent present from about 5% to about 25% by weight, based on the total weight of the composition; and water from about 25% to about 60% by weight based on the total weight of the composition. 16. The sunscreen composition according to claim 15, wherein the hydrating agent is glycerin present from about 10% to about 18% by weight based on the total weight of the composition. 17. The sunscreen composition according to claim 16, further comprising one or more of a surfactant, a cosmetic powder, and an emollient, and wherein the UV system comprises one or a combination of organic UV filter selected from:
1) butyl methoxydibenzoylmethane; 2) ethylhexyl salicylate; 3) zinc oxide (and) triethoxycaprylylsilane; 4) octocrylene; and 5) homosalate. 18. A sunscreen composition, comprising:
a) a silicone phase that comprises:
1) at least one silicone acrylate film former present from about 0.1% to about 5.0% by weight, based on the total weight of the composition;
2) a blend of silicones present from about 20% to about 35% by weight, based on the total weight of the composition, the blend of silicones comprising at least one of each of
i. a low viscosity silicone fluid present from about 5% to about 20% by weight;
ii. a silicone co-emulsifier present from about 0.1% to about 2.0% by weight; and,
iii. a self-emulsifying silicone elastomer present from about 2% to about 15% by weight,
each based on the total weight of the composition
a UV filter system that comprises one or more UV filters, the UV filter system present from about 20% to about 30% by weight, based on the total weight of the composition; and an aqueous phase comprising: a hydrating agent present from about 5% to about 25% by weight, based on the total weight of the composition; and water from about 25% to about 60% by weight based on the total weight of the composition wherein the silicone film former and blend of silicones are present in quantities sufficient to provide an SPF that is boosted by at least 100% as compared to a composition that lacks silicone film former. 19. The sunscreen composition according to claim 18, the composition further comprising one or more of a surfactant, a cosmetic powder, and an emollient, and wherein the UV system comprises one or a combination of organic UV filter selected from:
1) butyl methoxydibenzoylmethane; 2) ethylhexyl salicylate; 3) zinc oxide (and) triethoxycaprylylsilane; 4) octocrylene; and 5) homosalate. 20. The sunscreen composition according to claim 18, wherein the UV filter system comprises one or a combination of inorganic UV filters selected from:
1) titanium dioxide; and 2) titanium dioxide (and) silica; and wherein the hydrating agent is glycerin and is present from about 10% to about 18% by weight based on the total weight of the composition.
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A sunscreen composition includes a silicone phase that includes at least one silicone film former, a blend of silicones that includes at least one of each of a low viscosity silicone fluid, a silicone co-emulsifier and a self-emulsifying silicone elastomer. The composition includes a UV filter system that includes one or more UV filters. The silicone film former and blend of silicones are present in quantities sufficient to provide an SPF that is boosted by at least 100% as compared to a composition that lacks silicone film former, and the cosmetic composition has a unique texture that provides low friction and high glide.1. A sunscreen composition, comprising:
a) a silicone phase that comprises:
1) at least one silicone film former present from about 0.1% to about 5.0% by weight, based on the total weight of the composition;
2) a blend of silicones present from about 20% to about 35% by weight, based on the total weight of the composition, the blend of silicones comprising at least one of each of
i. a low viscosity silicone fluid;
ii. at least one silicone co-emulsifier; and,
iii. at least one self-emulsifying silicone elastomer; and
a UV filter system that comprises one or more UV filters, the UV filter system present from about 20% to about 30% by weight, based on the total weight of the composition wherein the silicone film former and blend of silicones are present in quantities sufficient such that the composition has an SPF that is boosted by at least 100% as compared to a composition that lacks silicone film former. 2. The sunscreen composition according to claim 1, wherein
a) the at least one silicone fluid is present from about 5% to about 20% by weight; b) the at least one silicone co-emulsifier is present from about 0.1% to about 2.0% by weight; and, c) the at least one self-emulsifying silicone elastomer is present from about 2% to about 15% by weight,
each based on the total weight of the composition. 3. The sunscreen composition according to claim 1, wherein the UV filter system comprises at least one or a combination of inorganic UV filters, or at least one or a combination of organic UV filters. 4. The sunscreen composition according to claim 1, wherein the UV filter system comprises one or more of:
a) inorganic UV filters selected from
1) titanium dioxide;
2) Zinc oxide; and
3) titanium dioxide (and) silica; and
b) organic UV filter selected from
1) butyl methoxydibenzoylmethane;
2) ethylhexyl salicylate;
3) triethoxycaprylylsilane;
4) octocrylene; and
5) homosalate. 5. The sunscreen composition according to claim 1, wherein the at least one silicone film former comprises a silicone acrylate co-polymer. 6. The sunscreen composition according to claim 1, wherein the silicone film former comprises one or a combination of
a) dimethicone (and) dimethiconol present from about 0.5% to about 2.0% by weight based on the total weight of the composition, and b) dimethicone (and) acrylates/dimethicone copolymer present from about 2.0% to about 2.5% by weight based on the total weight of the composition. 7. The sunscreen composition according to claim 1, comprising two or more silicone film formers. 8. The sunscreen composition according to claim 1, wherein the at least one low viscosity silicone fluid in the blend of silicones comprises one or more volatile and nonvolatile silicone oils. 9. The sunscreen composition according to claim 1, wherein the at least one silicone fluid in the blend of silicones comprises dimethicone present from about 5% to about 18% by weight based on the total weight of the composition. 10. The sunscreen composition according to claim 1, wherein the at least one silicone co-emulsifier is selected from polyether-modified silicones. 11. The sunscreen composition according to claim 1, wherein the at least one silicone co-emulsifier in the blend of silicones comprises lauryl PEG-9 polydimethylsiloxyethyl dimethicone present from about 0.2% to about 0.7% by weight based on the total weight of the composition. 12. The sunscreen composition according to claim 1, wherein the at least one self-emulsifying silicone elastomer in the blend of silicones comprises a substituted or unsubstituted dimethicone crosspolymer. 13. The sunscreen composition according to claim 1, wherein the at least one self-emulsifying silicone elastomer in the blend of silicones comprises one or more of
a) dimethicone (and) dimethicone/vinyl dimethicone crosspolymer present from about 2% to about 15% by weight based on the total weight of the composition, b) dimethicone (and) dimethicone/polyglycerin-3 crosspolymer present from about 4% to about 10% by weight based on the total weight of the composition, c) dimethicone (and) dimethicone/PEG-10/15 crosspolymer present from about 3% to about 7% by weight based on the total weight of the composition, and d) dimethicone (and) dimethicone crosspolymer present from about 4% to about 8% by weight based on the total weight of the composition. 14. The sunscreen composition according to claim 1, wherein the composition is a water-in-silicone emulsion that comprises an aqueous phase. 15. The sunscreen composition according to claim 14, the aqueous phase comprising: a hydrating agent present from about 5% to about 25% by weight, based on the total weight of the composition; and water from about 25% to about 60% by weight based on the total weight of the composition. 16. The sunscreen composition according to claim 15, wherein the hydrating agent is glycerin present from about 10% to about 18% by weight based on the total weight of the composition. 17. The sunscreen composition according to claim 16, further comprising one or more of a surfactant, a cosmetic powder, and an emollient, and wherein the UV system comprises one or a combination of organic UV filter selected from:
1) butyl methoxydibenzoylmethane; 2) ethylhexyl salicylate; 3) zinc oxide (and) triethoxycaprylylsilane; 4) octocrylene; and 5) homosalate. 18. A sunscreen composition, comprising:
a) a silicone phase that comprises:
1) at least one silicone acrylate film former present from about 0.1% to about 5.0% by weight, based on the total weight of the composition;
2) a blend of silicones present from about 20% to about 35% by weight, based on the total weight of the composition, the blend of silicones comprising at least one of each of
i. a low viscosity silicone fluid present from about 5% to about 20% by weight;
ii. a silicone co-emulsifier present from about 0.1% to about 2.0% by weight; and,
iii. a self-emulsifying silicone elastomer present from about 2% to about 15% by weight,
each based on the total weight of the composition
a UV filter system that comprises one or more UV filters, the UV filter system present from about 20% to about 30% by weight, based on the total weight of the composition; and an aqueous phase comprising: a hydrating agent present from about 5% to about 25% by weight, based on the total weight of the composition; and water from about 25% to about 60% by weight based on the total weight of the composition wherein the silicone film former and blend of silicones are present in quantities sufficient to provide an SPF that is boosted by at least 100% as compared to a composition that lacks silicone film former. 19. The sunscreen composition according to claim 18, the composition further comprising one or more of a surfactant, a cosmetic powder, and an emollient, and wherein the UV system comprises one or a combination of organic UV filter selected from:
1) butyl methoxydibenzoylmethane; 2) ethylhexyl salicylate; 3) zinc oxide (and) triethoxycaprylylsilane; 4) octocrylene; and 5) homosalate. 20. The sunscreen composition according to claim 18, wherein the UV filter system comprises one or a combination of inorganic UV filters selected from:
1) titanium dioxide; and 2) titanium dioxide (and) silica; and wherein the hydrating agent is glycerin and is present from about 10% to about 18% by weight based on the total weight of the composition.
| 1,600 |
1,280 | 15,052,016 | 1,623 |
The present invention relates to a process for producing a low endotoxin alkali chitosan, and also to a process for producing low endotoxin neutral chitosan, chitosan salt and chitosan derivatives, and to the products of such processes. The process comprises contacting chitosan with an alkali solution to form a mixture and leaving the mixture for at least about 12 hours. The low endotoxin alkali chitosan may be used the manufacture of other useful chitosan based products.
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1-17. (canceled) 18: A low endotoxin alkali chitosan produced by a process comprising the steps of:
(a) contacting chitosan with an alkali solution to form a mixture; and (b) leaving the mixture for at least about 12 hours. 19: An alkali chitosan, a neutral chitosan, a chitosan salt, or a chitosan derivative comprising an endotoxin concentration of less than 100 EU/g. 20-37. (canceled) 38: A low endotoxin chitosan salt of claim 43 for use as a haemostat for stemming blood flow or for use in a wound dressing for superficial non-life threatening bleeding or life threatening bleeding. 39. (canceled) 40: A haemostatic wound dressing comprising a low endotoxin chitosan salt of claim 43. 41-42. (canceled) 43: A low endotoxin neutral chitosan, a chitosan salt, or a chitosan derivative produced by a process comprising the step of contacting an alkali chitosan of claim 18 with an acid.
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The present invention relates to a process for producing a low endotoxin alkali chitosan, and also to a process for producing low endotoxin neutral chitosan, chitosan salt and chitosan derivatives, and to the products of such processes. The process comprises contacting chitosan with an alkali solution to form a mixture and leaving the mixture for at least about 12 hours. The low endotoxin alkali chitosan may be used the manufacture of other useful chitosan based products.1-17. (canceled) 18: A low endotoxin alkali chitosan produced by a process comprising the steps of:
(a) contacting chitosan with an alkali solution to form a mixture; and (b) leaving the mixture for at least about 12 hours. 19: An alkali chitosan, a neutral chitosan, a chitosan salt, or a chitosan derivative comprising an endotoxin concentration of less than 100 EU/g. 20-37. (canceled) 38: A low endotoxin chitosan salt of claim 43 for use as a haemostat for stemming blood flow or for use in a wound dressing for superficial non-life threatening bleeding or life threatening bleeding. 39. (canceled) 40: A haemostatic wound dressing comprising a low endotoxin chitosan salt of claim 43. 41-42. (canceled) 43: A low endotoxin neutral chitosan, a chitosan salt, or a chitosan derivative produced by a process comprising the step of contacting an alkali chitosan of claim 18 with an acid.
| 1,600 |
1,281 | 14,893,627 | 1,617 |
The present invention relates to a cosmetic composition in the form of an O/W emulsion, comprising, in a cosmetically acceptable medium: (a) at least one aqueous phase comprising water; (b) at least one fatty phase comprising, (i) at least one polar oil, (ii) at least one lipophilic UV filter, and (iii) at least one fatty acid; (c) at least one associative polymer; and (d) at least one hollow particle. The cosmetic composition according to the present invention can have high UV-shielding ability, while providing a fresh, water-like texture, and therefore, it can simultaneously provide both effective UV protection and good feeling during use.
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1.-15. (canceled) 16. A cosmetic composition in the form of an O/W emulsion, comprising, in a cosmetically acceptable medium:
(a) at least one aqueous phase comprising water; (b) at least one fatty phase comprising,
(i) at least one polar oil,
(ii) at least one lipophilic UV filter, and
(iii) at least one fatty acid;
(c) at least one associative polymer; and (d) at least one hollow particle. 17. The cosmetic composition according to claim 16, wherein the water is present in an amount of at least about 55% by weight, relative to the total weight of the composition. 18. The cosmetic composition according to claim 16, wherein the at least one polar oil is chosen from C12-C15 alcohol benzoate, diisopropyl sebacate, isopropyl lauroyl sarcosinate, dicaprylyl carbonate, 2-phenylethyl benzoate, butyloctyl salicylate, 2-octyldodecyl neopentanoate, dicaprylyl ether, isocetyl stearate, isodecyl neopentanoate, isononyl isononate, isopropyl myristate, isopropyl palmitate, isostearyl behenate, myristyl myristate, octyl palmitate, or tridecyl trimellitate. 19. The cosmetic composition according to any one claim 16, wherein the at least one lipophilic UV filter is chosen from:
butylmethoxydibenzoylmethane, ethylhexyl methoxycinnamate, ethylhexyl salicylate, homosalate, butylmethoxydibenzoylmethane, octocrylene, benzophenone-3, n-hexyl 2-(4-diethylamino-2-hydroxybenzoyl)benzoate, 4-methylbenzylidenecamphor, bis(ethylhexyloxyphenyl)methoxyphenyltriazine, ethylhexyl triazone, diethylhexyl butamido triazone, 2,4,6-tris(dineopentyl 4′-aminobenzalmalonate)-s-triazine, 2,4,6-tris(diisobutyl 4′-aminobenzalmalonate)-s-triazine, 2,4-bis(dineopentyl 4′-aminobenzalmalonate)-6-(n-butyl 4′-aminobenzoate)-s-triazine, 2,4,6-tris(biphenyl-4-yl)-1,3,5-triazine, 2,4,6-tris(terphenyl)-1,3,5-triazine, drometrizole trisiloxane, polysilicone-15, 1,1-dicarboxy(2,2′-dimethylpropyl)-4,4-diphenylbutadiene, 2,4-bis[4-[5-(1,1-dimethylpropyl)benzoxazol-2-yl]phenylimino]-6-[(2-ethylhexyl)imino]-1,3,5-triazine, and mixtures thereof. 20. The cosmetic composition according to claim 16, wherein the at least one fatty acid is chosen from linear or branched fatty acids comprising a carbon chain length of C10-30. 21. The cosmetic composition according to claim 16, wherein the at least one associative polymer is chosen from polymers comprising at least one hydrophilic unit of unsaturated olefinic carboxylic acid type or a (C10-C30) alkyl ester of an unsaturated carboxylic acid. 22. The cosmetic composition according to claim 16, wherein the at least one hollow particle is made from a copolymer of styrene and (meth)acrylic acid or one of its C1-C20 alkyl esters. 23. The cosmetic composition according to claim 16, wherein the at least one fatty phase is present in an amount ranging from about 5% to about 30% by weight, relative to the total weight of the composition. 24. The cosmetic composition according to claim 16, wherein the at least one polar oil is present in an amount ranging from about 1% to about 15% by weight, relative to the total weight of the composition. 25. The cosmetic composition according to claim 16, wherein the at least one lipophilic UV filter is present in an amount ranging from about 3% to about 20% by weight, relative to the total weight of the composition. 26. The cosmetic composition according to claim 16, wherein the at least one fatty acid is present in an amount ranging from about 0.1% to about 5% by weight, relative to the total weight of the composition. 27. The cosmetic composition according to claim 16, wherein the at least one associative polymer is present in an amount ranging from about 0.01% to about 5% by weight, relative to the total weight of the composition. 28. The cosmetic composition according to claim 16, wherein the at least one hollow particle is present in an amount ranging from about 0.1% to about 5% by weight, relative to the total weight of the composition. 29. A non-therapeutic method for treating the skin, the hair, the eyelashes, the eyebrows, and/or the scalp, said method comprising:
applying a cosmetic composition to the skin, the hair, the eyelashes, the eyebrows, and/or the scalp, wherein the cosmetic composition is in the form of an O/W emulsion and comprises, in a cosmetically acceptable medium:
(a) at least one aqueous phase comprising water;
(b) at least one fatty phase comprising,
(i) at least one polar oil,
(ii) at least one lipophilic UV filter, and
(iii) at least one fatty acid;
(c) at least one associative polymer; and
(d) at least one hollow particle. 30. A non-therapeutic method for forming a film on the skin, said method comprising:
applying a cosmetic composition to the skin, wherein the composition is in the form of an O/W emulsion and comprises, in a cosmetically acceptable medium:
(a) at least one aqueous phase comprising water;
(b) at least one fatty phase comprising,
(i) at least one polar oil,
(ii) at least one lipophilic UV filter, and
(iii) at least one fatty acid;
(c) at least one associative polymer; and
(d) at least one hollow particle.
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The present invention relates to a cosmetic composition in the form of an O/W emulsion, comprising, in a cosmetically acceptable medium: (a) at least one aqueous phase comprising water; (b) at least one fatty phase comprising, (i) at least one polar oil, (ii) at least one lipophilic UV filter, and (iii) at least one fatty acid; (c) at least one associative polymer; and (d) at least one hollow particle. The cosmetic composition according to the present invention can have high UV-shielding ability, while providing a fresh, water-like texture, and therefore, it can simultaneously provide both effective UV protection and good feeling during use.1.-15. (canceled) 16. A cosmetic composition in the form of an O/W emulsion, comprising, in a cosmetically acceptable medium:
(a) at least one aqueous phase comprising water; (b) at least one fatty phase comprising,
(i) at least one polar oil,
(ii) at least one lipophilic UV filter, and
(iii) at least one fatty acid;
(c) at least one associative polymer; and (d) at least one hollow particle. 17. The cosmetic composition according to claim 16, wherein the water is present in an amount of at least about 55% by weight, relative to the total weight of the composition. 18. The cosmetic composition according to claim 16, wherein the at least one polar oil is chosen from C12-C15 alcohol benzoate, diisopropyl sebacate, isopropyl lauroyl sarcosinate, dicaprylyl carbonate, 2-phenylethyl benzoate, butyloctyl salicylate, 2-octyldodecyl neopentanoate, dicaprylyl ether, isocetyl stearate, isodecyl neopentanoate, isononyl isononate, isopropyl myristate, isopropyl palmitate, isostearyl behenate, myristyl myristate, octyl palmitate, or tridecyl trimellitate. 19. The cosmetic composition according to any one claim 16, wherein the at least one lipophilic UV filter is chosen from:
butylmethoxydibenzoylmethane, ethylhexyl methoxycinnamate, ethylhexyl salicylate, homosalate, butylmethoxydibenzoylmethane, octocrylene, benzophenone-3, n-hexyl 2-(4-diethylamino-2-hydroxybenzoyl)benzoate, 4-methylbenzylidenecamphor, bis(ethylhexyloxyphenyl)methoxyphenyltriazine, ethylhexyl triazone, diethylhexyl butamido triazone, 2,4,6-tris(dineopentyl 4′-aminobenzalmalonate)-s-triazine, 2,4,6-tris(diisobutyl 4′-aminobenzalmalonate)-s-triazine, 2,4-bis(dineopentyl 4′-aminobenzalmalonate)-6-(n-butyl 4′-aminobenzoate)-s-triazine, 2,4,6-tris(biphenyl-4-yl)-1,3,5-triazine, 2,4,6-tris(terphenyl)-1,3,5-triazine, drometrizole trisiloxane, polysilicone-15, 1,1-dicarboxy(2,2′-dimethylpropyl)-4,4-diphenylbutadiene, 2,4-bis[4-[5-(1,1-dimethylpropyl)benzoxazol-2-yl]phenylimino]-6-[(2-ethylhexyl)imino]-1,3,5-triazine, and mixtures thereof. 20. The cosmetic composition according to claim 16, wherein the at least one fatty acid is chosen from linear or branched fatty acids comprising a carbon chain length of C10-30. 21. The cosmetic composition according to claim 16, wherein the at least one associative polymer is chosen from polymers comprising at least one hydrophilic unit of unsaturated olefinic carboxylic acid type or a (C10-C30) alkyl ester of an unsaturated carboxylic acid. 22. The cosmetic composition according to claim 16, wherein the at least one hollow particle is made from a copolymer of styrene and (meth)acrylic acid or one of its C1-C20 alkyl esters. 23. The cosmetic composition according to claim 16, wherein the at least one fatty phase is present in an amount ranging from about 5% to about 30% by weight, relative to the total weight of the composition. 24. The cosmetic composition according to claim 16, wherein the at least one polar oil is present in an amount ranging from about 1% to about 15% by weight, relative to the total weight of the composition. 25. The cosmetic composition according to claim 16, wherein the at least one lipophilic UV filter is present in an amount ranging from about 3% to about 20% by weight, relative to the total weight of the composition. 26. The cosmetic composition according to claim 16, wherein the at least one fatty acid is present in an amount ranging from about 0.1% to about 5% by weight, relative to the total weight of the composition. 27. The cosmetic composition according to claim 16, wherein the at least one associative polymer is present in an amount ranging from about 0.01% to about 5% by weight, relative to the total weight of the composition. 28. The cosmetic composition according to claim 16, wherein the at least one hollow particle is present in an amount ranging from about 0.1% to about 5% by weight, relative to the total weight of the composition. 29. A non-therapeutic method for treating the skin, the hair, the eyelashes, the eyebrows, and/or the scalp, said method comprising:
applying a cosmetic composition to the skin, the hair, the eyelashes, the eyebrows, and/or the scalp, wherein the cosmetic composition is in the form of an O/W emulsion and comprises, in a cosmetically acceptable medium:
(a) at least one aqueous phase comprising water;
(b) at least one fatty phase comprising,
(i) at least one polar oil,
(ii) at least one lipophilic UV filter, and
(iii) at least one fatty acid;
(c) at least one associative polymer; and
(d) at least one hollow particle. 30. A non-therapeutic method for forming a film on the skin, said method comprising:
applying a cosmetic composition to the skin, wherein the composition is in the form of an O/W emulsion and comprises, in a cosmetically acceptable medium:
(a) at least one aqueous phase comprising water;
(b) at least one fatty phase comprising,
(i) at least one polar oil,
(ii) at least one lipophilic UV filter, and
(iii) at least one fatty acid;
(c) at least one associative polymer; and
(d) at least one hollow particle.
| 1,600 |
1,282 | 16,236,899 | 1,618 |
A new nanoparticle (NP)-based, multicomponent delivery/reporter construct can mediate the controlled, spatiotemporal, active release of an appended cargo to the cytosol of mammalian cells. The construct comprises components including (1) a central NP scaffold, for example a photoluminescent quantum dot (QD); (2) a bridging structure that self-assembles to the NP surface (for example, histidine-tagged maltose binding protein); and (3) a cargo, for example a ligand-dye/drug conjugate, incorporating a ligand that allows the cargo to releasably bind to the bridging structure (e.g., a β-cyclodextrin ligand for binding to maltose binding protein).
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1. A nanoparticle construct comprising:
a nanoparticle configured as a central scaffold; a molecule configured as a bridging structure and comprising a first binding element configured for attachment to the nanoparticle and a second binding element; and a cargo incorporating a ligand configured to allow for releasable binding of the cargo from the second binding element of the bridging structure. 2. The construct of claim 1, wherein the nanoparticle is a quantum dot. 3. The construct of claim 1, wherein the molecule configured as a bridging structure is maltose binding protein. 4. The construct of claim 1, wherein the ligand is β-cyclodextrin. 5. The construct of claim 1, wherein the cargo comprises TideFluor3 or doxorubicin. 6. A nanoparticle construct comprising:
a quantum dot configured as a central scaffold; maltose binding protein configured as a bridging structure and comprising a domain for binding to the quantum dot and a binding pocket; and a cargo incorporating a β-cyclodextrin ligand configured to allow for releasable binding of the cargo from the binding pocket of the maltose binding protein. 7. The nanoparticle of claim 6, wherein the cargo comprises TideFluor3 or doxorubicin. 8. A method of delivery comprising:
providing a nanoparticle construct comprising a nanoparticle configured as a central scaffold, a molecule configured as a bridging structure and comprising a first binding element configured for attachment to the nanoparticle and a second binding element, and a cargo incorporating a ligand configured to allow for releasable binding of the cargo from the second binding element of the bridging structure; and causing the construct to be contacted with an analog of the ligand, thereby resulting in release of the cargo from the construct. 9. The method of claim 8, further comprising monitoring the release with Förster resonance energy transfer (FRET). 10. The method of claim 8, wherein the nanoparticle is a quantum dot. 11. The method of claim 8, wherein the molecule configured as a bridging structure is maltose binding protein. 12. The method of claim 8, wherein the ligand is β-cyclodextrin. 13. The method of claim 8, wherein the cargo comprises TideFluor3 or doxorubicin.
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A new nanoparticle (NP)-based, multicomponent delivery/reporter construct can mediate the controlled, spatiotemporal, active release of an appended cargo to the cytosol of mammalian cells. The construct comprises components including (1) a central NP scaffold, for example a photoluminescent quantum dot (QD); (2) a bridging structure that self-assembles to the NP surface (for example, histidine-tagged maltose binding protein); and (3) a cargo, for example a ligand-dye/drug conjugate, incorporating a ligand that allows the cargo to releasably bind to the bridging structure (e.g., a β-cyclodextrin ligand for binding to maltose binding protein).1. A nanoparticle construct comprising:
a nanoparticle configured as a central scaffold; a molecule configured as a bridging structure and comprising a first binding element configured for attachment to the nanoparticle and a second binding element; and a cargo incorporating a ligand configured to allow for releasable binding of the cargo from the second binding element of the bridging structure. 2. The construct of claim 1, wherein the nanoparticle is a quantum dot. 3. The construct of claim 1, wherein the molecule configured as a bridging structure is maltose binding protein. 4. The construct of claim 1, wherein the ligand is β-cyclodextrin. 5. The construct of claim 1, wherein the cargo comprises TideFluor3 or doxorubicin. 6. A nanoparticle construct comprising:
a quantum dot configured as a central scaffold; maltose binding protein configured as a bridging structure and comprising a domain for binding to the quantum dot and a binding pocket; and a cargo incorporating a β-cyclodextrin ligand configured to allow for releasable binding of the cargo from the binding pocket of the maltose binding protein. 7. The nanoparticle of claim 6, wherein the cargo comprises TideFluor3 or doxorubicin. 8. A method of delivery comprising:
providing a nanoparticle construct comprising a nanoparticle configured as a central scaffold, a molecule configured as a bridging structure and comprising a first binding element configured for attachment to the nanoparticle and a second binding element, and a cargo incorporating a ligand configured to allow for releasable binding of the cargo from the second binding element of the bridging structure; and causing the construct to be contacted with an analog of the ligand, thereby resulting in release of the cargo from the construct. 9. The method of claim 8, further comprising monitoring the release with Förster resonance energy transfer (FRET). 10. The method of claim 8, wherein the nanoparticle is a quantum dot. 11. The method of claim 8, wherein the molecule configured as a bridging structure is maltose binding protein. 12. The method of claim 8, wherein the ligand is β-cyclodextrin. 13. The method of claim 8, wherein the cargo comprises TideFluor3 or doxorubicin.
| 1,600 |
1,283 | 16,263,464 | 1,612 |
The present invention relates to a mousse composition including water, at least one C2-C5 alcohol, at least one salt, at least one amphiphilic polymer, and at least one hydrophobic surface-treated pigment, as well as to methods for making-up and enhancing the appearance of keratinous materials using the mousse composition.
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1. A mousse composition comprising water, at least one C2-C5 alcohol, at least one salt, at least one amphiphilic polymer, and at least one hydrophobic surface-treated pigment, wherein the mousse composition is free of propellants and wherein the at least one hydrophobic surface-treated pigment has a hydrophobic surface treatment comprising at least one of salt(s) of amino acid(s), salt(s) of fatty acid(s), silicone compound(s), organofluorine compound(s), and fluorosilicone compound(s). 2. The mousse composition of claim 1, wherein the mousse composition is free of waxes and film formers. 3. The mousse composition of claim 1, wherein the mousse composition is free of oils. 4. The mousse composition of claim 1, wherein the mousse composition is free of surfactants. 5. The mousse composition of claim 1, wherein the at least one C2-C5 alcohol is present in an amount of from about 5% to about 30% by weight of the total weight of the composition. 6. The mousse composition of claim 1, wherein the at least one C2-C5 alcohol is ethanol. 7. The mousse composition of claim 1, wherein the at least one salt is present in an amount of from about 0.1% to about 10% by weight of the total weight of the composition. 8. The mousse composition of claim 1, wherein the at least one salt is selected from the group consisting of calcium chloride, magnesium chloride, sodium chloride, and mixtures thereof. 9. The mousse composition according to claim 1, wherein the at least one amphiphilic polymer is selected from the group consisting of Ammonium Acryloyldimethyltaurate/VP Copolymer, Ammonium Acryloyldimethyltaurate/Beheneth-25 Methacrylate Crosspolymer, Ammonium Acryloyldimethyltaurate/Steareth-25 Methacrylate Crosspolymer, crosslinked ethoxylated AMPS/C16-C18, noncrosslinked AMPS/C12-C14, and mixtures thereof. 10. The mousse composition according to claim 1, wherein the at least one amphiphilic polymer is selected from the group consisting of Ammonium Acryloyldimethyltaurate/Beheneth-25 Methacrylate Crosspolymer, Ammonium Acryloyldimethyltaurate/Steareth-25 Methacrylate Crosspolymer, and mixtures thereof. 11. The mousse composition according to claim 1, wherein the at least one amphiphilic polymer is present in an amount of from about 0.1% to about 0.5% by weight of the total weight of the composition. 12. The mousse composition according to claim 1, wherein the at least one hydrophobic surface-treated pigment is present in an amount of from about 0.5% to about 20% by weight of the total weight of the composition. 13. The mousse composition according to claim 1, wherein the hydrophobic surface-treated pigment comprises the at least one salt. 14. The mousse composition according to claim 1, wherein the weight ratio of hydrophobic surface-treated pigment to amphiphilic polymer present ranges from about 50:1 to about 5:1. 15. A method of enhancing the appearance of a keratinous material comprising applying the mousse composition of claim 1 to the keratinous material in an amount sufficient to enhance the appearance of the keratinous material. 16. A method of making-up the appearance of a keratinous material comprising applying the mousse composition of claim 1 to the keratinous material in an amount sufficient to make-up the appearance of the keratinous material. 17. The mousse composition according to claim 1, wherein the G* (complex modulus) of the composition is greater than 1000 Pa. 18. The mousse composition according to claim 17, wherein the G* (complex modulus) of the composition is from 1000 Pa to 50,000 Pa. 19. The mousse composition according to claim 17, wherein the G* (complex modulus) of the composition is from 1000 Pa to 35,000 Pa. 20. The mousse composition according to claim 7, wherein the at least one hydrophobic surface-treated pigment is present in an amount of from about 0.5% to about 20% by weight of the total weight of the composition. 21. The mousse composition according to claim 1, wherein the at least one hydrophobic surface-treated pigment has a hydrophobic surface treatment comprising at least one of isopropyl titanium triisostearate, triethoxycaprylylsilane, perfluorooctyl triethoxysilane, methicone, and disodium stearoyl glutamate.
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The present invention relates to a mousse composition including water, at least one C2-C5 alcohol, at least one salt, at least one amphiphilic polymer, and at least one hydrophobic surface-treated pigment, as well as to methods for making-up and enhancing the appearance of keratinous materials using the mousse composition.1. A mousse composition comprising water, at least one C2-C5 alcohol, at least one salt, at least one amphiphilic polymer, and at least one hydrophobic surface-treated pigment, wherein the mousse composition is free of propellants and wherein the at least one hydrophobic surface-treated pigment has a hydrophobic surface treatment comprising at least one of salt(s) of amino acid(s), salt(s) of fatty acid(s), silicone compound(s), organofluorine compound(s), and fluorosilicone compound(s). 2. The mousse composition of claim 1, wherein the mousse composition is free of waxes and film formers. 3. The mousse composition of claim 1, wherein the mousse composition is free of oils. 4. The mousse composition of claim 1, wherein the mousse composition is free of surfactants. 5. The mousse composition of claim 1, wherein the at least one C2-C5 alcohol is present in an amount of from about 5% to about 30% by weight of the total weight of the composition. 6. The mousse composition of claim 1, wherein the at least one C2-C5 alcohol is ethanol. 7. The mousse composition of claim 1, wherein the at least one salt is present in an amount of from about 0.1% to about 10% by weight of the total weight of the composition. 8. The mousse composition of claim 1, wherein the at least one salt is selected from the group consisting of calcium chloride, magnesium chloride, sodium chloride, and mixtures thereof. 9. The mousse composition according to claim 1, wherein the at least one amphiphilic polymer is selected from the group consisting of Ammonium Acryloyldimethyltaurate/VP Copolymer, Ammonium Acryloyldimethyltaurate/Beheneth-25 Methacrylate Crosspolymer, Ammonium Acryloyldimethyltaurate/Steareth-25 Methacrylate Crosspolymer, crosslinked ethoxylated AMPS/C16-C18, noncrosslinked AMPS/C12-C14, and mixtures thereof. 10. The mousse composition according to claim 1, wherein the at least one amphiphilic polymer is selected from the group consisting of Ammonium Acryloyldimethyltaurate/Beheneth-25 Methacrylate Crosspolymer, Ammonium Acryloyldimethyltaurate/Steareth-25 Methacrylate Crosspolymer, and mixtures thereof. 11. The mousse composition according to claim 1, wherein the at least one amphiphilic polymer is present in an amount of from about 0.1% to about 0.5% by weight of the total weight of the composition. 12. The mousse composition according to claim 1, wherein the at least one hydrophobic surface-treated pigment is present in an amount of from about 0.5% to about 20% by weight of the total weight of the composition. 13. The mousse composition according to claim 1, wherein the hydrophobic surface-treated pigment comprises the at least one salt. 14. The mousse composition according to claim 1, wherein the weight ratio of hydrophobic surface-treated pigment to amphiphilic polymer present ranges from about 50:1 to about 5:1. 15. A method of enhancing the appearance of a keratinous material comprising applying the mousse composition of claim 1 to the keratinous material in an amount sufficient to enhance the appearance of the keratinous material. 16. A method of making-up the appearance of a keratinous material comprising applying the mousse composition of claim 1 to the keratinous material in an amount sufficient to make-up the appearance of the keratinous material. 17. The mousse composition according to claim 1, wherein the G* (complex modulus) of the composition is greater than 1000 Pa. 18. The mousse composition according to claim 17, wherein the G* (complex modulus) of the composition is from 1000 Pa to 50,000 Pa. 19. The mousse composition according to claim 17, wherein the G* (complex modulus) of the composition is from 1000 Pa to 35,000 Pa. 20. The mousse composition according to claim 7, wherein the at least one hydrophobic surface-treated pigment is present in an amount of from about 0.5% to about 20% by weight of the total weight of the composition. 21. The mousse composition according to claim 1, wherein the at least one hydrophobic surface-treated pigment has a hydrophobic surface treatment comprising at least one of isopropyl titanium triisostearate, triethoxycaprylylsilane, perfluorooctyl triethoxysilane, methicone, and disodium stearoyl glutamate.
| 1,600 |
1,284 | 13,784,578 | 1,653 |
Methods for processing and sorting sperm are disclosed. Portions of sperm sorting or staining processes may include standardizing sperm samples by adjusting the concentration of the sperm sample to a predetermined concentration and adjusting the pH of the sample to a predetermined value. Sperm may also be stained in a single staining buffer having a DNA selective dye and a quenching dye.
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1. A method of processing sperm comprising the steps of:
a) obtaining a sperm sample; b) adjusting the concentration of the sperm sample to a predetermined concentration; c) adjusting the pH of the sperm sample towards a predetermined pH; and d) staining the sperm sample with a DNA selective dye. 2. The method of claim 1, wherein the steps of adjusting the concentration and the pH of the sperm sample further comprise the steps of:
a) extending the sperm sample in an initial extender at the predetermined pH; b) centrifuging the extended sperm sample; and c) removing supernatant until the predetermined concentration is reached. 3. The method of claim 2, wherein the initial extender comprises a pH buffering extender with a high buffering capacity. 4. The method of claims 2 wherein the step of extending the sperm sample with the initial extender further comprises diluting the sperm sample with an initial extender at a ratio between about 1:1 and 1:10. 5. The method of claim 2, wherein the initial extender comprises one or more selected from the group of: sodium bicarbonate, TRIS citrate, sodium citrate, HEPES, TRIS, TEST, MOPS, KMT, TALP, and combinations thereof. 6. The method of claim 5, wherein the initial extender further comprises egg yolk. 7. The method of claim 6, wherein the initial extender further comprises between about 1 percent and 10 percent egg yolk. 8. The method of claim 5, wherein the initial extender further comprises citric acid or citrates. 9. The method of claim 5, wherein the initial extender further comprises one or more antioxidants. 10. The method of claim 5, wherein the extender initial extender has a pH of about 7.2. 11. The method of claim 1, wherein the step of adjusting the concentration comprises adjusting the concentration to between about 900 million sperm per ml and about 2100 million sperm per ml. 12. The method of claim 1, wherein the step of adjusting the concentration comprises adjusting the concentration to between about 1400 million sperm per ml and about 2100 million sperm per ml. 13. The method of claim 1, wherein the step of staining the sperm comprises staining the sperm with a single staining solution comprising the DNA selective dye and a quenching dye. 14. The method of claim 1, wherein the predetermined pH is selected based on the species sperm being processed. 15. The method of claim 14, wherein the predetermined pH is selected at about 7.2 for bovine. 16. The method of claim 1, wherein the step of staining is performed with a modified TALP having a DNA selective dye and quenching dye. 17. The method of claim 16, wherein the modified TALP has a pH of about 7.4. 18. The method of claim 1, wherein the stain is applied in a volume to arrive at a stained sperm concentration of 160 million sperm per ml. 19. The method of claim 1, further comprising the step of sorting the stained sperm sample. 20. The method of claim 19, wherein the step of sorting the stained sperm sample is performed with a flow cytometer. 21. The method of claim 19, wherein the step of sorting the stained sperm sample further comprises collecting viable X-chromosome bearing sperm and/or viable Y-chromosome bearing sperm. 22. The method of claim 19, wherein the predetermined pH is maintained through the steps of staining and sorting. 23. The method of claim 19, wherein the pH of the sperm sample is maintained within 0.5 of the predetermined pH through the steps of staining and sorting. 24. The method of claim 19, wherein the pH of the sperm sample is maintained between about 6.75 and about 7.3 through the steps of staining and sorting. 25. The method of claim 19, further comprising the step of freezing the sorted sperm. 26. The method of claim 25, wherein the predetermined pH is maintained through the steps of staining, sorting, and freezing. 27. The method of claim 1, further comprising the step of: preparing a single staining solution comprising the DNA selective dye and the quenching dye. 28. A method of sorting sperm comprising the steps of:
a) obtaining a sperm sample; b) staining the sperm sample with a single staining buffer having a DNA selective dye and a quenching dye; and c) sorting the stained sperm sample. 29. The method of claim 28, wherein the single staining buffer comprises modified TALP with a pH of about 7.4. 30. The method of claim 28, wherein the single staining buffer is applied in a volume to arrive at a stained sperm concentration of between about 640 million sperm per ml and about 80 million sperm per ml. 31. The method of claim 28, wherein the DNA selective dye comprises the fluorescent dye Hoechst 33342. 32. The method of claim 28, wherein the quenching dye comprises yellow food dye No. 6. 33. The method of claim 28, wherein the step of sorting the stained sperm sample is performed with a flow cytometer. 34. The method of claim 28, wherein the step of sorting the stained sperm sample further comprises collecting viable X-chromosome bearing sperm and/or viable Y-chromosome bearing sperm. 35. The method of claim 28, wherein the pH of the sperm sample is maintained at a predetermined level through the steps of staining and sorting. 36. The method of claim 35, wherein the pH of the sperm sample is maintained within 0.5 of the predetermined pH through the steps of staining and sorting. 37. The method of claim 28, wherein the pH of the sperm sample is maintained between about 6.75 and about 7.3 through the steps of staining and sorting. 38. The method of claim 28, further comprising the step of freezing the sorted sperm. 39. The method of claim 38, wherein the pH of the sperm sample is maintained at a predetermined level through the steps of staining, sorting, and freezing. 40. The method of claim 28, further comprising the steps of adjusting the concentration of the sperm sample to a predetermined concentration and adjusting the pH of the sample to a predetermined value prior to the step of staining the sperm sample. 41. The method of claim 40, wherein the initial extender comprises a pH buffering extender with a high buffering capacity. 42. The method of claim 40, wherein the step of extending the sperm sample with the initial extender further comprises diluting the sperm sample with an initial extender at a ratio between about 1:1 and 1:10. 43. The method of claim 40, wherein the initial extender comprises one or more selected from the group of: sodium bicarbonate, TRIS citrate, sodium citrate, HEPES, TRIS, TEST, MOPS, KMT, TALP, and combinations thereof. 44. The method of claim 43, wherein the initial extender further comprises egg yolk. 45. The method of claim 44, wherein the initial extender further comprises between about 1 percent and 10 percent egg yolk. 46. The method of claim 43, wherein the initial extender further comprises citric acid or citrates. 47. The method of claim 43, wherein the initial extender further comprises one or more antioxidants. 48. The method of claim 43, wherein the extender initial extender has a pH of about 7.2 49. A method of sorting sperm comprising the steps of:
a) obtaining a sperm sample; b) staining the sperm sample with a staining buffer having a DNA selective dye at an elevated pH; c) staining the sperm sample with a quenching dye; d) sorting the stained sperm sample, wherein the elevated pH introduced with the DNA selective dye is maintained until the time of sorting. 50. The method of claim 49, wherein the staining buffer comprises modified TALP with a pH of about 7.4. 51. The method of claim 49, wherein the staining buffer is applied in a volume to arrive at a stained sperm concentration of 160 million sperm per ml. 52. The method of claim 49, wherein the quenching dye is applied in the same staining buffer as the DNA selective dye. 53. The method of claim 49, wherein the quenching dye is applied a second buffer. 54. The method of claim 53, wherein the pH of the second buffer is about 7.4.
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Methods for processing and sorting sperm are disclosed. Portions of sperm sorting or staining processes may include standardizing sperm samples by adjusting the concentration of the sperm sample to a predetermined concentration and adjusting the pH of the sample to a predetermined value. Sperm may also be stained in a single staining buffer having a DNA selective dye and a quenching dye.1. A method of processing sperm comprising the steps of:
a) obtaining a sperm sample; b) adjusting the concentration of the sperm sample to a predetermined concentration; c) adjusting the pH of the sperm sample towards a predetermined pH; and d) staining the sperm sample with a DNA selective dye. 2. The method of claim 1, wherein the steps of adjusting the concentration and the pH of the sperm sample further comprise the steps of:
a) extending the sperm sample in an initial extender at the predetermined pH; b) centrifuging the extended sperm sample; and c) removing supernatant until the predetermined concentration is reached. 3. The method of claim 2, wherein the initial extender comprises a pH buffering extender with a high buffering capacity. 4. The method of claims 2 wherein the step of extending the sperm sample with the initial extender further comprises diluting the sperm sample with an initial extender at a ratio between about 1:1 and 1:10. 5. The method of claim 2, wherein the initial extender comprises one or more selected from the group of: sodium bicarbonate, TRIS citrate, sodium citrate, HEPES, TRIS, TEST, MOPS, KMT, TALP, and combinations thereof. 6. The method of claim 5, wherein the initial extender further comprises egg yolk. 7. The method of claim 6, wherein the initial extender further comprises between about 1 percent and 10 percent egg yolk. 8. The method of claim 5, wherein the initial extender further comprises citric acid or citrates. 9. The method of claim 5, wherein the initial extender further comprises one or more antioxidants. 10. The method of claim 5, wherein the extender initial extender has a pH of about 7.2. 11. The method of claim 1, wherein the step of adjusting the concentration comprises adjusting the concentration to between about 900 million sperm per ml and about 2100 million sperm per ml. 12. The method of claim 1, wherein the step of adjusting the concentration comprises adjusting the concentration to between about 1400 million sperm per ml and about 2100 million sperm per ml. 13. The method of claim 1, wherein the step of staining the sperm comprises staining the sperm with a single staining solution comprising the DNA selective dye and a quenching dye. 14. The method of claim 1, wherein the predetermined pH is selected based on the species sperm being processed. 15. The method of claim 14, wherein the predetermined pH is selected at about 7.2 for bovine. 16. The method of claim 1, wherein the step of staining is performed with a modified TALP having a DNA selective dye and quenching dye. 17. The method of claim 16, wherein the modified TALP has a pH of about 7.4. 18. The method of claim 1, wherein the stain is applied in a volume to arrive at a stained sperm concentration of 160 million sperm per ml. 19. The method of claim 1, further comprising the step of sorting the stained sperm sample. 20. The method of claim 19, wherein the step of sorting the stained sperm sample is performed with a flow cytometer. 21. The method of claim 19, wherein the step of sorting the stained sperm sample further comprises collecting viable X-chromosome bearing sperm and/or viable Y-chromosome bearing sperm. 22. The method of claim 19, wherein the predetermined pH is maintained through the steps of staining and sorting. 23. The method of claim 19, wherein the pH of the sperm sample is maintained within 0.5 of the predetermined pH through the steps of staining and sorting. 24. The method of claim 19, wherein the pH of the sperm sample is maintained between about 6.75 and about 7.3 through the steps of staining and sorting. 25. The method of claim 19, further comprising the step of freezing the sorted sperm. 26. The method of claim 25, wherein the predetermined pH is maintained through the steps of staining, sorting, and freezing. 27. The method of claim 1, further comprising the step of: preparing a single staining solution comprising the DNA selective dye and the quenching dye. 28. A method of sorting sperm comprising the steps of:
a) obtaining a sperm sample; b) staining the sperm sample with a single staining buffer having a DNA selective dye and a quenching dye; and c) sorting the stained sperm sample. 29. The method of claim 28, wherein the single staining buffer comprises modified TALP with a pH of about 7.4. 30. The method of claim 28, wherein the single staining buffer is applied in a volume to arrive at a stained sperm concentration of between about 640 million sperm per ml and about 80 million sperm per ml. 31. The method of claim 28, wherein the DNA selective dye comprises the fluorescent dye Hoechst 33342. 32. The method of claim 28, wherein the quenching dye comprises yellow food dye No. 6. 33. The method of claim 28, wherein the step of sorting the stained sperm sample is performed with a flow cytometer. 34. The method of claim 28, wherein the step of sorting the stained sperm sample further comprises collecting viable X-chromosome bearing sperm and/or viable Y-chromosome bearing sperm. 35. The method of claim 28, wherein the pH of the sperm sample is maintained at a predetermined level through the steps of staining and sorting. 36. The method of claim 35, wherein the pH of the sperm sample is maintained within 0.5 of the predetermined pH through the steps of staining and sorting. 37. The method of claim 28, wherein the pH of the sperm sample is maintained between about 6.75 and about 7.3 through the steps of staining and sorting. 38. The method of claim 28, further comprising the step of freezing the sorted sperm. 39. The method of claim 38, wherein the pH of the sperm sample is maintained at a predetermined level through the steps of staining, sorting, and freezing. 40. The method of claim 28, further comprising the steps of adjusting the concentration of the sperm sample to a predetermined concentration and adjusting the pH of the sample to a predetermined value prior to the step of staining the sperm sample. 41. The method of claim 40, wherein the initial extender comprises a pH buffering extender with a high buffering capacity. 42. The method of claim 40, wherein the step of extending the sperm sample with the initial extender further comprises diluting the sperm sample with an initial extender at a ratio between about 1:1 and 1:10. 43. The method of claim 40, wherein the initial extender comprises one or more selected from the group of: sodium bicarbonate, TRIS citrate, sodium citrate, HEPES, TRIS, TEST, MOPS, KMT, TALP, and combinations thereof. 44. The method of claim 43, wherein the initial extender further comprises egg yolk. 45. The method of claim 44, wherein the initial extender further comprises between about 1 percent and 10 percent egg yolk. 46. The method of claim 43, wherein the initial extender further comprises citric acid or citrates. 47. The method of claim 43, wherein the initial extender further comprises one or more antioxidants. 48. The method of claim 43, wherein the extender initial extender has a pH of about 7.2 49. A method of sorting sperm comprising the steps of:
a) obtaining a sperm sample; b) staining the sperm sample with a staining buffer having a DNA selective dye at an elevated pH; c) staining the sperm sample with a quenching dye; d) sorting the stained sperm sample, wherein the elevated pH introduced with the DNA selective dye is maintained until the time of sorting. 50. The method of claim 49, wherein the staining buffer comprises modified TALP with a pH of about 7.4. 51. The method of claim 49, wherein the staining buffer is applied in a volume to arrive at a stained sperm concentration of 160 million sperm per ml. 52. The method of claim 49, wherein the quenching dye is applied in the same staining buffer as the DNA selective dye. 53. The method of claim 49, wherein the quenching dye is applied a second buffer. 54. The method of claim 53, wherein the pH of the second buffer is about 7.4.
| 1,600 |
1,285 | 15,298,757 | 1,644 |
A pharmaceutical product containing β2-microglobulin or a functional variant thereof as an active ingredient in the form of liposomes is provided. The product can increase the concentration of β2-microglobulin in the blood, and can also restore a normal HC/β2-microglobulin molar ratio within membrane MHC-I complexes, or prevent a β2-microglobulin deficit from occurring in the MHC-I complexes, of patients suffering from autoimmune diseases. Methods of treating patients with the pharmaceutical product are also presented.
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1. A method of treating an autoimmune disease, comprising administering to a subject in need thereof an effective amount of a pharmaceutical product comprising as an active ingredient β2-microglobulin or a functional variant thereof presenting at least 90% identity with the human 62-microglobulin protein, in a pharmaceutically acceptable carrier. 2. The method according to claim 1, wherein the autoimmune disease is selected from the group consisting of rheumatoid polyarthritis, systemic lupus erythematosus, Sjögren's syndrome, scleroderma, fibromyalgia, myositis, ankylosing spondylitis, insulin dependent diabetes of type I, Hashimoto's thyroiditis, Addison's disease, Crohn's disease, Celiac's disease, multiple sclerosis and amyotrophic lateral sclerosis. 3. The method according to claim 1, wherein the active ingredient consists of β2-microglobulin. 4. The method according to claim 1, wherein the active ingredient consists of human β2-microglobulin. 5. The method according to claim 1, wherein the pharmaceutical product consists of β2-microglobulin or a functional variant thereof presenting at least 90% identity with the human β2-microglobulin protein, as an active ingredient, in a pharmaceutically acceptable carrier. 6. A method of increasing the ratio of blood β2-microglobulin to a concentration between 2.5 mg/l to 12 mg/l in a patient suffering from an auto-immune disease, comprising administering to said patient an effective amount of a pharmaceutical product comprising as an active ingredient 62-microglobulin or a functional variant thereof presenting at least 90% identity with the human β2-microglobulin protein, in a pharmaceutically acceptable carrier. 7. The method according to claim 6, wherein the autoimmune disease is selected from the group consisting of rheumatoid polyarthritis, systemic lupus erythematosus, Sjögren's syndrome, scleroderma, fibromyalgia, myositis, ankylosing spondylitis, insulin dependent diabetes of type I, Hashimoto's thyroiditis, Addison's disease, Crohn's disease, Celiac's disease, multiple sclerosis and amyotrophic lateral sclerosis. 8. The method according to claim 6, wherein the active ingredient consists of β2-microglobulin. 9. The method according to claim 6, wherein the active ingredient consists of human β2-microglobulin. 10. The method according to claim 6, wherein the pharmaceutical product consists of β2-microglobulin or a functional variant thereof presenting at least 90% identity with the human β2-microglobulin protein, as an active ingredient, in a pharmaceutically acceptable carrier. 11. A method of restoring a normal HC/β2-microglobulin molar ratio within the membrane MHC-I complexes in a patient suffering from an auto-immune disease, comprising administering to said patient an effective amount of a pharmaceutical product comprising as an active ingredient 62-microglobulin or a functional variant thereof presenting at least 90% identity with the human β2-microglobulin protein, in a pharmaceutically acceptable carrier. 12. The method according to claim 11, wherein the autoimmune disease is selected from the group consisting of rheumatoid polyarthritis, systemic lupus erythematosus, Sjögren's syndrome, scleroderma, fibromyalgia, myositis, ankylosing spondylitis, insulin dependent diabetes of type I, Hashimoto's thyroiditis, Addison's disease, Crohn's disease, Celiac's disease, multiple sclerosis and amyotrophic lateral sclerosis. 13. The method according to claim 11, wherein the active ingredient consists of β2-microglobulin. 14. The method according to claim 11, wherein the active ingredient consists of human β2-microglobulin. 15. The method according to claim 11, wherein the pharmaceutical product consists of β2-microglobulin or a functional variant thereof presenting at least 90% identity with the human β2-microglobulin protein, as an active ingredient, in a pharmaceutically acceptable carrier. 16. A method of preventing a β2-microglobulin deficit from occurring in the MHC-I complexes in a patient suffering from an auto-immune disease, comprising administering to said patient an effective amount of a pharmaceutical product comprising as an active ingredient β2-microglobulin or a functional variant thereof presenting at least 90% identity with the human 62-microglobulin protein, in a pharmaceutically acceptable carrier. 17. The method according to claim 16, wherein the autoimmune disease is selected from the group consisting of rheumatoid polyarthritis, systemic lupus erythematosus, Sjögren's syndrome, scleroderma, fibromyalgia, myositis, ankylosing spondylitis, insulin dependent diabetes of type I, Hashimoto's thyroiditis, Addison's disease, Crohn's disease, Celiac's disease, multiple sclerosis and amyotrophic lateral sclerosis. 18. The method according to claim 16, wherein the active ingredient consists of β2-microglobulin. 19. The method according to claim 16, wherein the active ingredient consists of human β2-microglobulin. 20. The method according to claim 16, wherein the pharmaceutical product consists of β2-microglobulin or a functional variant thereof presenting at least 90% identity with the human β2-microglobulin protein, as an active ingredient in a pharmaceutically acceptable carrier.
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A pharmaceutical product containing β2-microglobulin or a functional variant thereof as an active ingredient in the form of liposomes is provided. The product can increase the concentration of β2-microglobulin in the blood, and can also restore a normal HC/β2-microglobulin molar ratio within membrane MHC-I complexes, or prevent a β2-microglobulin deficit from occurring in the MHC-I complexes, of patients suffering from autoimmune diseases. Methods of treating patients with the pharmaceutical product are also presented.1. A method of treating an autoimmune disease, comprising administering to a subject in need thereof an effective amount of a pharmaceutical product comprising as an active ingredient β2-microglobulin or a functional variant thereof presenting at least 90% identity with the human 62-microglobulin protein, in a pharmaceutically acceptable carrier. 2. The method according to claim 1, wherein the autoimmune disease is selected from the group consisting of rheumatoid polyarthritis, systemic lupus erythematosus, Sjögren's syndrome, scleroderma, fibromyalgia, myositis, ankylosing spondylitis, insulin dependent diabetes of type I, Hashimoto's thyroiditis, Addison's disease, Crohn's disease, Celiac's disease, multiple sclerosis and amyotrophic lateral sclerosis. 3. The method according to claim 1, wherein the active ingredient consists of β2-microglobulin. 4. The method according to claim 1, wherein the active ingredient consists of human β2-microglobulin. 5. The method according to claim 1, wherein the pharmaceutical product consists of β2-microglobulin or a functional variant thereof presenting at least 90% identity with the human β2-microglobulin protein, as an active ingredient, in a pharmaceutically acceptable carrier. 6. A method of increasing the ratio of blood β2-microglobulin to a concentration between 2.5 mg/l to 12 mg/l in a patient suffering from an auto-immune disease, comprising administering to said patient an effective amount of a pharmaceutical product comprising as an active ingredient 62-microglobulin or a functional variant thereof presenting at least 90% identity with the human β2-microglobulin protein, in a pharmaceutically acceptable carrier. 7. The method according to claim 6, wherein the autoimmune disease is selected from the group consisting of rheumatoid polyarthritis, systemic lupus erythematosus, Sjögren's syndrome, scleroderma, fibromyalgia, myositis, ankylosing spondylitis, insulin dependent diabetes of type I, Hashimoto's thyroiditis, Addison's disease, Crohn's disease, Celiac's disease, multiple sclerosis and amyotrophic lateral sclerosis. 8. The method according to claim 6, wherein the active ingredient consists of β2-microglobulin. 9. The method according to claim 6, wherein the active ingredient consists of human β2-microglobulin. 10. The method according to claim 6, wherein the pharmaceutical product consists of β2-microglobulin or a functional variant thereof presenting at least 90% identity with the human β2-microglobulin protein, as an active ingredient, in a pharmaceutically acceptable carrier. 11. A method of restoring a normal HC/β2-microglobulin molar ratio within the membrane MHC-I complexes in a patient suffering from an auto-immune disease, comprising administering to said patient an effective amount of a pharmaceutical product comprising as an active ingredient 62-microglobulin or a functional variant thereof presenting at least 90% identity with the human β2-microglobulin protein, in a pharmaceutically acceptable carrier. 12. The method according to claim 11, wherein the autoimmune disease is selected from the group consisting of rheumatoid polyarthritis, systemic lupus erythematosus, Sjögren's syndrome, scleroderma, fibromyalgia, myositis, ankylosing spondylitis, insulin dependent diabetes of type I, Hashimoto's thyroiditis, Addison's disease, Crohn's disease, Celiac's disease, multiple sclerosis and amyotrophic lateral sclerosis. 13. The method according to claim 11, wherein the active ingredient consists of β2-microglobulin. 14. The method according to claim 11, wherein the active ingredient consists of human β2-microglobulin. 15. The method according to claim 11, wherein the pharmaceutical product consists of β2-microglobulin or a functional variant thereof presenting at least 90% identity with the human β2-microglobulin protein, as an active ingredient, in a pharmaceutically acceptable carrier. 16. A method of preventing a β2-microglobulin deficit from occurring in the MHC-I complexes in a patient suffering from an auto-immune disease, comprising administering to said patient an effective amount of a pharmaceutical product comprising as an active ingredient β2-microglobulin or a functional variant thereof presenting at least 90% identity with the human 62-microglobulin protein, in a pharmaceutically acceptable carrier. 17. The method according to claim 16, wherein the autoimmune disease is selected from the group consisting of rheumatoid polyarthritis, systemic lupus erythematosus, Sjögren's syndrome, scleroderma, fibromyalgia, myositis, ankylosing spondylitis, insulin dependent diabetes of type I, Hashimoto's thyroiditis, Addison's disease, Crohn's disease, Celiac's disease, multiple sclerosis and amyotrophic lateral sclerosis. 18. The method according to claim 16, wherein the active ingredient consists of β2-microglobulin. 19. The method according to claim 16, wherein the active ingredient consists of human β2-microglobulin. 20. The method according to claim 16, wherein the pharmaceutical product consists of β2-microglobulin or a functional variant thereof presenting at least 90% identity with the human β2-microglobulin protein, as an active ingredient in a pharmaceutically acceptable carrier.
| 1,600 |
1,286 | 14,730,396 | 1,649 |
The present invention relates to peptides derived from human Basic Proline-rich Lacrimal Protein (BPLP), notably opiorphin, for use as psychostimulants. These peptides are useful in the treatment or prevention of diseases such as obsessive-compulsive disorder (OCD), narcolepsy, hypersomnia, vigilance drop, attention-deficit/hyperactivity disorder (ADHD), attention deficit and/or hyperactivity in adults and in children, depression, bipolar disease, dysthymic disorder and cyclothymic disorder.
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1. A peptide for a use as a psychostimulant, wherein said peptide:
comprises a maturation product of the Basic Proline-rich Lacrimal Protein (BPLP) of sequence SEQ ID NO: 5 or a derivative of said maturation product; and exerts a psychostimulant activity. 2. A peptide for activating an opioidergic pathway depending on p- and/or 6-opioid receptors, wherein said peptide:
comprises a maturation product of the Basic Proline-rich Lacrimal Protein (BPLP) of sequence SEQ ID NO: 5 or a derivative of said maturation product; and exerts a psychostimulant activity. 3. The peptide according to claim 1, wherein said peptide comprises the sequence X1-X2-Arg-Phe-Ser-Arg (SEQ ID NO: 1), wherein:
X1 represents a hydrogen atom, a tyrosine or a cysteine; when X1 is a hydrogen atom, X2 represents a glutamine or pyroglutamate; when X1 is a tyrosine or a cysteine, X2 represents a glutamine; and the sequence of the terminal extremity of said peptide consists of X1-X2-Arg-Phe-Ser-Arg. 4. The peptide according to claim 3, wherein said peptide consists of the sequence X1-X2-Arg-Phe-Ser-Arg. 5. The peptide according to claim 1, wherein said peptide consists of a sequence selected from the sequences QRFSR (SEQ ID NO: 2), YQRFSR (SEQ ID NO: 3) and CQRFSR (SEQ ID NO: 4). 6. The peptide according to claim 1, the sequence of which differs from a sequence selected from sequences SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4 by conservative substitutions. 7. The peptide according to claim 1, wherein said peptide includes a chemical modification improving its stability and/or bioavailability. 8. The peptide according to claim 1, for treating or preventing a disease selected in the group consisting of an obsessive-compulsive disorder (OCD), narcolepsy, hypersomnia, vigilance drop, attention-deficit/hyperactivity disorder (ADHD), attention deficit and/or hyperactivity in adults and in children, depression, bipolar disease, dysthymic disorder and cyclothymic disorder. 9. The peptide according to claim 8, wherein said diseases is selected from the group consisting of an obsessive-compulsive disorder, narcolepsy, hypersomnia, vigilance drop, attention deficit and/or hyperactivity in children, bipolar disease, dysthymic disorder and cyclothymic disorder. 10. The peptide according to claim 9, wherein said diseases is selected from the group consisting of an obsessive-compulsive disorder, narcolepsy, hypersomnia and vigilance drop. 11. The peptide according to claim 1, intended to be administered to an adult at a dose less than or equal to 75 mg per day. 12. The peptide according to claim 1, intended to be administered to a child at a dose less than or equal to 25 mg per day. 13. The peptide according to claim 11, intended to be administered three times daily. 14. The peptide according to claim 1, intended to be
administered via a route selected from the oral, transdermal, nasal, sublingual and intravenous route. 15. The peptide according to claim 1, intended to be administered in combination with a second active ingredient selected from the group consisting of a psychostimulant, an antidepressant and an anxiolytic. 16. A method for treating or preventing a disease selected from the group consisting of an obsessive-compulsive disorder, narcolepsy, hypersomnia, vigilance drop, attention-deficit/hyperactivity disorder, attention deficit and/or hyperactivity in adults and in children, depression, bipolar disease, dysthyrnic disorder and cyclothymic disorder comprising the step of administering an effective amount of a peptide according to claim 1 to an individual in need thereof.
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The present invention relates to peptides derived from human Basic Proline-rich Lacrimal Protein (BPLP), notably opiorphin, for use as psychostimulants. These peptides are useful in the treatment or prevention of diseases such as obsessive-compulsive disorder (OCD), narcolepsy, hypersomnia, vigilance drop, attention-deficit/hyperactivity disorder (ADHD), attention deficit and/or hyperactivity in adults and in children, depression, bipolar disease, dysthymic disorder and cyclothymic disorder.1. A peptide for a use as a psychostimulant, wherein said peptide:
comprises a maturation product of the Basic Proline-rich Lacrimal Protein (BPLP) of sequence SEQ ID NO: 5 or a derivative of said maturation product; and exerts a psychostimulant activity. 2. A peptide for activating an opioidergic pathway depending on p- and/or 6-opioid receptors, wherein said peptide:
comprises a maturation product of the Basic Proline-rich Lacrimal Protein (BPLP) of sequence SEQ ID NO: 5 or a derivative of said maturation product; and exerts a psychostimulant activity. 3. The peptide according to claim 1, wherein said peptide comprises the sequence X1-X2-Arg-Phe-Ser-Arg (SEQ ID NO: 1), wherein:
X1 represents a hydrogen atom, a tyrosine or a cysteine; when X1 is a hydrogen atom, X2 represents a glutamine or pyroglutamate; when X1 is a tyrosine or a cysteine, X2 represents a glutamine; and the sequence of the terminal extremity of said peptide consists of X1-X2-Arg-Phe-Ser-Arg. 4. The peptide according to claim 3, wherein said peptide consists of the sequence X1-X2-Arg-Phe-Ser-Arg. 5. The peptide according to claim 1, wherein said peptide consists of a sequence selected from the sequences QRFSR (SEQ ID NO: 2), YQRFSR (SEQ ID NO: 3) and CQRFSR (SEQ ID NO: 4). 6. The peptide according to claim 1, the sequence of which differs from a sequence selected from sequences SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4 by conservative substitutions. 7. The peptide according to claim 1, wherein said peptide includes a chemical modification improving its stability and/or bioavailability. 8. The peptide according to claim 1, for treating or preventing a disease selected in the group consisting of an obsessive-compulsive disorder (OCD), narcolepsy, hypersomnia, vigilance drop, attention-deficit/hyperactivity disorder (ADHD), attention deficit and/or hyperactivity in adults and in children, depression, bipolar disease, dysthymic disorder and cyclothymic disorder. 9. The peptide according to claim 8, wherein said diseases is selected from the group consisting of an obsessive-compulsive disorder, narcolepsy, hypersomnia, vigilance drop, attention deficit and/or hyperactivity in children, bipolar disease, dysthymic disorder and cyclothymic disorder. 10. The peptide according to claim 9, wherein said diseases is selected from the group consisting of an obsessive-compulsive disorder, narcolepsy, hypersomnia and vigilance drop. 11. The peptide according to claim 1, intended to be administered to an adult at a dose less than or equal to 75 mg per day. 12. The peptide according to claim 1, intended to be administered to a child at a dose less than or equal to 25 mg per day. 13. The peptide according to claim 11, intended to be administered three times daily. 14. The peptide according to claim 1, intended to be
administered via a route selected from the oral, transdermal, nasal, sublingual and intravenous route. 15. The peptide according to claim 1, intended to be administered in combination with a second active ingredient selected from the group consisting of a psychostimulant, an antidepressant and an anxiolytic. 16. A method for treating or preventing a disease selected from the group consisting of an obsessive-compulsive disorder, narcolepsy, hypersomnia, vigilance drop, attention-deficit/hyperactivity disorder, attention deficit and/or hyperactivity in adults and in children, depression, bipolar disease, dysthyrnic disorder and cyclothymic disorder comprising the step of administering an effective amount of a peptide according to claim 1 to an individual in need thereof.
| 1,600 |
1,287 | 15,252,267 | 1,644 |
Methods are provided for treating metastatic cancer in patients having metastatic cancer or for preventing metastasis in cancer patients at risk for metastasis comprising administering to the patient an antibody to B7x, or an active antibody fragment that binds B7x, in an amount effective to treat or prevent metastasis.
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1. A method for treating metastatic cancer in a patient having metastatic cancer or for preventing metastasis in a cancer patient at risk for metastasis comprising administering to the patient a monoclonal antibody, or a fragment thereof, that binds to B7x, in an amount effective to treat or prevent metastasis in a patient, wherein the antibody or antibody fragment binds to amino acid residues 35-148 of SEQ ID NO:1. 2. The method of claim 1 comprising determining the level of B7x expression in a tumor sample from the patient, and if B7x is over-expressed in the tumor sample compared to healthy tissue, administering to the patient an antibody to B7x, or an antibody fragment that binds B7x, in an amount effective to treat or prevent metastasis in a patient. 3. The method of claim 1, wherein the patient has metastatic cancer. 4. The method of claim 1, wherein the patient is a cancer patient at risk for metastasis. 5. The method of claim 1, wherein the cancer is a cancer of the skin, breast, pancreas, prostate, ovary, kidney, esophagus, gastrointestional tract, colon, brain, liver, lung, head and/or neck. 6-7. (canceled) 8. The method of claim 1, wherein the antibody is an IgG monoclonal antibody. 9. The method of claim 1, wherein the antibody is an IgG1 monoclonal antibody. 10. The method of claim 1, wherein administration of the antibody or antibody fragment decreases the number of tumor nodules in the patient. 11. The method of claim 1, wherein administration of the antibody or antibody fragment reduces the number of metastases. 12. The method of claim 1, wherein administration of the antibody or antibody fragment prevents the occurrence or reoccurrence of metastasis. 13. The method of claim 1, wherein administration of the antibody or antibody fragment increases the patient's survival time. 14. The method of claim 1, wherein the antibody or antibody fragment does not include an antibody-partner molecule conjugate. 15. The method of claim 1, wherein the antibody or antibody fragment is the sole therapeutic anti-cancer agent administered to the patient. 16. The method of claim 1, wherein the antibody or antibody fragment is administered in combination with another anti-cancer agent. 17-18. (canceled) 19. The method of claim 1, wherein administration of the antibody or antibody fragment prevents the reoccurrence of a tumor in the patient. 20. A method for preventing reoccurrence of a tumor in a patient comprising administering to the patient a monoclonal antibody, or a fragment thereof, that binds B7x, in an amount effective to prevent reoccurrence of a tumor in a patient, wherein the antibody or antibody fragment binds to amino acid residues 35-148 of SEQ ID NO:1. 21. A method of producing a monoclonal antibody to B7x comprising:
immunizing a B7x knockout mouse with a B7x-Ig fusion protein, generating a hybridoma from spleen cells from the mouse, and testing supernatant from the hybridoma for its ability to react with immobilized B7x-Ig or a cell line expressing B7x, but not with control Igs or cell lines expressing other B7 family members, to identify a monoclonal antibody to B7x. 22. The method of claim 21 further comprising generating a B7x knockout mouse. 23. The method of claim 21 further comprising purifying the antibody from the supernatant. 24. A method of screening monoclonal antibodies to B7x to identify an antibody that inhibits tumor growth in vivo, the method comprising
injecting tumor cells expressing B7x on their cell surface into a mouse to induce a tumor in the mouse, wherein B7x is stably expressed on the tumor cells using a retroviral expression vector, and injecting a monclonal antibody to B7x into the mouse to identify an antibody that inhibits tumor growth in vivo. 25-26. (canceled)
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Methods are provided for treating metastatic cancer in patients having metastatic cancer or for preventing metastasis in cancer patients at risk for metastasis comprising administering to the patient an antibody to B7x, or an active antibody fragment that binds B7x, in an amount effective to treat or prevent metastasis.1. A method for treating metastatic cancer in a patient having metastatic cancer or for preventing metastasis in a cancer patient at risk for metastasis comprising administering to the patient a monoclonal antibody, or a fragment thereof, that binds to B7x, in an amount effective to treat or prevent metastasis in a patient, wherein the antibody or antibody fragment binds to amino acid residues 35-148 of SEQ ID NO:1. 2. The method of claim 1 comprising determining the level of B7x expression in a tumor sample from the patient, and if B7x is over-expressed in the tumor sample compared to healthy tissue, administering to the patient an antibody to B7x, or an antibody fragment that binds B7x, in an amount effective to treat or prevent metastasis in a patient. 3. The method of claim 1, wherein the patient has metastatic cancer. 4. The method of claim 1, wherein the patient is a cancer patient at risk for metastasis. 5. The method of claim 1, wherein the cancer is a cancer of the skin, breast, pancreas, prostate, ovary, kidney, esophagus, gastrointestional tract, colon, brain, liver, lung, head and/or neck. 6-7. (canceled) 8. The method of claim 1, wherein the antibody is an IgG monoclonal antibody. 9. The method of claim 1, wherein the antibody is an IgG1 monoclonal antibody. 10. The method of claim 1, wherein administration of the antibody or antibody fragment decreases the number of tumor nodules in the patient. 11. The method of claim 1, wherein administration of the antibody or antibody fragment reduces the number of metastases. 12. The method of claim 1, wherein administration of the antibody or antibody fragment prevents the occurrence or reoccurrence of metastasis. 13. The method of claim 1, wherein administration of the antibody or antibody fragment increases the patient's survival time. 14. The method of claim 1, wherein the antibody or antibody fragment does not include an antibody-partner molecule conjugate. 15. The method of claim 1, wherein the antibody or antibody fragment is the sole therapeutic anti-cancer agent administered to the patient. 16. The method of claim 1, wherein the antibody or antibody fragment is administered in combination with another anti-cancer agent. 17-18. (canceled) 19. The method of claim 1, wherein administration of the antibody or antibody fragment prevents the reoccurrence of a tumor in the patient. 20. A method for preventing reoccurrence of a tumor in a patient comprising administering to the patient a monoclonal antibody, or a fragment thereof, that binds B7x, in an amount effective to prevent reoccurrence of a tumor in a patient, wherein the antibody or antibody fragment binds to amino acid residues 35-148 of SEQ ID NO:1. 21. A method of producing a monoclonal antibody to B7x comprising:
immunizing a B7x knockout mouse with a B7x-Ig fusion protein, generating a hybridoma from spleen cells from the mouse, and testing supernatant from the hybridoma for its ability to react with immobilized B7x-Ig or a cell line expressing B7x, but not with control Igs or cell lines expressing other B7 family members, to identify a monoclonal antibody to B7x. 22. The method of claim 21 further comprising generating a B7x knockout mouse. 23. The method of claim 21 further comprising purifying the antibody from the supernatant. 24. A method of screening monoclonal antibodies to B7x to identify an antibody that inhibits tumor growth in vivo, the method comprising
injecting tumor cells expressing B7x on their cell surface into a mouse to induce a tumor in the mouse, wherein B7x is stably expressed on the tumor cells using a retroviral expression vector, and injecting a monclonal antibody to B7x into the mouse to identify an antibody that inhibits tumor growth in vivo. 25-26. (canceled)
| 1,600 |
1,288 | 16,022,835 | 1,631 |
The present disclosure provides, in some embodiments, a computing device comprising an improved user interface. In some embodiments, the improved user interface enables the visualization of clinically relevant information pertaining to interacting gene variants, including therapeutic recommendations. In some embodiments, the improved user interface facilitates the contemporaneous visualization of clinically relevant information pertaining to individual gene variants and the visualization of clinically relevant information pertaining to an interaction between gene variants, including therapeutic recommendations. In some embodiments, the visualization(s), through the improved user interface, facilitates the rapid interpretation of clinically relevant information by a medical professional such that decisions regarding patient care may be made accurately and efficiently.
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1-12. (canceled) 13. A method for treating a human patient comprising:
receiving a user input of a diagnosed disease or condition of a human patient, wherein the diagnosed disease or condition is a type of cancer; based on the received user input, displaying, on a computing device having a display screen, a first representation comprising (i) one or more therapeutic recommendations based on an identified clinically relevant interaction between at least two human gene variants of a plurality of human gene variants for the diagnosed disease or condition of the human patient, and (ii) an identification of the at least two human gene variants for which the clinically relevant interaction was identified, wherein the one or more therapeutic recommendations are one or more therapies sensitive for the diagnosed disease or condition; contemporaneously displaying, on the display screen, and based on the received user input, a second representation comprising clinically relevant information pertaining to at least one of the at least two human gene variants for which the interaction was identified; wherein the plurality of human gene variants are derived from sequence data derived from a genomic sample collected from the patient, and wherein the plurality of human gene variants are obtained from one or more memories communicatively coupled to the computing device, wherein the clinically relevant information is selected from the group consisting of summaries of biological and functional information pertaining to the gene variant, cross references to source material, hyperlinks to source material, and gene variant location; and administering to the human patient at least one of the therapies sensitive for the diagnosed disease or condition. 14. (canceled) 15. (canceled) 16. (canceled) 17. The method of claim 16, wherein the one or more therapies sensitive for the diagnosed disease or condition are marked in the first representation with a first indicia. 18. The method of claim 13, wherein the first and second representations are displayed within a single panel, wherein the second representation is visualized in a first portion of an individual gene panel representation and wherein the first representation is visualized in a second portion of the individual gene panel representation. 19. The method of claim 13, wherein the first and second representations are displayed within separate panels. 20. (canceled) 21. (canceled) 22. (canceled) 23. (canceled) 24. The method of claim 13, wherein the administered therapy sensitive for the type of cancer is selected from the group consisting of a targeted therapy, a combination therapy, and a clinical treatment protocol. 25. The method of claim 13, further comprising displaying of one or more therapies resistant to the diagnosed disease or condition within the first representation. 26. A method of treating a human patient comprising:
obtaining a plurality of human gene variants derived from a human genomic sample collected from the human patient; receiving a first user input of a diagnosed disease or condition of the human patient, wherein the diagnosed disease or condition is a type of cancer; identifying a subset of human gene variants from the plurality of human gene variants that are relevant to the diagnosed disease or condition of the human patient; retrieving clinical data associated with at least some of the subset of human gene variants from one or more databases, wherein the clinical data comprises treatment therapy data; automatically identifying a clinically relevant interaction between a first gene variant and a second gene variant from the identified subset of human gene variants relevant to the diagnosed disease or condition of the human patient, wherein the first gene variant is associated with a therapeutic recommendation comprising one or more treatment options sensitive to the diagnosed disease or condition of the human patient, and wherein the second gene variant is associated with a resistance to at least one of the treatment options; and displaying on the display screen a first representation comprising (i) an identification of the first gene variant and the second gene variant for which the clinically relevant interaction was identified, (ii) a listing of each of the one or more treatment options associated with the first gene variant, wherein the at least one treatment option that is associated with the resistance is distinguished graphically from the other treatment options; and administering to the human patient at least one of the treatment options sensitive to the diagnosed disease or condition of the human patient. 27. The method of claim 26, wherein the administered treatment option is a targeted therapy. 28. The method of claim 26, wherein the administered treatment option is a combination therapy. 29. The method of claim 26, wherein the administered treatment option is a clinical treatment protocol. 30. The method of claim 26, wherein the first representation is displayed on an interactive panel on the display screen, and wherein the computing device is further configured to: display a second representation when the interactive panel is selected, wherein the second representation comprises additional clinically relevant information pertaining to the first gene variant and/or the second gene variant for which the clinically relevant interaction was identified, wherein the additional clinically relevant information is selected from the group consisting of therapeutic options, clinical briefs and summaries, summaries of biological and functional information pertaining to the gene variant, classification information, statistics, cross references to source material, hyperlinks to source material, graphical variant alignment representations, and gene variant location. 31. A method of treating a human patient inflicted with cancer comprising:
obtaining a plurality of human gene variants derived from a human genomic sample collected from a human patient; receiving a first user input of a diagnosed type of cancer of the human patient; based on the received first user input of the type of cancer, provide a first representation comprising (i) one or more therapeutic recommendations based on an identified clinically relevant interaction between at least two human gene variants of the obtained plurality of human gene variants for the diagnosed disease or condition; and (ii) an identification of the at least two human gene variants for which the clinically relevant interaction was identified; and contemporaneously with providing the first representation, and based on the received user input, provide a second representation comprising clinically relevant information pertaining to a first of the at least two human gene variants for which the clinically relevant interaction was identified, wherein the clinically relevant information is selected from the group consisting of summaries of biological and functional information pertaining to the gene variant, cross references to source material, hyperlinks to source material, and gene variant location; and administering to the human patient at least one therapeutic recommendation of the one or more therapeutic recommendations provided within the first representation. 32. The method of claim 31, wherein the administered at least one therapeutic recommendation is a therapy sensitive for the type of cancer. 33. The method of claim 32, wherein the therapy sensitive for the type of cancer is a targeted therapy. 34. The method of claim 32, wherein the therapy sensitive for the type of cancer is a combination therapy. 35. The method of claim 32, wherein the therapy sensitive for the type of cancer is a clinical treatment protocol. 36. The method of claim 32, wherein the therapy sensitive for the type of cancer is an off-label use of a therapeutic agent. 37. The method of claim 31, wherein the therapy sensitive for the diagnosed disease or condition is marked with a first indicia; and wherein a therapy resistant for the diagnosed disease or condition is marked with a second indicia. 38. The method of claim 31, further comprising visualizing a third representation comprising clinically relevant information pertaining to a second of the at least two human gene variants for which the clinically relevant interaction was identified.
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The present disclosure provides, in some embodiments, a computing device comprising an improved user interface. In some embodiments, the improved user interface enables the visualization of clinically relevant information pertaining to interacting gene variants, including therapeutic recommendations. In some embodiments, the improved user interface facilitates the contemporaneous visualization of clinically relevant information pertaining to individual gene variants and the visualization of clinically relevant information pertaining to an interaction between gene variants, including therapeutic recommendations. In some embodiments, the visualization(s), through the improved user interface, facilitates the rapid interpretation of clinically relevant information by a medical professional such that decisions regarding patient care may be made accurately and efficiently.1-12. (canceled) 13. A method for treating a human patient comprising:
receiving a user input of a diagnosed disease or condition of a human patient, wherein the diagnosed disease or condition is a type of cancer; based on the received user input, displaying, on a computing device having a display screen, a first representation comprising (i) one or more therapeutic recommendations based on an identified clinically relevant interaction between at least two human gene variants of a plurality of human gene variants for the diagnosed disease or condition of the human patient, and (ii) an identification of the at least two human gene variants for which the clinically relevant interaction was identified, wherein the one or more therapeutic recommendations are one or more therapies sensitive for the diagnosed disease or condition; contemporaneously displaying, on the display screen, and based on the received user input, a second representation comprising clinically relevant information pertaining to at least one of the at least two human gene variants for which the interaction was identified; wherein the plurality of human gene variants are derived from sequence data derived from a genomic sample collected from the patient, and wherein the plurality of human gene variants are obtained from one or more memories communicatively coupled to the computing device, wherein the clinically relevant information is selected from the group consisting of summaries of biological and functional information pertaining to the gene variant, cross references to source material, hyperlinks to source material, and gene variant location; and administering to the human patient at least one of the therapies sensitive for the diagnosed disease or condition. 14. (canceled) 15. (canceled) 16. (canceled) 17. The method of claim 16, wherein the one or more therapies sensitive for the diagnosed disease or condition are marked in the first representation with a first indicia. 18. The method of claim 13, wherein the first and second representations are displayed within a single panel, wherein the second representation is visualized in a first portion of an individual gene panel representation and wherein the first representation is visualized in a second portion of the individual gene panel representation. 19. The method of claim 13, wherein the first and second representations are displayed within separate panels. 20. (canceled) 21. (canceled) 22. (canceled) 23. (canceled) 24. The method of claim 13, wherein the administered therapy sensitive for the type of cancer is selected from the group consisting of a targeted therapy, a combination therapy, and a clinical treatment protocol. 25. The method of claim 13, further comprising displaying of one or more therapies resistant to the diagnosed disease or condition within the first representation. 26. A method of treating a human patient comprising:
obtaining a plurality of human gene variants derived from a human genomic sample collected from the human patient; receiving a first user input of a diagnosed disease or condition of the human patient, wherein the diagnosed disease or condition is a type of cancer; identifying a subset of human gene variants from the plurality of human gene variants that are relevant to the diagnosed disease or condition of the human patient; retrieving clinical data associated with at least some of the subset of human gene variants from one or more databases, wherein the clinical data comprises treatment therapy data; automatically identifying a clinically relevant interaction between a first gene variant and a second gene variant from the identified subset of human gene variants relevant to the diagnosed disease or condition of the human patient, wherein the first gene variant is associated with a therapeutic recommendation comprising one or more treatment options sensitive to the diagnosed disease or condition of the human patient, and wherein the second gene variant is associated with a resistance to at least one of the treatment options; and displaying on the display screen a first representation comprising (i) an identification of the first gene variant and the second gene variant for which the clinically relevant interaction was identified, (ii) a listing of each of the one or more treatment options associated with the first gene variant, wherein the at least one treatment option that is associated with the resistance is distinguished graphically from the other treatment options; and administering to the human patient at least one of the treatment options sensitive to the diagnosed disease or condition of the human patient. 27. The method of claim 26, wherein the administered treatment option is a targeted therapy. 28. The method of claim 26, wherein the administered treatment option is a combination therapy. 29. The method of claim 26, wherein the administered treatment option is a clinical treatment protocol. 30. The method of claim 26, wherein the first representation is displayed on an interactive panel on the display screen, and wherein the computing device is further configured to: display a second representation when the interactive panel is selected, wherein the second representation comprises additional clinically relevant information pertaining to the first gene variant and/or the second gene variant for which the clinically relevant interaction was identified, wherein the additional clinically relevant information is selected from the group consisting of therapeutic options, clinical briefs and summaries, summaries of biological and functional information pertaining to the gene variant, classification information, statistics, cross references to source material, hyperlinks to source material, graphical variant alignment representations, and gene variant location. 31. A method of treating a human patient inflicted with cancer comprising:
obtaining a plurality of human gene variants derived from a human genomic sample collected from a human patient; receiving a first user input of a diagnosed type of cancer of the human patient; based on the received first user input of the type of cancer, provide a first representation comprising (i) one or more therapeutic recommendations based on an identified clinically relevant interaction between at least two human gene variants of the obtained plurality of human gene variants for the diagnosed disease or condition; and (ii) an identification of the at least two human gene variants for which the clinically relevant interaction was identified; and contemporaneously with providing the first representation, and based on the received user input, provide a second representation comprising clinically relevant information pertaining to a first of the at least two human gene variants for which the clinically relevant interaction was identified, wherein the clinically relevant information is selected from the group consisting of summaries of biological and functional information pertaining to the gene variant, cross references to source material, hyperlinks to source material, and gene variant location; and administering to the human patient at least one therapeutic recommendation of the one or more therapeutic recommendations provided within the first representation. 32. The method of claim 31, wherein the administered at least one therapeutic recommendation is a therapy sensitive for the type of cancer. 33. The method of claim 32, wherein the therapy sensitive for the type of cancer is a targeted therapy. 34. The method of claim 32, wherein the therapy sensitive for the type of cancer is a combination therapy. 35. The method of claim 32, wherein the therapy sensitive for the type of cancer is a clinical treatment protocol. 36. The method of claim 32, wherein the therapy sensitive for the type of cancer is an off-label use of a therapeutic agent. 37. The method of claim 31, wherein the therapy sensitive for the diagnosed disease or condition is marked with a first indicia; and wherein a therapy resistant for the diagnosed disease or condition is marked with a second indicia. 38. The method of claim 31, further comprising visualizing a third representation comprising clinically relevant information pertaining to a second of the at least two human gene variants for which the clinically relevant interaction was identified.
| 1,600 |
1,289 | 15,953,287 | 1,633 |
Methods of identifying a xenohormetic induced phenotype in an organism are provided. Also provided are methods if using organisms having a known xenohormetically induced phenotype in a number of different applications, such as the identification of xenohormetic agents and the generation of chemical entities and foodstuffs under specific conditions of production governed by xenohormetic effects.
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1-20. (canceled) 21. A method of identifying a xenohormetic agent, said method comprising:
a) identifying a first organism as a xenohormetic organism; b) screening the proteome of said first organism for one or more candidate xenohormetic agents; c) contacting said one or more candidate xenohormetic agents with a test organism to determine whether said agent is a xenohormetic agent. 22. The method according to claim 21, wherein said one or more candidate agents are small organic compounds. 23. The method according to claim 21, wherein said one or more candidate agents are peptides. 24. The method according to claim 23, wherein the peptides are proteins.
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Methods of identifying a xenohormetic induced phenotype in an organism are provided. Also provided are methods if using organisms having a known xenohormetically induced phenotype in a number of different applications, such as the identification of xenohormetic agents and the generation of chemical entities and foodstuffs under specific conditions of production governed by xenohormetic effects.1-20. (canceled) 21. A method of identifying a xenohormetic agent, said method comprising:
a) identifying a first organism as a xenohormetic organism; b) screening the proteome of said first organism for one or more candidate xenohormetic agents; c) contacting said one or more candidate xenohormetic agents with a test organism to determine whether said agent is a xenohormetic agent. 22. The method according to claim 21, wherein said one or more candidate agents are small organic compounds. 23. The method according to claim 21, wherein said one or more candidate agents are peptides. 24. The method according to claim 23, wherein the peptides are proteins.
| 1,600 |
1,290 | 14,020,694 | 1,662 |
An Engineered Transgene Integration Platform (ETIP) is described that can be inserted randomly or at targeted locations in plant genomes to facilitate rapid selection and detection of a GOI that is perfectly targeted (both the 3′ and 5′ ends) at the ETIP genomic location. One element in the invention is the introduction of specific double stranded breaks within the ETIP. In some embodiments, an ETIP is described using zinc finger nuclease binding sites, but may utilize other targeting technologies such as meganucleases, TALs, CRISPRs, or leucine zippers. Also described are compositions of, and methods for producing, transgenic plants wherein the donor or payload DNA expresses one or more products of an exogenous nucleic acid sequence (e.g. protein or RNA) that has been stably-integrated into an ETIP in a plant cell. In embodiments, the ETIP facilitates testing of gene candidates and plant expression vectors from ideation through Development phases.
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1. A method for generating a plant from a population of plant cells comprising isolating a plant protoplast comprising a polynucleotide of interest, the method comprising:
providing a population of plant protoplasts having at least one protoplast comprising a polynucleotide of interest and a fluorescent marker, wherein the population is substantially free of plant protoplasts comprising the fluorescent marker and not comprising the polynucleotide of interest; wherein the plant protoplast is encapsulated by sodium alginate; separating the at least one protoplast comprising the polynucleotide of interest and the fluorescent marker from the remaining plant protoplasts in the population, thereby isolating a plant protoplast comprising the polynucleotide of interest; regenerating a plant from said isolated plant protoplast; and culturing said plant. 2. The method according to claim 1, wherein separating the at least one protoplast comprises utilizing flow cytometry. 3. The method according to claim 1, wherein separating the at least one protoplast comprises utilizing fluorescence-activated cell sorting (FACS). 4. The method according to claim 1, wherein the fluorescent marker is a fluorescent polypeptide that is expressed from a polynucleotide in the plant protoplast. 5. The method according to claim 1, wherein the polynucleotide of interest encodes a polypeptide of interest. 6. The method according to claim 5, wherein the polypeptide of interest is a zinc-finger nuclease. 7. The method according to claim 1, wherein the population of plant protoplasts is obtained from a plant tissue. 8. The method according to claim 1, comprising separating a plurality of protoplasts comprising the polynucleotide of interest and the fluorescent marker. 9. The method according to claim 1, wherein the plant is a monocot or dicot. 10. A plant regenerated by isolating a plant protoplast comprising a polynucleotide of interest integrated into the genome of the plant protoplast, the method comprising:
providing a population of plant protoplasts having at least one protoplast comprising a polynucleotide of interest and a fluorescent marker; wherein the plant protoplast is encapsulated by sodium alginate; recovering microcalli from the population of protoplasts comprising the polynucleotide of interest and the fluorescent marker wherein the at least one protoplast comprises the polynucleotide of interest and the fluorescent marker has been transformed with the polynucleotide of interest and a polynucleotide encoding the fluorescent marker; regenerating a plant from said microcalli; and culturing said plant. 11. The method according to claim 9, wherein the polynucleotide of interest and the polynucleotide encoding the fluorescent marker were both present in a nucleic acid molecule used to transform the at least one protoplast comprising the polynucleotide of interest and the fluorescent marker. 12. The method according to claim 9, wherein the polynucleotide of interest and the polynucleotide encoding the fluorescent marker are integrated in the genome of the at least one protoplast comprising the polynucleotide of interest and the fluorescent marker. 13. The method according to claim 12, wherein the polynucleotide of interest and the polynucleotide encoding the fluorescent marker are integrated in a site-specific manner in the genome of the at least one protoplast. 14. The method according to claim 13, wherein the polynucleotide of interest and the polynucleotide encoding the fluorescent marker are integrated in a site-specific manner by utilizing a zinc-finger nuclease. 15. A method for producing a transgenic plant, the method comprising:
providing a population of plant protoplasts having at least one protoplast comprising a polynucleotide of interest and a fluorescent marker, wherein the at least one protoplast comprises a site-specific nuclease, such that the polynucleotide of interest is capable of being integrated in the genome of the at least one plant protoplast by homologous recombination at a recognition site of the site-specific nuclease and wherein the plant protoplast is encapsulated by sodium alginate; separating the at least one protoplast comprising the polynucleotide of interest and the fluorescent marker from the remaining plant protoplasts in the population; regenerating the transgenic plant from the at least one protoplast; and culturing said transgenic plant. 16. The plant produced by the method according to claim 15, wherein the plant produces a polypeptide of interest that is encoded by the polynucleotide of interest. 17. The plant produced by the method according to claim 15, wherein the plant comprises a value-added trait conferred to the plant by the polynucleotide of interest. 18. A method of producing seed comprising FACS sorting, culturing/optimizing and regeneration, culture plant, recover seed.
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An Engineered Transgene Integration Platform (ETIP) is described that can be inserted randomly or at targeted locations in plant genomes to facilitate rapid selection and detection of a GOI that is perfectly targeted (both the 3′ and 5′ ends) at the ETIP genomic location. One element in the invention is the introduction of specific double stranded breaks within the ETIP. In some embodiments, an ETIP is described using zinc finger nuclease binding sites, but may utilize other targeting technologies such as meganucleases, TALs, CRISPRs, or leucine zippers. Also described are compositions of, and methods for producing, transgenic plants wherein the donor or payload DNA expresses one or more products of an exogenous nucleic acid sequence (e.g. protein or RNA) that has been stably-integrated into an ETIP in a plant cell. In embodiments, the ETIP facilitates testing of gene candidates and plant expression vectors from ideation through Development phases.1. A method for generating a plant from a population of plant cells comprising isolating a plant protoplast comprising a polynucleotide of interest, the method comprising:
providing a population of plant protoplasts having at least one protoplast comprising a polynucleotide of interest and a fluorescent marker, wherein the population is substantially free of plant protoplasts comprising the fluorescent marker and not comprising the polynucleotide of interest; wherein the plant protoplast is encapsulated by sodium alginate; separating the at least one protoplast comprising the polynucleotide of interest and the fluorescent marker from the remaining plant protoplasts in the population, thereby isolating a plant protoplast comprising the polynucleotide of interest; regenerating a plant from said isolated plant protoplast; and culturing said plant. 2. The method according to claim 1, wherein separating the at least one protoplast comprises utilizing flow cytometry. 3. The method according to claim 1, wherein separating the at least one protoplast comprises utilizing fluorescence-activated cell sorting (FACS). 4. The method according to claim 1, wherein the fluorescent marker is a fluorescent polypeptide that is expressed from a polynucleotide in the plant protoplast. 5. The method according to claim 1, wherein the polynucleotide of interest encodes a polypeptide of interest. 6. The method according to claim 5, wherein the polypeptide of interest is a zinc-finger nuclease. 7. The method according to claim 1, wherein the population of plant protoplasts is obtained from a plant tissue. 8. The method according to claim 1, comprising separating a plurality of protoplasts comprising the polynucleotide of interest and the fluorescent marker. 9. The method according to claim 1, wherein the plant is a monocot or dicot. 10. A plant regenerated by isolating a plant protoplast comprising a polynucleotide of interest integrated into the genome of the plant protoplast, the method comprising:
providing a population of plant protoplasts having at least one protoplast comprising a polynucleotide of interest and a fluorescent marker; wherein the plant protoplast is encapsulated by sodium alginate; recovering microcalli from the population of protoplasts comprising the polynucleotide of interest and the fluorescent marker wherein the at least one protoplast comprises the polynucleotide of interest and the fluorescent marker has been transformed with the polynucleotide of interest and a polynucleotide encoding the fluorescent marker; regenerating a plant from said microcalli; and culturing said plant. 11. The method according to claim 9, wherein the polynucleotide of interest and the polynucleotide encoding the fluorescent marker were both present in a nucleic acid molecule used to transform the at least one protoplast comprising the polynucleotide of interest and the fluorescent marker. 12. The method according to claim 9, wherein the polynucleotide of interest and the polynucleotide encoding the fluorescent marker are integrated in the genome of the at least one protoplast comprising the polynucleotide of interest and the fluorescent marker. 13. The method according to claim 12, wherein the polynucleotide of interest and the polynucleotide encoding the fluorescent marker are integrated in a site-specific manner in the genome of the at least one protoplast. 14. The method according to claim 13, wherein the polynucleotide of interest and the polynucleotide encoding the fluorescent marker are integrated in a site-specific manner by utilizing a zinc-finger nuclease. 15. A method for producing a transgenic plant, the method comprising:
providing a population of plant protoplasts having at least one protoplast comprising a polynucleotide of interest and a fluorescent marker, wherein the at least one protoplast comprises a site-specific nuclease, such that the polynucleotide of interest is capable of being integrated in the genome of the at least one plant protoplast by homologous recombination at a recognition site of the site-specific nuclease and wherein the plant protoplast is encapsulated by sodium alginate; separating the at least one protoplast comprising the polynucleotide of interest and the fluorescent marker from the remaining plant protoplasts in the population; regenerating the transgenic plant from the at least one protoplast; and culturing said transgenic plant. 16. The plant produced by the method according to claim 15, wherein the plant produces a polypeptide of interest that is encoded by the polynucleotide of interest. 17. The plant produced by the method according to claim 15, wherein the plant comprises a value-added trait conferred to the plant by the polynucleotide of interest. 18. A method of producing seed comprising FACS sorting, culturing/optimizing and regeneration, culture plant, recover seed.
| 1,600 |
1,291 | 15,514,651 | 1,699 |
The use of neridronic acid or a salt thereof in the treatment of osteoarthritis is described. In particular, neridronic acid or a salt thereof has been shown to be able to reduce significantly the symptoms of osteoarthritis, such as pain and physical and mobility disabilities, as well as subchondral bone marrow lesions underlying the onset of such symptoms.
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1. A method of treating osteoarthritis comprising administering a therapeutically effective amount of neridronic acid or a salt thereof to patients in need thereofs. 2. The method of claim 1, wherein the treatment of osteoarthritis comprises alleviating the pain symptomathology of joint pain. 3. The method of claim 1, wherein the treatment of osteoarthritis comprises alleviating joint stiffness and improving mobility and physical functionality. 4. The method of claim 1, wherein the treatment of osteoarthritis comprises reducing the size and extent of bone marrow lesions. 5. The method of claim 1, wherein said salt of neridronic acid is sodium neridronate. 6. The method of claim 1, wherein said neridronic acid or a salt thereof is to be administered at a dosage of 10-500 mg. 7. The method of claim 1, wherein said neridronic acid or a salt thereof is to be administered orally, intramuscularly, intravenously, intraarticularly, transdermally, subcutaneously or topically. 8. The method of claim 7, wherein said neridronic acid or a salt thereof is to be administered intravenously. 9. The method of claim 8, wherein said neridronic acid or a salt thereof is to be administered intravenously at a dosage of 25-400 mg, at least 2 times, with at least 1 day between an administration and a subsequent one. 10-14. (canceled) 15. The method of claim 9, wherein said salt of neridronic acid is sodium neridronate to be administered intravenously at a dosage equivalent to 100 mg of neridronic acid, 4 times over a period of 10 days, with 3 days between an administration and a subsequent one. 16. The method of claim 15, wherein sodium neridronate is to be administered intravenously on days 1, 4, 7 and 10. 17. The method of claim 1 comprising administering a therapeutically effective amount of a pharmaceutical composition comprising neridronic acid or a salt thereof, and pharmaceutically acceptable vehicles for the oral, intramuscular, intravenous, intra-articular, transdermal, sub-cutaneous or topical administration. 18. The method of claim 17, wherein said pharmaceutical composition is administered intravenously, and comprises sodium neridronate, sodium chloride, citric acid and sodium citrate or sodium neridronate, sodium chloride and sodium bicarbonate . 19. (canceled) 20. The method of claim 16 wherein said pharmaceutical composition is present as a unit dose comprising 1-10 ml of aqueous solution in a vial or bottle, said unit dose preferably comprising 70-150 mg of neridronic acid or a salt thereof. 21. The method of claim 1 wherein said therapeutically effective amount of neridronic acid or salt thereof is administered by a vial or bottle for intravenous administration comprising neridronic acid or a salt thereof. 22. The method of claim 21 wherein said vial or bottle comprises a unit dose of 70-150 mg of neridronic acid or a salt thereof. 23. The method of claim 22 wherein said vial or bottle comprises 100 mg of neridronic acid or a salt thereof in an amount equivalent to 100 mg of neridronic acid. 24. The method of claim 21, wherein said salt of neridronic acid is sodium neridronate. 25. (canceled) 26. The method of claim 7, wherein said neridronic acid or a salt thereof is administered intramuscularly. 27. The method of claim 26, wherein said neridronic acid or a salt thereof is administered intramuscularly at a dosage of 10-100 mg. 28. The method of claim 27, wherein said salt of neridronic acid is sodium neridronate to be administered intramuscularly at a dosage equivalent to 25 mg of neridronic acid. 29. (canceled)
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The use of neridronic acid or a salt thereof in the treatment of osteoarthritis is described. In particular, neridronic acid or a salt thereof has been shown to be able to reduce significantly the symptoms of osteoarthritis, such as pain and physical and mobility disabilities, as well as subchondral bone marrow lesions underlying the onset of such symptoms.1. A method of treating osteoarthritis comprising administering a therapeutically effective amount of neridronic acid or a salt thereof to patients in need thereofs. 2. The method of claim 1, wherein the treatment of osteoarthritis comprises alleviating the pain symptomathology of joint pain. 3. The method of claim 1, wherein the treatment of osteoarthritis comprises alleviating joint stiffness and improving mobility and physical functionality. 4. The method of claim 1, wherein the treatment of osteoarthritis comprises reducing the size and extent of bone marrow lesions. 5. The method of claim 1, wherein said salt of neridronic acid is sodium neridronate. 6. The method of claim 1, wherein said neridronic acid or a salt thereof is to be administered at a dosage of 10-500 mg. 7. The method of claim 1, wherein said neridronic acid or a salt thereof is to be administered orally, intramuscularly, intravenously, intraarticularly, transdermally, subcutaneously or topically. 8. The method of claim 7, wherein said neridronic acid or a salt thereof is to be administered intravenously. 9. The method of claim 8, wherein said neridronic acid or a salt thereof is to be administered intravenously at a dosage of 25-400 mg, at least 2 times, with at least 1 day between an administration and a subsequent one. 10-14. (canceled) 15. The method of claim 9, wherein said salt of neridronic acid is sodium neridronate to be administered intravenously at a dosage equivalent to 100 mg of neridronic acid, 4 times over a period of 10 days, with 3 days between an administration and a subsequent one. 16. The method of claim 15, wherein sodium neridronate is to be administered intravenously on days 1, 4, 7 and 10. 17. The method of claim 1 comprising administering a therapeutically effective amount of a pharmaceutical composition comprising neridronic acid or a salt thereof, and pharmaceutically acceptable vehicles for the oral, intramuscular, intravenous, intra-articular, transdermal, sub-cutaneous or topical administration. 18. The method of claim 17, wherein said pharmaceutical composition is administered intravenously, and comprises sodium neridronate, sodium chloride, citric acid and sodium citrate or sodium neridronate, sodium chloride and sodium bicarbonate . 19. (canceled) 20. The method of claim 16 wherein said pharmaceutical composition is present as a unit dose comprising 1-10 ml of aqueous solution in a vial or bottle, said unit dose preferably comprising 70-150 mg of neridronic acid or a salt thereof. 21. The method of claim 1 wherein said therapeutically effective amount of neridronic acid or salt thereof is administered by a vial or bottle for intravenous administration comprising neridronic acid or a salt thereof. 22. The method of claim 21 wherein said vial or bottle comprises a unit dose of 70-150 mg of neridronic acid or a salt thereof. 23. The method of claim 22 wherein said vial or bottle comprises 100 mg of neridronic acid or a salt thereof in an amount equivalent to 100 mg of neridronic acid. 24. The method of claim 21, wherein said salt of neridronic acid is sodium neridronate. 25. (canceled) 26. The method of claim 7, wherein said neridronic acid or a salt thereof is administered intramuscularly. 27. The method of claim 26, wherein said neridronic acid or a salt thereof is administered intramuscularly at a dosage of 10-100 mg. 28. The method of claim 27, wherein said salt of neridronic acid is sodium neridronate to be administered intramuscularly at a dosage equivalent to 25 mg of neridronic acid. 29. (canceled)
| 1,600 |
1,292 | 15,652,679 | 1,616 |
Compounds contained herein relate to polyalkoxylated polyol polyesters having a viscosity that allows a product to be poured, yet retained on a desired surface to which it is applied. Embodiments of the compounds may be exemplified by the formula:
Q-[(OA) n —OR] m
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1. A polyalkoxylated polyols polyester comprising the formula:
Q-[(OA)n—OR]m Formula-2
Q is a radical of natural or synthetic organic polyol compounds having from 6 to 50 carbon atoms forming a straight, a branched, a cyclic, a saturated, or an unsaturated structure, with each carbon atom being independently substituted with 6 to 25 groups having the formula —[(OA)n—OR],
wherein each of the 6 to 50 carbon atoms may independently be substituted with hydrogen, oxygen, or nitrogen;
A is selected from —C2H4— or —C3H6—; R is independently selected from hydrogen or —COR1,
R1 is independently selected from C6-C22-alkyl, C6-C22-hydroxyalkyl, or C6-C22-alkenyl,
n is an integer selected from 1-125 and may be the same or different for each polyalkoxylated hydrophilic arm; wherein the average total number of COR1 is ≧2.5, preferably ≧3, and most preferably ≧4; m is an integer selected from 6-25, and preferably from 6-12. 2. The formula of claim 1 wherein n per hydrophilic poly-(alkylene glycol) arm is equal to 25 to 120, more preferably 30 to 85, and most preferably 30 to 70. 3. The formula of claim 1 wherein R1 is derived from stearic, isostearic, oleic moieties, or mixtures thereof. 4. The formula of claim 1 wherein Q is the radical of the following polyols compounds:
a. Sugar alcohols, having the general formula of HOCH2(CHOH)xCH2OH;
b. Disaccharide, having a glycosidic linkage;
c. (C6H10O5)n, where no is from 2 to 20;
d. Di-Pentaerythritol;
e. Dendrimer polyols; and
f. Polyglyceryls having 3 to 10 glycerin units, with 6 or more hydroxyl groups. 5. The formula of claim 1 wherein Q is selected from the polyols of the following compounds:
a. Sugar alcohols, having the general formula of HOCH2(CHOH)xCH2OH;
b. Disaccharide, having a glycosidic linkage;
c. (C6H10O5)n, where n0 is from 2 to 20;
d. Di-Pentaerythritol; and
e. Dendrimer polyols. 6. The formula of claim 1, wherein Q is selected from the polyols of sorbitol, trehalose, mannitol, Di-pentaerythritol, sucrose, lactose, chitobiose, cellobiose, and maltose. 7. A cosmetic, dermatological, or pharmaceutical composition comprising the polyalkoxylated polyols polyester of claim 1 or mixtures thereof. 8. A cosmetic, dermatological, or pharmaceutical composition comprising the polyalkoxylated polyols polyester of claim 2 or mixtures thereof. 9. A cosmetic, dermatological, or pharmaceutical composition comprising the polyalkoxylated polyols polyester of claim 3 or mixtures thereof. 10. A cosmetic, dermatological, or pharmaceutical composition comprising the polyalkoxylated polyols polyester of claim 4 or mixtures thereof. 11. A cosmetic, dermatological, or pharmaceutical composition of claim 1, wherein Q is a radical of sorbitol of Formula-3:
A is independently —C2H4— or —C3H6—;
R is hydrogen or a group of formula —COR1,
wherein R1 is derived from stearic, isostearic, or oleic moiety, or mixtures thereof;
wherein the average total number of —COR1 groups is from 3-6; and
n1 to n6 are independently integers from 1-125. 12. A cosmetic, dermatological, and pharmaceutical composition of claim 7 further comprising:
water;
1% - 50% by weight of surfactants selected from the groups consisting of anionic surfactant, cationic surfactant, non-ionic surfactant, amphoteric surfactant, and mixtures thereof;
0.1% to 10% by weight of the polyols polyester of Formula-2; and
0.1 to 50% by weight of other ingredients selected from the groups consisting of:
skin and hair benefit actives, stabilizer, further thickeners, colorants, preservatives, and pearlizing agents. 13. A cosmetic, dermatological, and pharmaceutical composition of claim 8 further comprising:
water;
2%-50% by weight of surfactants selected from the groups consisting of: sulfate-free anionic surfactants, non-ionic surfactant, amphoteric surfactant, and mixtures thereof;
0.1% to 10% by weight of the polyalkoxylated polyols polyester of Formula-2; and
0.1% to 50% by weight of other ingredients selected from the group consisting of:
skin and hair benefit actives, stabilizer, further thickeners, colorants, and preservatives. 14. The cosmetic, dermatological, and pharmaceutical composition of claim 9 further comprising:
water; and
1%-50% by weight of surfactants selected from the groups consisting of: anionic surfactant, cationic surfactant, non-ionic surfactant, amphoteric surfactant, and mixtures thereof;
0.1% to 10% by weight of the polyols polyester of Formula-2; and
0.1 to 50% by weight of other ingredients selected from the groups consisting of:
skin and hair benefit actives, stabilizer, further thickeners, colorants, preservatives, and pearlizing agents. 15. The cosmetic, dermatological, and pharmaceutical composition of claim 10 further comprising:
water; and
1%-50% by weight of surfactants selected from the groups consisting of: anionic surfactant, cationic surfactant, non-ionic surfactant, amphoteric surfactant, and mixtures thereof;
0.1% to 10% by weight of the polyols polyester of Formula-2; and
0.1 to 50% by weight of other ingredients selected from the groups consisting of:
skin and hair benefit actives, stabilizer, further thickeners, colorants, preservatives, and pearlizing agents. 16. The cosmetic, dermatological, and pharmaceutical composition of claim 11 further comprising:
water; and
1%-50% by weight of surfactants selected from the groups consisting of: anionic surfactant, cationic surfactant, non-ionic surfactant, amphoteric surfactant, and mixtures thereof;
0.1% to 10% by weight of the polyalkoxylated polyols polyester of Formula-3; and
0.1 to 50% by weight of other ingredients selected from the groups consisting of:
skin and hair benefit actives, stabilizer, further thickeners, colorants, preservatives, and pearlizing agents. 17. The cosmetic, dermatological, and pharmaceutical composition of claim 7 further comprising:
water; and
about 1% to 30% by weight of a skin and hair active ingredient selected from the group consisting of: UV filters, moisturizers, conditioners, antiseptic agents, deodorant actives, reducing agents for permanent wave products, colorants for coloring hair, anti-aging actives, proteins/protein derivatives, perfume, petrolatum, vegetable oils, cationic conditioning polymers, and mixtures thereof; and
about 1% to 10% by weight of the polyalkoxylated polyols polyester of Formula-1. 18. A method of thickening the composition of claim 10 by adding the polyalkoxylated polyols polyester of Formula-2 to the mixture of surfactants.
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Compounds contained herein relate to polyalkoxylated polyol polyesters having a viscosity that allows a product to be poured, yet retained on a desired surface to which it is applied. Embodiments of the compounds may be exemplified by the formula:
Q-[(OA) n —OR] m1. A polyalkoxylated polyols polyester comprising the formula:
Q-[(OA)n—OR]m Formula-2
Q is a radical of natural or synthetic organic polyol compounds having from 6 to 50 carbon atoms forming a straight, a branched, a cyclic, a saturated, or an unsaturated structure, with each carbon atom being independently substituted with 6 to 25 groups having the formula —[(OA)n—OR],
wherein each of the 6 to 50 carbon atoms may independently be substituted with hydrogen, oxygen, or nitrogen;
A is selected from —C2H4— or —C3H6—; R is independently selected from hydrogen or —COR1,
R1 is independently selected from C6-C22-alkyl, C6-C22-hydroxyalkyl, or C6-C22-alkenyl,
n is an integer selected from 1-125 and may be the same or different for each polyalkoxylated hydrophilic arm; wherein the average total number of COR1 is ≧2.5, preferably ≧3, and most preferably ≧4; m is an integer selected from 6-25, and preferably from 6-12. 2. The formula of claim 1 wherein n per hydrophilic poly-(alkylene glycol) arm is equal to 25 to 120, more preferably 30 to 85, and most preferably 30 to 70. 3. The formula of claim 1 wherein R1 is derived from stearic, isostearic, oleic moieties, or mixtures thereof. 4. The formula of claim 1 wherein Q is the radical of the following polyols compounds:
a. Sugar alcohols, having the general formula of HOCH2(CHOH)xCH2OH;
b. Disaccharide, having a glycosidic linkage;
c. (C6H10O5)n, where no is from 2 to 20;
d. Di-Pentaerythritol;
e. Dendrimer polyols; and
f. Polyglyceryls having 3 to 10 glycerin units, with 6 or more hydroxyl groups. 5. The formula of claim 1 wherein Q is selected from the polyols of the following compounds:
a. Sugar alcohols, having the general formula of HOCH2(CHOH)xCH2OH;
b. Disaccharide, having a glycosidic linkage;
c. (C6H10O5)n, where n0 is from 2 to 20;
d. Di-Pentaerythritol; and
e. Dendrimer polyols. 6. The formula of claim 1, wherein Q is selected from the polyols of sorbitol, trehalose, mannitol, Di-pentaerythritol, sucrose, lactose, chitobiose, cellobiose, and maltose. 7. A cosmetic, dermatological, or pharmaceutical composition comprising the polyalkoxylated polyols polyester of claim 1 or mixtures thereof. 8. A cosmetic, dermatological, or pharmaceutical composition comprising the polyalkoxylated polyols polyester of claim 2 or mixtures thereof. 9. A cosmetic, dermatological, or pharmaceutical composition comprising the polyalkoxylated polyols polyester of claim 3 or mixtures thereof. 10. A cosmetic, dermatological, or pharmaceutical composition comprising the polyalkoxylated polyols polyester of claim 4 or mixtures thereof. 11. A cosmetic, dermatological, or pharmaceutical composition of claim 1, wherein Q is a radical of sorbitol of Formula-3:
A is independently —C2H4— or —C3H6—;
R is hydrogen or a group of formula —COR1,
wherein R1 is derived from stearic, isostearic, or oleic moiety, or mixtures thereof;
wherein the average total number of —COR1 groups is from 3-6; and
n1 to n6 are independently integers from 1-125. 12. A cosmetic, dermatological, and pharmaceutical composition of claim 7 further comprising:
water;
1% - 50% by weight of surfactants selected from the groups consisting of anionic surfactant, cationic surfactant, non-ionic surfactant, amphoteric surfactant, and mixtures thereof;
0.1% to 10% by weight of the polyols polyester of Formula-2; and
0.1 to 50% by weight of other ingredients selected from the groups consisting of:
skin and hair benefit actives, stabilizer, further thickeners, colorants, preservatives, and pearlizing agents. 13. A cosmetic, dermatological, and pharmaceutical composition of claim 8 further comprising:
water;
2%-50% by weight of surfactants selected from the groups consisting of: sulfate-free anionic surfactants, non-ionic surfactant, amphoteric surfactant, and mixtures thereof;
0.1% to 10% by weight of the polyalkoxylated polyols polyester of Formula-2; and
0.1% to 50% by weight of other ingredients selected from the group consisting of:
skin and hair benefit actives, stabilizer, further thickeners, colorants, and preservatives. 14. The cosmetic, dermatological, and pharmaceutical composition of claim 9 further comprising:
water; and
1%-50% by weight of surfactants selected from the groups consisting of: anionic surfactant, cationic surfactant, non-ionic surfactant, amphoteric surfactant, and mixtures thereof;
0.1% to 10% by weight of the polyols polyester of Formula-2; and
0.1 to 50% by weight of other ingredients selected from the groups consisting of:
skin and hair benefit actives, stabilizer, further thickeners, colorants, preservatives, and pearlizing agents. 15. The cosmetic, dermatological, and pharmaceutical composition of claim 10 further comprising:
water; and
1%-50% by weight of surfactants selected from the groups consisting of: anionic surfactant, cationic surfactant, non-ionic surfactant, amphoteric surfactant, and mixtures thereof;
0.1% to 10% by weight of the polyols polyester of Formula-2; and
0.1 to 50% by weight of other ingredients selected from the groups consisting of:
skin and hair benefit actives, stabilizer, further thickeners, colorants, preservatives, and pearlizing agents. 16. The cosmetic, dermatological, and pharmaceutical composition of claim 11 further comprising:
water; and
1%-50% by weight of surfactants selected from the groups consisting of: anionic surfactant, cationic surfactant, non-ionic surfactant, amphoteric surfactant, and mixtures thereof;
0.1% to 10% by weight of the polyalkoxylated polyols polyester of Formula-3; and
0.1 to 50% by weight of other ingredients selected from the groups consisting of:
skin and hair benefit actives, stabilizer, further thickeners, colorants, preservatives, and pearlizing agents. 17. The cosmetic, dermatological, and pharmaceutical composition of claim 7 further comprising:
water; and
about 1% to 30% by weight of a skin and hair active ingredient selected from the group consisting of: UV filters, moisturizers, conditioners, antiseptic agents, deodorant actives, reducing agents for permanent wave products, colorants for coloring hair, anti-aging actives, proteins/protein derivatives, perfume, petrolatum, vegetable oils, cationic conditioning polymers, and mixtures thereof; and
about 1% to 10% by weight of the polyalkoxylated polyols polyester of Formula-1. 18. A method of thickening the composition of claim 10 by adding the polyalkoxylated polyols polyester of Formula-2 to the mixture of surfactants.
| 1,600 |
1,293 | 15,652,602 | 1,616 |
Compounds contained herein relate to polyalkoxylated polyol polyester having a viscosity that allows a product to be poured, yet retained on a desired surface to which it is applied. Embodiments of the compounds may be exemplified by the formula:
Q-[(OA) n -OR] m
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1. A liquid thickener composition comprising:
1) 20%-80% of the polyalkoxylated polyols polyester of the formula;
Q-[(OA)n-OR]m Formula-2
Q is a radical of organic polyol compounds, having 6 to 50 carbon atoms, and is saturated or unsaturated, straight, branched or cyclic chain structure, and independently substituted with from 6 to 25 groups having the formula of [(OA)n—OR],
wherein each of the 6 to 50 carbon atoms may independently be substituted with hydrogen, oxygen, or nitrogen;
A is selected from —C2H4— or —C3H6—; R is independently selected from hydrogen or —COR1,
wherein the averaged total number of COR1 is ≧2;
R1 is independently selected from C6-C22-alkyl, C6-C22-hydroxyalkyl, C6-C22-alkenyl,
wherein R1 is preferably derived from stearic, isostearic, oleic oils, or mixtures thereof;
n is an integer independently selected from 1-125; m is an integer selected from 6-25; 2) an organic carrier, selected from the group consisting of: organic solvents, hydrophobic thickeners, or mixtures thereof,
a) the organic solvents are selected from the group consisting of: mono- or polyhydric alcohols and their ether, ester, or amide derivatives, glycerol, propylene glycol, 1.3-propanediol, butylene glycol, dipropylene glycol, pentylene glycol, methoxy diglycol, glycerol, polyglyceryl-3, polyglyceryl-2, glycereth-7, glycereth-26, diglyerol, sorbitol, glucose, methyl glucose, methyl glucomide, glyceryl laurate, glyceryl oleate, glyceryl isostearte, propylene glycol monolaurate, PEG-6 caprylic/capric glyceride, sorbitan carpylate/caprate, sorbitan sesquicaprylate, sorbitane laurate, methyl glucose caprate/caprylate/oleate, PEG-7 glyceryl cocoate, fatty methyl ester ethoxylates, alkylpolyglucosides, decyl glucoside, cocoa glucoside, polysorbate 20, polysorbate 60, and polysorbate 80, alkyoyl methyl glucomide, lauroyl methyl glucamide, capryloyl/caproyl methyl glucomide; and
b) the hydrophobic thickeners are selected from the group consisting of: non-ionic alkanolamides, liquid alkanolamides, ethoxylated C10-C14 alcohols, Laureth-1 to Laureth-5, dimethyl lauramide/myristamide, PPG-2 Hydroxyethyl Cocamide, Cocamide DIPA, lauramide DIPA, soyamide DIPA; and
3) water, wherein the ratio of water to organic solvent carrier by weight is from 4:1 to 1:4. 2. The liquid composition of claim 1 wherein the liquid composition further comprises:
1) 20-80% of the polyalkoxylated polyol polyester of the Formula-2,
wherein the Q is a radical of the following polyols compounds:
a) sugar alcohols, polyhydric alcohol, or polyalcohol with at least six hydroxyl groups, having the general formula of HOCH2(CHOH)nCH2OH, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotritol, and maltotetraitol;
b) disaccharide having a glycosidic linkage;
c) di-pentaerythritol;
d) dextrin with a chemical structure of (C6H10O5)n, where n is from 2 to 20;
e) dendrimer polyols; and
f) polyglyceryls with 3 to 10 glycerin units and 6 or more hydroxyl groups;
2) an organic carrier, selected from the group consisting of: organic solvents, hydrophobic thickener, or mixtures thereof,
a) the organic solvents are selected from the group consisting of: mono- or polyhydric alcohols and their ether, ester, or amide derivatives, glycerol, propylene glycol, 1.3-propanediol, butylene glycol, dipropylene glycol, pentylene glycol, methoxy diglycol, glycerol, polyglyceryl-3, polyglyceryl-2, glycereth-7, glycereth-26, diglyerol, sorbitol, glucose, methyl glucose, methyl glucomide, glyceryl laurate, glyceryl oleate, glyceryl isostearte, propylene glycol monolaurate, PEG-6 caprylic/capric glyceride, sorbitan carpylate/caprate, sorbitan sesquicaprylate, sorbitane laurate, methyl glucose caprate/caprylate/oleate, PEG-7 glyceryl cocoate, fatty methyl ester ethoxylates, alkylpolyglucosides, decyl glucoside, cocoa glucoside, polysorbate 20, polysorbate 60, and polysorbate 80, alkyoyl methyl glucomide, lauroyl methyl glucamide, capryloyl/caproyl methyl glucamide; and
b) the hydrophobic thickeners are selected from the group consisting of: non-ionic alkanolamides, liquid alkanolamides, ethoxylated C10-C14 alcohols, Laureth-1 to Laureth-5, dimethyl lauramide/myristamide, PPG-2 Hydroxyethyl Cocamide, Cocamide DIPA, lauramide DIPA, soyamide DIPA; and
3) water, wherein the ratio of water to organic solvent carrier by weight is from 4:1 to 1:4. 3. A liquid composition of claim 1 wherein the liquid thickener composition further comprises:
1) 20-80% of the polyalkoxylated polyols polyester of the Formula-2,
wherein the Q is the radical of the following polyols compounds:
a) sugar alcohols, polyhydric alcohol, or polyalcohol with at least six hydroxyl groups, having the general formula of HOCH2(CHOH)nCH2OH, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotritol, maltotetraitol, and polyglycitol;
b) disaccharide, which is formed from two monosaccharides by dehydration via glycosidic linkage;
c) di-pentaerythritol;
d) dextrin with a chemical structure of (C6H10O5)n, where n is from 2 to 20;
e) dendrimer polyols;
2) the organic carrier is selected from the group consisting of: organic solvents, hydrophobic thickeners, or mixtures thereof,
a) the organic solvents are selected from the group consisting of: mono- or polyhydric alcohols and their ether, ester, or amide derivatives, glycerol, propylene glycol, 1.3-propanediol, butylene glycol, dipropylene glycol, pentylene glycol, methoxy diglycol, glycerol, polyglyceryl-3, polyglyceryl-2, glycereth-7, glycereth-26, diglyerol, sorbitol, glucose, methyl glucose, methyl glucomide; glyceryl laurate, glyceryl oleate, glyceryl isostearte, propylene glycol monolaurate, PEG-6 caprylic/capric glyceride, sorbitan carpylate/caprate, sorbitan sesquicaprylate, sorbitane laurate, methyl glucose caprate/caprylate/oleate, PEG-7 glyceryl cocoate, fatty methyl ester ethoxylates, alkylpolyglucosides such as decyl glucoside, cocoa glucoside, polysorbate 20, polysorbate 60, and polysorbate 80, alkyoyl methyl glucomide, lauroyl methyl glucamide, capryloyl/caproyl methyl glucamide; and
b) the hydrophobic thickeners are selected from the group consisting of: non-ionic alkanolamides, liquid alkanolamides, ethoxylated C10-C14 alcohols, Laureth-1 to Laureth-5, and dimethyl lauramide/myristamide, PPG-2 Hydroxyethyl Cocamide, Cocamide DIPA, lauramide DIPA, soyamide DIPA; and
3) water, wherein the ratio of water to organic solvent carrier by weight is from 4:1 to 1:4. 4. A liquid composition of claim 1 wherein the liquid composition further comprises:
1) 20%-80% of Formula-2, wherein Q is the radical of sorbitol, trehalose, mannitol, di-pentaerythritol, sucrose, lactose, chitobiose, cellobiose, and maltose;
2) the organic carrier is selected from the group consisting of: organic solvents, hydrophobic thickeners, or mixtures thereof, wherein
a) the organic solvents are selected from the groups consisting of: mono- or polyhydric alcohols and their ether, ester, or amide derivatives, glycerol, propylene glycol, 1.3-propanediol, butylene glycol, dipropylene glycol, pentylene glycol, methoxy diglycol, glycerol, polyglyceryl-3, polyglyceryl-2, glycereth-7, glycereth-26, diglyerol, sorbitol, glucose, methyl glucose, methyl glucomide, glyceryl laurate, glyceryl oleate, glyceryl isostearte, propylene glycol monolaurate, PEG-6 caprylic/capric glyceride, sorbitan carpylate/caprate, sorbitan sesquicaprylate, sorbitane laurate, methyl glucose caprate/caprylate/oleate, PEG-7 glyceryl cocoate, fatty methyl ester ethoxylates, alkylpolyglucosides, decyl glucoside, cocoa glucoside, polysorbate 20, polysorbate 60, and polysorbate 80, alkyoyl methyl glucomide, lauroyl methyl glucamide, and capryloyl/caproyl methyl glucamide; and
b) the hydrophobic thickeners are selected from the groups consisting of: non-ionic alkanolamides, liquid alkanolamides, ethoxylated C10-C14 alcohols, Laureth-1 to Laureth-5, dimethyl lauramide/myristamide; PPG-2 Hydroxyethyl Cocamide, Cocamide DIPA, lauramide DIPA, soyamide DIPA; and
3) water, wherein the ratio of water to organic solvent carrier by weight is from 4:1 to 1:4. 5. A liquid composition of claim 1 wherein the liquid composition further comprises:
1) 20%-80% of Formula-2,
wherein Q is a radical of sorbitol, trehalose, mannitol, di-pentaerythritol, sucrose, lactose, chitobiose, cellobiose, and maltose;
2) the organic carrier or mixtures thereof, selected from the group consisting of alkyl polyglucosides, alkyol methyl glucomide, sorbitan laurate, sorbitan caprylate/caprate, liquid non-ionic alkanolamide surfactants, laureth-1, laureth-2, laureth-3, glyceryl caprylate/caprate, and glyceryl laurate; and
3) water, wherein the ratio of water to organic solvent carrier by weight is from 4:1 to 1:4. 6. A liquid composition of claim 1 wherein the liquid composition further comprises:
1) 20%-80% of Formula-2,
wherein Q is the radical of sorbitol, trehalose, mannitol, di-pentaerythritol, sucrose, lactose, chitobiose, cellobiose, and maltose;
2) the organic carrier or mixtures thereof, selected from the groups consisting of the alkanolamides; and
3) water, wherein the ratio of water to organic solvent carrier by weight is from 4:1 to 1:4. 7. A cosmetic, dermatological, or pharmaceutical composition, in the form of hair cleansing/treatment formulation, skin and body cleansing/treatment formulations, and other toiletry formulations, comprising the liquid thickener composition of claim 1. 8. A cosmetic, dermatological, or pharmaceutical composition comprising the liquid thickener composition of claim 4, in the form of hair cleansing/treatment formulation, skin and body cleansing/treatment formulations, and other toiletry formulations. 9. A cosmetic, dermatological, and pharmaceutical composition of claim 7 further comprising water, and
1) 1% -50% by weight of surfactants selected from the group consisting of: anionic surfactant, cationic surfactant, non-ionic surfactant, amphoteric surfactant, and mixtures thereof;
2) 0.1% to 15% of the liquid thickener composition of Formula-2; and
3) 0.1% to 60% of other ingredients selected from the group consisting of: skin and hair actives, stabilizer, further thickeners, and other customary personal cleansing ingredients. 10. A cosmetic, dermatological, and pharmaceutical composition of claim 8 further comprising water, and
1) 1% - 50% by weight of surfactants selected from the group consisting of: anionic surfactant, cationic surfactant, non-ionic surfactant, amphoteric surfactant, and mixtures thereof;
2) 0.1% to 15% of the liquid thickener composition of Formula-1; and
3) 0.1% to 60% of other ingredients selected from the group consisting of: skin and hair actives, stabilizer, further thickeners, and other customary personal cleansing ingredients. 11. A method of thickening the composition of claim 7 by adding the liquid thickener composition comprising of Formula-2 to the mixture of surfactants. 12. A cosmetic, dermatological, or pharmaceutical composition of about 1% to 8% of the liquid composition of claim 1 further comprising:
about 1% to 25% by weight of a skin and hair active ingredient selected from the group consisting of: UV filters, moisturizers, conditioners, antiseptic agents, deodorant actives, reducing agents for permanent wave products, colorants for coloring hair, anti-aging actives, perfume, petrolatum, vegetable oils, cationic conditioning polymers, and mixtures thereof; and water.
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Compounds contained herein relate to polyalkoxylated polyol polyester having a viscosity that allows a product to be poured, yet retained on a desired surface to which it is applied. Embodiments of the compounds may be exemplified by the formula:
Q-[(OA) n -OR] m1. A liquid thickener composition comprising:
1) 20%-80% of the polyalkoxylated polyols polyester of the formula;
Q-[(OA)n-OR]m Formula-2
Q is a radical of organic polyol compounds, having 6 to 50 carbon atoms, and is saturated or unsaturated, straight, branched or cyclic chain structure, and independently substituted with from 6 to 25 groups having the formula of [(OA)n—OR],
wherein each of the 6 to 50 carbon atoms may independently be substituted with hydrogen, oxygen, or nitrogen;
A is selected from —C2H4— or —C3H6—; R is independently selected from hydrogen or —COR1,
wherein the averaged total number of COR1 is ≧2;
R1 is independently selected from C6-C22-alkyl, C6-C22-hydroxyalkyl, C6-C22-alkenyl,
wherein R1 is preferably derived from stearic, isostearic, oleic oils, or mixtures thereof;
n is an integer independently selected from 1-125; m is an integer selected from 6-25; 2) an organic carrier, selected from the group consisting of: organic solvents, hydrophobic thickeners, or mixtures thereof,
a) the organic solvents are selected from the group consisting of: mono- or polyhydric alcohols and their ether, ester, or amide derivatives, glycerol, propylene glycol, 1.3-propanediol, butylene glycol, dipropylene glycol, pentylene glycol, methoxy diglycol, glycerol, polyglyceryl-3, polyglyceryl-2, glycereth-7, glycereth-26, diglyerol, sorbitol, glucose, methyl glucose, methyl glucomide, glyceryl laurate, glyceryl oleate, glyceryl isostearte, propylene glycol monolaurate, PEG-6 caprylic/capric glyceride, sorbitan carpylate/caprate, sorbitan sesquicaprylate, sorbitane laurate, methyl glucose caprate/caprylate/oleate, PEG-7 glyceryl cocoate, fatty methyl ester ethoxylates, alkylpolyglucosides, decyl glucoside, cocoa glucoside, polysorbate 20, polysorbate 60, and polysorbate 80, alkyoyl methyl glucomide, lauroyl methyl glucamide, capryloyl/caproyl methyl glucomide; and
b) the hydrophobic thickeners are selected from the group consisting of: non-ionic alkanolamides, liquid alkanolamides, ethoxylated C10-C14 alcohols, Laureth-1 to Laureth-5, dimethyl lauramide/myristamide, PPG-2 Hydroxyethyl Cocamide, Cocamide DIPA, lauramide DIPA, soyamide DIPA; and
3) water, wherein the ratio of water to organic solvent carrier by weight is from 4:1 to 1:4. 2. The liquid composition of claim 1 wherein the liquid composition further comprises:
1) 20-80% of the polyalkoxylated polyol polyester of the Formula-2,
wherein the Q is a radical of the following polyols compounds:
a) sugar alcohols, polyhydric alcohol, or polyalcohol with at least six hydroxyl groups, having the general formula of HOCH2(CHOH)nCH2OH, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotritol, and maltotetraitol;
b) disaccharide having a glycosidic linkage;
c) di-pentaerythritol;
d) dextrin with a chemical structure of (C6H10O5)n, where n is from 2 to 20;
e) dendrimer polyols; and
f) polyglyceryls with 3 to 10 glycerin units and 6 or more hydroxyl groups;
2) an organic carrier, selected from the group consisting of: organic solvents, hydrophobic thickener, or mixtures thereof,
a) the organic solvents are selected from the group consisting of: mono- or polyhydric alcohols and their ether, ester, or amide derivatives, glycerol, propylene glycol, 1.3-propanediol, butylene glycol, dipropylene glycol, pentylene glycol, methoxy diglycol, glycerol, polyglyceryl-3, polyglyceryl-2, glycereth-7, glycereth-26, diglyerol, sorbitol, glucose, methyl glucose, methyl glucomide, glyceryl laurate, glyceryl oleate, glyceryl isostearte, propylene glycol monolaurate, PEG-6 caprylic/capric glyceride, sorbitan carpylate/caprate, sorbitan sesquicaprylate, sorbitane laurate, methyl glucose caprate/caprylate/oleate, PEG-7 glyceryl cocoate, fatty methyl ester ethoxylates, alkylpolyglucosides, decyl glucoside, cocoa glucoside, polysorbate 20, polysorbate 60, and polysorbate 80, alkyoyl methyl glucomide, lauroyl methyl glucamide, capryloyl/caproyl methyl glucamide; and
b) the hydrophobic thickeners are selected from the group consisting of: non-ionic alkanolamides, liquid alkanolamides, ethoxylated C10-C14 alcohols, Laureth-1 to Laureth-5, dimethyl lauramide/myristamide, PPG-2 Hydroxyethyl Cocamide, Cocamide DIPA, lauramide DIPA, soyamide DIPA; and
3) water, wherein the ratio of water to organic solvent carrier by weight is from 4:1 to 1:4. 3. A liquid composition of claim 1 wherein the liquid thickener composition further comprises:
1) 20-80% of the polyalkoxylated polyols polyester of the Formula-2,
wherein the Q is the radical of the following polyols compounds:
a) sugar alcohols, polyhydric alcohol, or polyalcohol with at least six hydroxyl groups, having the general formula of HOCH2(CHOH)nCH2OH, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotritol, maltotetraitol, and polyglycitol;
b) disaccharide, which is formed from two monosaccharides by dehydration via glycosidic linkage;
c) di-pentaerythritol;
d) dextrin with a chemical structure of (C6H10O5)n, where n is from 2 to 20;
e) dendrimer polyols;
2) the organic carrier is selected from the group consisting of: organic solvents, hydrophobic thickeners, or mixtures thereof,
a) the organic solvents are selected from the group consisting of: mono- or polyhydric alcohols and their ether, ester, or amide derivatives, glycerol, propylene glycol, 1.3-propanediol, butylene glycol, dipropylene glycol, pentylene glycol, methoxy diglycol, glycerol, polyglyceryl-3, polyglyceryl-2, glycereth-7, glycereth-26, diglyerol, sorbitol, glucose, methyl glucose, methyl glucomide; glyceryl laurate, glyceryl oleate, glyceryl isostearte, propylene glycol monolaurate, PEG-6 caprylic/capric glyceride, sorbitan carpylate/caprate, sorbitan sesquicaprylate, sorbitane laurate, methyl glucose caprate/caprylate/oleate, PEG-7 glyceryl cocoate, fatty methyl ester ethoxylates, alkylpolyglucosides such as decyl glucoside, cocoa glucoside, polysorbate 20, polysorbate 60, and polysorbate 80, alkyoyl methyl glucomide, lauroyl methyl glucamide, capryloyl/caproyl methyl glucamide; and
b) the hydrophobic thickeners are selected from the group consisting of: non-ionic alkanolamides, liquid alkanolamides, ethoxylated C10-C14 alcohols, Laureth-1 to Laureth-5, and dimethyl lauramide/myristamide, PPG-2 Hydroxyethyl Cocamide, Cocamide DIPA, lauramide DIPA, soyamide DIPA; and
3) water, wherein the ratio of water to organic solvent carrier by weight is from 4:1 to 1:4. 4. A liquid composition of claim 1 wherein the liquid composition further comprises:
1) 20%-80% of Formula-2, wherein Q is the radical of sorbitol, trehalose, mannitol, di-pentaerythritol, sucrose, lactose, chitobiose, cellobiose, and maltose;
2) the organic carrier is selected from the group consisting of: organic solvents, hydrophobic thickeners, or mixtures thereof, wherein
a) the organic solvents are selected from the groups consisting of: mono- or polyhydric alcohols and their ether, ester, or amide derivatives, glycerol, propylene glycol, 1.3-propanediol, butylene glycol, dipropylene glycol, pentylene glycol, methoxy diglycol, glycerol, polyglyceryl-3, polyglyceryl-2, glycereth-7, glycereth-26, diglyerol, sorbitol, glucose, methyl glucose, methyl glucomide, glyceryl laurate, glyceryl oleate, glyceryl isostearte, propylene glycol monolaurate, PEG-6 caprylic/capric glyceride, sorbitan carpylate/caprate, sorbitan sesquicaprylate, sorbitane laurate, methyl glucose caprate/caprylate/oleate, PEG-7 glyceryl cocoate, fatty methyl ester ethoxylates, alkylpolyglucosides, decyl glucoside, cocoa glucoside, polysorbate 20, polysorbate 60, and polysorbate 80, alkyoyl methyl glucomide, lauroyl methyl glucamide, and capryloyl/caproyl methyl glucamide; and
b) the hydrophobic thickeners are selected from the groups consisting of: non-ionic alkanolamides, liquid alkanolamides, ethoxylated C10-C14 alcohols, Laureth-1 to Laureth-5, dimethyl lauramide/myristamide; PPG-2 Hydroxyethyl Cocamide, Cocamide DIPA, lauramide DIPA, soyamide DIPA; and
3) water, wherein the ratio of water to organic solvent carrier by weight is from 4:1 to 1:4. 5. A liquid composition of claim 1 wherein the liquid composition further comprises:
1) 20%-80% of Formula-2,
wherein Q is a radical of sorbitol, trehalose, mannitol, di-pentaerythritol, sucrose, lactose, chitobiose, cellobiose, and maltose;
2) the organic carrier or mixtures thereof, selected from the group consisting of alkyl polyglucosides, alkyol methyl glucomide, sorbitan laurate, sorbitan caprylate/caprate, liquid non-ionic alkanolamide surfactants, laureth-1, laureth-2, laureth-3, glyceryl caprylate/caprate, and glyceryl laurate; and
3) water, wherein the ratio of water to organic solvent carrier by weight is from 4:1 to 1:4. 6. A liquid composition of claim 1 wherein the liquid composition further comprises:
1) 20%-80% of Formula-2,
wherein Q is the radical of sorbitol, trehalose, mannitol, di-pentaerythritol, sucrose, lactose, chitobiose, cellobiose, and maltose;
2) the organic carrier or mixtures thereof, selected from the groups consisting of the alkanolamides; and
3) water, wherein the ratio of water to organic solvent carrier by weight is from 4:1 to 1:4. 7. A cosmetic, dermatological, or pharmaceutical composition, in the form of hair cleansing/treatment formulation, skin and body cleansing/treatment formulations, and other toiletry formulations, comprising the liquid thickener composition of claim 1. 8. A cosmetic, dermatological, or pharmaceutical composition comprising the liquid thickener composition of claim 4, in the form of hair cleansing/treatment formulation, skin and body cleansing/treatment formulations, and other toiletry formulations. 9. A cosmetic, dermatological, and pharmaceutical composition of claim 7 further comprising water, and
1) 1% -50% by weight of surfactants selected from the group consisting of: anionic surfactant, cationic surfactant, non-ionic surfactant, amphoteric surfactant, and mixtures thereof;
2) 0.1% to 15% of the liquid thickener composition of Formula-2; and
3) 0.1% to 60% of other ingredients selected from the group consisting of: skin and hair actives, stabilizer, further thickeners, and other customary personal cleansing ingredients. 10. A cosmetic, dermatological, and pharmaceutical composition of claim 8 further comprising water, and
1) 1% - 50% by weight of surfactants selected from the group consisting of: anionic surfactant, cationic surfactant, non-ionic surfactant, amphoteric surfactant, and mixtures thereof;
2) 0.1% to 15% of the liquid thickener composition of Formula-1; and
3) 0.1% to 60% of other ingredients selected from the group consisting of: skin and hair actives, stabilizer, further thickeners, and other customary personal cleansing ingredients. 11. A method of thickening the composition of claim 7 by adding the liquid thickener composition comprising of Formula-2 to the mixture of surfactants. 12. A cosmetic, dermatological, or pharmaceutical composition of about 1% to 8% of the liquid composition of claim 1 further comprising:
about 1% to 25% by weight of a skin and hair active ingredient selected from the group consisting of: UV filters, moisturizers, conditioners, antiseptic agents, deodorant actives, reducing agents for permanent wave products, colorants for coloring hair, anti-aging actives, perfume, petrolatum, vegetable oils, cationic conditioning polymers, and mixtures thereof; and water.
| 1,600 |
1,294 | 15,099,909 | 1,649 |
The present invention relates to injecting a high specificity cytokine antagonist into a diseased intervertebral disc.
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1. A method of treating degenerative disc disease (DDD), comprising:
obtaining an MRI of a proximal tissue in a patient having DDD; assigning a quantified value for the selected tissue based upon the MRI; and comparing the quantified value against a pre-determined value, wherein if the quantified value is greater than the pre-determined value, providing a therapy comprising:
inserting a tip of an elongate instrument through the proximal tissue and into a region distal a portion of the proximal tissue, and
releasing a therapeutic device from the elongate element into the distal region. 2. The method of claim 1, wherein the elongate instrument is inserted into the proximal tissue via a path created by a tubular instrument. 3. The method of claim 1, wherein the therapeutic device comprises a polymer. 4. A method of treating degenerative disc disease (DDD), comprising:
obtaining an MRI of a selected tissue in a patient having DDD; assigning a quantified value for the selected tissue based upon the MRI; and comparing the quantified value against a pre-determined value, wherein if the quantified value exceeds the pre-determined value, performing a procedure comprising:
puncturing the skin of the patient,
advancing an elongate element through the puncture and into the selected tissue, and
contacting the selected tissue with a sensing element associated with the elongate element. 5. The method of claim 4, wherein the elongate element comprises an outer tube and an inner stylet. 6. The method of claim 5, further comprising the step of removing the stylet from the outer tube prior to delivering the sensing element. 7. The method of claim 4, further comprising the step of delivering a therapeutic agent through the puncture to a region distal a portion of an annulus fibrosus associated with the DDD. 8. A method of treating degenerative disc disease (DDD) in an individual, comprising:
determining a profile of the individual via a diagnostic procedure; comparing the profile of the individual against a pre-determined profile of at-risk humans, wherein if the profile of the individual indicates a risk greater than the pre-determined profile of at-risk humans, providing a procedure to the individual comprising:
inserting into a selected tissue of the patient at least a portion of an elongate element comprising i) an outer tube having a substantially smooth outer surface, and ii) an inner elongate member housed within the outer tube,
advancing at least a portion of the elongate element within the selected tissue of the patient, and
exposing the selected tissue to a sensing element associated with the elongate element. 9. The method of claim 8, wherein in the step of advancing at least a portion of the elongate element within the selected tissue of the patient, the elongate element is simultaneously rotated. 10. The method of claim 8, wherein the elongate instrument is inserted into a region distal a portion of an annulus fibrosus associated with the DDD via a path created by the outer tube. 11. A method of treating a patient having degenerative disc disease (DDD) with a device comprising i) a tubular member having a longitudinal passageway therein, and ii) an elongate member disposed substantially parallel to the tubular member, comprising:
inserting the elongate member into an annulus fibrosus of the patient associated with the DDD while keeping the tubular member outside the annulus fibrosus, and exposing a selected tissue to a sensing element associated with the elongate element. 12. A method of treating a patient having degenerative disc disease (DDD) with a device comprising i) a tubular member having a longitudinal passageway therein, and ii) an elongate member disposed substantially parallel to the tubular member, comprising:
inserting the elongate member into an annulus fibrosus of the patient associated with the DDD while keeping the tubular member outside the annulus fibrosus, and delivering a therapeutic agent via the elongate member to a region distal a portion of the annulus fibrosus associated with the DDD.
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The present invention relates to injecting a high specificity cytokine antagonist into a diseased intervertebral disc.1. A method of treating degenerative disc disease (DDD), comprising:
obtaining an MRI of a proximal tissue in a patient having DDD; assigning a quantified value for the selected tissue based upon the MRI; and comparing the quantified value against a pre-determined value, wherein if the quantified value is greater than the pre-determined value, providing a therapy comprising:
inserting a tip of an elongate instrument through the proximal tissue and into a region distal a portion of the proximal tissue, and
releasing a therapeutic device from the elongate element into the distal region. 2. The method of claim 1, wherein the elongate instrument is inserted into the proximal tissue via a path created by a tubular instrument. 3. The method of claim 1, wherein the therapeutic device comprises a polymer. 4. A method of treating degenerative disc disease (DDD), comprising:
obtaining an MRI of a selected tissue in a patient having DDD; assigning a quantified value for the selected tissue based upon the MRI; and comparing the quantified value against a pre-determined value, wherein if the quantified value exceeds the pre-determined value, performing a procedure comprising:
puncturing the skin of the patient,
advancing an elongate element through the puncture and into the selected tissue, and
contacting the selected tissue with a sensing element associated with the elongate element. 5. The method of claim 4, wherein the elongate element comprises an outer tube and an inner stylet. 6. The method of claim 5, further comprising the step of removing the stylet from the outer tube prior to delivering the sensing element. 7. The method of claim 4, further comprising the step of delivering a therapeutic agent through the puncture to a region distal a portion of an annulus fibrosus associated with the DDD. 8. A method of treating degenerative disc disease (DDD) in an individual, comprising:
determining a profile of the individual via a diagnostic procedure; comparing the profile of the individual against a pre-determined profile of at-risk humans, wherein if the profile of the individual indicates a risk greater than the pre-determined profile of at-risk humans, providing a procedure to the individual comprising:
inserting into a selected tissue of the patient at least a portion of an elongate element comprising i) an outer tube having a substantially smooth outer surface, and ii) an inner elongate member housed within the outer tube,
advancing at least a portion of the elongate element within the selected tissue of the patient, and
exposing the selected tissue to a sensing element associated with the elongate element. 9. The method of claim 8, wherein in the step of advancing at least a portion of the elongate element within the selected tissue of the patient, the elongate element is simultaneously rotated. 10. The method of claim 8, wherein the elongate instrument is inserted into a region distal a portion of an annulus fibrosus associated with the DDD via a path created by the outer tube. 11. A method of treating a patient having degenerative disc disease (DDD) with a device comprising i) a tubular member having a longitudinal passageway therein, and ii) an elongate member disposed substantially parallel to the tubular member, comprising:
inserting the elongate member into an annulus fibrosus of the patient associated with the DDD while keeping the tubular member outside the annulus fibrosus, and exposing a selected tissue to a sensing element associated with the elongate element. 12. A method of treating a patient having degenerative disc disease (DDD) with a device comprising i) a tubular member having a longitudinal passageway therein, and ii) an elongate member disposed substantially parallel to the tubular member, comprising:
inserting the elongate member into an annulus fibrosus of the patient associated with the DDD while keeping the tubular member outside the annulus fibrosus, and delivering a therapeutic agent via the elongate member to a region distal a portion of the annulus fibrosus associated with the DDD.
| 1,600 |
1,295 | 15,452,067 | 1,615 |
An object is to provide a tablet manufacturing apparatus capable of supplying an IC chip to a desired position of pharmaceutical powder with a high accuracy and suppressing a positional displacement. The IC chip is supported by a positioning guide with a chip main body in a downward manner, and is held in a state of being positioned above pharmaceutical powder filled in a die hole before compression. The IC chip is supplied by a pusher.
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1. An apparatus, comprising:
a medical tablet including an integrated circuit (IC) chip member equipped with an IC therein, said medical tablet having a first surface and a second surface opposite the first surface, wherein an engraved stamp or cleavage line is formed in said first surface, an engraved stamp or cleavage line is not formed or an engraved stamp or cleavage line shallower than that in said first surface is formed in said second surface, and said IC chip member has a base plane and a convex portion protruding more on one side than on the other side with respect to said base plane, and the convex portion is arranged within the medical tablet to face the second surface. 2. The apparatus of claim 1, wherein the engraved stamp or cleavage line formed in said first surface is formed in an upper pestle of a tableting machine. 3. The apparatus of claim 1, wherein the IC chip member is configured to be supplied on pharmaceutical powder in a die hole by a supply portion, the IC chip member is configured to be held in a downward manner by the supply portion such that the convex portion faces downward when said supply portion supplies the IC chip member on the pharmaceutical powder. 4. The apparatus of claim 1, wherein the IC chip member is configured to be held by a carrier tape having an accommodation portion in an upward manner where the convex portion faces upward,
the IC chip member in the upward manner is configured to be removed from the accommodation portion, reversed upside down and changed to said downward manner, prior to being supplied onto pharmaceutical powder. 5. The apparatus of claim 1, wherein the medical tablet includes first pharmaceutical powder and second pharmaceutical powder, the IC chip member is configured to be supplied onto the first pharmaceutical powder in a downward manner such that the convex portion faces downward and contacts the first pharmaceutical powder prior to the second pharmaceutical powder being supplied onto the IC chip member. 6. The apparatus of claim 1, wherein the IC chip member is configured to be compressed between first pharmaceutical powder and second pharmaceutical powder by a set of pestles. 7. The apparatus of claim 1, wherein the IC chip member is configured to be held within a through-hole defined by a positioning guide and having a plurality of protrusions protruding toward a center of the through-hole to hold the IC chip member in a downward manner where the convex portion faces downward, the IC chip member configured to be pushed out of the positioning guide and onto first pharmaceutical powder filled in a die hold such that second pharmaceutical powder can be filled onto the IC chip member to define the medical tablet.
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An object is to provide a tablet manufacturing apparatus capable of supplying an IC chip to a desired position of pharmaceutical powder with a high accuracy and suppressing a positional displacement. The IC chip is supported by a positioning guide with a chip main body in a downward manner, and is held in a state of being positioned above pharmaceutical powder filled in a die hole before compression. The IC chip is supplied by a pusher.1. An apparatus, comprising:
a medical tablet including an integrated circuit (IC) chip member equipped with an IC therein, said medical tablet having a first surface and a second surface opposite the first surface, wherein an engraved stamp or cleavage line is formed in said first surface, an engraved stamp or cleavage line is not formed or an engraved stamp or cleavage line shallower than that in said first surface is formed in said second surface, and said IC chip member has a base plane and a convex portion protruding more on one side than on the other side with respect to said base plane, and the convex portion is arranged within the medical tablet to face the second surface. 2. The apparatus of claim 1, wherein the engraved stamp or cleavage line formed in said first surface is formed in an upper pestle of a tableting machine. 3. The apparatus of claim 1, wherein the IC chip member is configured to be supplied on pharmaceutical powder in a die hole by a supply portion, the IC chip member is configured to be held in a downward manner by the supply portion such that the convex portion faces downward when said supply portion supplies the IC chip member on the pharmaceutical powder. 4. The apparatus of claim 1, wherein the IC chip member is configured to be held by a carrier tape having an accommodation portion in an upward manner where the convex portion faces upward,
the IC chip member in the upward manner is configured to be removed from the accommodation portion, reversed upside down and changed to said downward manner, prior to being supplied onto pharmaceutical powder. 5. The apparatus of claim 1, wherein the medical tablet includes first pharmaceutical powder and second pharmaceutical powder, the IC chip member is configured to be supplied onto the first pharmaceutical powder in a downward manner such that the convex portion faces downward and contacts the first pharmaceutical powder prior to the second pharmaceutical powder being supplied onto the IC chip member. 6. The apparatus of claim 1, wherein the IC chip member is configured to be compressed between first pharmaceutical powder and second pharmaceutical powder by a set of pestles. 7. The apparatus of claim 1, wherein the IC chip member is configured to be held within a through-hole defined by a positioning guide and having a plurality of protrusions protruding toward a center of the through-hole to hold the IC chip member in a downward manner where the convex portion faces downward, the IC chip member configured to be pushed out of the positioning guide and onto first pharmaceutical powder filled in a die hold such that second pharmaceutical powder can be filled onto the IC chip member to define the medical tablet.
| 1,600 |
1,296 | 15,189,177 | 1,617 |
A composition and method of treating patients diagnosed with NAFLD is disclosed. The composition contains n-3 polyunsaturated fatty acids (PUFAs) for treatment of NAFLD patients, wherein the amount of PCB 153 in the composition has been minimized. The composition is administered to a patient in a sufficient amount and for a sufficient time to increase the level of n-3 PUFAs or to correct a deficiency of n-3 PUFAs in the patient's blood. The method increases the level of n-3 PUFAs without contributing to the body burden of PCB 153.
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1. A method of treating a patient diagnosed with non-alcoholic fatty liver disease (NAFLD) comprising administering an n-3 polyunsaturated fatty acids (n-3 PUFAs) composition to the patient in a sufficient amount to increase a level of n-3 PUFAs or to correct a deficiency of n-3 PUFAs in the blood of the patient, wherein the composition comprises at least 40 weight % of at least one of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), or derivatives thereof, by weight of the fatty acids therein, and an amount of PCB 153 in the composition is less than 5.0 ng/g. 2. The method of claim 1 wherein the composition comprises at least 60% of at least one of EPA and DHA by weight of the fatty acids therein. 3. The method of claim 1 wherein a weight ratio of EPA:DHA in the composition ranges from about 1:10 to about 10:1. 4. The method of claim 1 wherein the composition originates from a marine oil. 5. The method of claim 1 wherein the PUFAs are present in at least one of a free fatty acid form; an esterified form; a phospholipid form; a mono/di/tri-glyceride form, and salts thereof. 6. The method of claim 1 wherein the composition comprises a sum of about 84 weight % EPA and DHA. 7. The method of claim 1 wherein the composition comprises 460 mg EPA-ethyl ester and 380 mg DHA-ethyl ester per gram. 8. The method of claim 1 wherein the amount of PCB 153 is less than 4.0 ng/g. 9. The method of claim 8 wherein the amount of PCB 153 is less than 3.0 ng/g. 10. The method of claim 9 wherein the amount of PCB 153 is less than 1.0 ng/g. 11. The method of claim 10 wherein the amount of PCB 153 is less than 0.7 ng/g. 12. The method of claim 1 wherein the increase of n-3 PUFAs in the blood is at least 10%, measured as a change obtained in erythrocyte EPA and DHA as a percentage of total fatty acids. 13. The method of claim 1 wherein a level of n-3 PUFAs in blood is increased to above about 8.0 wt % of total plasma or serum phospholipid fatty acid level in the blood. 14. The method of claim 1 wherein an Omega-3 Index (%) is increased by at least 20%. 15. The method of claim 1 wherein the composition is selected from the group of Enteral Formulas for Special Medical use, Foods for Specified Health Uses, Food for Special Medical Purposes (FSMP), Food for Special Dietary Use (FSDU), Medical Nutrition, and a Medical food. 16. The method of claim 1 wherein an Omega-3 Index (%) is increased to above about 6.0% of the total fatty acids in the blood. 17. The method of claim 1 wherein the method corrects an imbalance in a ratio of n-6 PUFAs to n-3 PUFAs in the blood. 18. The method of claim 1 wherein the composition is administered to the patient over a sufficient time to increase a level of 3-PUFAs or correct a deficiency of 3-PUFAs in the blood of the patient. 19. An n-3 polyunsaturated fatty acids (PUFAs) composition comprising at least 40% of at least one of EPA and DHA, or derivatives thereof, by weight of the fatty acids therein, wherein an amount of PCB 153 in the composition is less than 5.0 ng/g. 20. The composition of claim 19 further comprising an antioxidant. 21. The composition of claim 20 wherein the antioxidant comprises mixed tocopherol. 22. The composition of claim 19 comprising at least 60% of at least one of EPA and DHA, by weight of the fatty acids therein. 23. The composition of claim 19 wherein a weight ratio of EPA:DHA in the composition ranges from about 1:10 about 10:1. 24. The composition of claim 19 wherein the PUFAs are present in at least one of a free fatty acid form; an esterified form; a phospholipid form; a mono/di/tri-glyceride form, and salts thereof. 25. The composition of claim 19 wherein the amount of PCB 153 in the composition is less than 2.0 ng/g. 26. The composition of claim 25 wherein the amount of PCB 153 in the composition is less than 0.7 ng/g.
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A composition and method of treating patients diagnosed with NAFLD is disclosed. The composition contains n-3 polyunsaturated fatty acids (PUFAs) for treatment of NAFLD patients, wherein the amount of PCB 153 in the composition has been minimized. The composition is administered to a patient in a sufficient amount and for a sufficient time to increase the level of n-3 PUFAs or to correct a deficiency of n-3 PUFAs in the patient's blood. The method increases the level of n-3 PUFAs without contributing to the body burden of PCB 153.1. A method of treating a patient diagnosed with non-alcoholic fatty liver disease (NAFLD) comprising administering an n-3 polyunsaturated fatty acids (n-3 PUFAs) composition to the patient in a sufficient amount to increase a level of n-3 PUFAs or to correct a deficiency of n-3 PUFAs in the blood of the patient, wherein the composition comprises at least 40 weight % of at least one of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), or derivatives thereof, by weight of the fatty acids therein, and an amount of PCB 153 in the composition is less than 5.0 ng/g. 2. The method of claim 1 wherein the composition comprises at least 60% of at least one of EPA and DHA by weight of the fatty acids therein. 3. The method of claim 1 wherein a weight ratio of EPA:DHA in the composition ranges from about 1:10 to about 10:1. 4. The method of claim 1 wherein the composition originates from a marine oil. 5. The method of claim 1 wherein the PUFAs are present in at least one of a free fatty acid form; an esterified form; a phospholipid form; a mono/di/tri-glyceride form, and salts thereof. 6. The method of claim 1 wherein the composition comprises a sum of about 84 weight % EPA and DHA. 7. The method of claim 1 wherein the composition comprises 460 mg EPA-ethyl ester and 380 mg DHA-ethyl ester per gram. 8. The method of claim 1 wherein the amount of PCB 153 is less than 4.0 ng/g. 9. The method of claim 8 wherein the amount of PCB 153 is less than 3.0 ng/g. 10. The method of claim 9 wherein the amount of PCB 153 is less than 1.0 ng/g. 11. The method of claim 10 wherein the amount of PCB 153 is less than 0.7 ng/g. 12. The method of claim 1 wherein the increase of n-3 PUFAs in the blood is at least 10%, measured as a change obtained in erythrocyte EPA and DHA as a percentage of total fatty acids. 13. The method of claim 1 wherein a level of n-3 PUFAs in blood is increased to above about 8.0 wt % of total plasma or serum phospholipid fatty acid level in the blood. 14. The method of claim 1 wherein an Omega-3 Index (%) is increased by at least 20%. 15. The method of claim 1 wherein the composition is selected from the group of Enteral Formulas for Special Medical use, Foods for Specified Health Uses, Food for Special Medical Purposes (FSMP), Food for Special Dietary Use (FSDU), Medical Nutrition, and a Medical food. 16. The method of claim 1 wherein an Omega-3 Index (%) is increased to above about 6.0% of the total fatty acids in the blood. 17. The method of claim 1 wherein the method corrects an imbalance in a ratio of n-6 PUFAs to n-3 PUFAs in the blood. 18. The method of claim 1 wherein the composition is administered to the patient over a sufficient time to increase a level of 3-PUFAs or correct a deficiency of 3-PUFAs in the blood of the patient. 19. An n-3 polyunsaturated fatty acids (PUFAs) composition comprising at least 40% of at least one of EPA and DHA, or derivatives thereof, by weight of the fatty acids therein, wherein an amount of PCB 153 in the composition is less than 5.0 ng/g. 20. The composition of claim 19 further comprising an antioxidant. 21. The composition of claim 20 wherein the antioxidant comprises mixed tocopherol. 22. The composition of claim 19 comprising at least 60% of at least one of EPA and DHA, by weight of the fatty acids therein. 23. The composition of claim 19 wherein a weight ratio of EPA:DHA in the composition ranges from about 1:10 about 10:1. 24. The composition of claim 19 wherein the PUFAs are present in at least one of a free fatty acid form; an esterified form; a phospholipid form; a mono/di/tri-glyceride form, and salts thereof. 25. The composition of claim 19 wherein the amount of PCB 153 in the composition is less than 2.0 ng/g. 26. The composition of claim 25 wherein the amount of PCB 153 in the composition is less than 0.7 ng/g.
| 1,600 |
1,297 | 11,004,617 | 1,627 |
The present invention is a cosmetic or dermatological preparation comprising 0.01% by weight to 5% by weight of at least one red light-filtering dye and 0.0001% by weight to 10% by weight of at least one anti-inflammatory active ingredient. The preparation can be used for the prophylaxis and treatment of sun-irritated skin and to aid the body's own repair mechanisms.
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1. A cosmetic or dermatological preparation, comprising:
0.01% by weight to 5% by weight of at least one red light-filtering dye; and 0.0001% by weight to 10% by weight of at least one anti-inflammatory active ingredient. 2. The preparation according to claim 1, wherein the anti-inflammatory active ingredient includes as least one anti-inflammatory active ingredient selected from the group consisting of hamamelis, Glycyrrhiza inflata, panthenol and camomile extract. 3. The preparation according to claim 1, wherein the anti-inflammatory ingredient includes hamamelis, Glycyrrhiza inflata and panthenol. 4. The preparation according to claim 1, wherein the anti-inflammatory ingredient is present in an amount of from 0.01 to 7% by weight. 5. The preparation according to claim 1, wherein the anti-inflammatory ingredient is present in an amount of from 0.05 to 5% by weight. 6. The preparation according to claim 1, wherein the anti-inflammatory ingredient is present in an amount of from 0.1 to 2% by weight. 7. The preparation according to claim 1, wherein the dye includes a green pigment. 8. The preparation according to claim 7, wherein the green pigment includes a green pigment having a CI number selected from the group consisting of CI 77288, CI 77289, CI 77007, CI 77891, CI 77491, CI 77499, CI 77891, CI 77499, CI 77288 and CI 77492. 9. The preparation according to claim 7, wherein the dye further includes a blue pigment. 10. The preparation according to claim 9, wherein the weight ratio of blue pigment to green pigment is 1:1 to 1:100. 11. The preparation according to claim 9, wherein the dye further includes a white pigment. 12. The preparation according to claim 1, in the form of an emulsion-based cream or lotion, an aerosol, a gel, a concealer or a wipe. 13. A method for treating photodamaged or shaving-stressed skin, for alleviating the after-reaction of the skin to the effect of UV radiation or shaving, or for treating reddened skin caused by disease, irritation or inflammation, comprising the step of applying to the skin a cosmetic or dermatological preparation, comprising 0.01% by weight to 5% by weight of at least one red light-filtering dye; and 0.0001% by weight to 10% by weight of at least one anti-inflammatory active ingredient. 14. The method according to claim 13, for treating photodamaged skin or for alleviating the after-reaction of the skin to the effect of UV radiation. 15. The method according to claim 13, for treating shaving-stressed skin or for alleviating the after-reaction of the skin to shaving. 16. The method according to claim 13, for treating reddened skin caused by disease, irritation or inflammation. 17. The method according to claim 16, for treating rosacea. 18. A method for concealing rosacea or reddened skin, comprising the step of applying to the skin a cosmetic or dermatological preparation, comprising 0.01% by weight to 5% by weight of at least one red light-filtering dye; and 0.0001% by weight to 10% by weight of at least one anti-inflammatory active ingredient. 19. The method according to claim 18, wherein the reddened skin is caused by solar irradiation.
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The present invention is a cosmetic or dermatological preparation comprising 0.01% by weight to 5% by weight of at least one red light-filtering dye and 0.0001% by weight to 10% by weight of at least one anti-inflammatory active ingredient. The preparation can be used for the prophylaxis and treatment of sun-irritated skin and to aid the body's own repair mechanisms.1. A cosmetic or dermatological preparation, comprising:
0.01% by weight to 5% by weight of at least one red light-filtering dye; and 0.0001% by weight to 10% by weight of at least one anti-inflammatory active ingredient. 2. The preparation according to claim 1, wherein the anti-inflammatory active ingredient includes as least one anti-inflammatory active ingredient selected from the group consisting of hamamelis, Glycyrrhiza inflata, panthenol and camomile extract. 3. The preparation according to claim 1, wherein the anti-inflammatory ingredient includes hamamelis, Glycyrrhiza inflata and panthenol. 4. The preparation according to claim 1, wherein the anti-inflammatory ingredient is present in an amount of from 0.01 to 7% by weight. 5. The preparation according to claim 1, wherein the anti-inflammatory ingredient is present in an amount of from 0.05 to 5% by weight. 6. The preparation according to claim 1, wherein the anti-inflammatory ingredient is present in an amount of from 0.1 to 2% by weight. 7. The preparation according to claim 1, wherein the dye includes a green pigment. 8. The preparation according to claim 7, wherein the green pigment includes a green pigment having a CI number selected from the group consisting of CI 77288, CI 77289, CI 77007, CI 77891, CI 77491, CI 77499, CI 77891, CI 77499, CI 77288 and CI 77492. 9. The preparation according to claim 7, wherein the dye further includes a blue pigment. 10. The preparation according to claim 9, wherein the weight ratio of blue pigment to green pigment is 1:1 to 1:100. 11. The preparation according to claim 9, wherein the dye further includes a white pigment. 12. The preparation according to claim 1, in the form of an emulsion-based cream or lotion, an aerosol, a gel, a concealer or a wipe. 13. A method for treating photodamaged or shaving-stressed skin, for alleviating the after-reaction of the skin to the effect of UV radiation or shaving, or for treating reddened skin caused by disease, irritation or inflammation, comprising the step of applying to the skin a cosmetic or dermatological preparation, comprising 0.01% by weight to 5% by weight of at least one red light-filtering dye; and 0.0001% by weight to 10% by weight of at least one anti-inflammatory active ingredient. 14. The method according to claim 13, for treating photodamaged skin or for alleviating the after-reaction of the skin to the effect of UV radiation. 15. The method according to claim 13, for treating shaving-stressed skin or for alleviating the after-reaction of the skin to shaving. 16. The method according to claim 13, for treating reddened skin caused by disease, irritation or inflammation. 17. The method according to claim 16, for treating rosacea. 18. A method for concealing rosacea or reddened skin, comprising the step of applying to the skin a cosmetic or dermatological preparation, comprising 0.01% by weight to 5% by weight of at least one red light-filtering dye; and 0.0001% by weight to 10% by weight of at least one anti-inflammatory active ingredient. 19. The method according to claim 18, wherein the reddened skin is caused by solar irradiation.
| 1,600 |
1,298 | 13,545,473 | 1,653 |
A temperature sensor for monitoring an organ or tissue is configured to measure a temperature inside of a container configured to contain the organ or tissue. The temperature sensor is disposed exterior to the organ container and the temperature sensor is a non-contact temperature sensor. The temperature sensor may be part of an apparatus for perfusing, transporting, and/or storing an organ or tissue. A coolant container may have an aperture through which the temperature sensor measures a temperature of at least one of the organ or tissue or a perfusate fluid surrounding the organ or tissue. The temperature sensor is preferably an infrared temperature sensor. Multiple temperature sensors may be provided that measure the temperature organ or tissue or perfusate fluid surrounding the organ or tissue, for example in case one of the temperature sensors fails.
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1. An apparatus for perfusing, transporting, and/or storing an organ or tissue, comprising:
a coolant container configured to contain coolant and define a compartment to hold another container; and a non-contact temperature sensor configured to measure a temperature of a space inside of the compartment, the non-contact temperature sensor being disposed exterior to the compartment. 2. The apparatus of claim 1, further comprising:
an organ or tissue container configured to fit in the compartment, wherein the coolant container has an aperture through which the non-contact temperature sensor measures a temperature of at least one of an organ or tissue or a perfusate surrounding the organ or tissue in the organ or tissue container. 3. The apparatus of claim 1, further comprising at least one flow path configured for recirculation of perfusate in the apparatus. 4. The apparatus of claim 1, wherein the temperature sensor is configured to measure a temperature of an organ or tissue in the compartment. 5. The apparatus of claim 1, wherein the temperature sensor is configured to measure a temperature of a perfusate bath in which an organ or tissue can be at least partially immersed in the compartment. 6. The apparatus of claim 1, wherein the temperature sensor is an infrared temperature sensor. 7. The apparatus of claim 1, further comprising a second non-contact temperature sensor configured to measure a temperature inside of the compartment, the second non-contact temperature sensor being disposed exterior to the compartment. 8. The apparatus of claim 1, wherein the coolant container has a double wall structure, the double wall structure having an inner wall and an outer wall. 9. The apparatus of claim 8, wherein the inner wall and the outer wall both have an aperture through which the non-contact temperature sensor is situated to measure a temperature of at least one of an organ, tissue, or perfusate fluid surrounding an organ or the tissue in the compartment. 10-21. (canceled) 22. The apparatus of claim 2, wherein the non-contact temperature sensor is disposed within the aperture. 23. The apparatus of claim 22, further comprising a second non-contact temperature sensor disposed within the aperture. 24. The apparatus of claim 2, wherein the non-contact temperature sensor is disposed exterior to the coolant container. 25. A method for monitoring the temperature of an organ or tissue, the method comprising:
disposing an organ or tissue in a compartment in a coolant container; and measuring a temperature inside the compartment with a first infrared temperature sensor that is located exterior to the compartment. 26. The method of claim 25, further comprising:
measuring a second temperature within the compartment with a second infrared temperature sensor that is located exterior to the compartment. 27. The method of claim 26, wherein the second temperature is measured with the second infrared temperature sensor upon a failure of the first infrared temperature sensor. 28. The method of claim 25, wherein the temperature is a temperature of a perfusate bath surrounding the organ or tissue. 29. The method of claim 25, wherein the temperature is a temperature of the organ or tissue that is directly measured with the first infrared temperature sensor. 30. The method of claim 26, wherein the second temperature is a temperature of a perfusate bath surrounding the organ or tissue. 31. The method of claim 26, wherein the second temperature is a temperature of the organ or tissue that is directly measured with both the first infrared temperature sensor and the second infrared temperature sensor. 32. The method of claim 25, wherein the measuring is performed during perfusion of the organ or tissue in the compartment.
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A temperature sensor for monitoring an organ or tissue is configured to measure a temperature inside of a container configured to contain the organ or tissue. The temperature sensor is disposed exterior to the organ container and the temperature sensor is a non-contact temperature sensor. The temperature sensor may be part of an apparatus for perfusing, transporting, and/or storing an organ or tissue. A coolant container may have an aperture through which the temperature sensor measures a temperature of at least one of the organ or tissue or a perfusate fluid surrounding the organ or tissue. The temperature sensor is preferably an infrared temperature sensor. Multiple temperature sensors may be provided that measure the temperature organ or tissue or perfusate fluid surrounding the organ or tissue, for example in case one of the temperature sensors fails.1. An apparatus for perfusing, transporting, and/or storing an organ or tissue, comprising:
a coolant container configured to contain coolant and define a compartment to hold another container; and a non-contact temperature sensor configured to measure a temperature of a space inside of the compartment, the non-contact temperature sensor being disposed exterior to the compartment. 2. The apparatus of claim 1, further comprising:
an organ or tissue container configured to fit in the compartment, wherein the coolant container has an aperture through which the non-contact temperature sensor measures a temperature of at least one of an organ or tissue or a perfusate surrounding the organ or tissue in the organ or tissue container. 3. The apparatus of claim 1, further comprising at least one flow path configured for recirculation of perfusate in the apparatus. 4. The apparatus of claim 1, wherein the temperature sensor is configured to measure a temperature of an organ or tissue in the compartment. 5. The apparatus of claim 1, wherein the temperature sensor is configured to measure a temperature of a perfusate bath in which an organ or tissue can be at least partially immersed in the compartment. 6. The apparatus of claim 1, wherein the temperature sensor is an infrared temperature sensor. 7. The apparatus of claim 1, further comprising a second non-contact temperature sensor configured to measure a temperature inside of the compartment, the second non-contact temperature sensor being disposed exterior to the compartment. 8. The apparatus of claim 1, wherein the coolant container has a double wall structure, the double wall structure having an inner wall and an outer wall. 9. The apparatus of claim 8, wherein the inner wall and the outer wall both have an aperture through which the non-contact temperature sensor is situated to measure a temperature of at least one of an organ, tissue, or perfusate fluid surrounding an organ or the tissue in the compartment. 10-21. (canceled) 22. The apparatus of claim 2, wherein the non-contact temperature sensor is disposed within the aperture. 23. The apparatus of claim 22, further comprising a second non-contact temperature sensor disposed within the aperture. 24. The apparatus of claim 2, wherein the non-contact temperature sensor is disposed exterior to the coolant container. 25. A method for monitoring the temperature of an organ or tissue, the method comprising:
disposing an organ or tissue in a compartment in a coolant container; and measuring a temperature inside the compartment with a first infrared temperature sensor that is located exterior to the compartment. 26. The method of claim 25, further comprising:
measuring a second temperature within the compartment with a second infrared temperature sensor that is located exterior to the compartment. 27. The method of claim 26, wherein the second temperature is measured with the second infrared temperature sensor upon a failure of the first infrared temperature sensor. 28. The method of claim 25, wherein the temperature is a temperature of a perfusate bath surrounding the organ or tissue. 29. The method of claim 25, wherein the temperature is a temperature of the organ or tissue that is directly measured with the first infrared temperature sensor. 30. The method of claim 26, wherein the second temperature is a temperature of a perfusate bath surrounding the organ or tissue. 31. The method of claim 26, wherein the second temperature is a temperature of the organ or tissue that is directly measured with both the first infrared temperature sensor and the second infrared temperature sensor. 32. The method of claim 25, wherein the measuring is performed during perfusion of the organ or tissue in the compartment.
| 1,600 |
1,299 | 15,463,752 | 1,644 |
The invention provides non-human cells and mammals having a genome encoding chimeric antibodies and methods of producing transgenic cells and mammals. Certain aspects of the invention include chimeric antibodies, humanized antibodies, pharmaceutical compositions and kits. Certain aspects of the invention also relate to diagnostic and treatment methods using the antibodies of the invention.
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1. A chimeric immunoglobulin heavy chain comprising a human variable domain and a chimeric constant region comprising a human CH1 domain, a human upper hinge region, a non-human CH2 domain, and a non-human CH3 domain. 2. The chimeric immunoglobulin heavy chain according to claim 1, wherein the CH1 domain isotype is IgM, IgD, IgG1, IgG2, IgG3, IgG4, IgA, or IgE. 3. The chimeric immunoglobulin heavy chain according to claim 1, wherein the upper hinge region isotype is IgM, IgD, IgG1, IgG2, IgG3, IgG4, IgA, or IgE. 4. A chimeric antibody, or an antigen-binding fragment thereof, comprising (1) the chimeric immunoglobulin heavy chain according to claim 1 and (2) an immunoglobulin light chain. 5. The chimeric antibody, or antigen-binding fragment thereof, according to claim 4, wherein the immunoglobulin light chain is an immunoglobulin lambda light chain. 6. The chimeric antibody, or antigen-binding fragment thereof, according to claim 4, wherein the immunoglobulin light chain is an immunoglobulin kappa light chain. 7. The chimeric antibody, or antigen-binding fragment thereof, according to claim 4, wherein the immunoglobulin light chain is human. 8. The chimeric antibody, or antigen-binding fragment thereof, according to claim 7, wherein the non-human CH2 domain and the non-human CH3 domain are mouse. 9. The chimeric antibody, or antigen-binding fragment thereof, according to claim 4, wherein the immunoglobulin light chain is murine. 10. The chimeric antibody, or antigen-binding fragment thereof, according to claim 9, wherein the immunoglobulin light chain is mouse. 11. The chimeric antibody, or antigen-binding fragment thereof, according to claim 4, wherein the non-human CH2 domain and the non-human CH3 domain are murine. 12. The chimeric antibody, or antigen-binding fragment thereof, according to claim 11, wherein the non-human CH2 domain and the non-human CH3 domain are mouse. 13. A polynucleotide encoding the chimeric immunoglobulin heavy chain according to claim 1. 14. A construct comprising the polynucleotide according to claim 13.
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The invention provides non-human cells and mammals having a genome encoding chimeric antibodies and methods of producing transgenic cells and mammals. Certain aspects of the invention include chimeric antibodies, humanized antibodies, pharmaceutical compositions and kits. Certain aspects of the invention also relate to diagnostic and treatment methods using the antibodies of the invention.1. A chimeric immunoglobulin heavy chain comprising a human variable domain and a chimeric constant region comprising a human CH1 domain, a human upper hinge region, a non-human CH2 domain, and a non-human CH3 domain. 2. The chimeric immunoglobulin heavy chain according to claim 1, wherein the CH1 domain isotype is IgM, IgD, IgG1, IgG2, IgG3, IgG4, IgA, or IgE. 3. The chimeric immunoglobulin heavy chain according to claim 1, wherein the upper hinge region isotype is IgM, IgD, IgG1, IgG2, IgG3, IgG4, IgA, or IgE. 4. A chimeric antibody, or an antigen-binding fragment thereof, comprising (1) the chimeric immunoglobulin heavy chain according to claim 1 and (2) an immunoglobulin light chain. 5. The chimeric antibody, or antigen-binding fragment thereof, according to claim 4, wherein the immunoglobulin light chain is an immunoglobulin lambda light chain. 6. The chimeric antibody, or antigen-binding fragment thereof, according to claim 4, wherein the immunoglobulin light chain is an immunoglobulin kappa light chain. 7. The chimeric antibody, or antigen-binding fragment thereof, according to claim 4, wherein the immunoglobulin light chain is human. 8. The chimeric antibody, or antigen-binding fragment thereof, according to claim 7, wherein the non-human CH2 domain and the non-human CH3 domain are mouse. 9. The chimeric antibody, or antigen-binding fragment thereof, according to claim 4, wherein the immunoglobulin light chain is murine. 10. The chimeric antibody, or antigen-binding fragment thereof, according to claim 9, wherein the immunoglobulin light chain is mouse. 11. The chimeric antibody, or antigen-binding fragment thereof, according to claim 4, wherein the non-human CH2 domain and the non-human CH3 domain are murine. 12. The chimeric antibody, or antigen-binding fragment thereof, according to claim 11, wherein the non-human CH2 domain and the non-human CH3 domain are mouse. 13. A polynucleotide encoding the chimeric immunoglobulin heavy chain according to claim 1. 14. A construct comprising the polynucleotide according to claim 13.
| 1,600 |
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