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1,100 | 15,281,543 | 1,619 | The present invention relates to new rifaximin forms comprising solid dispersions of rifaximin, methods of making same and to their use in medicinal preparations and therapeutic methods. | 1. A pharmaceutical composition comprising
from about 33 wt % to about 35 wt % rifaximin; from about 33 wt % to about 35 wt % HPMC-AS; from about 3 wt % to about 5 wt % poloxamer 407; from about 4 wt % to about 14 wt % croscarmellose sodium; from about 10 wt % to about 19 wt % microcrystalline cellulose; from about 0.15 wt % to about 0.25 wt % colloidal silicon dioxide; and from about 0.45 wt % to about 0.55 wt % magnesium stearate. 2. The pharmaceutical composition of claim 1, wherein the croscarmellose sodium is present in an amount of from about 12 wt % to about 14 wt %. 3. The pharmaceutical composition of claim 1, wherein the croscarmellose sodium is present in an amount of about 13%. 4. The pharmaceutical composition of claim 1, wherein the microcrystalline cellulose is present in an amount from about 10 wt % to about 12 wt %. 5. The pharmaceutical composition of claim 1, wherein the microcrystalline cellulose is present in an amount of about 11 wt %. 6. The pharmaceutical composition of claim 1, wherein the croscarmellose sodium is present in an amount from about 4 wt % to about 6 wt %. 7. The pharmaceutical composition of claim 1, wherein the croscarmellose sodium is present in an amount of about 5 wt % 8. The pharmaceutical composition of claim 1, wherein the microcrystalline cellulose is present in an amount from about 17 wt % to about 19 wt %. 9. The pharmaceutical composition of claim 1, wherein the microcrystalline cellulose is present in an amount of about 18 wt %. 10. The pharmaceutical composition of claim 1, wherein the poloxamer 407 is present in an amount of about 4%. 11. The pharmaceutical composition of claim 1, wherein the colloidal silicon dioxide is present in an amount of about 0.20 wt %. 12. The pharmaceutical composition of claim 1, wherein the magnesium stearate is present in an amount of about 0.50 wt %. 13. The pharmaceutical composition of claim 1, wherein the rifaximin is present in an amount of about 34%. 14. The pharmaceutical composition of claim 1, wherein the HPMC-AS is present in an amount of about 34%. 15. The pharmaceutical composition of claim 1, wherein the total amount of rifaximin is about 80 mg. 16. A pharmaceutical composition comprising
from about 16 wt % to about 18 wt % rifaximin; from about 16 wt % to about 18 wt % HPMC-AS; from about 1 wt % to about 2 wt % poloxamer 407; from about 4 wt % to about 10 wt % croscarmellose sodium; from about 49 wt % to about 55 wt % microcrystalline cellulose; from about 0.15 wt % to about 0.25 wt % colloidal silicon dioxide; and from about 0.45 wt % to about 0.55 wt % magnesium stearate. 17. The pharmaceutical composition of claim 16, wherein the croscarmellose sodium is present in an amount from about 8 wt % to about 10 wt %. 18. The pharmaceutical composition of claim 16, wherein the croscarmellose sodium is present in an amount of about 9 wt %. 19. The pharmaceutical composition of claim 16, wherein the microcrystalline cellulose is present in an amount from about 49 wt % to about 51 wt %. 20. The pharmaceutical composition of claim 16, wherein the microcrystalline cellulose is present in an amount of about 51 wt %. 21. The pharmaceutical composition of claim 16, wherein the croscarmellose sodium is present in an amount from about 4 wt % to about 6 wt %. 22. The pharmaceutical composition of claim 16, wherein the croscarmellose sodium is present in an amount of about 5 wt % 23. The pharmaceutical composition of claim 16, wherein the microcrystalline cellulose is present in an amount from about 53 wt % to about 55 wt %. 24. The pharmaceutical composition of claim 16, wherein the microcrystalline cellulose is present in an amount of about 54 wt %. 25. The pharmaceutical composition of claim 16, wherein colloidal silicon dioxide is present in an amount of about 0.20 wt %. 26. The pharmaceutical composition of claim 16, wherein the magnesium stearate is present in an amount of about 0.50 wt %. 27. The pharmaceutical composition of claim 16, wherein the rifaximin is present in an amount of about 17 wt %. 28. The pharmaceutical composition of claim 16, wherein the HMPC-AS is present in an amount of about 17 wt %. 29. The pharmaceutical composition of claim 16, wherein the total amount of rifaximin is 40 mg. 30. The pharmaceutical composition of claim 1, wherein the composition is in the form of a tablet. 31. The pharmaceutical composition of claim 16, wherein the composition is in the form of a tablet. 32. The pharmaceutical composition of claim 30, wherein the composition is immediate release or sustained extended release. 33. The pharmaceutical composition of claim 31, wherein the composition is immediate release or sustained extended release. 34. A method of reducing the time to hospitalization associated with a complication of liver disease in a subject, comprising administering to the subject a composition of any claim 1. 35. The method of claim 34, wherein the complication of liver disease is selected from one or more of HE, EVB, SBP, and HRS. 36. A method of reducing the time to hospitalization associated with a complication of liver disease in a subject, comprising administering to the subject a composition of any claim 16. 37. The method of claim 36, wherein the complication of liver disease is selected from one or more of HE, EVB, SBP, and HRS. 38. A method of reducing the time to development of refractory ascites in a subject, comprising administering to the subject a composition of claim 1. 39. A method of reducing the time to development of refractory ascites in a subject, comprising administering to the subject a composition of claim 16. | The present invention relates to new rifaximin forms comprising solid dispersions of rifaximin, methods of making same and to their use in medicinal preparations and therapeutic methods.1. A pharmaceutical composition comprising
from about 33 wt % to about 35 wt % rifaximin; from about 33 wt % to about 35 wt % HPMC-AS; from about 3 wt % to about 5 wt % poloxamer 407; from about 4 wt % to about 14 wt % croscarmellose sodium; from about 10 wt % to about 19 wt % microcrystalline cellulose; from about 0.15 wt % to about 0.25 wt % colloidal silicon dioxide; and from about 0.45 wt % to about 0.55 wt % magnesium stearate. 2. The pharmaceutical composition of claim 1, wherein the croscarmellose sodium is present in an amount of from about 12 wt % to about 14 wt %. 3. The pharmaceutical composition of claim 1, wherein the croscarmellose sodium is present in an amount of about 13%. 4. The pharmaceutical composition of claim 1, wherein the microcrystalline cellulose is present in an amount from about 10 wt % to about 12 wt %. 5. The pharmaceutical composition of claim 1, wherein the microcrystalline cellulose is present in an amount of about 11 wt %. 6. The pharmaceutical composition of claim 1, wherein the croscarmellose sodium is present in an amount from about 4 wt % to about 6 wt %. 7. The pharmaceutical composition of claim 1, wherein the croscarmellose sodium is present in an amount of about 5 wt % 8. The pharmaceutical composition of claim 1, wherein the microcrystalline cellulose is present in an amount from about 17 wt % to about 19 wt %. 9. The pharmaceutical composition of claim 1, wherein the microcrystalline cellulose is present in an amount of about 18 wt %. 10. The pharmaceutical composition of claim 1, wherein the poloxamer 407 is present in an amount of about 4%. 11. The pharmaceutical composition of claim 1, wherein the colloidal silicon dioxide is present in an amount of about 0.20 wt %. 12. The pharmaceutical composition of claim 1, wherein the magnesium stearate is present in an amount of about 0.50 wt %. 13. The pharmaceutical composition of claim 1, wherein the rifaximin is present in an amount of about 34%. 14. The pharmaceutical composition of claim 1, wherein the HPMC-AS is present in an amount of about 34%. 15. The pharmaceutical composition of claim 1, wherein the total amount of rifaximin is about 80 mg. 16. A pharmaceutical composition comprising
from about 16 wt % to about 18 wt % rifaximin; from about 16 wt % to about 18 wt % HPMC-AS; from about 1 wt % to about 2 wt % poloxamer 407; from about 4 wt % to about 10 wt % croscarmellose sodium; from about 49 wt % to about 55 wt % microcrystalline cellulose; from about 0.15 wt % to about 0.25 wt % colloidal silicon dioxide; and from about 0.45 wt % to about 0.55 wt % magnesium stearate. 17. The pharmaceutical composition of claim 16, wherein the croscarmellose sodium is present in an amount from about 8 wt % to about 10 wt %. 18. The pharmaceutical composition of claim 16, wherein the croscarmellose sodium is present in an amount of about 9 wt %. 19. The pharmaceutical composition of claim 16, wherein the microcrystalline cellulose is present in an amount from about 49 wt % to about 51 wt %. 20. The pharmaceutical composition of claim 16, wherein the microcrystalline cellulose is present in an amount of about 51 wt %. 21. The pharmaceutical composition of claim 16, wherein the croscarmellose sodium is present in an amount from about 4 wt % to about 6 wt %. 22. The pharmaceutical composition of claim 16, wherein the croscarmellose sodium is present in an amount of about 5 wt % 23. The pharmaceutical composition of claim 16, wherein the microcrystalline cellulose is present in an amount from about 53 wt % to about 55 wt %. 24. The pharmaceutical composition of claim 16, wherein the microcrystalline cellulose is present in an amount of about 54 wt %. 25. The pharmaceutical composition of claim 16, wherein colloidal silicon dioxide is present in an amount of about 0.20 wt %. 26. The pharmaceutical composition of claim 16, wherein the magnesium stearate is present in an amount of about 0.50 wt %. 27. The pharmaceutical composition of claim 16, wherein the rifaximin is present in an amount of about 17 wt %. 28. The pharmaceutical composition of claim 16, wherein the HMPC-AS is present in an amount of about 17 wt %. 29. The pharmaceutical composition of claim 16, wherein the total amount of rifaximin is 40 mg. 30. The pharmaceutical composition of claim 1, wherein the composition is in the form of a tablet. 31. The pharmaceutical composition of claim 16, wherein the composition is in the form of a tablet. 32. The pharmaceutical composition of claim 30, wherein the composition is immediate release or sustained extended release. 33. The pharmaceutical composition of claim 31, wherein the composition is immediate release or sustained extended release. 34. A method of reducing the time to hospitalization associated with a complication of liver disease in a subject, comprising administering to the subject a composition of any claim 1. 35. The method of claim 34, wherein the complication of liver disease is selected from one or more of HE, EVB, SBP, and HRS. 36. A method of reducing the time to hospitalization associated with a complication of liver disease in a subject, comprising administering to the subject a composition of any claim 16. 37. The method of claim 36, wherein the complication of liver disease is selected from one or more of HE, EVB, SBP, and HRS. 38. A method of reducing the time to development of refractory ascites in a subject, comprising administering to the subject a composition of claim 1. 39. A method of reducing the time to development of refractory ascites in a subject, comprising administering to the subject a composition of claim 16. | 1,600 |
1,101 | 14,764,751 | 1,611 | The invention relates to a composition comprising, in a physiologically acceptable aqueous medium, a dicarboxylic acid containing from 2 to 8 carbon atoms, and a plant oil of triglyceride type with a fatty acid fraction comprising not more than 20% by weight of oleic acid, the composition having a pH ranging from 7 to 11. Process for straightening African-type hair using the composition and a straightening step with an iron at a temperature of at least 100° C. | 1-12. (canceled) 13. A composition comprising, in a physiologically acceptable aqueous medium:
a dicarboxylic acid containing from 2 to 8 carbon atoms, and a plant oil of triglyceride type with a fatty acid fraction comprising not more than 20% by weight of oleic acid, wherein the composition has a pH ranging from about 7 to about 11. 14. The composition according to claim 13, wherein the dicarboxylic acid is chosen from maleic acid, malic acid, itaconic acid, oxalic acid, malonic acid, oxomalonic acid, fumaric acid, succinic acid, tartaric acid, adipic acid, glutaric acid, α-ketoglutaric acid, or galactaric acid, salts thereof, or mixtures thereof. 15. The composition according to claim 13, wherein the dicarboxylic acid is maleic acid. 16. The composition according to claim 13, wherein the dicarboxylic acid is chosen from alkali metal salts or alkaline-earth metal salts of maleic acid, malic acid, itaconic acid, oxalic acid, malonic acid, oxomalonic acid, fumaric acid, succinic acid, tartaric acid, adipic acid, glutaric acid, α-ketoglutaric acid, or galactaric acid. 17. The composition according to claim 13, wherein the dicarboxylic acid is present in an amount ranging from about 0.5% to about 10% by weight, relative to the total weight of the composition. 18. The composition according to claim 13, wherein the dicarboxylic acid is present in an amount ranging from about 1% to about 5% by weight, relative to the total weight of the composition. 19. The composition according to claim 13, wherein the plant oil of triglyceride type with a fatty acid fraction comprising not more than 20% by weight of oleic acid is chosen from avocado oil, olive oil, or coriander oil. 20. The composition according to claim 13, wherein the plant oil of triglyceride type with a fatty acid fraction comprising not more than 20% by weight of oleic acid is avocado oil. 21. The composition according to claim 13, wherein the plant oil of triglyceride type with a fatty acid fraction comprising not more than 20% by weight of oleic acid is present in an amount ranging from about 1% to about 50% by weight, relative to the total weight of the composition. 22. The composition according to claim 13, wherein the plant oil of triglyceride type with a fatty acid fraction comprising not more than 20% by weight of oleic acid is present in an amount ranging from about 3% to about 40% by weight, relative to the total weight of the composition. 23. The composition according to claim 13, wherein the plant oil of triglyceride type with a fatty acid fraction comprising not more than 20% by weight of oleic acid is present in an amount ranging from about 5% to about 30% by weight, relative to the total weight of the composition. 24. The composition according to claim 13, further comprising a base. 25. The composition according to claim 13, further comprising a thickening polymer chosen from (meth)acryloyloxy(C1-C4)alkyltri(C1-C4)alkylammonium salt polymers, or nonionic cellulose-based polymers. 26. A process for straightening hair, the method comprising:
applying to the hair a composition comprising, in a physiologically acceptable aqueous medium:
a dicarboxylic acid containing from 2 to 8 carbon atoms, and
a plant oil of triglyceride type with a fatty acid fraction comprising not more than 20% by weight of oleic acid,
wherein the composition has a pH ranging from about 7 to about 11; and
straightening the hair using a curling iron at a temperature of at least about 100° C. 27. The process according to claim 26, wherein the curling iron is at a temperature ranging from about 100° C. to about 250° C. 28. A kit comprising:
a container comprising a cosmetic composition, wherein the cosmetic composition comprises, in a physiologically acceptable aqueous medium:
a dicarboxylic acid containing from 2 to 8 carbon atoms, and
a plant oil of triglyceride type with a fatty acid fraction comprising not more than 20% by weight of oleic acid; and
an iron configured to produce a temperature of at least about 100° C. | The invention relates to a composition comprising, in a physiologically acceptable aqueous medium, a dicarboxylic acid containing from 2 to 8 carbon atoms, and a plant oil of triglyceride type with a fatty acid fraction comprising not more than 20% by weight of oleic acid, the composition having a pH ranging from 7 to 11. Process for straightening African-type hair using the composition and a straightening step with an iron at a temperature of at least 100° C.1-12. (canceled) 13. A composition comprising, in a physiologically acceptable aqueous medium:
a dicarboxylic acid containing from 2 to 8 carbon atoms, and a plant oil of triglyceride type with a fatty acid fraction comprising not more than 20% by weight of oleic acid, wherein the composition has a pH ranging from about 7 to about 11. 14. The composition according to claim 13, wherein the dicarboxylic acid is chosen from maleic acid, malic acid, itaconic acid, oxalic acid, malonic acid, oxomalonic acid, fumaric acid, succinic acid, tartaric acid, adipic acid, glutaric acid, α-ketoglutaric acid, or galactaric acid, salts thereof, or mixtures thereof. 15. The composition according to claim 13, wherein the dicarboxylic acid is maleic acid. 16. The composition according to claim 13, wherein the dicarboxylic acid is chosen from alkali metal salts or alkaline-earth metal salts of maleic acid, malic acid, itaconic acid, oxalic acid, malonic acid, oxomalonic acid, fumaric acid, succinic acid, tartaric acid, adipic acid, glutaric acid, α-ketoglutaric acid, or galactaric acid. 17. The composition according to claim 13, wherein the dicarboxylic acid is present in an amount ranging from about 0.5% to about 10% by weight, relative to the total weight of the composition. 18. The composition according to claim 13, wherein the dicarboxylic acid is present in an amount ranging from about 1% to about 5% by weight, relative to the total weight of the composition. 19. The composition according to claim 13, wherein the plant oil of triglyceride type with a fatty acid fraction comprising not more than 20% by weight of oleic acid is chosen from avocado oil, olive oil, or coriander oil. 20. The composition according to claim 13, wherein the plant oil of triglyceride type with a fatty acid fraction comprising not more than 20% by weight of oleic acid is avocado oil. 21. The composition according to claim 13, wherein the plant oil of triglyceride type with a fatty acid fraction comprising not more than 20% by weight of oleic acid is present in an amount ranging from about 1% to about 50% by weight, relative to the total weight of the composition. 22. The composition according to claim 13, wherein the plant oil of triglyceride type with a fatty acid fraction comprising not more than 20% by weight of oleic acid is present in an amount ranging from about 3% to about 40% by weight, relative to the total weight of the composition. 23. The composition according to claim 13, wherein the plant oil of triglyceride type with a fatty acid fraction comprising not more than 20% by weight of oleic acid is present in an amount ranging from about 5% to about 30% by weight, relative to the total weight of the composition. 24. The composition according to claim 13, further comprising a base. 25. The composition according to claim 13, further comprising a thickening polymer chosen from (meth)acryloyloxy(C1-C4)alkyltri(C1-C4)alkylammonium salt polymers, or nonionic cellulose-based polymers. 26. A process for straightening hair, the method comprising:
applying to the hair a composition comprising, in a physiologically acceptable aqueous medium:
a dicarboxylic acid containing from 2 to 8 carbon atoms, and
a plant oil of triglyceride type with a fatty acid fraction comprising not more than 20% by weight of oleic acid,
wherein the composition has a pH ranging from about 7 to about 11; and
straightening the hair using a curling iron at a temperature of at least about 100° C. 27. The process according to claim 26, wherein the curling iron is at a temperature ranging from about 100° C. to about 250° C. 28. A kit comprising:
a container comprising a cosmetic composition, wherein the cosmetic composition comprises, in a physiologically acceptable aqueous medium:
a dicarboxylic acid containing from 2 to 8 carbon atoms, and
a plant oil of triglyceride type with a fatty acid fraction comprising not more than 20% by weight of oleic acid; and
an iron configured to produce a temperature of at least about 100° C. | 1,600 |
1,102 | 14,410,887 | 1,627 | Disclosed herein are methods and compositions related to the discovery that cholesterol inhibitors induce the anti-proliferative protein, estrogen receptor beta (ERβ), in both ERα-positive and ERα-negative breast cancer cell lines, including triple negative cells. | 1.-49. (canceled) 50. A method of treatment of cancer in a subject, comprising:
i) administering an amount of cholesterol biosynthesis inhibitor sufficient to induce ERβ in cancer cells; and ii) administering a therapeutically effective amount of a selective or nonselective ERβ agonist;
wherein these steps may be performed sequentially or concurrently. 51. The method as recited in claim 50, wherein the cholesterol biosynthesis inhibitor is an inhibitor of OSC. 52. The method as recited in claim 50, wherein the cancer is a type of cancer selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, lung cancer, and combinations thereof. 53. The method as recited in claim 50, wherein the ERβ agonist is a selective ERβ agonist. 54. The method as recited in claim 50, additionally comprising administering an antihormone. 55. A method of treatment of cancer in a subject, comprising:
i) administering an amount of cholesterol biosynthesis inhibitor sufficient to induce ERβ in cancer cells; and ii) administering a therapeutically effective amount of an antihormone;
wherein these steps may be performed sequentially or concurrently. 56. The method as recited in claim 55, wherein the cholesterol biosynthesis inhibitor is an inhibitor of OSC. 57. The method as recited in claim 55, wherein the cancer is a type of cancer selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, lung cancer, and combinations thereof. 58. The method as recited in claim 55, wherein the antihormone is an antiestrogen. 59. A method of treatment of a disease responsive to chemotherapy, comprising:
i) administering an amount of cholesterol biosynthesis inhibitor sufficient to induce ERβ in cancer cells; and ii) administering a subtherapeutic amount of a chemotherapeutic drug;
wherein these steps may be performed sequentially or concurrently. 60. The method as recited in claim 59, wherein the cholesterol biosynthesis inhibitor is an inhibitor of OSC. 61. The method as recited in claim 59, wherein the disease is cancer. 62. A pharmaceutical composition selected from the group consisting of a composition comprising a cholesterol inhibitor and a selective or nonselective ERβ agonist, a composition comprising a cholesterol inhibitor and an antihormone, and combinations thereof. 63. The pharmaceutical composition as recited in claim 62, wherein the cholesterol inhibitor is an inhibitor of cholesterol biosynthesis. 64. The pharmaceutical composition as recited in claim 62, wherein the ERβ agonist is s selective ERβ agonist. 65. The pharmaceutical composition as recited in claim 62, wherein the antihormone is an antiestrogen. 66. A kit comprising:
i) a cholesterol biosynthesis inhibitor formulated for administration to a patient; ii) a therapeutically effective amount of a selective or nonselective ERβ agonist formulated for administration to a patient; iii) instructions for administration to a patient. 67. The kit as recited in claim 66, wherein the cholesterol biosynthesis inhibitor is an inhibitor of OSC. 68. The kit as recited in claim 66, wherein the ERβ agonist is a selective ERβ agonist. 69. The kit as recited in claim 66, additionally comprising administering an antihormone. | Disclosed herein are methods and compositions related to the discovery that cholesterol inhibitors induce the anti-proliferative protein, estrogen receptor beta (ERβ), in both ERα-positive and ERα-negative breast cancer cell lines, including triple negative cells.1.-49. (canceled) 50. A method of treatment of cancer in a subject, comprising:
i) administering an amount of cholesterol biosynthesis inhibitor sufficient to induce ERβ in cancer cells; and ii) administering a therapeutically effective amount of a selective or nonselective ERβ agonist;
wherein these steps may be performed sequentially or concurrently. 51. The method as recited in claim 50, wherein the cholesterol biosynthesis inhibitor is an inhibitor of OSC. 52. The method as recited in claim 50, wherein the cancer is a type of cancer selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, lung cancer, and combinations thereof. 53. The method as recited in claim 50, wherein the ERβ agonist is a selective ERβ agonist. 54. The method as recited in claim 50, additionally comprising administering an antihormone. 55. A method of treatment of cancer in a subject, comprising:
i) administering an amount of cholesterol biosynthesis inhibitor sufficient to induce ERβ in cancer cells; and ii) administering a therapeutically effective amount of an antihormone;
wherein these steps may be performed sequentially or concurrently. 56. The method as recited in claim 55, wherein the cholesterol biosynthesis inhibitor is an inhibitor of OSC. 57. The method as recited in claim 55, wherein the cancer is a type of cancer selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, lung cancer, and combinations thereof. 58. The method as recited in claim 55, wherein the antihormone is an antiestrogen. 59. A method of treatment of a disease responsive to chemotherapy, comprising:
i) administering an amount of cholesterol biosynthesis inhibitor sufficient to induce ERβ in cancer cells; and ii) administering a subtherapeutic amount of a chemotherapeutic drug;
wherein these steps may be performed sequentially or concurrently. 60. The method as recited in claim 59, wherein the cholesterol biosynthesis inhibitor is an inhibitor of OSC. 61. The method as recited in claim 59, wherein the disease is cancer. 62. A pharmaceutical composition selected from the group consisting of a composition comprising a cholesterol inhibitor and a selective or nonselective ERβ agonist, a composition comprising a cholesterol inhibitor and an antihormone, and combinations thereof. 63. The pharmaceutical composition as recited in claim 62, wherein the cholesterol inhibitor is an inhibitor of cholesterol biosynthesis. 64. The pharmaceutical composition as recited in claim 62, wherein the ERβ agonist is s selective ERβ agonist. 65. The pharmaceutical composition as recited in claim 62, wherein the antihormone is an antiestrogen. 66. A kit comprising:
i) a cholesterol biosynthesis inhibitor formulated for administration to a patient; ii) a therapeutically effective amount of a selective or nonselective ERβ agonist formulated for administration to a patient; iii) instructions for administration to a patient. 67. The kit as recited in claim 66, wherein the cholesterol biosynthesis inhibitor is an inhibitor of OSC. 68. The kit as recited in claim 66, wherein the ERβ agonist is a selective ERβ agonist. 69. The kit as recited in claim 66, additionally comprising administering an antihormone. | 1,600 |
1,103 | 16,038,929 | 1,612 | An oral care composition, including a structurant including a carboxypolymethylene polymer, a humectant including glycerin, a whitening agent including hydrogen peroxide, and a carrier including water, wherein the oral care composition has a pH from about 4 to about 6, a transmission rate of at least 58%, a refraction index of about 1.40 or less, and a transmission loss rate of 2% or less at a surface interface due to refraction of light, for light in the wavelength of about 400 nm to about 420 nm. | 1. An oral care composition, comprising:
from about 2 weight % to about 6 weight % of a structurant comprising a carboxypolymethylene polymer, based on a total weight of the oral care composition; from about 20 weight % to about 40 weight % of a humectant comprising glycerin, based on the total weight of the oral care composition; from about 0.1 weight % to about 15 weight % of a whitening agent comprising hydrogen peroxide, based on the total weight of the oral care composition; and at least 40 weight % of a carrier comprising water, based on the total weight of the oral care composition, wherein the oral care composition has a pH from about 4 to about 6, wherein the oral care composition has a transmission rate of at least 58% for light in the wavelength of about 400 nm to about 420 nm, wherein the oral care composition has a refraction index of about 1.40 or less for light in the wavelength of about 400 nm to about 420 nm, and wherein the oral care composition has a transmission loss rate of 2% or less at a surface interface due to refraction of light in the wavelength of about 400 nm to about 420 nm. 2. The oral care composition of claim 1, wherein all the ingredients of the oral care composition are orally acceptable and water-soluble. 3. The oral care composition of claim 1, wherein the oral care composition lacks oil-based or non-water-soluble ingredients. 4. The oral care composition of claim 1, wherein the structurant comprises at least one of Carbopol 974 NF, Carbopol 980 NF, and Carbopol 971P NF. 5. The oral care composition of claim 1, wherein the structurant consists essentially of Carbopol 974 NF. 6. The oral care composition of claim 1, comprising:
about 3 weight % of the structurant; from about 30 weight % to about 35 weight % of the humectant; and from about 6 weight % to about 9 weight % of the whitening agent, wherein the oral care composition has a pH from about 4.8 to about 5.8. 7. The oral care composition of claim 1, wherein the oral care composition has a transmission rate of at least 68% for light in the wavelength of about 400 nm to about 420 nm, and
wherein the oral care composition has a transmission loss rate of 1% or less at the surface interface due to refraction of light in the wavelength of about 400 nm to about 420 nm. 8. The oral care composition of claim 1, further comprising:
0.01weight % or less of a stabilizer, based on the total weight of the oral care composition; from about 0.5 weight % to about 2.0 weight % of a pH regulating agent, based on the total weight of the oral care composition; from about 0.1 weight % to about 2.0 weight % of a flavorant, based on the total weight of the oral care composition; and from about 0.1 weight % to about 5.0 weight % of a hypersensitivity agent, based on the total weight of the oral care composition, wherein the flavorant is water-soluble and is not oil-based. 9. The oral care composition of claim 8, comprising:
0.01weight % or less stabilizer; from about 0.5 weight % to about 2.0 weight % of the pH regulating agent; wherein the stabilizer comprises EDTA, the pH regulating agent comprises NaOH, and the hypersensitivity agent comprises potassium nitrate. 10. The oral care composition of claim 1, wherein the oral care composition has a static yield of about 50 Pa or more. 11. The oral care composition of claim 1, wherein a hydrogen peroxide content of the oral care composition is greater than about 70% of an initial hydrogen peroxide content of the oral care composition, after 8 weeks of aging at 40° C. 12. The oral care composition of claim 1, wherein a hydrogen peroxide content of the oral care composition is greater than about 70% of an initial hydrogen peroxide content of the oral care composition, after 13 weeks of aging at 40° C. 13. An oral care composition, consisting essentially of:
about 3 weight % of a structurant comprising a carboxypolymethylene polymer, based on a total weight of the oral care composition; from about 30 weight % to about 35 weight % of a humectant comprising glycerin, based on the total weight of the oral care composition; from about 6 weight % to about 9 weight % of a whitening agent comprising hydrogen peroxide, based on the total weight of the oral care composition; and at least 40 weight % of an aqueous carrier, based on the total weight of the oral care composition, wherein all the ingredients of the oral care composition are orally acceptable and water-soluble, wherein the oral care composition has a static yield of about 30 Pa or more, and wherein a hydrogen peroxide content of the oral care composition is greater than about 70% of an initial hydrogen peroxide content of the oral care composition, after 13 weeks of aging at 40° C. 14. The oral care composition of claim 13, further comprising 0.01weight % or less of a stabilizer comprising EDTA;
from about 0.5 weight % to about 2.0 weight % of a pH regulating agent comprising NaOH; from about 0.1 weight % to about 2.0 weight % of a water-soluble flavorant; and from about 0.1 weight % to about 5.0 weight % of a hypersensitivity agent comprising potassium nitrate. 15. The oral care composition of claim 13, wherein the oral care composition has a pH from about 4.8 to about 5.8,
wherein the oral care composition has a transmission rate of at least 68% for light in the wavelength of about 400 nm to about 420 nm, wherein the oral care composition has a refraction index of about 1.39 or less for light in the wavelength of about 400 nm to about 420 nm, and wherein the oral care composition has a transmission loss rate of 2% or less at a surface interface due to refraction of light in the wavelength of about 400 nm to about 420 nm 16. The oral care composition of claim 13, wherein the structurant comprises Carbopol 974 NF. 17. The oral care composition of claim 13, wherein the oral care composition is a teeth whitening gel configured for use with a mouth tray and a light source. | An oral care composition, including a structurant including a carboxypolymethylene polymer, a humectant including glycerin, a whitening agent including hydrogen peroxide, and a carrier including water, wherein the oral care composition has a pH from about 4 to about 6, a transmission rate of at least 58%, a refraction index of about 1.40 or less, and a transmission loss rate of 2% or less at a surface interface due to refraction of light, for light in the wavelength of about 400 nm to about 420 nm.1. An oral care composition, comprising:
from about 2 weight % to about 6 weight % of a structurant comprising a carboxypolymethylene polymer, based on a total weight of the oral care composition; from about 20 weight % to about 40 weight % of a humectant comprising glycerin, based on the total weight of the oral care composition; from about 0.1 weight % to about 15 weight % of a whitening agent comprising hydrogen peroxide, based on the total weight of the oral care composition; and at least 40 weight % of a carrier comprising water, based on the total weight of the oral care composition, wherein the oral care composition has a pH from about 4 to about 6, wherein the oral care composition has a transmission rate of at least 58% for light in the wavelength of about 400 nm to about 420 nm, wherein the oral care composition has a refraction index of about 1.40 or less for light in the wavelength of about 400 nm to about 420 nm, and wherein the oral care composition has a transmission loss rate of 2% or less at a surface interface due to refraction of light in the wavelength of about 400 nm to about 420 nm. 2. The oral care composition of claim 1, wherein all the ingredients of the oral care composition are orally acceptable and water-soluble. 3. The oral care composition of claim 1, wherein the oral care composition lacks oil-based or non-water-soluble ingredients. 4. The oral care composition of claim 1, wherein the structurant comprises at least one of Carbopol 974 NF, Carbopol 980 NF, and Carbopol 971P NF. 5. The oral care composition of claim 1, wherein the structurant consists essentially of Carbopol 974 NF. 6. The oral care composition of claim 1, comprising:
about 3 weight % of the structurant; from about 30 weight % to about 35 weight % of the humectant; and from about 6 weight % to about 9 weight % of the whitening agent, wherein the oral care composition has a pH from about 4.8 to about 5.8. 7. The oral care composition of claim 1, wherein the oral care composition has a transmission rate of at least 68% for light in the wavelength of about 400 nm to about 420 nm, and
wherein the oral care composition has a transmission loss rate of 1% or less at the surface interface due to refraction of light in the wavelength of about 400 nm to about 420 nm. 8. The oral care composition of claim 1, further comprising:
0.01weight % or less of a stabilizer, based on the total weight of the oral care composition; from about 0.5 weight % to about 2.0 weight % of a pH regulating agent, based on the total weight of the oral care composition; from about 0.1 weight % to about 2.0 weight % of a flavorant, based on the total weight of the oral care composition; and from about 0.1 weight % to about 5.0 weight % of a hypersensitivity agent, based on the total weight of the oral care composition, wherein the flavorant is water-soluble and is not oil-based. 9. The oral care composition of claim 8, comprising:
0.01weight % or less stabilizer; from about 0.5 weight % to about 2.0 weight % of the pH regulating agent; wherein the stabilizer comprises EDTA, the pH regulating agent comprises NaOH, and the hypersensitivity agent comprises potassium nitrate. 10. The oral care composition of claim 1, wherein the oral care composition has a static yield of about 50 Pa or more. 11. The oral care composition of claim 1, wherein a hydrogen peroxide content of the oral care composition is greater than about 70% of an initial hydrogen peroxide content of the oral care composition, after 8 weeks of aging at 40° C. 12. The oral care composition of claim 1, wherein a hydrogen peroxide content of the oral care composition is greater than about 70% of an initial hydrogen peroxide content of the oral care composition, after 13 weeks of aging at 40° C. 13. An oral care composition, consisting essentially of:
about 3 weight % of a structurant comprising a carboxypolymethylene polymer, based on a total weight of the oral care composition; from about 30 weight % to about 35 weight % of a humectant comprising glycerin, based on the total weight of the oral care composition; from about 6 weight % to about 9 weight % of a whitening agent comprising hydrogen peroxide, based on the total weight of the oral care composition; and at least 40 weight % of an aqueous carrier, based on the total weight of the oral care composition, wherein all the ingredients of the oral care composition are orally acceptable and water-soluble, wherein the oral care composition has a static yield of about 30 Pa or more, and wherein a hydrogen peroxide content of the oral care composition is greater than about 70% of an initial hydrogen peroxide content of the oral care composition, after 13 weeks of aging at 40° C. 14. The oral care composition of claim 13, further comprising 0.01weight % or less of a stabilizer comprising EDTA;
from about 0.5 weight % to about 2.0 weight % of a pH regulating agent comprising NaOH; from about 0.1 weight % to about 2.0 weight % of a water-soluble flavorant; and from about 0.1 weight % to about 5.0 weight % of a hypersensitivity agent comprising potassium nitrate. 15. The oral care composition of claim 13, wherein the oral care composition has a pH from about 4.8 to about 5.8,
wherein the oral care composition has a transmission rate of at least 68% for light in the wavelength of about 400 nm to about 420 nm, wherein the oral care composition has a refraction index of about 1.39 or less for light in the wavelength of about 400 nm to about 420 nm, and wherein the oral care composition has a transmission loss rate of 2% or less at a surface interface due to refraction of light in the wavelength of about 400 nm to about 420 nm 16. The oral care composition of claim 13, wherein the structurant comprises Carbopol 974 NF. 17. The oral care composition of claim 13, wherein the oral care composition is a teeth whitening gel configured for use with a mouth tray and a light source. | 1,600 |
1,104 | 15,444,445 | 1,633 | A method is used for preparing a product for use in repairing a lesion or defect at a tissue site in a human or animal patient body. The method includes obtaining tissue from a donor human or animal body and freezing the obtained tissue. The method further includes pulverizing the frozen tissue and suspending the pulverized tissue in a fluid. The method further includes homogenizing the tissue suspension and precipitating tissue particles from the homogenized tissue suspension. The method further includes re-suspending the precipitated tissue particles and lyophilizing the tissue re-suspension to provide the product to be used in repairing the lesion or defect. | 1. A method for preparing a product for use in repairing a lesion or defect at a tissue site in a human or animal patient body, the method comprising:
obtaining tissue from a donor human or animal body; freezing the obtained tissue; pulverizing the frozen tissue; suspending the pulverized tissue in a fluid; homogenizing the tissue suspension; precipitating tissue particles from the homogenized tissue suspension; re-suspending the precipitated tissue particles; and lyophilizing the tissue re-suspension to provide the product to be used in repairing the lesion or defect. 2. The method of claim 1, further comprising:
rehydrating the lyophilized tissue to form a slurry. 3. The method of claim 2, further comprising:
forming a porous solid scaffold consisting of the slurry. 4. The method of claim 3, wherein:
forming the porous solid scaffold includes molding the slurry to have a size and geometry determined by the tissue site. 5. The method of claim 4, wherein:
molding the slurry includes:
casting the slurry into a mold,
cross-linking the cast slurry, and
freeze-drying the cross-linked slurry. 6. The method of claim 1, wherein:
the obtained tissue is a substantially non-mineralized soft tissue. 7. The method of claim 6, wherein:
the substantially non-mineralized soft tissue is a same type of tissue as a tissue at the tissue site in the human or animal patient body. 8. The method of claim 1, wherein:
pulverizing the frozen tissue includes pulverizing the frozen tissue to form particles having a particle size of less than about 800 μm. 9. The method of claim 8, wherein the particle size is in a range of 1 μm to 100 μm. 10. The method of claim 1, further comprising:
freezing the tissue re-suspension prior to lyophilizing the tissue re-suspension. 11. The method of claim 1, further comprising:
mincing the obtained tissue into small pieces prior to freezing the obtained tissue. 12. The method of claim 11, wherein:
the small pieces have a piece size in a range of 1 mm2 to 5 mm2. 13. A product produced according to the method of claim 1. 14. A method for repairing a lesion or defect at a tissue site in a human or animal patient body, the method comprising:
obtaining tissue from a donor human or animal body; freezing the obtained tissue; pulverizing the frozen tissue; suspending the pulverized tissue in a fluid; homogenizing the tissue suspension; precipitating tissue particles from the homogenized tissue suspension; re-suspending the precipitated tissue particles; lyophilizing the tissue re-suspension to form a dry formulation; reconstituting the dry formulation to form a slurry; and implanting the slurry into the lesion or defect at the tissue site in the human or animal patient body. 15. The method of claim 14, further comprising:
forming a porous solid scaffold of the slurry, wherein implanting the slurry into the lesion or defect includes implanting the porous solid scaffold into the lesion or defect. 16. The method of claim 14, further comprising:
binding the slurry to a scaffold, wherein implanting the slurry into the lesion or defect includes implanting the scaffold into the lesion or defect. 17. The method of claim 14, further comprising:
combining the slurry with cells, wherein implanting the slurry into the lesion or defect includes implanting the slurry-cell combination into the lesion or defect. 18. The method of claim 14, further comprising:
combining the slurry with exogenously introduced biologically active molecules, wherein implanting the slurry into the lesion or defect includes implanting the slurry-molecule combination into the lesion or defect. 19. The method of claim 14, further comprising:
obtaining a fluid from the human or animal patient body, wherein reconstituting the dry formulation includes reconstituting the dry formulation with the fluid from the human or animal patient body to form the slurry. 20. A product for introduction within a tissue site of the human or animal body, the product comprising:
a matrix of a substantially non-mineralized native soft tissue of the human or animal body, the matrix including a plurality of pores, the matrix formed by lyophilizing a tissue suspension, wherein: the tissue suspension includes precipitated tissue particles suspended in a fluid, the precipitated tissue particles are tissue particles precipitated from a homogenized tissue suspension, the homogenized tissue suspension is a homogenization of pulverized tissue suspended in a second fluid, and the pulverized tissue is frozen tissue obtained from a donor human or animal body that has been pulverized. | A method is used for preparing a product for use in repairing a lesion or defect at a tissue site in a human or animal patient body. The method includes obtaining tissue from a donor human or animal body and freezing the obtained tissue. The method further includes pulverizing the frozen tissue and suspending the pulverized tissue in a fluid. The method further includes homogenizing the tissue suspension and precipitating tissue particles from the homogenized tissue suspension. The method further includes re-suspending the precipitated tissue particles and lyophilizing the tissue re-suspension to provide the product to be used in repairing the lesion or defect.1. A method for preparing a product for use in repairing a lesion or defect at a tissue site in a human or animal patient body, the method comprising:
obtaining tissue from a donor human or animal body; freezing the obtained tissue; pulverizing the frozen tissue; suspending the pulverized tissue in a fluid; homogenizing the tissue suspension; precipitating tissue particles from the homogenized tissue suspension; re-suspending the precipitated tissue particles; and lyophilizing the tissue re-suspension to provide the product to be used in repairing the lesion or defect. 2. The method of claim 1, further comprising:
rehydrating the lyophilized tissue to form a slurry. 3. The method of claim 2, further comprising:
forming a porous solid scaffold consisting of the slurry. 4. The method of claim 3, wherein:
forming the porous solid scaffold includes molding the slurry to have a size and geometry determined by the tissue site. 5. The method of claim 4, wherein:
molding the slurry includes:
casting the slurry into a mold,
cross-linking the cast slurry, and
freeze-drying the cross-linked slurry. 6. The method of claim 1, wherein:
the obtained tissue is a substantially non-mineralized soft tissue. 7. The method of claim 6, wherein:
the substantially non-mineralized soft tissue is a same type of tissue as a tissue at the tissue site in the human or animal patient body. 8. The method of claim 1, wherein:
pulverizing the frozen tissue includes pulverizing the frozen tissue to form particles having a particle size of less than about 800 μm. 9. The method of claim 8, wherein the particle size is in a range of 1 μm to 100 μm. 10. The method of claim 1, further comprising:
freezing the tissue re-suspension prior to lyophilizing the tissue re-suspension. 11. The method of claim 1, further comprising:
mincing the obtained tissue into small pieces prior to freezing the obtained tissue. 12. The method of claim 11, wherein:
the small pieces have a piece size in a range of 1 mm2 to 5 mm2. 13. A product produced according to the method of claim 1. 14. A method for repairing a lesion or defect at a tissue site in a human or animal patient body, the method comprising:
obtaining tissue from a donor human or animal body; freezing the obtained tissue; pulverizing the frozen tissue; suspending the pulverized tissue in a fluid; homogenizing the tissue suspension; precipitating tissue particles from the homogenized tissue suspension; re-suspending the precipitated tissue particles; lyophilizing the tissue re-suspension to form a dry formulation; reconstituting the dry formulation to form a slurry; and implanting the slurry into the lesion or defect at the tissue site in the human or animal patient body. 15. The method of claim 14, further comprising:
forming a porous solid scaffold of the slurry, wherein implanting the slurry into the lesion or defect includes implanting the porous solid scaffold into the lesion or defect. 16. The method of claim 14, further comprising:
binding the slurry to a scaffold, wherein implanting the slurry into the lesion or defect includes implanting the scaffold into the lesion or defect. 17. The method of claim 14, further comprising:
combining the slurry with cells, wherein implanting the slurry into the lesion or defect includes implanting the slurry-cell combination into the lesion or defect. 18. The method of claim 14, further comprising:
combining the slurry with exogenously introduced biologically active molecules, wherein implanting the slurry into the lesion or defect includes implanting the slurry-molecule combination into the lesion or defect. 19. The method of claim 14, further comprising:
obtaining a fluid from the human or animal patient body, wherein reconstituting the dry formulation includes reconstituting the dry formulation with the fluid from the human or animal patient body to form the slurry. 20. A product for introduction within a tissue site of the human or animal body, the product comprising:
a matrix of a substantially non-mineralized native soft tissue of the human or animal body, the matrix including a plurality of pores, the matrix formed by lyophilizing a tissue suspension, wherein: the tissue suspension includes precipitated tissue particles suspended in a fluid, the precipitated tissue particles are tissue particles precipitated from a homogenized tissue suspension, the homogenized tissue suspension is a homogenization of pulverized tissue suspended in a second fluid, and the pulverized tissue is frozen tissue obtained from a donor human or animal body that has been pulverized. | 1,600 |
1,105 | 15,850,416 | 1,616 | A method and corresponding pharmaceutical composition for inhibiting the growth of fungi. The method uses an antifungal composition containing as the active ingredient one or more nylon-3 copolymers having a formula:
or a salt thereof,
wherein:
each R is independently hydrogen or C 1 -C 6 -alkyl;
each R 1 , R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen or substituted or unsubstituted C 1 -C 6 -alkyl;
each R 2 is C 1 -C 6 -alkylene;
“A” is hydrogen or an amino-protecting group;
“B” is hydroxyl or a carboxy-protecting group; and
“X,” “Y,” and “Z” are positive numbers. | 1. A method of inhibiting fungal growth, the method comprising:
contacting fungi with a composition comprising a nylon-3 copolymer having a formula:
or a salt thereof,
wherein:
each R is independently hydrogen or C1-C6-alkyl;
each R1, R3, R4, R5, and R6 are each independently selected from the group consisting of hydrogen or substituted or unsubstituted C1-C6-alkyl;
each R2 is C1-C6-alkylene;
“A” is hydrogen or an amino-protecting group;
“B” is hydroxyl or a carboxy-protecting group; and
“X,” “Y,” and “Z” are positive numbers. 2. The method of claim 1, wherein the nylon-3 copolymer is a random copolymer. 3. The method of claim 1, wherein the nylon-3 copolymer is a block copolymer. 4. The method of claim 1, wherein:
R1, R3, R4, R5, and R6 are each methyl; and R2 is methylene. 5. The method of claim 1, wherein:
“A” is
and
“B” is
wherein R is hydrogen or C1-C6-alkyl. 6. The method of claim 1, wherein X is a number between 0.1 and 0.9, Y is a number between 0.1 and 0.9, and Z is a number between 5 and 100. 7. The method of claim 1, wherein X is a number between 0.1 and 0.9, Y is a number between 0.1 and 0.9, and Z is a number between 10 and 50. 8. The method of claim 1, wherein X is a number between 0.1 and 0.9, Y is a number between 0.1 and 0.9, and Z is a number between 10 and 20. 9. The method of claim 1, comprising contacting the composition to a fungi of the genera Aspergillus, Candida, Cryptococcus, and/or Fusarium. 10. A method of inhibiting fungal infections in mammals, the method comprising:
administering to a mammalian subject in need thereof a fungal growth-inhibiting amount of a nylon-3 copolymer having a formula:
or a salt thereof,
wherein:
R1, R3, R4, R5, and R6 are each independently selected from the group consisting of hydrogen or substituted or unsubstituted C1-C6-alkyl;
R2 is C1-C6-alkylene;
“A” is hydrogen or an amino-protecting group;
“B” is hydroxyl or a carboxy-protecting group; and
“X,” “Y,” and “Z” are positive numbers. 11. The method of claim 10, which is a method treating a fungal infection by a fungus within the genera Aspergillus, Candida, Cryptococcus, and/or Fusarium. 12. The method of claim 10, wherein the nylon-3 copolymer is a random copolymer. 13. The method of claim 10, wherein the nylon-3 copolymer is a block copolymer. 14. The method of claim 10, wherein:
R1, R3, R4, R5, and R6 are each methyl; and R2 is methylene. 15. The method of claim 10, wherein:
“A” is
and
“B” is
wherein R is hydrogen or C1-C6-alkyl. 16. The method of claim 10, wherein X is a number between 0.1 and 0.9, Y is a number between 0.1 and 0.9, and Z is a number between 5 and 100. 17. The method of claim 10, wherein X is a number between 0.1 and 0.9, Y is a number between 0.1 and 0.9, and Z is a number between 10 and 50. 18. The method of claim 10, wherein X is a number between 0.1 and 0.9, Y is a number between 0.1 and 0.9, and Z is a number between 10 and 20. 19. A pharmaceutical composition comprising:
a fungal growth-inhibiting amount of a nylon-3 copolymer having a formula:
or a pharmaceutically suitable salt thereof,
wherein:
R1, R3, R4, R5, and R6 are each independently selected from the group consisting of hydrogen or substituted or unsubstituted C1-C6-alkyl;
R2 is C1-C6-alkylene;
“A” is hydrogen or an amino-protecting group;
“B” is hydroxyl or a carboxy-protecting group; and
“X,” “Y,” and “Z” are positive numbers;
in combination with a pharmaceutically suitable carrier. 20. The composition of claim 19, wherein the nylon-3 copolymer is a random copolymer. 21. The composition of claim 19, wherein the nylon-3 copolymer is a block copolymer. 22. The composition of claim 19, wherein:
R1, R3, R4, R5, and R6 are each methyl; and R2 is methylene. 23. The composition of claim 19, wherein:
“A” is
and
“B” is
wherein R is hydrogen or C1-C6-alkyl. 24. The composition of claim 19, wherein X is a number between 0.1 and 0.9, Y is a number between 0.1 and 0.9, and Z is a number between 5 and 100. 25. The composition of claim 19, wherein X is a number between 0.1 and 0.9, Y is a number between 0.1 and 0.9, and Z is a number between 10 and 50. 26. The composition of claim 19, wherein X is a number between 0.1 and 0.9, Y is a number between 0.1 and 0.9, and Z is a number between 10 and 20. | A method and corresponding pharmaceutical composition for inhibiting the growth of fungi. The method uses an antifungal composition containing as the active ingredient one or more nylon-3 copolymers having a formula:
or a salt thereof,
wherein:
each R is independently hydrogen or C 1 -C 6 -alkyl;
each R 1 , R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen or substituted or unsubstituted C 1 -C 6 -alkyl;
each R 2 is C 1 -C 6 -alkylene;
“A” is hydrogen or an amino-protecting group;
“B” is hydroxyl or a carboxy-protecting group; and
“X,” “Y,” and “Z” are positive numbers.1. A method of inhibiting fungal growth, the method comprising:
contacting fungi with a composition comprising a nylon-3 copolymer having a formula:
or a salt thereof,
wherein:
each R is independently hydrogen or C1-C6-alkyl;
each R1, R3, R4, R5, and R6 are each independently selected from the group consisting of hydrogen or substituted or unsubstituted C1-C6-alkyl;
each R2 is C1-C6-alkylene;
“A” is hydrogen or an amino-protecting group;
“B” is hydroxyl or a carboxy-protecting group; and
“X,” “Y,” and “Z” are positive numbers. 2. The method of claim 1, wherein the nylon-3 copolymer is a random copolymer. 3. The method of claim 1, wherein the nylon-3 copolymer is a block copolymer. 4. The method of claim 1, wherein:
R1, R3, R4, R5, and R6 are each methyl; and R2 is methylene. 5. The method of claim 1, wherein:
“A” is
and
“B” is
wherein R is hydrogen or C1-C6-alkyl. 6. The method of claim 1, wherein X is a number between 0.1 and 0.9, Y is a number between 0.1 and 0.9, and Z is a number between 5 and 100. 7. The method of claim 1, wherein X is a number between 0.1 and 0.9, Y is a number between 0.1 and 0.9, and Z is a number between 10 and 50. 8. The method of claim 1, wherein X is a number between 0.1 and 0.9, Y is a number between 0.1 and 0.9, and Z is a number between 10 and 20. 9. The method of claim 1, comprising contacting the composition to a fungi of the genera Aspergillus, Candida, Cryptococcus, and/or Fusarium. 10. A method of inhibiting fungal infections in mammals, the method comprising:
administering to a mammalian subject in need thereof a fungal growth-inhibiting amount of a nylon-3 copolymer having a formula:
or a salt thereof,
wherein:
R1, R3, R4, R5, and R6 are each independently selected from the group consisting of hydrogen or substituted or unsubstituted C1-C6-alkyl;
R2 is C1-C6-alkylene;
“A” is hydrogen or an amino-protecting group;
“B” is hydroxyl or a carboxy-protecting group; and
“X,” “Y,” and “Z” are positive numbers. 11. The method of claim 10, which is a method treating a fungal infection by a fungus within the genera Aspergillus, Candida, Cryptococcus, and/or Fusarium. 12. The method of claim 10, wherein the nylon-3 copolymer is a random copolymer. 13. The method of claim 10, wherein the nylon-3 copolymer is a block copolymer. 14. The method of claim 10, wherein:
R1, R3, R4, R5, and R6 are each methyl; and R2 is methylene. 15. The method of claim 10, wherein:
“A” is
and
“B” is
wherein R is hydrogen or C1-C6-alkyl. 16. The method of claim 10, wherein X is a number between 0.1 and 0.9, Y is a number between 0.1 and 0.9, and Z is a number between 5 and 100. 17. The method of claim 10, wherein X is a number between 0.1 and 0.9, Y is a number between 0.1 and 0.9, and Z is a number between 10 and 50. 18. The method of claim 10, wherein X is a number between 0.1 and 0.9, Y is a number between 0.1 and 0.9, and Z is a number between 10 and 20. 19. A pharmaceutical composition comprising:
a fungal growth-inhibiting amount of a nylon-3 copolymer having a formula:
or a pharmaceutically suitable salt thereof,
wherein:
R1, R3, R4, R5, and R6 are each independently selected from the group consisting of hydrogen or substituted or unsubstituted C1-C6-alkyl;
R2 is C1-C6-alkylene;
“A” is hydrogen or an amino-protecting group;
“B” is hydroxyl or a carboxy-protecting group; and
“X,” “Y,” and “Z” are positive numbers;
in combination with a pharmaceutically suitable carrier. 20. The composition of claim 19, wherein the nylon-3 copolymer is a random copolymer. 21. The composition of claim 19, wherein the nylon-3 copolymer is a block copolymer. 22. The composition of claim 19, wherein:
R1, R3, R4, R5, and R6 are each methyl; and R2 is methylene. 23. The composition of claim 19, wherein:
“A” is
and
“B” is
wherein R is hydrogen or C1-C6-alkyl. 24. The composition of claim 19, wherein X is a number between 0.1 and 0.9, Y is a number between 0.1 and 0.9, and Z is a number between 5 and 100. 25. The composition of claim 19, wherein X is a number between 0.1 and 0.9, Y is a number between 0.1 and 0.9, and Z is a number between 10 and 50. 26. The composition of claim 19, wherein X is a number between 0.1 and 0.9, Y is a number between 0.1 and 0.9, and Z is a number between 10 and 20. | 1,600 |
1,106 | 16,216,225 | 1,616 | Proppants are used in oil and gas extraction, particularly in fracking operations. The invention relates to resin coated proppants. The coatings on proppants have antimicrobial materials incorporated within these coatings. The antimicrobially active agents are incorporated in a concentration less than 70% by weight of the coatings or the active agent from these coatings can be released from these coatings in the environment of the proppants. | 1. An oil field proppant comprising frac sand or an aluminum oxide-containing particulate wherein said proppant is coated with a polymer coating containing at least one antimicrobial material wherein the weight percent of the antimicrobial material is greater than 20 wt. % and less than 70 wt. % as compared to the weight of said polymer coating so that the polymer coating releases antimicrobial material or a component of the antimicrobial material with antimicrobial properties under conditions present in an oil well, thereby providing antimicrobial activity in the well. 2. The proppant of claim 1, wherein the antimicrobial material does not react with the coating. 3. The proppant of claim 1, wherein the said antimicrobial material is added to the coating in porous particles. 4. The proppant of claim 1, wherein the said polymer coating is partially cured prior to introduction of the proppant into the oil well. 5. The proppant of claim 1, wherein the said antimicrobial material is a liquid. 6. The proppant of claim 1, wherein the polymer coating comprises at least two layers where at least one layer contains the said antimicrobial material. 7. An oil field proppant comprising frac sand or an aluminum oxide-containing particulate wherein said proppant is coated with a polymer coating containing at least one antimicrobial material wherein the said antimicrobial material does not react with the said polymer coating, and the coating releases the antimicrobial material or a component of the antimicrobial material with antimicrobial properties under conditions present in an oil well, thereby providing antimicrobial activity in the well. 8. The proppant of claim 7, wherein the weight percent of the antimicrobial material is in the range of 0.05 to 70 wt. % as compared to the weight of said polymer coating. 9. The proppant of claim 7, wherein the weight percent of the antimicrobial material is greater than 20% and less than 70 wt. % as compared to the weight of said polymer coating. 10. The proppant of claim 7, having properties such that the polymer coating is uncured prior to introduction into an oil well and cures in the oil well. 11. The proppant of claim 7, wherein the polymer coating comprises porous particles containing the said antimicrobial material. 12. The proppant of claim 7, wherein the said antimicrobial material has a density greater than that of the polymer of the polymer coating. 13. The proppant of claim 7, wherein the said antimicrobial material is an organic material. 14. The proppant of claim 7, wherein the polymer coating comprises at least two layers where at least one layer of the at least two layers contains the said antimicrobial material. 15. The proppant of claim 11, wherein the porous particles have a BET surface area greater than 20 m2/g. 16. The proppant of claim 11, wherein the particle size of the porous particles is in the range of 0.3 to 20 μm. 17. The proppant of claim 11, wherein the said antimicrobial material is an organic material. 18. The proppant of claim 11, wherein the polymer coating comprises at least two layers where at least one layer contains the said antimicrobial material. 19. A method of forming oil-field proppant particles coated with a polymeric coating containing at least one antimicrobial material, the method comprising:
a) mixing said antimicrobial material with a polymeric coating formulation to form a polymeric coating mixture, wherein the antimicrobial material is greater than 20 wt % and less than 70 wt. % as compared to the weight of said polymeric coating; b) coating said polymeric coating mixture onto the oil-field proppant particles; and c) at least one of drying, partially curing and curing the polymeric coating mixture, such that the said oil-field proppant particles are coated with the polymeric coating that releases the antimicrobial material or a component of the antimicrobial material with antimicrobial properties under conditions present in an oil well. 20. A method of providing antimicrobial activity in an oil well, the method comprising:
supplying a proppant particle comprising a frac sand or an aluminum oxide-containing particulate into the oil well, wherein the proppant is coated with a polymeric coating containing at least one antimicrobial material; (a) wherein the antimicrobial material is greater than 20 wt. % and less than 70 wt. % as compared to the weight of said coating; (b) whereby the antimicrobial material or a component of the antimicrobial material with antimicrobial properties is released under the conditions present in the oil well, thereby providing antimicrobial activity in the well. 21. A method of providing antimicrobial activity in an oil well, the method comprising:
(c) supplying a proppant particle comprising a frac sand or an aluminum oxide-containing particulate into the oil well, wherein the proppant is mixed with a resin containing at least one antimicrobial material to form a mixture; wherein the antimicrobial material is greater than 0.05 wt. % and less than 70 wt. % as compared to the weight of said resin; and (d) dispensing said mixture in the oil well such that at least part of the resin cures in the well and the antimicrobial material or a component of the antimicrobial material with antimicrobial properties is released under the conditions present in the oil well, thereby providing antimicrobial activity in the well. | Proppants are used in oil and gas extraction, particularly in fracking operations. The invention relates to resin coated proppants. The coatings on proppants have antimicrobial materials incorporated within these coatings. The antimicrobially active agents are incorporated in a concentration less than 70% by weight of the coatings or the active agent from these coatings can be released from these coatings in the environment of the proppants.1. An oil field proppant comprising frac sand or an aluminum oxide-containing particulate wherein said proppant is coated with a polymer coating containing at least one antimicrobial material wherein the weight percent of the antimicrobial material is greater than 20 wt. % and less than 70 wt. % as compared to the weight of said polymer coating so that the polymer coating releases antimicrobial material or a component of the antimicrobial material with antimicrobial properties under conditions present in an oil well, thereby providing antimicrobial activity in the well. 2. The proppant of claim 1, wherein the antimicrobial material does not react with the coating. 3. The proppant of claim 1, wherein the said antimicrobial material is added to the coating in porous particles. 4. The proppant of claim 1, wherein the said polymer coating is partially cured prior to introduction of the proppant into the oil well. 5. The proppant of claim 1, wherein the said antimicrobial material is a liquid. 6. The proppant of claim 1, wherein the polymer coating comprises at least two layers where at least one layer contains the said antimicrobial material. 7. An oil field proppant comprising frac sand or an aluminum oxide-containing particulate wherein said proppant is coated with a polymer coating containing at least one antimicrobial material wherein the said antimicrobial material does not react with the said polymer coating, and the coating releases the antimicrobial material or a component of the antimicrobial material with antimicrobial properties under conditions present in an oil well, thereby providing antimicrobial activity in the well. 8. The proppant of claim 7, wherein the weight percent of the antimicrobial material is in the range of 0.05 to 70 wt. % as compared to the weight of said polymer coating. 9. The proppant of claim 7, wherein the weight percent of the antimicrobial material is greater than 20% and less than 70 wt. % as compared to the weight of said polymer coating. 10. The proppant of claim 7, having properties such that the polymer coating is uncured prior to introduction into an oil well and cures in the oil well. 11. The proppant of claim 7, wherein the polymer coating comprises porous particles containing the said antimicrobial material. 12. The proppant of claim 7, wherein the said antimicrobial material has a density greater than that of the polymer of the polymer coating. 13. The proppant of claim 7, wherein the said antimicrobial material is an organic material. 14. The proppant of claim 7, wherein the polymer coating comprises at least two layers where at least one layer of the at least two layers contains the said antimicrobial material. 15. The proppant of claim 11, wherein the porous particles have a BET surface area greater than 20 m2/g. 16. The proppant of claim 11, wherein the particle size of the porous particles is in the range of 0.3 to 20 μm. 17. The proppant of claim 11, wherein the said antimicrobial material is an organic material. 18. The proppant of claim 11, wherein the polymer coating comprises at least two layers where at least one layer contains the said antimicrobial material. 19. A method of forming oil-field proppant particles coated with a polymeric coating containing at least one antimicrobial material, the method comprising:
a) mixing said antimicrobial material with a polymeric coating formulation to form a polymeric coating mixture, wherein the antimicrobial material is greater than 20 wt % and less than 70 wt. % as compared to the weight of said polymeric coating; b) coating said polymeric coating mixture onto the oil-field proppant particles; and c) at least one of drying, partially curing and curing the polymeric coating mixture, such that the said oil-field proppant particles are coated with the polymeric coating that releases the antimicrobial material or a component of the antimicrobial material with antimicrobial properties under conditions present in an oil well. 20. A method of providing antimicrobial activity in an oil well, the method comprising:
supplying a proppant particle comprising a frac sand or an aluminum oxide-containing particulate into the oil well, wherein the proppant is coated with a polymeric coating containing at least one antimicrobial material; (a) wherein the antimicrobial material is greater than 20 wt. % and less than 70 wt. % as compared to the weight of said coating; (b) whereby the antimicrobial material or a component of the antimicrobial material with antimicrobial properties is released under the conditions present in the oil well, thereby providing antimicrobial activity in the well. 21. A method of providing antimicrobial activity in an oil well, the method comprising:
(c) supplying a proppant particle comprising a frac sand or an aluminum oxide-containing particulate into the oil well, wherein the proppant is mixed with a resin containing at least one antimicrobial material to form a mixture; wherein the antimicrobial material is greater than 0.05 wt. % and less than 70 wt. % as compared to the weight of said resin; and (d) dispensing said mixture in the oil well such that at least part of the resin cures in the well and the antimicrobial material or a component of the antimicrobial material with antimicrobial properties is released under the conditions present in the oil well, thereby providing antimicrobial activity in the well. | 1,600 |
1,107 | 14,706,165 | 1,633 | The present invention discloses recovery and isolation of mesenchymal stem cells from the peripheral blood. This has an advantage of being able to obtain multilineage inducible cells from readily obtainable and autologous allogenic blood. With the present invention it is no longer necessary to depend on cadaver donor bone marrow, a technically complicated and an expensive process. Instead the patient may obtain the needed stem cells from a relatively small amount of his/her own blood, or from readily available blood donors. | 1. A composition of isolated, post-natal, multilineage inducible, morphologically distinct cells from the peripheral blood which express at least CD90. 2. The composition of claim 1 wherein the cells are isolated from a biological sample of the peripheral blood, human or animal. 3. The composition of claim 1 wherein the cells do not express markers comprising HLADR and CD34 or high levels of CD45. 4. The composition of claim 1 provided in a kit containing a defined and purified population of multilineage-inducible cells, the kit comprising:
a vial or container of the cells; and
a syringe for removing the cells from the vial or container for delivering the cells to a patient. 5. A method of isolating post-natal, multilineage inducible, morphologically distinct cells from the peripheral blood which express at least CD90 inducing osteogenic or chondrogenic differentiation of a composition, comprising the steps of culturing of the multilineage induced cells in a chondrogenic medium including TBF beta 3, ascorbic acid, dexamethasone, sodium pyruvate, insulin, transferrin and glucose or in osteogenic medium. 6. The method of claim 5 wherein the cells are grown on a thin bone plate with or without perforation. 7. The method of claim 6 wherein cells are grown on decalcified thin bone plate. 8. The method of claim 5 wherein the cells are contacted with freeze-dried, dried, dehydrated, frozen, cryopreserved or fresh particulate cartilage to induce chondrogenic differentiation. 9. The method of claim 5 wherein the cells are contacted with dried, freeze-dried, dehydrated, frozen, cryopreserved or fresh particulate bone to induce osteogenic differentiation. 10. The method of claim 5 wherein cells are contacted with freeze-dried, dried, dehydrated, frozen, or fresh particulate periosteum to induce osteogenic differentiation. 11. The method of claim 5 wherein cells are contacted with freeze-dried, dried, dehydrated, frozen, cryopreserved or fresh particulate endosteum to effect osteogenic differentiation. 12. The method of claim 5 wherein cells are placed in contact with freeze-dried, dried, dehydrated, frozen, cryopreserved or fresh particulate nervous tissue derived from the spinal cord, peripheral nerves or brain to effect neural differentiation. 13. A method of treating a human patient-donor with cells from his or her own peripheral blood using a therapeutically effective amount of a composition of isolated, post-natal, multilineage inducible, morphologically distinct cells from the peripheral blood which express at least CD90 comprising the steps of:
extracting peripheral blood from the patient-donor to be treated; isolating the cells from the peripheral blood which express at least CD90 marker; acquiring a therapeutically effective amount of said cells for treating the patient-donor; and treating said patient-donor with his or her isolated cells taken from the peripheral blood wherein said patient-donor has a nerve or orthopaedic bone or cartilage or connective tissue condition that is treated by the administration of the patient-donor isolated cells to induce repair of said condition. 14. (canceled) 15. (canceled) 16. The method of claim 13 wherein the cells are contacted with freeze-dried, dried, dehydrated, frozen, cryopreserved or fresh particulate cartilage to induce chondrogenic differentiation. 17. The method of claim 13 wherein the cells are contacted with, freeze-dried, dehydrated, cryopreserved or fresh particulate bone to induce osteogenic differentiation. 18. The method of claim 13 wherein cells are contacted with freeze-dried, dried, dehydrated, frozen, or fresh particulate periosteum to induce osteogenic differentiation. 19. The method of claim 13 wherein cells are contacted with freeze-dried, dried, dehydrated, frozen, cryopreserved or fresh particulate endosteum to effect osteogenic differentiation. 20. The method of claim 13 wherein cells are placed in contact with freeze-dried, dried, dehydrated, frozen, cryopreserved or fresh particulate nervous tissue derived from the spinal cord, peripheral nerves or brain to effect neural differentiation. | The present invention discloses recovery and isolation of mesenchymal stem cells from the peripheral blood. This has an advantage of being able to obtain multilineage inducible cells from readily obtainable and autologous allogenic blood. With the present invention it is no longer necessary to depend on cadaver donor bone marrow, a technically complicated and an expensive process. Instead the patient may obtain the needed stem cells from a relatively small amount of his/her own blood, or from readily available blood donors.1. A composition of isolated, post-natal, multilineage inducible, morphologically distinct cells from the peripheral blood which express at least CD90. 2. The composition of claim 1 wherein the cells are isolated from a biological sample of the peripheral blood, human or animal. 3. The composition of claim 1 wherein the cells do not express markers comprising HLADR and CD34 or high levels of CD45. 4. The composition of claim 1 provided in a kit containing a defined and purified population of multilineage-inducible cells, the kit comprising:
a vial or container of the cells; and
a syringe for removing the cells from the vial or container for delivering the cells to a patient. 5. A method of isolating post-natal, multilineage inducible, morphologically distinct cells from the peripheral blood which express at least CD90 inducing osteogenic or chondrogenic differentiation of a composition, comprising the steps of culturing of the multilineage induced cells in a chondrogenic medium including TBF beta 3, ascorbic acid, dexamethasone, sodium pyruvate, insulin, transferrin and glucose or in osteogenic medium. 6. The method of claim 5 wherein the cells are grown on a thin bone plate with or without perforation. 7. The method of claim 6 wherein cells are grown on decalcified thin bone plate. 8. The method of claim 5 wherein the cells are contacted with freeze-dried, dried, dehydrated, frozen, cryopreserved or fresh particulate cartilage to induce chondrogenic differentiation. 9. The method of claim 5 wherein the cells are contacted with dried, freeze-dried, dehydrated, frozen, cryopreserved or fresh particulate bone to induce osteogenic differentiation. 10. The method of claim 5 wherein cells are contacted with freeze-dried, dried, dehydrated, frozen, or fresh particulate periosteum to induce osteogenic differentiation. 11. The method of claim 5 wherein cells are contacted with freeze-dried, dried, dehydrated, frozen, cryopreserved or fresh particulate endosteum to effect osteogenic differentiation. 12. The method of claim 5 wherein cells are placed in contact with freeze-dried, dried, dehydrated, frozen, cryopreserved or fresh particulate nervous tissue derived from the spinal cord, peripheral nerves or brain to effect neural differentiation. 13. A method of treating a human patient-donor with cells from his or her own peripheral blood using a therapeutically effective amount of a composition of isolated, post-natal, multilineage inducible, morphologically distinct cells from the peripheral blood which express at least CD90 comprising the steps of:
extracting peripheral blood from the patient-donor to be treated; isolating the cells from the peripheral blood which express at least CD90 marker; acquiring a therapeutically effective amount of said cells for treating the patient-donor; and treating said patient-donor with his or her isolated cells taken from the peripheral blood wherein said patient-donor has a nerve or orthopaedic bone or cartilage or connective tissue condition that is treated by the administration of the patient-donor isolated cells to induce repair of said condition. 14. (canceled) 15. (canceled) 16. The method of claim 13 wherein the cells are contacted with freeze-dried, dried, dehydrated, frozen, cryopreserved or fresh particulate cartilage to induce chondrogenic differentiation. 17. The method of claim 13 wherein the cells are contacted with, freeze-dried, dehydrated, cryopreserved or fresh particulate bone to induce osteogenic differentiation. 18. The method of claim 13 wherein cells are contacted with freeze-dried, dried, dehydrated, frozen, or fresh particulate periosteum to induce osteogenic differentiation. 19. The method of claim 13 wherein cells are contacted with freeze-dried, dried, dehydrated, frozen, cryopreserved or fresh particulate endosteum to effect osteogenic differentiation. 20. The method of claim 13 wherein cells are placed in contact with freeze-dried, dried, dehydrated, frozen, cryopreserved or fresh particulate nervous tissue derived from the spinal cord, peripheral nerves or brain to effect neural differentiation. | 1,600 |
1,108 | 12,058,387 | 1,612 | The invention relates to novel arginine salts, compositions comprising them, and their uses. | 1. A salt of arginine and one or more of the following conjugate acids:
a. an acidic polymer; b. a conjugate acid of an anionic surfactant salt; c. a polyphosphoric or polyphosphonic acid, or d. an acidic antimicrobial agent. 2. The salt of claim 1 in solid form. 3. The salt of claim 1, wherein the conjugate acid is an acidic polymer. 4. The salt of claim 1, wherein the conjugate acid is the conjugate acid of an anionic surfactant salt. 5. The salt of claim 1, wherein the conjugate acid is a polyphosphoric acid. 6. The salt of claim 1, wherein conjugate acid is a polyphosphonic acid. 7. The salt of claim 1, wherein the conjugate acid is an acidic antimicrobial agent. 8. The salt of claim 3, wherein the acidic polymer is a polycarboxylate polymer. 9. The salt of claim 8 wherein the polycarboxylate polymer is a copolymer of methyl vinyl ether and maleic anhydride. 10. The salt of claim 4, wherein the acid is lauroyl sulfuric acid. 11. The salt of claim 5, wherein the polyphosphoric acid is hexametaphosphoric acid. 12. The salt of claim 7 wherein the acid is a benzoic acid optionally substituted with carboxy and one or more hydroxys. 13. The salt of claim 12, wherein the acidic antimicrobial agent is gallic acid. 14. An oral care composition comprising the salt of claim 1. 15. A method comprising applying an effective amount of the salt of claim 1 or the composition of claim 14 to the oral cavity of a subject in need thereof to
i. reduce or inhibit formation of dental caries, ii. reduce, repair or inhibit early enamel lesions, 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 mouth, vii. reduce levels of acid producing bacteria, viii. to increase relative levels of arginolytic bacteria, ix. inhibit microbial biofilm formation in the oral cavity, x. raise and/or maintain plaque pH at levels of at least pH about 5.5 following sugar challenge, xi. reduce plaque accumulation. xii. treat, relieve or reduce dry mouth, xiii. whiten teeth, xiv. enhance systemic health, including cardiovascular health, xv. reduce erosion of the teeth, xvi. immunize the teeth against cariogenic bacteria, and/or xvii. clean the teeth and oral cavity. | The invention relates to novel arginine salts, compositions comprising them, and their uses.1. A salt of arginine and one or more of the following conjugate acids:
a. an acidic polymer; b. a conjugate acid of an anionic surfactant salt; c. a polyphosphoric or polyphosphonic acid, or d. an acidic antimicrobial agent. 2. The salt of claim 1 in solid form. 3. The salt of claim 1, wherein the conjugate acid is an acidic polymer. 4. The salt of claim 1, wherein the conjugate acid is the conjugate acid of an anionic surfactant salt. 5. The salt of claim 1, wherein the conjugate acid is a polyphosphoric acid. 6. The salt of claim 1, wherein conjugate acid is a polyphosphonic acid. 7. The salt of claim 1, wherein the conjugate acid is an acidic antimicrobial agent. 8. The salt of claim 3, wherein the acidic polymer is a polycarboxylate polymer. 9. The salt of claim 8 wherein the polycarboxylate polymer is a copolymer of methyl vinyl ether and maleic anhydride. 10. The salt of claim 4, wherein the acid is lauroyl sulfuric acid. 11. The salt of claim 5, wherein the polyphosphoric acid is hexametaphosphoric acid. 12. The salt of claim 7 wherein the acid is a benzoic acid optionally substituted with carboxy and one or more hydroxys. 13. The salt of claim 12, wherein the acidic antimicrobial agent is gallic acid. 14. An oral care composition comprising the salt of claim 1. 15. A method comprising applying an effective amount of the salt of claim 1 or the composition of claim 14 to the oral cavity of a subject in need thereof to
i. reduce or inhibit formation of dental caries, ii. reduce, repair or inhibit early enamel lesions, 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 mouth, vii. reduce levels of acid producing bacteria, viii. to increase relative levels of arginolytic bacteria, ix. inhibit microbial biofilm formation in the oral cavity, x. raise and/or maintain plaque pH at levels of at least pH about 5.5 following sugar challenge, xi. reduce plaque accumulation. xii. treat, relieve or reduce dry mouth, xiii. whiten teeth, xiv. enhance systemic health, including cardiovascular health, xv. reduce erosion of the teeth, xvi. immunize the teeth against cariogenic bacteria, and/or xvii. clean the teeth and oral cavity. | 1,600 |
1,109 | 15,805,219 | 1,612 | This application provides, among other things, novel aqueous biphasic compositions comprising two distinct aqueous phases, useful for combining and delivering poorly compatible ingredients, for example to deliver effective levels of cationic antibacterial agents in combination with anionic polymers, e.g. that protect against erosion and staining, by addition of a stabilizing amount of a polyamine, e.g. lysine, and methods for making and using the same. | 1. A composition comprising an aqueous solution of
a) an acidic polymer; b) a nonionic polymer; c) optionally an effective amount of cationic active agent; d) a stabilizing amount of a polyamine compound; and e) water; wherein the solution comprises two distinct aqueous phases having different composition and density. 2. The composition of claim 1 wherein the acidic polymer is selected from one or more of synthetic anionic linear polycarboxylates, phosphate/acrylate co-polymers, and combinations thereof. 3. The composition of claim 2 wherein the acidic polymer is selected from a combination of
a) 1:4 to 4:1 copolymers of maleic anhydride or acid with another polymerizable ethylenically unsaturated monomer, e.g., co-polymers of methyl vinyl ether/maleic anhydride, wherein some or all of the anhydride moieties are hydrolyzed to provide free carboxyl groups, and
b) co-polymerized products of a mixture of acrylic acid, methacrylic acid, and 2-hydroxyethyl methacrylate phosphates of Formula 1:
wherein n is 0, 1 or 2. 4. The composition of any foregoing claim wherein the nonionic polymer is selected from polyethylene glycols, polypropylene glycols, poloxamers, and random polyethylene glycol/polypropylene glycol copolymers, and mixtures thereof. 5. The composition of any foregoing claim comprising a cationic active agent selected from one or more of quaternary ammonium surfactants, bisguanides, cationic amino acids, metal cations, and combinations thereof. 6. The composition of any foregoing claim comprising a cationic active agent provided by an orally acceptable salt selected from zinc salts, stannous salts, chlorhexidine digluconate, and cetyl pyridinium chloride. 7. The composition of any foregoing claim wherein the polyamine is lysine, in free or salt form. 8. The composition of any foregoing claim wherein the composition comprises 70% to 95% water. 9. The composition of any foregoing claim wherein the composition comprises an anionic surfactant. 10. The composition of any foregoing claim having a pH of 5.5 to 8.0. 11. The composition of any foregoing claim which comprises less than 5% of hydrophobic ingredients. 12. The composition of any foregoing claim which is essentially oil-free, apart from flavoring agents. 13. The composition of any of claims 1-12 wherein the composition further comprises an oil phase. 14. The composition of any foregoing claim wherein the composition is an oral care composition, wherein the ingredients are orally acceptable, and wherein the composition comprises one or more of a thickener, a buffer, a humectant, a surfactant, an abrasive, a sweetener, a flavorant, a pigment, a dye, an anti-caries agent, an anti-bacterial agent, a whitening agent, a desensitizing agent, a preservative, or a mixture thereof. 15. The composition of any foregoing claim wherein the composition is a mouthwash. 16. The composition of claim 15 wherein:
a) the acidic polymer comprises a combination of a phosphate/acrylate co-polymer and a co-polymer of methyl vinyl ether/maleic anhydride in a total amount of 1% to 5%; e.g., about 2%;
b) the nonionic polymer comprises a combination of (i) polyethylene glycol having an average molecular weight of 5 kDa to 35 kDa, e.g., PEG 8 k or PEG 35 k, and (ii) poloxamer 407, in a total amount of 3 to 10%; e.g., 2-5% polyethylene glycol and 0.5-2% poloxamer;
c) the cationic active agent is present in an effective amount, in free or orally acceptable salt form and comprises cetyl pyridinium chloride, in an amount of 0.05 to 0.1%, e.g., about 0.075%;
d) the polyamine, in free or salt form, is lysine; and
e) the water is present in an amount of 70-95%, e.g., about 85-90%;
wherein the composition further comprises humectant, e.g., propylene glycol 1%-2.5%, e.g., about 1%, flavoring, sweetener, preservative (e.g. potassium sorbate 0.04%-0.06%), and dye (e.g., Blue Dye #1);
wherein all ingredients are orally acceptable, e.g., safe and palatable at relevant concentrations for use in a mouthwash; and
wherein all amounts are by weight of the total composition. 17. The composition of any foregoing claim wherein
a) the acidic polymer is selected from a phosphate/acrylate co-polymer, a co-polymer of methyl vinyl ether/maleic anhydride, and mixtures thereof, in a total amount of 1 to 12%; b) the nonionic polymer is selected from polyethylene glycol having a molecular weight of 5 kD to 35 kD, poloxamer 407 in an amount of 0 to 2%, and combinations thereof, in a total amount of 3 to 10%; c) the effective amount of orally acceptable cationic active agent, in free or orally acceptable salt form, is present and comprises cetyl pyridinium chloride, in an amount of 0.05 to 0.10% d) the polyamine compound comprises lysine in free or orally acceptable salt form, in a total amount of 1 to 10%; and e) the water is present in an amount of 35-95%; wherein the composition optionally further comprises an anionic surfactant and/or glutamic acid; and wherein all amounts are by weight of the total composition. 18. A composition according to any of Composition 1—1.86, supra. 19. A method according to any of Methods A-E, supra. | This application provides, among other things, novel aqueous biphasic compositions comprising two distinct aqueous phases, useful for combining and delivering poorly compatible ingredients, for example to deliver effective levels of cationic antibacterial agents in combination with anionic polymers, e.g. that protect against erosion and staining, by addition of a stabilizing amount of a polyamine, e.g. lysine, and methods for making and using the same.1. A composition comprising an aqueous solution of
a) an acidic polymer; b) a nonionic polymer; c) optionally an effective amount of cationic active agent; d) a stabilizing amount of a polyamine compound; and e) water; wherein the solution comprises two distinct aqueous phases having different composition and density. 2. The composition of claim 1 wherein the acidic polymer is selected from one or more of synthetic anionic linear polycarboxylates, phosphate/acrylate co-polymers, and combinations thereof. 3. The composition of claim 2 wherein the acidic polymer is selected from a combination of
a) 1:4 to 4:1 copolymers of maleic anhydride or acid with another polymerizable ethylenically unsaturated monomer, e.g., co-polymers of methyl vinyl ether/maleic anhydride, wherein some or all of the anhydride moieties are hydrolyzed to provide free carboxyl groups, and
b) co-polymerized products of a mixture of acrylic acid, methacrylic acid, and 2-hydroxyethyl methacrylate phosphates of Formula 1:
wherein n is 0, 1 or 2. 4. The composition of any foregoing claim wherein the nonionic polymer is selected from polyethylene glycols, polypropylene glycols, poloxamers, and random polyethylene glycol/polypropylene glycol copolymers, and mixtures thereof. 5. The composition of any foregoing claim comprising a cationic active agent selected from one or more of quaternary ammonium surfactants, bisguanides, cationic amino acids, metal cations, and combinations thereof. 6. The composition of any foregoing claim comprising a cationic active agent provided by an orally acceptable salt selected from zinc salts, stannous salts, chlorhexidine digluconate, and cetyl pyridinium chloride. 7. The composition of any foregoing claim wherein the polyamine is lysine, in free or salt form. 8. The composition of any foregoing claim wherein the composition comprises 70% to 95% water. 9. The composition of any foregoing claim wherein the composition comprises an anionic surfactant. 10. The composition of any foregoing claim having a pH of 5.5 to 8.0. 11. The composition of any foregoing claim which comprises less than 5% of hydrophobic ingredients. 12. The composition of any foregoing claim which is essentially oil-free, apart from flavoring agents. 13. The composition of any of claims 1-12 wherein the composition further comprises an oil phase. 14. The composition of any foregoing claim wherein the composition is an oral care composition, wherein the ingredients are orally acceptable, and wherein the composition comprises one or more of a thickener, a buffer, a humectant, a surfactant, an abrasive, a sweetener, a flavorant, a pigment, a dye, an anti-caries agent, an anti-bacterial agent, a whitening agent, a desensitizing agent, a preservative, or a mixture thereof. 15. The composition of any foregoing claim wherein the composition is a mouthwash. 16. The composition of claim 15 wherein:
a) the acidic polymer comprises a combination of a phosphate/acrylate co-polymer and a co-polymer of methyl vinyl ether/maleic anhydride in a total amount of 1% to 5%; e.g., about 2%;
b) the nonionic polymer comprises a combination of (i) polyethylene glycol having an average molecular weight of 5 kDa to 35 kDa, e.g., PEG 8 k or PEG 35 k, and (ii) poloxamer 407, in a total amount of 3 to 10%; e.g., 2-5% polyethylene glycol and 0.5-2% poloxamer;
c) the cationic active agent is present in an effective amount, in free or orally acceptable salt form and comprises cetyl pyridinium chloride, in an amount of 0.05 to 0.1%, e.g., about 0.075%;
d) the polyamine, in free or salt form, is lysine; and
e) the water is present in an amount of 70-95%, e.g., about 85-90%;
wherein the composition further comprises humectant, e.g., propylene glycol 1%-2.5%, e.g., about 1%, flavoring, sweetener, preservative (e.g. potassium sorbate 0.04%-0.06%), and dye (e.g., Blue Dye #1);
wherein all ingredients are orally acceptable, e.g., safe and palatable at relevant concentrations for use in a mouthwash; and
wherein all amounts are by weight of the total composition. 17. The composition of any foregoing claim wherein
a) the acidic polymer is selected from a phosphate/acrylate co-polymer, a co-polymer of methyl vinyl ether/maleic anhydride, and mixtures thereof, in a total amount of 1 to 12%; b) the nonionic polymer is selected from polyethylene glycol having a molecular weight of 5 kD to 35 kD, poloxamer 407 in an amount of 0 to 2%, and combinations thereof, in a total amount of 3 to 10%; c) the effective amount of orally acceptable cationic active agent, in free or orally acceptable salt form, is present and comprises cetyl pyridinium chloride, in an amount of 0.05 to 0.10% d) the polyamine compound comprises lysine in free or orally acceptable salt form, in a total amount of 1 to 10%; and e) the water is present in an amount of 35-95%; wherein the composition optionally further comprises an anionic surfactant and/or glutamic acid; and wherein all amounts are by weight of the total composition. 18. A composition according to any of Composition 1—1.86, supra. 19. A method according to any of Methods A-E, supra. | 1,600 |
1,110 | 12,841,331 | 1,618 | A nanodevice has a containment vessel defining a storage chamber therein and defining at least one port to provide access to and from said storage chamber, and a stopper assembly attached to the containment vessel. The stopper assembly has a blocking unit arranged proximate the at least one port and has a structure suitable to substantially prevent material after being loaded into the storage chamber from being released while the blocking unit is arranged in a blocking configuration. The stopper assembly is responsive to the presence of a predetermined stimulus such that the blocking unit is released in the presence of the predetermined stimulus to allow the material to be released from the storage chamber. The predetermined stimulus is a predetermined catalytic activity that is suitable to at least one of cleave, hydrolyze, oxidize, or reduce a portion of the stopper assembly, and the nanodevice has a maximum dimension of about 1 μm. | 1. A nanodevice, comprising:
a containment vessel defining a storage chamber therein and defining at least one port to provide access to and from said storage chamber; and a stopper assembly attached to said containment vessel, said stopper assembly comprising a blocking unit arranged proximate said at least one port and having a structure suitable to substantially prevent material after being loaded into said storage chamber from being released while said blocking unit is arranged in a blocking configuration, wherein said stopper assembly is responsive to the presence of a predetermined stimulus such that said blocking unit is released in the presence of said predetermined stimulus to allow said material to be released from said storage chamber, wherein said predetermined stimulus is a predetermined catalytic activity that is suitable to at least one of cleave, hydrolyze, oxidize, or reduce a portion of said stopper assembly, and wherein said nanodevice has a maximum dimension of about 1 μm. 2. A nanodevice according to claim 1, wherein said nanodevice has a maximum dimension of less than about 400 nm and greater than about 50 nm. 3. A nanodevice according to claim 1, wherein said nanodevice has a maximum dimension of less than about 300 nm and greater than about 50 nm. 4. A nanodevice according to claim 1, wherein said nanodevice has a maximum dimension of less than about 150 nm and greater than about 50 nm. 5. A nanodevice according to claim 1, further comprising a thread attached to said containment vessel proximate said port, said blocking unit having a structure so that it can become threaded over said thread. 6. A nanodevice according to claim 5, further comprising a stopper attached to said thread such that said stopper at least assists in holding said blocking unit in said blocking configuration. 7. A nanodevice according to claim 1, wherein said nanodevice is operable in an aqueous environment. 8. A nanodevice according to claim 1, wherein said nanodevice consists essentially of biocompatible materials in a composition thereof. 9. A nanodevice according to claim 1, wherein said containment vessel comprises silica in a material thereof. 10. A nanodevice according to claim 9, wherein said containment vessel is a mesoporous silica nanoparticle defining a plurality of substantially parallel pores therein, said storage chamber being one of said plurality of substantially parallel pores. 11. A nanodevice according to claim 1, wherein said stopper assembly comprises at least one of a [2]rotaxane or a [2]pseudorotaxane macromolecule. 12. A nanodevice according to claim 11, wherein said blocking unit of said stopper assembly is an α-cyclodextrin toroidal molecule. 13. A nanodevice according to claim 12, wherein said stopper assembly comprises a polyethylene thread attached to said containment vessel. 14. A nanodevice according to claim 13, wherein said stopper assembly further comprises a stopper attached to said polyethylene thread, said stopper being responsive to said predetermined stimulus to release said blocking unit, wherein said stopper is suitable to hold said blocking unit in said blocking configuration prior to being exposed to said predetermined stimulus. 15. A nanodevice according to claim 1, further comprising a plurality of anionic or electrostatic molecules attached to an outer surface of said containment vessel,
wherein said anionic or electrostatic molecules provide hydrophilicity or aqueous dispersability to said nanodevice and are suitable to provide repulsion between other similar nanodevices. 16. A nanodevice according to claim 15, wherein said anionic molecules comprise a phosphonate moiety. 17. A nanodevice according to claim 15, wherein said plurality of anionic molecules are trihydroxysilylpropyl methylphosphonate. 18. A nanodevice according to claim 1, further comprising folate ligands attached to said containment vessel. 19. A nanodevice according to claim 1, further comprising a nanoparticle of magnetic material formed within said containment vessel of said nanodevice. 20. A nanodevice according to claim 19, wherein said nanoparticle of magnetic material is an iron oxide nanoparticle. 21. A nanodevice according to claim 1, further comprising a nanoparticle of gold formed within said containment vessel of said nanodevice. 22. A composition of matter, comprising:
a plurality of nanoparticles, each defining a storage chamber therein; and a guest material contained within said storage chambers defined by said plurality of nanoparticles, said guest material being substantially chemically non-reactive with said nanoparticles, wherein said plurality of nanoparticles are operable to cause said guest material contained within said storage chambers to be released in a presence of a predetermined stimulus, and wherein each nanoparticle of said plurality of nanoparticles has a maximum dimension of about 1 μm. 23. A composition of matter according to claim 22, wherein said release in the presence of said predetermined stimulus comprises a predetermined enzyme cleaving a portion of a stopper assembly to release a stopper. 24. A composition according to claim 22, wherein said plurality of nanoparticles are each mesoporous silica nanoparticles, each defining a plurality of substantially parallel pores therein, said storage chambers each being a respective one of said plurality of substantially parallel pores. 25. A composition according to claim 22, wherein said stopper assembly comprises at least one of a [2]rotaxane or a [2]pseudorotaxane macromolecule. 26. A composition according to claim 22, wherein said blocking unit is an α-cyclodextrin toroidal molecule. 27. A composition according to claim 22, wherein said stopper assembly comprises a polyethylene thread attached to said containment vessel. 28. A composition according to claim 22, further comprising a hydrophilic silane. 29. A composition according to claim 22, further comprising folate. 30. A composition according to claim 22, further comprising a ligand for targeting a specific cell, a specific tissue, specific organ or specific biological component. 31. A method of administering at least one of a biologically active substance, a therapeutic substance, a neutraceutical substance, a cosmetic substance or a diagnostic substance, comprising:
administering a composition to at least one of a person, animal, plant, or organism, said composition comprising nanoparticles therein, wherein said nanoparticles contain said at least one of a biologically active substance or an imaging/tracking substance therein; and at least one of directing or allowing said nanoparticles of said administered composition to come into contact with a predetermined catalytic activity that is suitable to at least one of cleave, hydrolyze, oxidize, or reduce a portion of said nanoparticles to release said substance from said nanoparticles. 32. A nanodevice, comprising:
a containment vessel defining a storage chamber therein and defining at least one port to provide transfer of matter to or from said storage chamber; and a valve assembly attached to said containment vessel; wherein said valve assembly is operable in an aqueous environment, and wherein said nanodevice comprises biocompatible materials in a composition thereof and has a maximum dimension of less than about 1 μm and greater than about 50 nm. 33. A nanodevice according to claim 32, wherein said nanodevice has a maximum dimension of less than about 400 nm and greater than about 50 nm. 34. A nanodevice according to claim 32, wherein said nanodevice has a maximum dimension of less than about 300 nm and greater than about 50 nm. 35. A nanodevice according to claim 32, wherein said nanodevice has a maximum dimension of less than about 150 nm and greater than about 50 nm. 36. A nanodevice according to claim 32, wherein said valve assembly is operable to at least one of open and close in response to a change of pH in a local environment of said valve assembly. 37. A nanodevice according to claim 32, wherein said valve assembly is operable to open in response to a change to an acidic local environment and to close in response to a change to a non-acidic local environment of said valve assembly. 38. A nanodevice according to claim 32, wherein said nanodevice consists essentially of biocompatible materials in a composition thereof. 39. A nanodevice according to claim 32, wherein said containment vessel comprises silica in a material thereof. 40. A nanodevice according to claim 32, wherein said containment vessel is a mesoporous silica nanoparticle defining a plurality of substantially parallel pores therein, said storage chamber being one of said plurality of substantially parallel pores. 41. A nanodevice according to claim 32, wherein said valve assembly is at least a portion of one of a [2]rotaxane and a [2]pseudorotaxane supramolecular structure. 42. A nanodevice according to claim 41, wherein said at least said portion of one of said [2]rotaxane and said [2]pseudorotaxane comprises a cucurbituril molecule as a moving valve component thereof. 43. A nanodevice according to claim 41, wherein said at least said portion of one of said [2]rotaxane and said [2]pseudorotaxane comprises a cyclodextrin molecule. 44. A nanodevice according to claim 32, further comprising a plurality of anionic or electrostatic molecules attached to an outer surface of said containment vessel,
wherein said anionic or electrostatic molecules provide hydrophilicity or aqueous dispersability to said nanodevice and are suitable to provide repulsion between other similar nanodevices. 45. A nanodevice according to claim 44, wherein said plurality of anionic molecules comprise a phosphonate moiety. 46. A nanodevice according to claim 44, wherein said plurality of anionic molecules are trihydroxysilylpropyl methylphosphonate. 47. A nanodevice according to claim 32, further comprising folate ligands attached to said containment vessel. 48. A nanodevice according to claim 32, further comprising a nanoparticle of magnetic material formed within said containment vessel of said nanodevice. 49. A nanodevice according to claim 48, wherein said nanoparticle of magnetic material is an iron oxide nanoparticle. 50. A nanodevice according to claim 32, further comprising a nanoparticle of gold formed within said containment vessel of said nanodevice. 51. A composition of matter, comprising:
a plurality of nanoparticles, each defining a storage chamber therein; and a guest material contained within said storage chambers defined by said nanoparticles, said guest material being substantially chemically non-reactive with said nanoparticles, wherein each nanoparticle of said plurality of nanoparticles has a valve assembly to allow said guest material contained within said storage chambers to be selectively released, and wherein each nanoparticle of said plurality of nanoparticles comprises biocompatible materials in a composition thereof and has a maximum dimension of less than about 1 μm and greater than about 50 nm. 52. A composition of matter according to claim 51, wherein said valve assembly is operable to at least one of open and close in response to a change of pH in a local environment of said valve assembly. 53. A composition of matter according to claim 51, wherein said valve assembly is operable to open in response to a change to an acidic local environment and to close in response to a change to a non-acidic local environment of said valve assembly. 54. A composition of matter according to claim 51, wherein each nanoparticle of said plurality of nanoparticles comprises silica in a material thereof. 55. A composition of matter according to claim 51, wherein each nanoparticle of said plurality of nanoparticles is a mesoporous silica nanoparticle defining a plurality of substantially parallel pores therein, said storage chamber being one of said plurality of substantially parallel pores. 56. A composition of matter according to claim 51, wherein said valve assembly is at least a portion of one of a [2]rotaxane and a [2]pseudorotaxane supramolecular structure. 57. A composition of matter according to claim 56, wherein said at least said portion of one of said [2]rotaxane and said [2]pseudorotaxane comprises a cucurbituril molecule. 58. A composition of matter according to claim 51, wherein each nanoparticle of said plurality of nanoparticles comprises a surface coating of a hydrophilic group. 59. A composition of matter according to claim 51, wherein each nanoparticle of said plurality of nanoparticles comprises folate ligands attached thereto. 60. A method of administering at least one of a biologically active substance, a therapeutic substance, a neutraceutical substance, a cosmetic substance or a diagnostic substance, comprising:
administering a composition to at least one of a person, an animal, a plant, or an organism, said composition comprising nanoparticles therein, wherein said nanoparticles contain said at least one of biologically active substance, therapeutic substance, neutraceutical substance, cosmetic substance or diagnostic substance therein; and selectively opening a valve in each of said nanoparticles to allow said at least one of said biologically active substance, therapeutic substance, neutraceutical substance, cosmetic substance or diagnostic substance to escape from said nanoparticles. | A nanodevice has a containment vessel defining a storage chamber therein and defining at least one port to provide access to and from said storage chamber, and a stopper assembly attached to the containment vessel. The stopper assembly has a blocking unit arranged proximate the at least one port and has a structure suitable to substantially prevent material after being loaded into the storage chamber from being released while the blocking unit is arranged in a blocking configuration. The stopper assembly is responsive to the presence of a predetermined stimulus such that the blocking unit is released in the presence of the predetermined stimulus to allow the material to be released from the storage chamber. The predetermined stimulus is a predetermined catalytic activity that is suitable to at least one of cleave, hydrolyze, oxidize, or reduce a portion of the stopper assembly, and the nanodevice has a maximum dimension of about 1 μm.1. A nanodevice, comprising:
a containment vessel defining a storage chamber therein and defining at least one port to provide access to and from said storage chamber; and a stopper assembly attached to said containment vessel, said stopper assembly comprising a blocking unit arranged proximate said at least one port and having a structure suitable to substantially prevent material after being loaded into said storage chamber from being released while said blocking unit is arranged in a blocking configuration, wherein said stopper assembly is responsive to the presence of a predetermined stimulus such that said blocking unit is released in the presence of said predetermined stimulus to allow said material to be released from said storage chamber, wherein said predetermined stimulus is a predetermined catalytic activity that is suitable to at least one of cleave, hydrolyze, oxidize, or reduce a portion of said stopper assembly, and wherein said nanodevice has a maximum dimension of about 1 μm. 2. A nanodevice according to claim 1, wherein said nanodevice has a maximum dimension of less than about 400 nm and greater than about 50 nm. 3. A nanodevice according to claim 1, wherein said nanodevice has a maximum dimension of less than about 300 nm and greater than about 50 nm. 4. A nanodevice according to claim 1, wherein said nanodevice has a maximum dimension of less than about 150 nm and greater than about 50 nm. 5. A nanodevice according to claim 1, further comprising a thread attached to said containment vessel proximate said port, said blocking unit having a structure so that it can become threaded over said thread. 6. A nanodevice according to claim 5, further comprising a stopper attached to said thread such that said stopper at least assists in holding said blocking unit in said blocking configuration. 7. A nanodevice according to claim 1, wherein said nanodevice is operable in an aqueous environment. 8. A nanodevice according to claim 1, wherein said nanodevice consists essentially of biocompatible materials in a composition thereof. 9. A nanodevice according to claim 1, wherein said containment vessel comprises silica in a material thereof. 10. A nanodevice according to claim 9, wherein said containment vessel is a mesoporous silica nanoparticle defining a plurality of substantially parallel pores therein, said storage chamber being one of said plurality of substantially parallel pores. 11. A nanodevice according to claim 1, wherein said stopper assembly comprises at least one of a [2]rotaxane or a [2]pseudorotaxane macromolecule. 12. A nanodevice according to claim 11, wherein said blocking unit of said stopper assembly is an α-cyclodextrin toroidal molecule. 13. A nanodevice according to claim 12, wherein said stopper assembly comprises a polyethylene thread attached to said containment vessel. 14. A nanodevice according to claim 13, wherein said stopper assembly further comprises a stopper attached to said polyethylene thread, said stopper being responsive to said predetermined stimulus to release said blocking unit, wherein said stopper is suitable to hold said blocking unit in said blocking configuration prior to being exposed to said predetermined stimulus. 15. A nanodevice according to claim 1, further comprising a plurality of anionic or electrostatic molecules attached to an outer surface of said containment vessel,
wherein said anionic or electrostatic molecules provide hydrophilicity or aqueous dispersability to said nanodevice and are suitable to provide repulsion between other similar nanodevices. 16. A nanodevice according to claim 15, wherein said anionic molecules comprise a phosphonate moiety. 17. A nanodevice according to claim 15, wherein said plurality of anionic molecules are trihydroxysilylpropyl methylphosphonate. 18. A nanodevice according to claim 1, further comprising folate ligands attached to said containment vessel. 19. A nanodevice according to claim 1, further comprising a nanoparticle of magnetic material formed within said containment vessel of said nanodevice. 20. A nanodevice according to claim 19, wherein said nanoparticle of magnetic material is an iron oxide nanoparticle. 21. A nanodevice according to claim 1, further comprising a nanoparticle of gold formed within said containment vessel of said nanodevice. 22. A composition of matter, comprising:
a plurality of nanoparticles, each defining a storage chamber therein; and a guest material contained within said storage chambers defined by said plurality of nanoparticles, said guest material being substantially chemically non-reactive with said nanoparticles, wherein said plurality of nanoparticles are operable to cause said guest material contained within said storage chambers to be released in a presence of a predetermined stimulus, and wherein each nanoparticle of said plurality of nanoparticles has a maximum dimension of about 1 μm. 23. A composition of matter according to claim 22, wherein said release in the presence of said predetermined stimulus comprises a predetermined enzyme cleaving a portion of a stopper assembly to release a stopper. 24. A composition according to claim 22, wherein said plurality of nanoparticles are each mesoporous silica nanoparticles, each defining a plurality of substantially parallel pores therein, said storage chambers each being a respective one of said plurality of substantially parallel pores. 25. A composition according to claim 22, wherein said stopper assembly comprises at least one of a [2]rotaxane or a [2]pseudorotaxane macromolecule. 26. A composition according to claim 22, wherein said blocking unit is an α-cyclodextrin toroidal molecule. 27. A composition according to claim 22, wherein said stopper assembly comprises a polyethylene thread attached to said containment vessel. 28. A composition according to claim 22, further comprising a hydrophilic silane. 29. A composition according to claim 22, further comprising folate. 30. A composition according to claim 22, further comprising a ligand for targeting a specific cell, a specific tissue, specific organ or specific biological component. 31. A method of administering at least one of a biologically active substance, a therapeutic substance, a neutraceutical substance, a cosmetic substance or a diagnostic substance, comprising:
administering a composition to at least one of a person, animal, plant, or organism, said composition comprising nanoparticles therein, wherein said nanoparticles contain said at least one of a biologically active substance or an imaging/tracking substance therein; and at least one of directing or allowing said nanoparticles of said administered composition to come into contact with a predetermined catalytic activity that is suitable to at least one of cleave, hydrolyze, oxidize, or reduce a portion of said nanoparticles to release said substance from said nanoparticles. 32. A nanodevice, comprising:
a containment vessel defining a storage chamber therein and defining at least one port to provide transfer of matter to or from said storage chamber; and a valve assembly attached to said containment vessel; wherein said valve assembly is operable in an aqueous environment, and wherein said nanodevice comprises biocompatible materials in a composition thereof and has a maximum dimension of less than about 1 μm and greater than about 50 nm. 33. A nanodevice according to claim 32, wherein said nanodevice has a maximum dimension of less than about 400 nm and greater than about 50 nm. 34. A nanodevice according to claim 32, wherein said nanodevice has a maximum dimension of less than about 300 nm and greater than about 50 nm. 35. A nanodevice according to claim 32, wherein said nanodevice has a maximum dimension of less than about 150 nm and greater than about 50 nm. 36. A nanodevice according to claim 32, wherein said valve assembly is operable to at least one of open and close in response to a change of pH in a local environment of said valve assembly. 37. A nanodevice according to claim 32, wherein said valve assembly is operable to open in response to a change to an acidic local environment and to close in response to a change to a non-acidic local environment of said valve assembly. 38. A nanodevice according to claim 32, wherein said nanodevice consists essentially of biocompatible materials in a composition thereof. 39. A nanodevice according to claim 32, wherein said containment vessel comprises silica in a material thereof. 40. A nanodevice according to claim 32, wherein said containment vessel is a mesoporous silica nanoparticle defining a plurality of substantially parallel pores therein, said storage chamber being one of said plurality of substantially parallel pores. 41. A nanodevice according to claim 32, wherein said valve assembly is at least a portion of one of a [2]rotaxane and a [2]pseudorotaxane supramolecular structure. 42. A nanodevice according to claim 41, wherein said at least said portion of one of said [2]rotaxane and said [2]pseudorotaxane comprises a cucurbituril molecule as a moving valve component thereof. 43. A nanodevice according to claim 41, wherein said at least said portion of one of said [2]rotaxane and said [2]pseudorotaxane comprises a cyclodextrin molecule. 44. A nanodevice according to claim 32, further comprising a plurality of anionic or electrostatic molecules attached to an outer surface of said containment vessel,
wherein said anionic or electrostatic molecules provide hydrophilicity or aqueous dispersability to said nanodevice and are suitable to provide repulsion between other similar nanodevices. 45. A nanodevice according to claim 44, wherein said plurality of anionic molecules comprise a phosphonate moiety. 46. A nanodevice according to claim 44, wherein said plurality of anionic molecules are trihydroxysilylpropyl methylphosphonate. 47. A nanodevice according to claim 32, further comprising folate ligands attached to said containment vessel. 48. A nanodevice according to claim 32, further comprising a nanoparticle of magnetic material formed within said containment vessel of said nanodevice. 49. A nanodevice according to claim 48, wherein said nanoparticle of magnetic material is an iron oxide nanoparticle. 50. A nanodevice according to claim 32, further comprising a nanoparticle of gold formed within said containment vessel of said nanodevice. 51. A composition of matter, comprising:
a plurality of nanoparticles, each defining a storage chamber therein; and a guest material contained within said storage chambers defined by said nanoparticles, said guest material being substantially chemically non-reactive with said nanoparticles, wherein each nanoparticle of said plurality of nanoparticles has a valve assembly to allow said guest material contained within said storage chambers to be selectively released, and wherein each nanoparticle of said plurality of nanoparticles comprises biocompatible materials in a composition thereof and has a maximum dimension of less than about 1 μm and greater than about 50 nm. 52. A composition of matter according to claim 51, wherein said valve assembly is operable to at least one of open and close in response to a change of pH in a local environment of said valve assembly. 53. A composition of matter according to claim 51, wherein said valve assembly is operable to open in response to a change to an acidic local environment and to close in response to a change to a non-acidic local environment of said valve assembly. 54. A composition of matter according to claim 51, wherein each nanoparticle of said plurality of nanoparticles comprises silica in a material thereof. 55. A composition of matter according to claim 51, wherein each nanoparticle of said plurality of nanoparticles is a mesoporous silica nanoparticle defining a plurality of substantially parallel pores therein, said storage chamber being one of said plurality of substantially parallel pores. 56. A composition of matter according to claim 51, wherein said valve assembly is at least a portion of one of a [2]rotaxane and a [2]pseudorotaxane supramolecular structure. 57. A composition of matter according to claim 56, wherein said at least said portion of one of said [2]rotaxane and said [2]pseudorotaxane comprises a cucurbituril molecule. 58. A composition of matter according to claim 51, wherein each nanoparticle of said plurality of nanoparticles comprises a surface coating of a hydrophilic group. 59. A composition of matter according to claim 51, wherein each nanoparticle of said plurality of nanoparticles comprises folate ligands attached thereto. 60. A method of administering at least one of a biologically active substance, a therapeutic substance, a neutraceutical substance, a cosmetic substance or a diagnostic substance, comprising:
administering a composition to at least one of a person, an animal, a plant, or an organism, said composition comprising nanoparticles therein, wherein said nanoparticles contain said at least one of biologically active substance, therapeutic substance, neutraceutical substance, cosmetic substance or diagnostic substance therein; and selectively opening a valve in each of said nanoparticles to allow said at least one of said biologically active substance, therapeutic substance, neutraceutical substance, cosmetic substance or diagnostic substance to escape from said nanoparticles. | 1,600 |
1,111 | 15,867,985 | 1,612 | The present invention is directed to carrier systems comprising ether-lipids conjugated to one or more bioactive ligands and exposed on the surface of the carrier system for use in targeted delivery and/or antigen display systems. Optionally one or more further bioactive agents may be encapsulated or embedded within or attached to or adsorbed onto the carrier system. The present invention is further directed to methods of their preparation and their uses in medical applications, such as targeted delivery of bioactive agents to specific tissues or cells and antigen display systems for the study, diagnosis, and treatment of traits, diseases and conditions that respond to said bioactive agents. | 1-18. (canceled) 19. A carrier system comprising a compound of formula I
wherein
Y represents O, N, S or a covalent bond,
S1, S2, S3 represent independently of each other a covalent bond or a spacer group,
X1, X2, X3 represent independently of each other H or a ligand group or any two of X1, X2, X3 may together form a ligand group, wherein at least one of X1, X2, X3 is a legumain targeting ligand group,
L is a group of formula (a)
wherein the dashed line represents the linkage to N,
R1 represents H or a group of formula —(CH2)2—ORb1,
R1′ represents H or a group of formula —(CH2)2—ORb2,
R2 represents H or a group of formula —CH2—ORc,
R2′ represents H or a group of formula —ORd or —CH2—ORd,
R3 represents H or a group of formula —(CH2)2—ORe or —(CH2)3—ORe,
Ra, Rb1, Rb2,
Rc, Rd, Re represent independently of each other a saturated or unsaturated, straight or branched hydrocarbon chain,
m is 1, 2 or 3,
with the proviso that at least one of R1, R1′, R2, R2′, R3 is not H. 20. A carrier system according to claim 19, wherein R3 is H, and L is a group of formulas (b) or (c)
wherein the dashed line represents the linkage to N, and
S1, S2, S3, X1, X2, X3, Y, Ra, and m are defined as for formula I,
with the proviso that in formula (b) one of R2 and R2′ is not H, and in formula (c) one of R1 and R1′ is not H, and at least one of X1, X2, X3 is a legumain targeting ligand group. 21. A carrier system according to claim 20, wherein L is a group of formula (b1), (b2), (b3) or (b4):
wherein the dashed line represents the linkage to N, and
wherein Ra, Rc and Rd are independently of each other a saturated or unsaturated, straight or branched hydrocarbon chain. 22. A carrier system according to claim 20, wherein L is a group of formula (c1) or (c2):
wherein the dashed line represents the linkage to N, and
wherein Ra, Rb1, Rb2 are independently of each other a saturated or unsaturated, straight or branched hydrocarbon chain. 23. A carrier system according to claim 19, wherein R1, R1′, R2, R2′ are H, R3 is a group of formula —(CH2)2—ORe or —(CH2)3—ORe, and S1, S2, S3, X1, X2, X3, Y, Ra, and m are defined as for formula I. 24. A carrier system according to claim 19, wherein Ra, Rb1, Rb2, Rc, Rd, Re are independently of each other straight or branched C(10-22)alkyl, C(10-22)alkenyl or C(10-22)alkynyl. 25. A carrier system according to claim 24, wherein C(10-22)alkenyl and C(10-22)alkynyl have 1, 2, 3 or 4 unsaturated bonds. 26. A carrier system according to claim 24, wherein C(10-22)alkenyl and C(10-22)alkynyl have 1 or 2 unsaturated bonds. 27. A carrier system according to claim 19, wherein the carrier system is a microparticulate or a nanoparticulate material. 28. A carrier system according to claim 27, wherein the microparticulate or a nanoparticulate material is a liposome or a micelle, comprising at least one compound of formula I and optionally one or more other co-lipids. 29. A carrier system according to claim 27, wherein the microparticulate or a nanoparticulate material is a lipid vesicle, a nanoparticle, a nanosphere and/or a nanorod, comprising at least one compound of formula I and optionally one or more other co-lipids. 30. A carrier system according to claim 29, wherein the lipid vesicle further contains at least one bioactive agent enclosed or embedded within its internal void or adsorbed onto or attached to its surface. 31. A carrier system according to claim 19, wherein the spacer group is polyethylene glycol or an end-capped polyethylene glycol. 32. A carrier system according to claim 19, wherein the at least one of X1, X2, X3 that is a legumain targeting ligand group is RR11a. 33. A carrier system according to claim 19, wherein the carrier system is a liposome, and the at least one of X1, X2, X3 that is a legumain targeting ligand group is RR11a. 34. A carrier system according to claim 19, wherein, in addition to at least one of X1, X2, X3 being a legumain targeting ligand group, at least one further of X1, X2, X3 or two of X1, X2, X3 together is a targeting ligand or an antigenic ligand or a therapeutic or diagnostic ligand or a combination thereof. 35. Pharmaceutical composition comprising a carrier system according to claim 19 and a pharmaceutically acceptable carrier. 36. A drug delivery system, diagnostic system or as an antigen display system, said system comprising a carrier system according to claim 19 and a pharmaceutically acceptable carrier. 37. A compound of formula I
wherein
Y represents O, N, S or a covalent bond,
S1, S2, S3 represent independently of each other a covalent bond or a spacer group,
X1, X2, X3 represent independently of each other H or a ligand group, wherein at least one of X1, X2, X3 is a legumain targeting ligand group,
L is a group of formula (a)
wherein the dashed line represents the linkage to N,
R1 represents H or a group of formula —(CH2)2—ORb1,
R1′ represents H or a group of formula —(CH2)2—ORb2,
R2 represents H or a group of formula —CH2—ORc,
R2′ represents H or a group of formula —ORd or —CH2—ORd,
R3 represents H or a group of formula —(CH2)2—ORe or —(CH2)3—ORe,
Ra, Rb1, Rb2,
Rc, Rd, Re represent independently of each other a saturated or unsaturated, straight or branched hydrocarbon chain,
m is 1, 2 or 3,
with the proviso that at least one of R1, R1′, R2, R2′, R3 is not H. 38. The compound according to claim 37, wherein the at least one of X1, X2, X3 that is a legumain targeting ligand group is RR11a. 39. A method for the treatment of a disease which responds to a therapeutic agent containing a legumain targeting ligand group, comprising administering to a host in need thereof a carrier system according to claim 19, wherein at least one of X1, X2, X3 is said therapeutic agent containing a legumain targeting ligand group. 40. A method for the diagnosis of a disease by a disease specific diagnostic agent containing a legumain targeting ligand group, comprising administering to a host in need thereof a carrier system according to claim 19, wherein at least one of X1, X2, X3 is said diagnostic agent containing a legumain targeting ligand group. 41. A method for modulating an immune response, comprising administering to a host in need thereof a carrier system according to claim 19, wherein at least one of X1, X2, X3 is an antigenic agent containing a legumain targeting ligand group. | The present invention is directed to carrier systems comprising ether-lipids conjugated to one or more bioactive ligands and exposed on the surface of the carrier system for use in targeted delivery and/or antigen display systems. Optionally one or more further bioactive agents may be encapsulated or embedded within or attached to or adsorbed onto the carrier system. The present invention is further directed to methods of their preparation and their uses in medical applications, such as targeted delivery of bioactive agents to specific tissues or cells and antigen display systems for the study, diagnosis, and treatment of traits, diseases and conditions that respond to said bioactive agents.1-18. (canceled) 19. A carrier system comprising a compound of formula I
wherein
Y represents O, N, S or a covalent bond,
S1, S2, S3 represent independently of each other a covalent bond or a spacer group,
X1, X2, X3 represent independently of each other H or a ligand group or any two of X1, X2, X3 may together form a ligand group, wherein at least one of X1, X2, X3 is a legumain targeting ligand group,
L is a group of formula (a)
wherein the dashed line represents the linkage to N,
R1 represents H or a group of formula —(CH2)2—ORb1,
R1′ represents H or a group of formula —(CH2)2—ORb2,
R2 represents H or a group of formula —CH2—ORc,
R2′ represents H or a group of formula —ORd or —CH2—ORd,
R3 represents H or a group of formula —(CH2)2—ORe or —(CH2)3—ORe,
Ra, Rb1, Rb2,
Rc, Rd, Re represent independently of each other a saturated or unsaturated, straight or branched hydrocarbon chain,
m is 1, 2 or 3,
with the proviso that at least one of R1, R1′, R2, R2′, R3 is not H. 20. A carrier system according to claim 19, wherein R3 is H, and L is a group of formulas (b) or (c)
wherein the dashed line represents the linkage to N, and
S1, S2, S3, X1, X2, X3, Y, Ra, and m are defined as for formula I,
with the proviso that in formula (b) one of R2 and R2′ is not H, and in formula (c) one of R1 and R1′ is not H, and at least one of X1, X2, X3 is a legumain targeting ligand group. 21. A carrier system according to claim 20, wherein L is a group of formula (b1), (b2), (b3) or (b4):
wherein the dashed line represents the linkage to N, and
wherein Ra, Rc and Rd are independently of each other a saturated or unsaturated, straight or branched hydrocarbon chain. 22. A carrier system according to claim 20, wherein L is a group of formula (c1) or (c2):
wherein the dashed line represents the linkage to N, and
wherein Ra, Rb1, Rb2 are independently of each other a saturated or unsaturated, straight or branched hydrocarbon chain. 23. A carrier system according to claim 19, wherein R1, R1′, R2, R2′ are H, R3 is a group of formula —(CH2)2—ORe or —(CH2)3—ORe, and S1, S2, S3, X1, X2, X3, Y, Ra, and m are defined as for formula I. 24. A carrier system according to claim 19, wherein Ra, Rb1, Rb2, Rc, Rd, Re are independently of each other straight or branched C(10-22)alkyl, C(10-22)alkenyl or C(10-22)alkynyl. 25. A carrier system according to claim 24, wherein C(10-22)alkenyl and C(10-22)alkynyl have 1, 2, 3 or 4 unsaturated bonds. 26. A carrier system according to claim 24, wherein C(10-22)alkenyl and C(10-22)alkynyl have 1 or 2 unsaturated bonds. 27. A carrier system according to claim 19, wherein the carrier system is a microparticulate or a nanoparticulate material. 28. A carrier system according to claim 27, wherein the microparticulate or a nanoparticulate material is a liposome or a micelle, comprising at least one compound of formula I and optionally one or more other co-lipids. 29. A carrier system according to claim 27, wherein the microparticulate or a nanoparticulate material is a lipid vesicle, a nanoparticle, a nanosphere and/or a nanorod, comprising at least one compound of formula I and optionally one or more other co-lipids. 30. A carrier system according to claim 29, wherein the lipid vesicle further contains at least one bioactive agent enclosed or embedded within its internal void or adsorbed onto or attached to its surface. 31. A carrier system according to claim 19, wherein the spacer group is polyethylene glycol or an end-capped polyethylene glycol. 32. A carrier system according to claim 19, wherein the at least one of X1, X2, X3 that is a legumain targeting ligand group is RR11a. 33. A carrier system according to claim 19, wherein the carrier system is a liposome, and the at least one of X1, X2, X3 that is a legumain targeting ligand group is RR11a. 34. A carrier system according to claim 19, wherein, in addition to at least one of X1, X2, X3 being a legumain targeting ligand group, at least one further of X1, X2, X3 or two of X1, X2, X3 together is a targeting ligand or an antigenic ligand or a therapeutic or diagnostic ligand or a combination thereof. 35. Pharmaceutical composition comprising a carrier system according to claim 19 and a pharmaceutically acceptable carrier. 36. A drug delivery system, diagnostic system or as an antigen display system, said system comprising a carrier system according to claim 19 and a pharmaceutically acceptable carrier. 37. A compound of formula I
wherein
Y represents O, N, S or a covalent bond,
S1, S2, S3 represent independently of each other a covalent bond or a spacer group,
X1, X2, X3 represent independently of each other H or a ligand group, wherein at least one of X1, X2, X3 is a legumain targeting ligand group,
L is a group of formula (a)
wherein the dashed line represents the linkage to N,
R1 represents H or a group of formula —(CH2)2—ORb1,
R1′ represents H or a group of formula —(CH2)2—ORb2,
R2 represents H or a group of formula —CH2—ORc,
R2′ represents H or a group of formula —ORd or —CH2—ORd,
R3 represents H or a group of formula —(CH2)2—ORe or —(CH2)3—ORe,
Ra, Rb1, Rb2,
Rc, Rd, Re represent independently of each other a saturated or unsaturated, straight or branched hydrocarbon chain,
m is 1, 2 or 3,
with the proviso that at least one of R1, R1′, R2, R2′, R3 is not H. 38. The compound according to claim 37, wherein the at least one of X1, X2, X3 that is a legumain targeting ligand group is RR11a. 39. A method for the treatment of a disease which responds to a therapeutic agent containing a legumain targeting ligand group, comprising administering to a host in need thereof a carrier system according to claim 19, wherein at least one of X1, X2, X3 is said therapeutic agent containing a legumain targeting ligand group. 40. A method for the diagnosis of a disease by a disease specific diagnostic agent containing a legumain targeting ligand group, comprising administering to a host in need thereof a carrier system according to claim 19, wherein at least one of X1, X2, X3 is said diagnostic agent containing a legumain targeting ligand group. 41. A method for modulating an immune response, comprising administering to a host in need thereof a carrier system according to claim 19, wherein at least one of X1, X2, X3 is an antigenic agent containing a legumain targeting ligand group. | 1,600 |
1,112 | 15,771,884 | 1,618 | A seal formulation for forming a physical barrier in the teat canal of a non-human animal for prophylactically controlling infection of a mammary gland by a mastitis-causing organism comprises a polymer in a gel base wherein the polymer is a lower alkyl vinyl ether-maleic anhydride copolymer or a salt derivative thereof. The lower alkyl vinyl ether-maleic anhydride copolymer salt derivative may comprise at least one cationic ion including monovalent, bivalent or trivalent cations and mixtures thereof. | 1-40. (canceled) 41. A seal formulation for forming a physical barrier in the teat canal of a non-human animal comprising a polymer in a gel base wherein the polymer is a lower alkyl vinyl ether-maleic anhydride copolymer or a salt derivative thereof. 42. A seal formulation as claimed in claim 41 wherein the lower alkyl vinyl ether-maleic anhydride copolymer salt derivative comprises at least one cationic ion including monovalent, bivalent or trivalent cations and mixtures thereof. 43. A seal formulation as claimed in claim 42 wherein the cationic ion is calcium, sodium or mixtures thereof. 44. A seal formulation as claimed in claim 41 wherein the polymer is a methyl vinyl ether-maleic anhydride copolymer or a salt derivative thereof. 45. A seal formulation as claimed in claim 41 wherein the copolymer is a mixed calcium and sodium salt derivative of a methyl vinyl ether-maleic anhydride copolymer. 46. A seal formulation as claimed in claim 41 wherein the seal formulation contains from 10% to 60% by weight of the polymer. 47. A seal formulation as claimed in claim 41 wherein the seal formulation contains from 20% to 60% by weight of the polymer. 48. A seal formulation as claimed in claim 41 wherein the seal formulation contains from 30% to 55% by weight of the polymer. 49. A seal formulation as claimed in claim 41 which further comprises a viscosity enhancing agent. 50. A seal formulation as claimed in claim 49 wherein the viscosity enhancing agent comprises zinc oxide. 51. A seal formulation as claimed in claim 49 wherein the seal formulation contains from 1% to 35% of the viscosity enhancing agent. 52. A seal formulation as claimed in claim 49 wherein the seal formulation contains from 5% to 25% of the viscosity enhancing agent. 53. A seal formulation as claimed in claim 49 wherein the seal formulation contains from 5% to 20% of the viscosity enhancing agent. 54. A seal formulation as claimed in claim 41 which further comprises a thixotrophic agent. 55. A seal formulation as claimed in claim 54 wherein the seal formulation contains from 0.1% to 1% of the thixotrophic agent. 56. A seal formulation as claimed in claim 54 wherein the seal formulation contains from 0.4 to 0.8% of the thixotrophic agent. 57. A seal formulation as claimed in claim 54 wherein the thixotrophic agent comprises fumed silica. 58. A seal formulation as claimed in claim 41 wherein the base is a gel based on aluminium stearate. 59. A seal formulation as claimed in claim 41 wherein the base includes liquid paraffin as a vehicle. 60. A seal formulation as claimed in claim 41 wherein the seal formulation contains from 30% to 50% of the base. | A seal formulation for forming a physical barrier in the teat canal of a non-human animal for prophylactically controlling infection of a mammary gland by a mastitis-causing organism comprises a polymer in a gel base wherein the polymer is a lower alkyl vinyl ether-maleic anhydride copolymer or a salt derivative thereof. The lower alkyl vinyl ether-maleic anhydride copolymer salt derivative may comprise at least one cationic ion including monovalent, bivalent or trivalent cations and mixtures thereof.1-40. (canceled) 41. A seal formulation for forming a physical barrier in the teat canal of a non-human animal comprising a polymer in a gel base wherein the polymer is a lower alkyl vinyl ether-maleic anhydride copolymer or a salt derivative thereof. 42. A seal formulation as claimed in claim 41 wherein the lower alkyl vinyl ether-maleic anhydride copolymer salt derivative comprises at least one cationic ion including monovalent, bivalent or trivalent cations and mixtures thereof. 43. A seal formulation as claimed in claim 42 wherein the cationic ion is calcium, sodium or mixtures thereof. 44. A seal formulation as claimed in claim 41 wherein the polymer is a methyl vinyl ether-maleic anhydride copolymer or a salt derivative thereof. 45. A seal formulation as claimed in claim 41 wherein the copolymer is a mixed calcium and sodium salt derivative of a methyl vinyl ether-maleic anhydride copolymer. 46. A seal formulation as claimed in claim 41 wherein the seal formulation contains from 10% to 60% by weight of the polymer. 47. A seal formulation as claimed in claim 41 wherein the seal formulation contains from 20% to 60% by weight of the polymer. 48. A seal formulation as claimed in claim 41 wherein the seal formulation contains from 30% to 55% by weight of the polymer. 49. A seal formulation as claimed in claim 41 which further comprises a viscosity enhancing agent. 50. A seal formulation as claimed in claim 49 wherein the viscosity enhancing agent comprises zinc oxide. 51. A seal formulation as claimed in claim 49 wherein the seal formulation contains from 1% to 35% of the viscosity enhancing agent. 52. A seal formulation as claimed in claim 49 wherein the seal formulation contains from 5% to 25% of the viscosity enhancing agent. 53. A seal formulation as claimed in claim 49 wherein the seal formulation contains from 5% to 20% of the viscosity enhancing agent. 54. A seal formulation as claimed in claim 41 which further comprises a thixotrophic agent. 55. A seal formulation as claimed in claim 54 wherein the seal formulation contains from 0.1% to 1% of the thixotrophic agent. 56. A seal formulation as claimed in claim 54 wherein the seal formulation contains from 0.4 to 0.8% of the thixotrophic agent. 57. A seal formulation as claimed in claim 54 wherein the thixotrophic agent comprises fumed silica. 58. A seal formulation as claimed in claim 41 wherein the base is a gel based on aluminium stearate. 59. A seal formulation as claimed in claim 41 wherein the base includes liquid paraffin as a vehicle. 60. A seal formulation as claimed in claim 41 wherein the seal formulation contains from 30% to 50% of the base. | 1,600 |
1,113 | 16,399,772 | 1,699 | A bodypainting ink includes a coloring agent, a solvent, and a resin. The coloring agent includes an anion coloring agent, the resin includes a cation monomer, and a molar ratio of cations, constituting the cation monomer, to anions, constituting the anion coloring agent, is 1 or more. | 1. A bodypainting ink, including:
a coloring agent; a solvent; and a resin, wherein the coloring agent comprises an anion coloring agent, the resin includes a cation monomer, and a molar ratio of cations, constituting the cation monomer, to anions, constituting the anion coloring agent, is 1 or more, and wherein the solvent includes water and an alcohol, and the coloring agent and the resin are solved in the solvent as a liquid. 2. The bodypainting ink according to claim 1, wherein the molar ratio of cations, constituting the cation monomer, to anions, constituting the anion coloring agent, is 2 or more. 3. The bodypainting ink according to claim 1, wherein the molar ratio of cations, constituting the cation monomer, to anions, constituting the anion coloring agent, is 3 or more. 4. The bodypainting ink according to claim 1, wherein an amount of the anion. coloring agent that is not bound to any cation monomers of the resin and is isolated, is 10 wt % or less of a total weight of the bodypainting ink. 5. The bodypainting ink according to claim 4, wherein the amount of the anion coloring agent that is not bound to any cation monomers of the resin and is isolated, is 5 wt % or less of the total weight of the bodypainting ink. 6. The bodypainting ink according to claim 4, wherein the amount of the anion coloring agent that is not bound to any cation monomers of the resin and is isolated, is 1 wt % or less of the total weight of the bodypainting ink. 7. The bodypainting ink according to claim 4, wherein the amount of the anion coloring agent that is not bound to any cation monomers of the resin and is isolated, is substantially 0 wt % of the total weight of the bodypainting ink. 8. The bodypainting ink according to claim 1, wherein the resin includes an amine to obtain the cations constituting the cation monomer. 9. The bodypainting ink according to claim 1, wherein the resin includes a methacrylate monomer to obtain the cation monomer. 10. The bodypainting ink according to claim 1, wherein the resin includes 2-(dimethylamino)ethyl methacrylate to obtain the cation monomer. 11. The bodypainting ink according to claim 1, wherein the resin is at least one resin selected from a group consisting of an acrylic resin, an acrylic copolymer, a methacrylic resin, and a methacrylic copolymer. 12. (canceled) 13. The bodypainting ink according to claim 1, wherein the alcohol includes an alcohol having 3 or less carbon atoms. 14. The bodypainting ink according to claim 1, wherein an amount of the alcohol contained in the bodypainting ink is larger than an amount of water contained in the bodypainting ink. 15. The bodypainting ink according to claim 1, wherein the bodypainting ink contains 10 wt % or more of water and 40 wt % or more of the alcohol. 16. The bodypainting ink according to claim 1, wherein the alcohol includes 1-propanol. 17. A bodypainting instrument including the bodypainting ink according to claim 1. 18. A method for manufacturing the bodypainting ink according to claim 1, the method including separating the anion coloring agent from the bodypainting ink to quantitatively measure an isolated anion coloring agent and to evaluate a resistance to coming off the skin. 19. The bodypainting ink according to claim 1, wherein the anion coloring agent comprises phloxine. 20. The bodypainting ink according to claim 1, wherein the resin including the cation monomer comprises one of:
a resin constituted by polymerizing cation monomers; and a resin constituted by co-polymerizing the cation monomer and another monomer 21. The bodypainting ink according to claim 1, wherein the anion coloring agent comprises phloxine being solved in the solvent as the liquid, and
wherein the cation monomer of the resin includes 2-(dimethylamino)ethyl methacrylate being solved in the solvent as the liquid. | A bodypainting ink includes a coloring agent, a solvent, and a resin. The coloring agent includes an anion coloring agent, the resin includes a cation monomer, and a molar ratio of cations, constituting the cation monomer, to anions, constituting the anion coloring agent, is 1 or more.1. A bodypainting ink, including:
a coloring agent; a solvent; and a resin, wherein the coloring agent comprises an anion coloring agent, the resin includes a cation monomer, and a molar ratio of cations, constituting the cation monomer, to anions, constituting the anion coloring agent, is 1 or more, and wherein the solvent includes water and an alcohol, and the coloring agent and the resin are solved in the solvent as a liquid. 2. The bodypainting ink according to claim 1, wherein the molar ratio of cations, constituting the cation monomer, to anions, constituting the anion coloring agent, is 2 or more. 3. The bodypainting ink according to claim 1, wherein the molar ratio of cations, constituting the cation monomer, to anions, constituting the anion coloring agent, is 3 or more. 4. The bodypainting ink according to claim 1, wherein an amount of the anion. coloring agent that is not bound to any cation monomers of the resin and is isolated, is 10 wt % or less of a total weight of the bodypainting ink. 5. The bodypainting ink according to claim 4, wherein the amount of the anion coloring agent that is not bound to any cation monomers of the resin and is isolated, is 5 wt % or less of the total weight of the bodypainting ink. 6. The bodypainting ink according to claim 4, wherein the amount of the anion coloring agent that is not bound to any cation monomers of the resin and is isolated, is 1 wt % or less of the total weight of the bodypainting ink. 7. The bodypainting ink according to claim 4, wherein the amount of the anion coloring agent that is not bound to any cation monomers of the resin and is isolated, is substantially 0 wt % of the total weight of the bodypainting ink. 8. The bodypainting ink according to claim 1, wherein the resin includes an amine to obtain the cations constituting the cation monomer. 9. The bodypainting ink according to claim 1, wherein the resin includes a methacrylate monomer to obtain the cation monomer. 10. The bodypainting ink according to claim 1, wherein the resin includes 2-(dimethylamino)ethyl methacrylate to obtain the cation monomer. 11. The bodypainting ink according to claim 1, wherein the resin is at least one resin selected from a group consisting of an acrylic resin, an acrylic copolymer, a methacrylic resin, and a methacrylic copolymer. 12. (canceled) 13. The bodypainting ink according to claim 1, wherein the alcohol includes an alcohol having 3 or less carbon atoms. 14. The bodypainting ink according to claim 1, wherein an amount of the alcohol contained in the bodypainting ink is larger than an amount of water contained in the bodypainting ink. 15. The bodypainting ink according to claim 1, wherein the bodypainting ink contains 10 wt % or more of water and 40 wt % or more of the alcohol. 16. The bodypainting ink according to claim 1, wherein the alcohol includes 1-propanol. 17. A bodypainting instrument including the bodypainting ink according to claim 1. 18. A method for manufacturing the bodypainting ink according to claim 1, the method including separating the anion coloring agent from the bodypainting ink to quantitatively measure an isolated anion coloring agent and to evaluate a resistance to coming off the skin. 19. The bodypainting ink according to claim 1, wherein the anion coloring agent comprises phloxine. 20. The bodypainting ink according to claim 1, wherein the resin including the cation monomer comprises one of:
a resin constituted by polymerizing cation monomers; and a resin constituted by co-polymerizing the cation monomer and another monomer 21. The bodypainting ink according to claim 1, wherein the anion coloring agent comprises phloxine being solved in the solvent as the liquid, and
wherein the cation monomer of the resin includes 2-(dimethylamino)ethyl methacrylate being solved in the solvent as the liquid. | 1,600 |
1,114 | 15,500,615 | 1,644 | The invention relates to an isolated anti-CD45RC antibody for use in preventing or treating transplant rejection, autoimmune diseases, unwanted immune responses against proteins expressed in the course of gene therapy and/or therapeutic proteins, allergy as well as lymphoma or cancer which are associated with CD45RC + cells. The invention relates to an isolated anti-CD45RC antibody for use in expanding and/or potentiating regulatory T cells. | 1. A method of i) preventing or reducing allogeneic transplant rejection or 2) preventing or treating an autoimmune disease, an unwanted immune response against therapeutic protein, an allergy, or a lymphoma or cancer which is associated with CD45RC+ cells in a patient in need thereof, comprising
administering to the patient a therapeutically effective amount of an anti-CD45RC antibody sufficient to prevent or reduce the allogeneic transplant rejection or prevent or treat the autoimmune disease, unwanted immune response against therapeutic protein, allergy and lymphoma or cancer which is associated with CD45RC+ cells. 2. The method according to claim 1, wherein said allogeneic transplant rejection is selected from the group consisting of allogeneic hematopoietic stem cell transplant rejection (GVHD), cardiac transplant rejection, pancreatic islet transplant rejection, vascular tissue transplant rejection, kidney transplant rejection, lung transplant rejection and liver transplant rejection. 3. The method according to claim 1, wherein said allogeneic transplant rejection is GVHD. 4. The method according to claim 2, wherein said allogeneic transplant rejection is cardiac allotransplant rejection. 5. The method according to claim 1, wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, juvenile oligoarthritis, collagen-induced arthritis, adjuvant-induced arthritis, Sjogren's syndrome, multiple sclerosis, experimental autoimmune encephalomyelitis, inflammatory bowel disease, autoimmune gastric atrophy, pemphigus vulgaris, psoriasis, vitiligo, type 1 diabetes, non-obese diabetes, myasthenia gravis, Grave's disease, Hashimoto's thyroiditis, sclerosing cholangitis, sclerosing sialadenitis, systemic lupus erythematosis, autoimmune thrombocytopenia purpura, Goodpasture's syndrome, Addison's disease, systemic sclerosis, polymyositis, dermatomyositis, acquired hemophilia and thrombotic thrombocytopenic purpura. 6. The method according to claim 1, wherein said anti-CD45RC antibody is an anti-CD45RC monoclonal antibody or a fragment thereof. 7. The method according to claim 6, wherein said anti-CD45RC monoclonal antibody is an anti-human CD45RC monoclonal antibody. 8. The method according to any one claim 1, wherein said anti-CD45RC antibody is a humanized antibody or a fully human antibody. 9. A pharmaceutical composition or a kit-of-part composition comprising an isolated anti-human CD45RC monoclonal antibody and a pharmaceutically acceptable excipient. 10. The pharmaceutical composition or a the kit-of-part composition according to claim 9, further comprising an immunosuppressive drug. 11. The pharmaceutical composition or a the kit-of-part composition according to claim 10, wherein the immunosuppressive drug is selected from the group consisting of cytostatics; alkylating agents, antimetabolites, therapeutic antibodies, calcineurin inhibitors, glucocorticoids and mycophenolate mofetil. 12. A method of preventing or treating allogeneic transplant rejection, autoimmune diseases, unwanted immune response against therapeutic proteins allergies and lymphoma or cancer which is associated with CD45RC+ cells in a patient in need thereof, comprising
administering to the patient a therapeutically effective amount of the pharmaceutical composition or the kit-of-part composition according to claim 9 sufficient to prevent or treat the allogeneic transplant rejection, autoimmune diseases, unwanted immune response against therapeutic proteins, allergies and lymphoma or cancer. 13. A method for expanding and/or potentiating regulatory T cells in a patient in need thereof, comprising a step of administering to said patient a therapeutically effective amount of an anti-CD45RC antibody sufficient to expand and/or potentiate the regulatory T cells. 14. (canceled) 15. A method for improving transplant survival in a transplant patient, comprising a step of administering to said patient a therapeutically effective amount of an anti-CD45RC antibody sufficient to improve the transplant survival of the patient. 16. The pharmaceutical composition or the kit-of-part composition according to claim 11, wherein the cytostatic is a mammalian target of rapamycin (mTOR) inhibitor or rapamycin (sirolimus). 17. The pharmaceutical composition or the kit-of-part composition according to claim 11, wherein the alkylating agent is cyclophosphamide. 18. The pharmaceutical composition or the kit-of-part composition according to claim 11, wherein the antimetabolites is azathioprine, mercaptopurine or methotrexate. 19. The pharmaceutical composition or the kit-of-part composition according to claim 11, wherein the therapeutic antibody is an anti-CD40L monoclonal antibody, an anti-IL-2R monoclonal antibody, an anti-CD3 monoclonal antibody, an anti-lymphocyte globulin (ALG) or an anti-thymocyte globulin (ATG). 20. The pharmaceutical composition or the kit-of-part composition according to claim 11, wherein the calcineurin inhibitor is cyclosporine. | The invention relates to an isolated anti-CD45RC antibody for use in preventing or treating transplant rejection, autoimmune diseases, unwanted immune responses against proteins expressed in the course of gene therapy and/or therapeutic proteins, allergy as well as lymphoma or cancer which are associated with CD45RC + cells. The invention relates to an isolated anti-CD45RC antibody for use in expanding and/or potentiating regulatory T cells.1. A method of i) preventing or reducing allogeneic transplant rejection or 2) preventing or treating an autoimmune disease, an unwanted immune response against therapeutic protein, an allergy, or a lymphoma or cancer which is associated with CD45RC+ cells in a patient in need thereof, comprising
administering to the patient a therapeutically effective amount of an anti-CD45RC antibody sufficient to prevent or reduce the allogeneic transplant rejection or prevent or treat the autoimmune disease, unwanted immune response against therapeutic protein, allergy and lymphoma or cancer which is associated with CD45RC+ cells. 2. The method according to claim 1, wherein said allogeneic transplant rejection is selected from the group consisting of allogeneic hematopoietic stem cell transplant rejection (GVHD), cardiac transplant rejection, pancreatic islet transplant rejection, vascular tissue transplant rejection, kidney transplant rejection, lung transplant rejection and liver transplant rejection. 3. The method according to claim 1, wherein said allogeneic transplant rejection is GVHD. 4. The method according to claim 2, wherein said allogeneic transplant rejection is cardiac allotransplant rejection. 5. The method according to claim 1, wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, juvenile oligoarthritis, collagen-induced arthritis, adjuvant-induced arthritis, Sjogren's syndrome, multiple sclerosis, experimental autoimmune encephalomyelitis, inflammatory bowel disease, autoimmune gastric atrophy, pemphigus vulgaris, psoriasis, vitiligo, type 1 diabetes, non-obese diabetes, myasthenia gravis, Grave's disease, Hashimoto's thyroiditis, sclerosing cholangitis, sclerosing sialadenitis, systemic lupus erythematosis, autoimmune thrombocytopenia purpura, Goodpasture's syndrome, Addison's disease, systemic sclerosis, polymyositis, dermatomyositis, acquired hemophilia and thrombotic thrombocytopenic purpura. 6. The method according to claim 1, wherein said anti-CD45RC antibody is an anti-CD45RC monoclonal antibody or a fragment thereof. 7. The method according to claim 6, wherein said anti-CD45RC monoclonal antibody is an anti-human CD45RC monoclonal antibody. 8. The method according to any one claim 1, wherein said anti-CD45RC antibody is a humanized antibody or a fully human antibody. 9. A pharmaceutical composition or a kit-of-part composition comprising an isolated anti-human CD45RC monoclonal antibody and a pharmaceutically acceptable excipient. 10. The pharmaceutical composition or a the kit-of-part composition according to claim 9, further comprising an immunosuppressive drug. 11. The pharmaceutical composition or a the kit-of-part composition according to claim 10, wherein the immunosuppressive drug is selected from the group consisting of cytostatics; alkylating agents, antimetabolites, therapeutic antibodies, calcineurin inhibitors, glucocorticoids and mycophenolate mofetil. 12. A method of preventing or treating allogeneic transplant rejection, autoimmune diseases, unwanted immune response against therapeutic proteins allergies and lymphoma or cancer which is associated with CD45RC+ cells in a patient in need thereof, comprising
administering to the patient a therapeutically effective amount of the pharmaceutical composition or the kit-of-part composition according to claim 9 sufficient to prevent or treat the allogeneic transplant rejection, autoimmune diseases, unwanted immune response against therapeutic proteins, allergies and lymphoma or cancer. 13. A method for expanding and/or potentiating regulatory T cells in a patient in need thereof, comprising a step of administering to said patient a therapeutically effective amount of an anti-CD45RC antibody sufficient to expand and/or potentiate the regulatory T cells. 14. (canceled) 15. A method for improving transplant survival in a transplant patient, comprising a step of administering to said patient a therapeutically effective amount of an anti-CD45RC antibody sufficient to improve the transplant survival of the patient. 16. The pharmaceutical composition or the kit-of-part composition according to claim 11, wherein the cytostatic is a mammalian target of rapamycin (mTOR) inhibitor or rapamycin (sirolimus). 17. The pharmaceutical composition or the kit-of-part composition according to claim 11, wherein the alkylating agent is cyclophosphamide. 18. The pharmaceutical composition or the kit-of-part composition according to claim 11, wherein the antimetabolites is azathioprine, mercaptopurine or methotrexate. 19. The pharmaceutical composition or the kit-of-part composition according to claim 11, wherein the therapeutic antibody is an anti-CD40L monoclonal antibody, an anti-IL-2R monoclonal antibody, an anti-CD3 monoclonal antibody, an anti-lymphocyte globulin (ALG) or an anti-thymocyte globulin (ATG). 20. The pharmaceutical composition or the kit-of-part composition according to claim 11, wherein the calcineurin inhibitor is cyclosporine. | 1,600 |
1,115 | 15,022,429 | 1,619 | The present invention discloses a scalable and solvent-free method to produce cocrystals in a particulate form. A method of making cocrystals comprises the steps of: a) feeding a molten mixture of at least a first substance and a second substance which are able to form cocrystals to an atomizer; b) atomizing the molten mixture to droplets; c) solidifying the droplets to particles; d) collecting the said particles. The invention also provides the use of cocrystals made according to the method of the invention in the formulation of a pharmaceutical composition. The invention also provides cocrystals obtainable or obtained by the method of the present invention, in particular cocrystals in the form of particles. Also provided is a pharmaceutical composition comprising cocrystals made according to the method of the invention, in particular, a pharmaceutical composition comprising cocrystals in the form of particles made according to the method of the invention. | 1. A method of making cocrystals, which method comprises the steps of:
a) feeding a molten mixture of at least a first substance and a second substance which are able to form cocrystals to an atomizer; b) atomizing the molten mixture to droplets; c) solidifying the droplets to particles; d) collecting the said particles. 2. The method according to claim 1, wherein the method is a batch process or continuous process. 3. A method according to claim 1 or 2, wherein the first and second substances are combined in a stoichiometric ratio, such as 1:1, 1:2, 2:1 or another integer ratio. 4. A method according to any preceding claim, wherein the first substance is an active or non-active ingredient. 5. A method according to claim 4 wherein the first substance is an active principle ingredient (API) or a pharmaceutically acceptable derivative, such as a salt, of an API. 6. A method according to claim 4 or 5, wherein the API or its pharmaceutically acceptable derivative has at least one functional group selected from: thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid, phosphonic acid, phosphinic acid, sulfonic acid, amide, primary amine, secondary amine, ammonia, tertiary amine, imine, thiocyanate, cyanamide, oxime, nitrile, diazo, organohalide, nitro, S-heterocyclic ring, thiophene, N-heterocyclic ring, pyrrole, O-heterocyclic ring, furan, epoxide, peroxide, hydroxamic acid, imidazole, and pyridine. 7. A method according to any preceding claim, wherein the second substance is a coformer able to form cocrystals. 8. A method according to claim 7, wherein the coformer is an active or non-active ingredient. 9. A method according to claim 8 wherein the conformer is a pharmaceutical excipient, vitamin, mineral, amino acid or is another API. 10. A method according to claim 7, 8 or 9, wherein the coformer has at least one functional group selected from: thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid, phosphonic acid, phosphinic acid, sulfonic acid, amide, primary amine, secondary amine, ammonia, tertiary amine, imine, thiocyanate, cyanamide, oxime, nitrile, diazo, organohalide, nitro, S-heterocyclic ring, thiophene, N-heterocyclic ring, pyrrole, O-heterocyclic ring, furan, epoxide, peroxide, hydroxamic acid, imidazole, and pyridine. 11. A method according to any preceding claim, wherein the first and second substances are exposed to heat for at least for 1 minute, optionally at least 2 minutes or longer, until a homogenous and molten mixture is formed. 12. A method according to any preceding claim, wherein shear and/or pressure are employed to facilitate the mixture and entanglement of the components in the mixture, as well as to decrease their viscosity. 13. A method according to claim 12, wherein shear and pressure are promoted by magnetic stirrer bars, paddles, or by an extrusion method. 14. A method according to claim 13, wherein the extrusion method is a screw-based extrusion apparatus connected to the atomization system. 15. A method according to claim 14, wherein the screw-based extrusion apparatus connected to the atomization system is a single-screw or twin-screw extrusion apparatus. 16. A method according to claim 15, wherein the twin-screw extrusion apparatus is a co-rotating or counter-rotating system. 17. A method according to any preceding claim, wherein the melting temperature of the mixture is between −120 to +300° C., typically between 0 and 200° C., optionally between 20 and 180° C. 18. A method according to any preceding claim, wherein the mixture further comprises one or more functional matrix material(s) to promote mixing between the first and second substances, and/or to decrease the melting temperature of the mixture, and/or to add functionality to the final product. 19. A method according to claim 18, wherein the one or more functional matrix material(s) comprises an, agent with a plasticizing effect, such as polyethylene glycol, or carbon dioxide, or one or more surfactant, or one or more polymers. 20. A method according to any preceding claim, wherein in step b) the atomizing nozzle has a rotary, pressure, fluid, or ultrasonic configuration. 21. A method according to any preceding claim, wherein in step c) cooling is promoted by a stream of co-current or counter-current cooling gas or liquid, with respect to the melt spray direction. 22. A method according to any preceding claim, wherein the residence time of the droplets is controlled through a counter-current stream of cooling gas or liquid. 23. A method according to claim 21 or 22, wherein the initial temperature of the stream of gas or liquid is between −20 and 200° C. 24. A method according to claim 21, 22 or 23, wherein the cooling gas is air, nitrogen or carbon dioxide. 25. A method according to claim 21, 22 or 23, wherein the cooling liquid is liquid carbon dioxide or liquid nitrogen. 26. A method according to claim 21 or 22, wherein the counter-current stream of cooling gas is air, nitrogen or carbon dioxide. 27. A method according to claim 21 or 22, wherein the counter-current stream of cooling liquid is liquid carbon dioxide or liquid nitrogen. 28. A method according to any preceding claim, wherein the particles obtained comprise at least 50% (w/w) cocrystal purity, more preferably at least 75% (w/w) cocrystal purity, especially 90% (w/w) or more cocrystal purity. 29. A method according to any preceding claim, wherein the particles obtained have a particle size from 1 to 500 μm. 30. Use of a cocrystal, manufactured according to any preceding claim in the formulation of a pharmaceutical composition. 31. A cocrystal compound obtained or obtainable in the form of particles through a process according to any of claims 1 to 29. 32. A pharmaceutical composition comprising cocrystal particles obtained or obtainable according to the process of any one of claims 1 to 29. | The present invention discloses a scalable and solvent-free method to produce cocrystals in a particulate form. A method of making cocrystals comprises the steps of: a) feeding a molten mixture of at least a first substance and a second substance which are able to form cocrystals to an atomizer; b) atomizing the molten mixture to droplets; c) solidifying the droplets to particles; d) collecting the said particles. The invention also provides the use of cocrystals made according to the method of the invention in the formulation of a pharmaceutical composition. The invention also provides cocrystals obtainable or obtained by the method of the present invention, in particular cocrystals in the form of particles. Also provided is a pharmaceutical composition comprising cocrystals made according to the method of the invention, in particular, a pharmaceutical composition comprising cocrystals in the form of particles made according to the method of the invention.1. A method of making cocrystals, which method comprises the steps of:
a) feeding a molten mixture of at least a first substance and a second substance which are able to form cocrystals to an atomizer; b) atomizing the molten mixture to droplets; c) solidifying the droplets to particles; d) collecting the said particles. 2. The method according to claim 1, wherein the method is a batch process or continuous process. 3. A method according to claim 1 or 2, wherein the first and second substances are combined in a stoichiometric ratio, such as 1:1, 1:2, 2:1 or another integer ratio. 4. A method according to any preceding claim, wherein the first substance is an active or non-active ingredient. 5. A method according to claim 4 wherein the first substance is an active principle ingredient (API) or a pharmaceutically acceptable derivative, such as a salt, of an API. 6. A method according to claim 4 or 5, wherein the API or its pharmaceutically acceptable derivative has at least one functional group selected from: thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid, phosphonic acid, phosphinic acid, sulfonic acid, amide, primary amine, secondary amine, ammonia, tertiary amine, imine, thiocyanate, cyanamide, oxime, nitrile, diazo, organohalide, nitro, S-heterocyclic ring, thiophene, N-heterocyclic ring, pyrrole, O-heterocyclic ring, furan, epoxide, peroxide, hydroxamic acid, imidazole, and pyridine. 7. A method according to any preceding claim, wherein the second substance is a coformer able to form cocrystals. 8. A method according to claim 7, wherein the coformer is an active or non-active ingredient. 9. A method according to claim 8 wherein the conformer is a pharmaceutical excipient, vitamin, mineral, amino acid or is another API. 10. A method according to claim 7, 8 or 9, wherein the coformer has at least one functional group selected from: thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid, phosphonic acid, phosphinic acid, sulfonic acid, amide, primary amine, secondary amine, ammonia, tertiary amine, imine, thiocyanate, cyanamide, oxime, nitrile, diazo, organohalide, nitro, S-heterocyclic ring, thiophene, N-heterocyclic ring, pyrrole, O-heterocyclic ring, furan, epoxide, peroxide, hydroxamic acid, imidazole, and pyridine. 11. A method according to any preceding claim, wherein the first and second substances are exposed to heat for at least for 1 minute, optionally at least 2 minutes or longer, until a homogenous and molten mixture is formed. 12. A method according to any preceding claim, wherein shear and/or pressure are employed to facilitate the mixture and entanglement of the components in the mixture, as well as to decrease their viscosity. 13. A method according to claim 12, wherein shear and pressure are promoted by magnetic stirrer bars, paddles, or by an extrusion method. 14. A method according to claim 13, wherein the extrusion method is a screw-based extrusion apparatus connected to the atomization system. 15. A method according to claim 14, wherein the screw-based extrusion apparatus connected to the atomization system is a single-screw or twin-screw extrusion apparatus. 16. A method according to claim 15, wherein the twin-screw extrusion apparatus is a co-rotating or counter-rotating system. 17. A method according to any preceding claim, wherein the melting temperature of the mixture is between −120 to +300° C., typically between 0 and 200° C., optionally between 20 and 180° C. 18. A method according to any preceding claim, wherein the mixture further comprises one or more functional matrix material(s) to promote mixing between the first and second substances, and/or to decrease the melting temperature of the mixture, and/or to add functionality to the final product. 19. A method according to claim 18, wherein the one or more functional matrix material(s) comprises an, agent with a plasticizing effect, such as polyethylene glycol, or carbon dioxide, or one or more surfactant, or one or more polymers. 20. A method according to any preceding claim, wherein in step b) the atomizing nozzle has a rotary, pressure, fluid, or ultrasonic configuration. 21. A method according to any preceding claim, wherein in step c) cooling is promoted by a stream of co-current or counter-current cooling gas or liquid, with respect to the melt spray direction. 22. A method according to any preceding claim, wherein the residence time of the droplets is controlled through a counter-current stream of cooling gas or liquid. 23. A method according to claim 21 or 22, wherein the initial temperature of the stream of gas or liquid is between −20 and 200° C. 24. A method according to claim 21, 22 or 23, wherein the cooling gas is air, nitrogen or carbon dioxide. 25. A method according to claim 21, 22 or 23, wherein the cooling liquid is liquid carbon dioxide or liquid nitrogen. 26. A method according to claim 21 or 22, wherein the counter-current stream of cooling gas is air, nitrogen or carbon dioxide. 27. A method according to claim 21 or 22, wherein the counter-current stream of cooling liquid is liquid carbon dioxide or liquid nitrogen. 28. A method according to any preceding claim, wherein the particles obtained comprise at least 50% (w/w) cocrystal purity, more preferably at least 75% (w/w) cocrystal purity, especially 90% (w/w) or more cocrystal purity. 29. A method according to any preceding claim, wherein the particles obtained have a particle size from 1 to 500 μm. 30. Use of a cocrystal, manufactured according to any preceding claim in the formulation of a pharmaceutical composition. 31. A cocrystal compound obtained or obtainable in the form of particles through a process according to any of claims 1 to 29. 32. A pharmaceutical composition comprising cocrystal particles obtained or obtainable according to the process of any one of claims 1 to 29. | 1,600 |
1,116 | 13,972,539 | 1,619 | Provided are functional segregated telodendrimers having, for example, two or three functional segments. The telodendrimers can have one or more crosslinking groups (e.g., reversible photocrosslinking groups). The telodendrimers can aggregate to form nanocarriers. Cargo such as drugs, imaging probes, and other materials may be sequestered in the core of the aggregates via non-covalent or covalent interactions with the telodendrimers. Such nanocarriers may be used in drug delivery applications and imaging applications. | 1. A compound of formula (I):
wherein
PEG is optionally present and is a polyethylene glycol moiety, wherein PEG has a molecular weight of 44 Da to 100 kDa;
A is a monomer or oligomer;
X is a branched monomer unit;
each L1 is independently optional and is a linker group;
each L2 is independently optional and is a linker group;
D1 is optional and is a dendritic polymer moiety having one or more branched monomer units (X), a plurality of end groups, and optionally, one or more linker groups L1;
D2 is a dendritic polymer having one or more branched monomer units (X), a plurality of end groups, and optionally, one or more linker groups (L3);
each L3 is independently optional or a linker group linked to the focal point group of the dendritic polymer and monomer unit (X);
R1 and R2 are end groups of the dendritic polymer and are independently at each occurrence in the compound selected from the group consisting of a hydrophobic group, a hydrophilic group, an amphiphilic group, a reversible photocrosslinking group, and a drug, such that when R1 and/or R2 are not end groups each R1 and/or R2 is linked to one of the end groups;
subscript x is an integer from 1 to 64, wherein subscript x is equal to the number of end groups on the dendritic polymer;
subscript y is an integer from 2 to 64, wherein subscript y is equal to the number of end groups on the dendritic polymer;
subscript p is an integer from 1 to 32; and
subscript m is an integer from 0 to 32. 2. The compound of claim 1, wherein at each occurrence in the compound the branched monomer unit (X) is independently selected from the group consisting of a diamino carboxylic acid moiety, a dihydroxy carboxylic acid moiety, and a hydroxylamino carboxylic acid moiety. 3. The compound of claim 2, wherein at each occurrence in the compound the diamino carboxylic acid is independently selected from the group consisting of 2,3-diamino propanoic acid, 2,4-diaminobutanoic acid, 2,5-diaminopentanoic acid (ornithine), 2,6-diaminohexanoic acid (lysine), (2-Aminoethyl)-cysteine, 3-amino-2-aminomethyl propanoic acid, 3-amino-2-aminomethyl-2-methyl propanoic acid, 4-amino-2-(2-aminoethyl) butyric acid, and 5-amino-2-(3-aminopropyl)pentanoic acid. 4. The compound of claim 2, wherein the diamino carboxylic acid moiety is an amino acid moiety. 5. The compound of claim 2, wherein each branched monomer unit X is lysine moiety. 6. The compound of claim 1, wherein the compound is selected from the group consisting of:
wherein each branched monomer unit is lysine moiety. 7. The compound of claim 1, wherein at each occurrence in the compound the linker L1, L2, and L3 each are independently selected from the group consisting of a polyethylene glycol moiety, polyserine moiety, enzyme cleavable peptide moiety, disulfide bond moiety and acid labile moiety, polyglycine moiety, poly(serine-glycine) moiety, aliphatic amino acid moieties, 6-amino hexanoic acid moiety, 5-amino pentanoic acid moiety, 4-amino butanoic acid moiety, and beta-alanine moiety. 8. The compound of claim 1, wherein at each occurrence in the compound the linker L1, L2, and L3 are independently selected from the group consisting of: 9. The compound of claim 1, wherein the linker L1, L2, L3, or a combination thereof comprises a cleavable group. 10. The compound of claim 9, wherein the cleavable group is a disulfide cleavable moiety. 11. The compound of claim 1, wherein the (PEG)m-A- portion of the compound is selected from the group consisting of:
wherein each K is lysine. 12. The compound of claim 1, wherein each R1 and R2 is independently selected from a rhein moiety or derivative or analog thereof, cholic acid moiety or derivative or analog thereof, cholesterol moiety or derivative or analog thereof, coumarin moiety or derivative or analog thereof, curcurmine moiety or derivative or analog thereof, flavin moiety or derivative or analog thereof, isoflavin moiety or derivative or analog thereof, riboflavin moiety or derivative or analog thereof, retinol moiety or derivative or analog thereof, retinoic acid moiety or derivative or analog thereof, chlorogenic acid moiety or derivative or analog thereof, anthraquinone moiety or derivative or analog thereof, xanthenone moiety or derivative or analog thereof, Vitamin E moiety or derivative or analog thereof, D-α-tocopherol succinate moiety or derivative or analog thereof, vitamins, lipids, fatty acids, bile acids, naturally-isolated compound moieties, and drugs. 13. The compound of claim 1, wherein each R1 and/or each R2 is a reversible photocrosslinking group. 14. The compound of claim 13, wherein the reversible photocrosslinking group is coumarin moiety, 4-methylcoumarin moiety, cinnamic acid moiety or derivative or analog thereof, chlorogenic acid moiety or derivative or analog thereof, or a combination thereof. 15. The compound of claim 6, wherein x=4; y=4, m=1, PEG is 5 kDa; R1 is a coumarin moiety; each R2 is independently selected from the group consisting of cholic acid moiety or derivative or analog thereof, cholesterol moiety or derivative or analog thereof, rhein moiety or derivative or analog thereof, Vitamin E moiety or derivative or analog thereof, coumarin moiety or derivative or analog thereof, curcurmin moiety or derivative or analog thereof, and riboflavin moiety or derivative or analog thereof; L1 is optional or a disulfide bond moiety; L2 is an ethylene glycol linker; and L3 is optional or an ethylene glycol linker. 16. The compound of claim 1, wherein x=2 to 16; y=2 to 64, m=1 to 8, PEG is 1 to 40 kDa; each R1 is independently selected from a coumarin moiety or derivative or analog thereof, a cinnamic acid moiety or derivative or analog thereof, and a chlorogenic acid moiety or derivative or analog thereof; each R2 is independently selected from the group consisting of cholic acid moiety or derivative or analog thereof, cholesterol moiety or derivative or analog thereof, rhein moiety or derivative or analog thereof, Vitamin E moiety or derivative or analog thereof, coumarin moiety or derivative or analog thereof, curcurmin moiety or derivative or analog thereof, and riboflavin moiety or derivative or analog thereof; L1 is optional or a disulfide bond moiety; L2 is an ethylene glycol linker; and L3 is optional or an ethylene glycol linker. 17. The compound of claim 6, wherein x=4; y=4, m=1, PEG is 5 kDa; R1 is a cholic acid moiety or derivative or analog thereof; each R2 is independently selected from the group consisting of cholesterol moiety or derivative or analog thereof, rhein moiety or derivative or analog thereof, Vitamin E moiety or derivative or analog thereof, coumarin moiety or derivative or analog thereof, curcurmin moiety or derivative or analog thereof, riboflavin moiety or derivative or analog thereof, retinoic acid moiety or derivative or analog thereof, and a chlorogenic acid moiety or derivative or analog thereof; L1 is optional or a disulfide bond moiety; L2 is an ethylene glycol linker; and L3 is optional or an ethylene glycol linker. 18. The compound of claim 1, wherein x=2 to 16; y=2 to 64, m=1 to 8, PEG is 1 to 40 kDa; each R1 is independently selected from the group consisting of a cholic acid moiety or derivative or analog thereof moiety, riboflavin moiety or derivative or analog thereof, and a chlorogenic acid moiety or derivative or analog thereof; each R2 is independently selected from the group consisting of cholic acid moiety or derivative or analog thereof, cholesterol moiety or derivative or analog thereof, rhein moiety or derivative or analog thereof, Vitamin E moiety or derivative or analog thereof, coumarin moiety or derivative or analog thereof, curcurmin moiety or derivative or analog thereof, riboflavin moiety or derivative or analog thereof, and retinoic acid moiety or derivative or analog thereof; L1 is optional or a disulfide bond moiety; L2 is an ethylene glycol linker; and L3 is optional or an ethylene glycol linker. 19. A nanocarrier comprising a plurality of compounds of claim 1. 20. The nanocarrier of claim 19, wherein the nanocarrier further comprises a hydrophobic drug or an imaging agent. | Provided are functional segregated telodendrimers having, for example, two or three functional segments. The telodendrimers can have one or more crosslinking groups (e.g., reversible photocrosslinking groups). The telodendrimers can aggregate to form nanocarriers. Cargo such as drugs, imaging probes, and other materials may be sequestered in the core of the aggregates via non-covalent or covalent interactions with the telodendrimers. Such nanocarriers may be used in drug delivery applications and imaging applications.1. A compound of formula (I):
wherein
PEG is optionally present and is a polyethylene glycol moiety, wherein PEG has a molecular weight of 44 Da to 100 kDa;
A is a monomer or oligomer;
X is a branched monomer unit;
each L1 is independently optional and is a linker group;
each L2 is independently optional and is a linker group;
D1 is optional and is a dendritic polymer moiety having one or more branched monomer units (X), a plurality of end groups, and optionally, one or more linker groups L1;
D2 is a dendritic polymer having one or more branched monomer units (X), a plurality of end groups, and optionally, one or more linker groups (L3);
each L3 is independently optional or a linker group linked to the focal point group of the dendritic polymer and monomer unit (X);
R1 and R2 are end groups of the dendritic polymer and are independently at each occurrence in the compound selected from the group consisting of a hydrophobic group, a hydrophilic group, an amphiphilic group, a reversible photocrosslinking group, and a drug, such that when R1 and/or R2 are not end groups each R1 and/or R2 is linked to one of the end groups;
subscript x is an integer from 1 to 64, wherein subscript x is equal to the number of end groups on the dendritic polymer;
subscript y is an integer from 2 to 64, wherein subscript y is equal to the number of end groups on the dendritic polymer;
subscript p is an integer from 1 to 32; and
subscript m is an integer from 0 to 32. 2. The compound of claim 1, wherein at each occurrence in the compound the branched monomer unit (X) is independently selected from the group consisting of a diamino carboxylic acid moiety, a dihydroxy carboxylic acid moiety, and a hydroxylamino carboxylic acid moiety. 3. The compound of claim 2, wherein at each occurrence in the compound the diamino carboxylic acid is independently selected from the group consisting of 2,3-diamino propanoic acid, 2,4-diaminobutanoic acid, 2,5-diaminopentanoic acid (ornithine), 2,6-diaminohexanoic acid (lysine), (2-Aminoethyl)-cysteine, 3-amino-2-aminomethyl propanoic acid, 3-amino-2-aminomethyl-2-methyl propanoic acid, 4-amino-2-(2-aminoethyl) butyric acid, and 5-amino-2-(3-aminopropyl)pentanoic acid. 4. The compound of claim 2, wherein the diamino carboxylic acid moiety is an amino acid moiety. 5. The compound of claim 2, wherein each branched monomer unit X is lysine moiety. 6. The compound of claim 1, wherein the compound is selected from the group consisting of:
wherein each branched monomer unit is lysine moiety. 7. The compound of claim 1, wherein at each occurrence in the compound the linker L1, L2, and L3 each are independently selected from the group consisting of a polyethylene glycol moiety, polyserine moiety, enzyme cleavable peptide moiety, disulfide bond moiety and acid labile moiety, polyglycine moiety, poly(serine-glycine) moiety, aliphatic amino acid moieties, 6-amino hexanoic acid moiety, 5-amino pentanoic acid moiety, 4-amino butanoic acid moiety, and beta-alanine moiety. 8. The compound of claim 1, wherein at each occurrence in the compound the linker L1, L2, and L3 are independently selected from the group consisting of: 9. The compound of claim 1, wherein the linker L1, L2, L3, or a combination thereof comprises a cleavable group. 10. The compound of claim 9, wherein the cleavable group is a disulfide cleavable moiety. 11. The compound of claim 1, wherein the (PEG)m-A- portion of the compound is selected from the group consisting of:
wherein each K is lysine. 12. The compound of claim 1, wherein each R1 and R2 is independently selected from a rhein moiety or derivative or analog thereof, cholic acid moiety or derivative or analog thereof, cholesterol moiety or derivative or analog thereof, coumarin moiety or derivative or analog thereof, curcurmine moiety or derivative or analog thereof, flavin moiety or derivative or analog thereof, isoflavin moiety or derivative or analog thereof, riboflavin moiety or derivative or analog thereof, retinol moiety or derivative or analog thereof, retinoic acid moiety or derivative or analog thereof, chlorogenic acid moiety or derivative or analog thereof, anthraquinone moiety or derivative or analog thereof, xanthenone moiety or derivative or analog thereof, Vitamin E moiety or derivative or analog thereof, D-α-tocopherol succinate moiety or derivative or analog thereof, vitamins, lipids, fatty acids, bile acids, naturally-isolated compound moieties, and drugs. 13. The compound of claim 1, wherein each R1 and/or each R2 is a reversible photocrosslinking group. 14. The compound of claim 13, wherein the reversible photocrosslinking group is coumarin moiety, 4-methylcoumarin moiety, cinnamic acid moiety or derivative or analog thereof, chlorogenic acid moiety or derivative or analog thereof, or a combination thereof. 15. The compound of claim 6, wherein x=4; y=4, m=1, PEG is 5 kDa; R1 is a coumarin moiety; each R2 is independently selected from the group consisting of cholic acid moiety or derivative or analog thereof, cholesterol moiety or derivative or analog thereof, rhein moiety or derivative or analog thereof, Vitamin E moiety or derivative or analog thereof, coumarin moiety or derivative or analog thereof, curcurmin moiety or derivative or analog thereof, and riboflavin moiety or derivative or analog thereof; L1 is optional or a disulfide bond moiety; L2 is an ethylene glycol linker; and L3 is optional or an ethylene glycol linker. 16. The compound of claim 1, wherein x=2 to 16; y=2 to 64, m=1 to 8, PEG is 1 to 40 kDa; each R1 is independently selected from a coumarin moiety or derivative or analog thereof, a cinnamic acid moiety or derivative or analog thereof, and a chlorogenic acid moiety or derivative or analog thereof; each R2 is independently selected from the group consisting of cholic acid moiety or derivative or analog thereof, cholesterol moiety or derivative or analog thereof, rhein moiety or derivative or analog thereof, Vitamin E moiety or derivative or analog thereof, coumarin moiety or derivative or analog thereof, curcurmin moiety or derivative or analog thereof, and riboflavin moiety or derivative or analog thereof; L1 is optional or a disulfide bond moiety; L2 is an ethylene glycol linker; and L3 is optional or an ethylene glycol linker. 17. The compound of claim 6, wherein x=4; y=4, m=1, PEG is 5 kDa; R1 is a cholic acid moiety or derivative or analog thereof; each R2 is independently selected from the group consisting of cholesterol moiety or derivative or analog thereof, rhein moiety or derivative or analog thereof, Vitamin E moiety or derivative or analog thereof, coumarin moiety or derivative or analog thereof, curcurmin moiety or derivative or analog thereof, riboflavin moiety or derivative or analog thereof, retinoic acid moiety or derivative or analog thereof, and a chlorogenic acid moiety or derivative or analog thereof; L1 is optional or a disulfide bond moiety; L2 is an ethylene glycol linker; and L3 is optional or an ethylene glycol linker. 18. The compound of claim 1, wherein x=2 to 16; y=2 to 64, m=1 to 8, PEG is 1 to 40 kDa; each R1 is independently selected from the group consisting of a cholic acid moiety or derivative or analog thereof moiety, riboflavin moiety or derivative or analog thereof, and a chlorogenic acid moiety or derivative or analog thereof; each R2 is independently selected from the group consisting of cholic acid moiety or derivative or analog thereof, cholesterol moiety or derivative or analog thereof, rhein moiety or derivative or analog thereof, Vitamin E moiety or derivative or analog thereof, coumarin moiety or derivative or analog thereof, curcurmin moiety or derivative or analog thereof, riboflavin moiety or derivative or analog thereof, and retinoic acid moiety or derivative or analog thereof; L1 is optional or a disulfide bond moiety; L2 is an ethylene glycol linker; and L3 is optional or an ethylene glycol linker. 19. A nanocarrier comprising a plurality of compounds of claim 1. 20. The nanocarrier of claim 19, wherein the nanocarrier further comprises a hydrophobic drug or an imaging agent. | 1,600 |
1,117 | 14,240,903 | 1,646 | The present invention relates to inhibitors of antithrombin III and the medical use thereof in treating or preventing bleeding. The inhibitors are preferably used in subjects suffering from an acquired or genetic bleeding disorder, such as haemophilia, or in a subjects having a clinical condition characterised by excessive bleeding, such as surgery, trauma and internal bleeding. The inhibitor of antithrombin III can e.g. a peptide, an aptamer or an antibody or antibody fragment that specifically binds to and inhibits antithrombin III. | 1-15. (canceled) 16. A method for treating or reducing the risk of bleeding in a subject who has a genetic or acquired bleeding disorder or a clinical condition characterized by excessive bleeding, which method comprises administering to the subject an effective amount of an inhibitor of antithrombin III. 17. The method of claim 16, wherein the inhibitor has the following properties:
when the inhibitor is added to pooled plasma from healthy subjects and mixed with thrombin, factor Xa or factor IXa, to form a mixture, the mixture prevents, by more than 20%, a reduction in activity of the thrombin, the factor Xa or the factor IXa by the plasma in an in vitro assay of thrombin, factor Xa or factor IXa activity, compared to the reduction in the activity of the thrombin, the factor Xa or the factor IXa in a mixture containing the same pooled plasma but in the absence of the added inhibitor. 18. The method according to claim 17 wherein the thrombin, the factor Xa or the factor IXa activity is determined in an assay that employs a chromogenic substrate for thrombin, factor Xa or factor IXa. 19. The method of claim 16, wherein the bleeding disorder is hemophilia. 20. The method of claim 19, wherein the hemophilic subject has antibodies that neutralize factor VIII or factor IX. 21. The method of claim 20, wherein the inhibitor is used in prophylactic bypass therapy of factor VIII or factor IX insufficiency. 22. The method of claim 16, wherein the clinical condition is a result of surgery, trauma or internal bleeding. 23. The method of claim 16, wherein the inhibitor is:
(a) a compound that inserts into the central β-sheet of antithrombin III; (b) an aptamer that specifically binds to antithrombin III and prevents or slows insertion of antithrombin III's reactive center loop (RCL) into the central β-sheet of antithrombin III; or, (c) an antibody or antibody fragment that specifically binds to antithrombin III. 24. The method of claim 23, wherein the compound of (a) is a peptide or peptidomimetic that mimics RCL amino acid residues P1-P14. 25. The method of claim 23, wherein the antibody or antibody fragment of (c) specifically binds to an antithrombin III epitope present in the RCL and impairs insertion of the RCL into the central β-sheet of antithrombin III. 26. The method of claim 25, wherein the RCL epitope to which the antibody or antibody fragment binds comprises one or more of RCL amino acid residues P1-P14. 27. The method of claim 26, wherein the RCL epitope to which the antibody or antibody fragments binds comprises:
(a) RCL residues around residue P10; (b) RCL residues P5-P10; or (c) RCL residues P3-P8. 28. A method for identifying a compound as an inhibitor of antithrombin III, comprising the steps of:
(a) combining the compound with pooled plasma from healthy subjects and isolated thrombin or isolated factor Xa to form a mixture; (b) determining the activity of the thrombin or the factor Xa in the mixture of (a) using an in vitro assay for thrombin or factor Xa activity; (c) determining the activity of thrombin or factor Xa, respectively, mixed with the same pooled plasma but in the absence of the compound using the assay of step (b); and, (d) comparing the activity of the thrombin or factor Xa in step (b) with the activity in step (c),
wherein, if reduction in the thrombin or the factor Xa activity caused by the plasma is inhibited in step (b) compared to step (c), the compound is identified as an inhibitor of antithrombin III. 29. The method of claim 28 wherein the thrombin or factor Xa activity is determined in an assay that employs a chromogenic substrate for thrombin or factor Xa. 30. The method of claim 28 wherein the compound is identified as an inhibitor of antithrombin III if reduction in the thrombin or the factor Xa activity caused by the plasma is inhibited more than 20%. 31. The method of claim 28, wherein prior to step (a), the compound that is selected by specific binding to antithrombin III. 31. A method for identifying an inhibitor of antithrombin III, comprising
(i) selecting a compound that binds specifically to antithrombin III, and (ii) carrying out the method of claim 28 with said selected candidate compound. 32. The method according to claim 31, wherein the antithrombin III-binding compound selected in step (i) is a peptide, an aptamer, an antibody or an antibody fragment. 33. The method of claim 32 wherein the peptide, aptamer, antibody or antibody fragment is one that binds specifically to an epitope in the RCL of antithrombin III. | The present invention relates to inhibitors of antithrombin III and the medical use thereof in treating or preventing bleeding. The inhibitors are preferably used in subjects suffering from an acquired or genetic bleeding disorder, such as haemophilia, or in a subjects having a clinical condition characterised by excessive bleeding, such as surgery, trauma and internal bleeding. The inhibitor of antithrombin III can e.g. a peptide, an aptamer or an antibody or antibody fragment that specifically binds to and inhibits antithrombin III.1-15. (canceled) 16. A method for treating or reducing the risk of bleeding in a subject who has a genetic or acquired bleeding disorder or a clinical condition characterized by excessive bleeding, which method comprises administering to the subject an effective amount of an inhibitor of antithrombin III. 17. The method of claim 16, wherein the inhibitor has the following properties:
when the inhibitor is added to pooled plasma from healthy subjects and mixed with thrombin, factor Xa or factor IXa, to form a mixture, the mixture prevents, by more than 20%, a reduction in activity of the thrombin, the factor Xa or the factor IXa by the plasma in an in vitro assay of thrombin, factor Xa or factor IXa activity, compared to the reduction in the activity of the thrombin, the factor Xa or the factor IXa in a mixture containing the same pooled plasma but in the absence of the added inhibitor. 18. The method according to claim 17 wherein the thrombin, the factor Xa or the factor IXa activity is determined in an assay that employs a chromogenic substrate for thrombin, factor Xa or factor IXa. 19. The method of claim 16, wherein the bleeding disorder is hemophilia. 20. The method of claim 19, wherein the hemophilic subject has antibodies that neutralize factor VIII or factor IX. 21. The method of claim 20, wherein the inhibitor is used in prophylactic bypass therapy of factor VIII or factor IX insufficiency. 22. The method of claim 16, wherein the clinical condition is a result of surgery, trauma or internal bleeding. 23. The method of claim 16, wherein the inhibitor is:
(a) a compound that inserts into the central β-sheet of antithrombin III; (b) an aptamer that specifically binds to antithrombin III and prevents or slows insertion of antithrombin III's reactive center loop (RCL) into the central β-sheet of antithrombin III; or, (c) an antibody or antibody fragment that specifically binds to antithrombin III. 24. The method of claim 23, wherein the compound of (a) is a peptide or peptidomimetic that mimics RCL amino acid residues P1-P14. 25. The method of claim 23, wherein the antibody or antibody fragment of (c) specifically binds to an antithrombin III epitope present in the RCL and impairs insertion of the RCL into the central β-sheet of antithrombin III. 26. The method of claim 25, wherein the RCL epitope to which the antibody or antibody fragment binds comprises one or more of RCL amino acid residues P1-P14. 27. The method of claim 26, wherein the RCL epitope to which the antibody or antibody fragments binds comprises:
(a) RCL residues around residue P10; (b) RCL residues P5-P10; or (c) RCL residues P3-P8. 28. A method for identifying a compound as an inhibitor of antithrombin III, comprising the steps of:
(a) combining the compound with pooled plasma from healthy subjects and isolated thrombin or isolated factor Xa to form a mixture; (b) determining the activity of the thrombin or the factor Xa in the mixture of (a) using an in vitro assay for thrombin or factor Xa activity; (c) determining the activity of thrombin or factor Xa, respectively, mixed with the same pooled plasma but in the absence of the compound using the assay of step (b); and, (d) comparing the activity of the thrombin or factor Xa in step (b) with the activity in step (c),
wherein, if reduction in the thrombin or the factor Xa activity caused by the plasma is inhibited in step (b) compared to step (c), the compound is identified as an inhibitor of antithrombin III. 29. The method of claim 28 wherein the thrombin or factor Xa activity is determined in an assay that employs a chromogenic substrate for thrombin or factor Xa. 30. The method of claim 28 wherein the compound is identified as an inhibitor of antithrombin III if reduction in the thrombin or the factor Xa activity caused by the plasma is inhibited more than 20%. 31. The method of claim 28, wherein prior to step (a), the compound that is selected by specific binding to antithrombin III. 31. A method for identifying an inhibitor of antithrombin III, comprising
(i) selecting a compound that binds specifically to antithrombin III, and (ii) carrying out the method of claim 28 with said selected candidate compound. 32. The method according to claim 31, wherein the antithrombin III-binding compound selected in step (i) is a peptide, an aptamer, an antibody or an antibody fragment. 33. The method of claim 32 wherein the peptide, aptamer, antibody or antibody fragment is one that binds specifically to an epitope in the RCL of antithrombin III. | 1,600 |
1,118 | 15,131,442 | 1,628 | A composition effective to relax smooth muscles in an individual in an altered state is described. The composition includes a dosage of GABA or GABA-a analogue, and a dosage of at least one of an ACE inhibitor and an ARB combined with the dosage of GABA or GABA-a analogue into a deliverable form. | 1-10. (canceled) 11. A method of relaxing smooth muscles in an individual having GABA receptors expressed in the individual's smooth muscles and endothelium, the method comprising the steps of:
providing a composition of a dosage of GABA or GABA-a analogue and a dosage of at least one of an ACE inhibitor and a ARB combined into a deliverable form; delivering the composition to an individual's circulatory system; reducing the level of angiotensin II in the individual through the action of the dosage of the at least one of the ACE inhibitor and the ARB during a period of time; and activating the GABA receptors through the action of the GABA or GABA-a analog during the period of time to promote production and release of smooth muscle relaxing substances by the activation of the GABA-a receptors. 12. A method as claimed in claim 11 wherein the step of providing a deliverable form of the composition includes providing the composition in one of tablets, capsules and IVs. 13. A method as claimed in claim 11 wherein the step of providing a deliverable form of the composition includes providing the composition as a tablet including the GABA or GABA-a analog in time release form. 14. A method as claimed in claim 11 wherein the step of providing a deliverable form of the composition includes providing the composition as a capsule including the GABA or GABA-a analog in time release form. 15. A method as claimed in claim 11 wherein the GABA or GABA-a analog dose is in the range of 1 mg/day to 10 gms/day, and at least one of the ACE-I dose being in the range of 1 mg/day to 450 mgs/day and the ARB dose being in the range of 1 mg/day to 1000 mg/day. 16. A method as claimed in claim 11 wherein activating the GABA receptors through the action of the GABA or GABA-a analog during the period of time includes delivering the GABA or GABA-a analog in a time release manner. | A composition effective to relax smooth muscles in an individual in an altered state is described. The composition includes a dosage of GABA or GABA-a analogue, and a dosage of at least one of an ACE inhibitor and an ARB combined with the dosage of GABA or GABA-a analogue into a deliverable form.1-10. (canceled) 11. A method of relaxing smooth muscles in an individual having GABA receptors expressed in the individual's smooth muscles and endothelium, the method comprising the steps of:
providing a composition of a dosage of GABA or GABA-a analogue and a dosage of at least one of an ACE inhibitor and a ARB combined into a deliverable form; delivering the composition to an individual's circulatory system; reducing the level of angiotensin II in the individual through the action of the dosage of the at least one of the ACE inhibitor and the ARB during a period of time; and activating the GABA receptors through the action of the GABA or GABA-a analog during the period of time to promote production and release of smooth muscle relaxing substances by the activation of the GABA-a receptors. 12. A method as claimed in claim 11 wherein the step of providing a deliverable form of the composition includes providing the composition in one of tablets, capsules and IVs. 13. A method as claimed in claim 11 wherein the step of providing a deliverable form of the composition includes providing the composition as a tablet including the GABA or GABA-a analog in time release form. 14. A method as claimed in claim 11 wherein the step of providing a deliverable form of the composition includes providing the composition as a capsule including the GABA or GABA-a analog in time release form. 15. A method as claimed in claim 11 wherein the GABA or GABA-a analog dose is in the range of 1 mg/day to 10 gms/day, and at least one of the ACE-I dose being in the range of 1 mg/day to 450 mgs/day and the ARB dose being in the range of 1 mg/day to 1000 mg/day. 16. A method as claimed in claim 11 wherein activating the GABA receptors through the action of the GABA or GABA-a analog during the period of time includes delivering the GABA or GABA-a analog in a time release manner. | 1,600 |
1,119 | 14,616,565 | 1,634 | The present invention discloses methods, kits, and apparatus as well as reagents and compositions associated therewith for deriving an indicator for use in diagnosing the presence, absence or degree of at least one condition in a biological subject or in prognosing at least one condition in a biological subject. Also disclosed is a biomarker signature for use in diagnosing the presence, absence or degree of at least one condition in a biological subject or in prognosing at least one condition in a biological subject. The present invention further discloses methods, kits and apparatus, as well as reagents and compositions associated therewith, for identifying biomarkers for use in a biomarker signature. | 1. A composition comprising at least one pair of reverse transcribed mRNAs and at least one oligonucleotide primer or probe that hybridizes to an individual one of the reverse transcribed mRNAs, the at least one pair of reverse transcribed mRNAs comprising a first pair and a second pair of reverse transcribed mRNAs, wherein the first pair comprises a PLAC8 reverse transcribed mRNA and a PLA2G7 reverse transcribed mRNA and wherein the second pair comprises a CEACAM4 reverse transcribed mRNA and a LAMP1 reverse transcribed mRNA. 2. The composition according to claim 1, wherein the at least one oligonucleotide primer or probe is hybridized to an individual one of the reverse transcribed mRNAs. 3. The composition according to claim 1, wherein the reverse transcribed mRNAs are derived from components of the immune system. 4. The composition according to claim 1, wherein the reverse transcribed mRNAs are derived from leukocytes. 5. The composition according to claim 1, wherein the reverse transcribed mRNAs are derived from blood cells. 6. The composition according to claim 1, wherein the reverse transcribed mRNAs are derived from peripheral blood cells. 7. The composition according to claim 1, further comprising a labeled reagent for detecting the reverse transcribed mRNAs. 8. The composition according to claim 6, wherein the labeled reagent is a labeled said at least one oligonucleotide primer or probe. 9. The composition according to claim 6, wherein the labeled reagent is a labeled said reverse transcribed mRNA. 10. A method for differentiating between inSIRS and ipSIRS in a biological subject, the method including:
a) obtaining a sample taken from a biological subject showing a clinical sign of SIRS, the sample including polynucleotide expression products; b) quantifying polynucleotide expression products within the sample to determine a pair of biomarker values, the pair of biomarker values being selected from the group consisting of:
i) a first pair of biomarker values indicative of a concentration of polynucleotide expression products of the PLA2G7 gene and PLAC8 gene;
ii) a second pair of biomarker values indicative of a concentration of polynucleotide expression products of the CEACAM4 gene and LAMP1 gene;
c) determining an indicator indicative of a ratio of concentrations of the polynucleotide expression products using the pair of biomarker values; d) comparing the indicator to first and second indicator references, the first and second indicator references being indicative of inSIRS and ipSIRS, respectively; and, e) determining a likelihood of the subject having inSIRS or ipSIRS in accordance with the results of the comparison. 11. The method according to claim 10, wherein the method includes:
a) determining a first derived biomarker value using the first pair of biomarker values; b) determining a second derived biomarker value using the second pair of biomarker values; and, c) determining the indicator by combining the first and second derived biomarker values. 12. The method according to claim 11, wherein the method includes combining the derived biomarker values using a combining function, the combining function being at least one of:
a) an additive model; b) a linear model; c) a support vector machine; d) a neural network model; e) a random forest model; f) a regression model; g) a genetic algorithm; h) an annealing algorithm; i) a weighted sum; j) a nearest neighbour model; and, k) a probabilistic model. 13. The method according to claim 10, wherein the method is performed at least in part using an electronic processing device. 14. The method according to claim 11, wherein the method includes, in at least one electronic processing device:
a) obtaining the pairs of biomarker values; b) determining the first derived biomarker value; c) determining the second derived biomarker value; and, d) determining the indicator by adding the first and second derived biomarker values. 15. The method according to claim 10, wherein the method includes, in at least one processing device, generating a representation of the indicator. 16. The method according to claim 15, wherein the representation includes:
a) an alphanumeric indication of the indicator; b) a graphical indication of a comparison of the indicator to one or more indicator references; c) an alphanumeric indication of a likelihood of the subject having at least one medical condition. 17. The method according to claim 10, wherein the indicator references are based on at least one of:
a) an indicator threshold range; b) an indicator threshold; and, c) an indicator distribution. 18. The method according to claim 10, wherein the indicator references are derived from indicators determined for a number of individuals in a reference population. 19. The method according to claim 18, wherein the indicator reference is based on a distribution of indicators determined for a group of a reference population, the group consisting of individuals diagnosed as having the medical condition or lacking the medical condition. 20. The method according to claim 18, wherein the reference population includes at least one of:
a) a plurality of individuals of different sexes; b) a plurality of individuals of different ethnicities; c) a plurality of healthy individuals; d) a plurality of individuals suffering from at least one of inSIRS and ipSIRS; e) a plurality of individuals lacking at least one of inSIRS and ipSIRS; f) a plurality of individuals showing clinical signs of at least one of inSIRS and ipSIRS; g) first and second groups of individuals, each group of individuals suffering from one of inSIRS and ipSIRS; and, h) first and second groups of individuals, the first group of individuals suffering from at least one of inSIRS and ipSIRS, and the second group lacking one or both of inSIRS and ipSIRS. 21. The method according to claim 10, wherein the likelihood is based on a probability generated using the results of the comparison. 22. The method according to claim 10, wherein the method includes:
a) determining first and second indicator probabilities using the results of the comparisons; and, b) combining the first and second indicator probabilities to determine a condition probability indicative of the likelihood. 23. The method according to claim 10, wherein the method includes:
a) quantifying polynucleotide expression products by:
i) amplifying at least some polynucleotide expression products in the sample; and,
ii) determining an amplification amount representing a degree of amplification required to obtain a defined level of each of a pair of polynucleotide expression products; and,
b) determining the indicator by determining a difference between the amplification amounts. 24. The method according to claim 23, wherein the amplification amount is at least one of:
a) a cycle time; b) a number of cycles; c) a cycle threshold; d) an amplification time; and, e) relative to an amplification amount of another amplified product. 25. The method according to claim 23, wherein the method includes determining:
a) a first derived biomarker value by determining a difference between the amplification amounts of a first pair of polynucleotide expression products; b) a second derived biomarker value by determining a difference between the amplification amounts of a second pair of polynucleotide expression products; c) determining the indicator by adding the first and second derived biomarker values. 26. A kit for determining an indicator indicative of the likelihood of the presence or absence of at least one condition selected from the group consisting of inSIRS and ipSIRS, the kit comprising at least one pair of reagents comprising a first pair of reagents and a second pair of reagents, wherein the first pair of reagents comprises (i) a reagent that allows quantification of a polynucleotide expression product of the PLA2G7 gene; and (ii) a reagent that allows quantification of a polynucleotide expression product of the PLAC8 gene, wherein the second pair of reagents comprises: (iii) a reagent that allows quantification of a polynucleotide expression product of the CEACAM4 gene; and (iv) a reagent that allows quantification of a polynucleotide expression product of the LAMP1 gene. 27. A method for inhibiting the development or progression in a subject of at least one condition selected from the group consisting of inSIRS and ipSIRS, the method comprising: exposing the subject to a treatment regimen for treating the at least one condition based on an indicator obtained from an indicator-determining method, wherein the indicator is indicative of the presence of the at least one condition in the subject, the indicator-determining method comprising: (a) determining at least one pair of biomarker values, each biomarker value being a value measured or derived for at least one corresponding immune system biomarker of the biological subject and being at least partially indicative of a concentration of the immune system biomarker in a sample taken from the subject, (b) determining at least one derived biomarker value using the at least one pair of biomarker values, the derived biomarker value being indicative of a ratio of concentrations of the at least one pair of immune system biomarkers; and (c) determining the indicator based on the at least one derived biomarker value, wherein the pair of biomarker values comprises at least one of:
a) a first pair of biomarker values comprising first and second biomarker values corresponding to first and second biomarkers, wherein the first immune system biomarker represents a polynucleotide expression product of the PLA2G7 gene and wherein the second immune system biomarker representing a polynucleotide expression product of the PLAC8 gene, and b) a second pair of biomarker values comprises third and fourth biomarker values corresponding to third and fourth immune system biomarkers, respectively, wherein the third immune system biomarker represents a polynucleotide expression product of the CEACAM4 gene and wherein the fourth immune system biomarker represents a polynucleotide expression product of the LAMP1 gene. 28. The method according to claim 27, wherein the indicator-determining method comprises: determining the first pair and second pair of biomarker values and determining a first derived biomarker value calculated using the first pair of biomarker values and a second derived biomarker value calculated using the second pair of biomarker values; and determining the indicator based on a combination of the first and second derived biomarker values. 29. The method according to claim 27, comprising: sending the sample taken from the subject to a laboratory at which the indicator is determined. 30. The method according to claim 27, wherein the sample comprises cells obtained from the subject or a nucleic acid sample thereof. | The present invention discloses methods, kits, and apparatus as well as reagents and compositions associated therewith for deriving an indicator for use in diagnosing the presence, absence or degree of at least one condition in a biological subject or in prognosing at least one condition in a biological subject. Also disclosed is a biomarker signature for use in diagnosing the presence, absence or degree of at least one condition in a biological subject or in prognosing at least one condition in a biological subject. The present invention further discloses methods, kits and apparatus, as well as reagents and compositions associated therewith, for identifying biomarkers for use in a biomarker signature.1. A composition comprising at least one pair of reverse transcribed mRNAs and at least one oligonucleotide primer or probe that hybridizes to an individual one of the reverse transcribed mRNAs, the at least one pair of reverse transcribed mRNAs comprising a first pair and a second pair of reverse transcribed mRNAs, wherein the first pair comprises a PLAC8 reverse transcribed mRNA and a PLA2G7 reverse transcribed mRNA and wherein the second pair comprises a CEACAM4 reverse transcribed mRNA and a LAMP1 reverse transcribed mRNA. 2. The composition according to claim 1, wherein the at least one oligonucleotide primer or probe is hybridized to an individual one of the reverse transcribed mRNAs. 3. The composition according to claim 1, wherein the reverse transcribed mRNAs are derived from components of the immune system. 4. The composition according to claim 1, wherein the reverse transcribed mRNAs are derived from leukocytes. 5. The composition according to claim 1, wherein the reverse transcribed mRNAs are derived from blood cells. 6. The composition according to claim 1, wherein the reverse transcribed mRNAs are derived from peripheral blood cells. 7. The composition according to claim 1, further comprising a labeled reagent for detecting the reverse transcribed mRNAs. 8. The composition according to claim 6, wherein the labeled reagent is a labeled said at least one oligonucleotide primer or probe. 9. The composition according to claim 6, wherein the labeled reagent is a labeled said reverse transcribed mRNA. 10. A method for differentiating between inSIRS and ipSIRS in a biological subject, the method including:
a) obtaining a sample taken from a biological subject showing a clinical sign of SIRS, the sample including polynucleotide expression products; b) quantifying polynucleotide expression products within the sample to determine a pair of biomarker values, the pair of biomarker values being selected from the group consisting of:
i) a first pair of biomarker values indicative of a concentration of polynucleotide expression products of the PLA2G7 gene and PLAC8 gene;
ii) a second pair of biomarker values indicative of a concentration of polynucleotide expression products of the CEACAM4 gene and LAMP1 gene;
c) determining an indicator indicative of a ratio of concentrations of the polynucleotide expression products using the pair of biomarker values; d) comparing the indicator to first and second indicator references, the first and second indicator references being indicative of inSIRS and ipSIRS, respectively; and, e) determining a likelihood of the subject having inSIRS or ipSIRS in accordance with the results of the comparison. 11. The method according to claim 10, wherein the method includes:
a) determining a first derived biomarker value using the first pair of biomarker values; b) determining a second derived biomarker value using the second pair of biomarker values; and, c) determining the indicator by combining the first and second derived biomarker values. 12. The method according to claim 11, wherein the method includes combining the derived biomarker values using a combining function, the combining function being at least one of:
a) an additive model; b) a linear model; c) a support vector machine; d) a neural network model; e) a random forest model; f) a regression model; g) a genetic algorithm; h) an annealing algorithm; i) a weighted sum; j) a nearest neighbour model; and, k) a probabilistic model. 13. The method according to claim 10, wherein the method is performed at least in part using an electronic processing device. 14. The method according to claim 11, wherein the method includes, in at least one electronic processing device:
a) obtaining the pairs of biomarker values; b) determining the first derived biomarker value; c) determining the second derived biomarker value; and, d) determining the indicator by adding the first and second derived biomarker values. 15. The method according to claim 10, wherein the method includes, in at least one processing device, generating a representation of the indicator. 16. The method according to claim 15, wherein the representation includes:
a) an alphanumeric indication of the indicator; b) a graphical indication of a comparison of the indicator to one or more indicator references; c) an alphanumeric indication of a likelihood of the subject having at least one medical condition. 17. The method according to claim 10, wherein the indicator references are based on at least one of:
a) an indicator threshold range; b) an indicator threshold; and, c) an indicator distribution. 18. The method according to claim 10, wherein the indicator references are derived from indicators determined for a number of individuals in a reference population. 19. The method according to claim 18, wherein the indicator reference is based on a distribution of indicators determined for a group of a reference population, the group consisting of individuals diagnosed as having the medical condition or lacking the medical condition. 20. The method according to claim 18, wherein the reference population includes at least one of:
a) a plurality of individuals of different sexes; b) a plurality of individuals of different ethnicities; c) a plurality of healthy individuals; d) a plurality of individuals suffering from at least one of inSIRS and ipSIRS; e) a plurality of individuals lacking at least one of inSIRS and ipSIRS; f) a plurality of individuals showing clinical signs of at least one of inSIRS and ipSIRS; g) first and second groups of individuals, each group of individuals suffering from one of inSIRS and ipSIRS; and, h) first and second groups of individuals, the first group of individuals suffering from at least one of inSIRS and ipSIRS, and the second group lacking one or both of inSIRS and ipSIRS. 21. The method according to claim 10, wherein the likelihood is based on a probability generated using the results of the comparison. 22. The method according to claim 10, wherein the method includes:
a) determining first and second indicator probabilities using the results of the comparisons; and, b) combining the first and second indicator probabilities to determine a condition probability indicative of the likelihood. 23. The method according to claim 10, wherein the method includes:
a) quantifying polynucleotide expression products by:
i) amplifying at least some polynucleotide expression products in the sample; and,
ii) determining an amplification amount representing a degree of amplification required to obtain a defined level of each of a pair of polynucleotide expression products; and,
b) determining the indicator by determining a difference between the amplification amounts. 24. The method according to claim 23, wherein the amplification amount is at least one of:
a) a cycle time; b) a number of cycles; c) a cycle threshold; d) an amplification time; and, e) relative to an amplification amount of another amplified product. 25. The method according to claim 23, wherein the method includes determining:
a) a first derived biomarker value by determining a difference between the amplification amounts of a first pair of polynucleotide expression products; b) a second derived biomarker value by determining a difference between the amplification amounts of a second pair of polynucleotide expression products; c) determining the indicator by adding the first and second derived biomarker values. 26. A kit for determining an indicator indicative of the likelihood of the presence or absence of at least one condition selected from the group consisting of inSIRS and ipSIRS, the kit comprising at least one pair of reagents comprising a first pair of reagents and a second pair of reagents, wherein the first pair of reagents comprises (i) a reagent that allows quantification of a polynucleotide expression product of the PLA2G7 gene; and (ii) a reagent that allows quantification of a polynucleotide expression product of the PLAC8 gene, wherein the second pair of reagents comprises: (iii) a reagent that allows quantification of a polynucleotide expression product of the CEACAM4 gene; and (iv) a reagent that allows quantification of a polynucleotide expression product of the LAMP1 gene. 27. A method for inhibiting the development or progression in a subject of at least one condition selected from the group consisting of inSIRS and ipSIRS, the method comprising: exposing the subject to a treatment regimen for treating the at least one condition based on an indicator obtained from an indicator-determining method, wherein the indicator is indicative of the presence of the at least one condition in the subject, the indicator-determining method comprising: (a) determining at least one pair of biomarker values, each biomarker value being a value measured or derived for at least one corresponding immune system biomarker of the biological subject and being at least partially indicative of a concentration of the immune system biomarker in a sample taken from the subject, (b) determining at least one derived biomarker value using the at least one pair of biomarker values, the derived biomarker value being indicative of a ratio of concentrations of the at least one pair of immune system biomarkers; and (c) determining the indicator based on the at least one derived biomarker value, wherein the pair of biomarker values comprises at least one of:
a) a first pair of biomarker values comprising first and second biomarker values corresponding to first and second biomarkers, wherein the first immune system biomarker represents a polynucleotide expression product of the PLA2G7 gene and wherein the second immune system biomarker representing a polynucleotide expression product of the PLAC8 gene, and b) a second pair of biomarker values comprises third and fourth biomarker values corresponding to third and fourth immune system biomarkers, respectively, wherein the third immune system biomarker represents a polynucleotide expression product of the CEACAM4 gene and wherein the fourth immune system biomarker represents a polynucleotide expression product of the LAMP1 gene. 28. The method according to claim 27, wherein the indicator-determining method comprises: determining the first pair and second pair of biomarker values and determining a first derived biomarker value calculated using the first pair of biomarker values and a second derived biomarker value calculated using the second pair of biomarker values; and determining the indicator based on a combination of the first and second derived biomarker values. 29. The method according to claim 27, comprising: sending the sample taken from the subject to a laboratory at which the indicator is determined. 30. The method according to claim 27, wherein the sample comprises cells obtained from the subject or a nucleic acid sample thereof. | 1,600 |
1,120 | 15,941,753 | 1,654 | Recent reports detail the pleiotropic roles sirtuins play in repressing premature aging, delaying cellular senescence, enhancing longevity, and ameliorating a wide range of aging disorders. Herein, we report our findings on the potent sirtuin activator, decapeptide-12, and compare its performance to the well documented oxyresveratrol. Treatment of human epidermal keratinocyte progenitors with 100 μM decapeptide-12 increased transcription of SIRT1 by 141±11 percent relative to control cells, whereas levels of SIRT3, SIRT6, and SIRT7 were increased by 121±13 percent, 147±8 percent and 95.4±14 percent, respectively. Decapeptide-12 upregulated sirtuin transcription to similar levels as oxyresveratrol but with reduced cytotoxicity. | 1. A peptide consisting of SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, or SEQ. ID NO: 12. 2. The peptide of claim 1 wherein the peptide consists of SEQ ID NO: 9 modified by a modifying group, the modifying group being either a palmitoyl group or an acetyl group at an amino-terminal end, or amidation of a carboxy-terminal end, or both. 3. The peptide according to any of claims 1-2 consisting of SEQ ID NO: 11 having a tyrosine amino acid at a position 6 as a D-isoform, and all other amino acids being L-isoforms. 4. A composition comprising a first peptide consisting of SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, or SEQ. ID NO: 12. 5. The composition of claim 4 wherein the peptide consists of SEQ ID NO: 9 modified by a modifying group, the modifying group being either a palmitoyl group or an acetyl group at an amino-terminal end, or amidation of a carboxy-terminal end, or both. 6. The composition according to any of claims 4-5 consisting of SEQ ID NO: 11 having a tyrosine amino acid at a position 6 as a D-isoform, and all other amino acids being L-isoforms. 7. The composition according to any of claims 4-6 wherein the peptide is present in a concentration of 1 μm or greater. 8. A method of treating a subject by modulating expression of a sirtuin gene in a skin cell to reduce symptoms of skin aging, the method comprising administering to a subject in need thereof a composition comprising an effective amount of one or more peptides, wherein the one or more peptides consist of, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, or SEQ. ID NO: 12. 9. The method according to claim 8 wherein the peptide consists of SEQ ID NO: 9 modified by a modifying group, the modifying group being either a palmitoyl group or an acetyl group at an amino-terminal end, or amidation of a carboxy-terminal end, or both. 10. The method according to any of claims 8-9 wherein the peptide consists of SEQ ID NO: 11 having a tyrosine amino acid at a position 6 as a D-isoform, and all other amino acids being L-isoforms. 11. The method according to any of claims 8-10 wherein the skin cell is a progenitor. 12. The method according to claim 11 wherein the progenitor is an epidermal keratinocyte progenitor, a melanoblast, a fibroblast, a histioblast, or a dendroblast. 13. The method according to any of claims 8-10 wherein the skin cell is terminally differentiated. 14. The method according to claim 13 wherein the skin cell is a keratinocyte, a melanocyte, a fibrocyte, a histiocyte, or a dendrocyte. 15. The method according to any of claims 8-14 wherein the peptide is present in a concentration of 1 μm or greater. 16. The method of according to any of claims 8-15 wherein the sirtuin gene comprises SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, or SEQ ID NO: 7. 17. The method according to any of claims 8-16 wherein the composition further comprises oxyresveratrol. 18. The method according to any of claims 8-17 wherein the skin cell is a mammal cell. 19. The method according to claims 18 wherein the skin cell is human. 20. A method of modulating expression of a sirtuin gene in a skin cell, the method comprising administering to a subject in need thereof a composition comprising an effective amount of one or more peptides, wherein the one or more peptides consist of, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, or SEQ. ID NO: 12. | Recent reports detail the pleiotropic roles sirtuins play in repressing premature aging, delaying cellular senescence, enhancing longevity, and ameliorating a wide range of aging disorders. Herein, we report our findings on the potent sirtuin activator, decapeptide-12, and compare its performance to the well documented oxyresveratrol. Treatment of human epidermal keratinocyte progenitors with 100 μM decapeptide-12 increased transcription of SIRT1 by 141±11 percent relative to control cells, whereas levels of SIRT3, SIRT6, and SIRT7 were increased by 121±13 percent, 147±8 percent and 95.4±14 percent, respectively. Decapeptide-12 upregulated sirtuin transcription to similar levels as oxyresveratrol but with reduced cytotoxicity.1. A peptide consisting of SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, or SEQ. ID NO: 12. 2. The peptide of claim 1 wherein the peptide consists of SEQ ID NO: 9 modified by a modifying group, the modifying group being either a palmitoyl group or an acetyl group at an amino-terminal end, or amidation of a carboxy-terminal end, or both. 3. The peptide according to any of claims 1-2 consisting of SEQ ID NO: 11 having a tyrosine amino acid at a position 6 as a D-isoform, and all other amino acids being L-isoforms. 4. A composition comprising a first peptide consisting of SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, or SEQ. ID NO: 12. 5. The composition of claim 4 wherein the peptide consists of SEQ ID NO: 9 modified by a modifying group, the modifying group being either a palmitoyl group or an acetyl group at an amino-terminal end, or amidation of a carboxy-terminal end, or both. 6. The composition according to any of claims 4-5 consisting of SEQ ID NO: 11 having a tyrosine amino acid at a position 6 as a D-isoform, and all other amino acids being L-isoforms. 7. The composition according to any of claims 4-6 wherein the peptide is present in a concentration of 1 μm or greater. 8. A method of treating a subject by modulating expression of a sirtuin gene in a skin cell to reduce symptoms of skin aging, the method comprising administering to a subject in need thereof a composition comprising an effective amount of one or more peptides, wherein the one or more peptides consist of, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, or SEQ. ID NO: 12. 9. The method according to claim 8 wherein the peptide consists of SEQ ID NO: 9 modified by a modifying group, the modifying group being either a palmitoyl group or an acetyl group at an amino-terminal end, or amidation of a carboxy-terminal end, or both. 10. The method according to any of claims 8-9 wherein the peptide consists of SEQ ID NO: 11 having a tyrosine amino acid at a position 6 as a D-isoform, and all other amino acids being L-isoforms. 11. The method according to any of claims 8-10 wherein the skin cell is a progenitor. 12. The method according to claim 11 wherein the progenitor is an epidermal keratinocyte progenitor, a melanoblast, a fibroblast, a histioblast, or a dendroblast. 13. The method according to any of claims 8-10 wherein the skin cell is terminally differentiated. 14. The method according to claim 13 wherein the skin cell is a keratinocyte, a melanocyte, a fibrocyte, a histiocyte, or a dendrocyte. 15. The method according to any of claims 8-14 wherein the peptide is present in a concentration of 1 μm or greater. 16. The method of according to any of claims 8-15 wherein the sirtuin gene comprises SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, or SEQ ID NO: 7. 17. The method according to any of claims 8-16 wherein the composition further comprises oxyresveratrol. 18. The method according to any of claims 8-17 wherein the skin cell is a mammal cell. 19. The method according to claims 18 wherein the skin cell is human. 20. A method of modulating expression of a sirtuin gene in a skin cell, the method comprising administering to a subject in need thereof a composition comprising an effective amount of one or more peptides, wherein the one or more peptides consist of, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, or SEQ. ID NO: 12. | 1,600 |
1,121 | 14,917,790 | 1,648 | A method for measuring influenza A virus by an immunoassay using an anti-influenza A virus monoclonal antibody which is highly reactive with a wide range of subtypes is disclosed. The method for measuring influenza A virus includes measuring influenza A virus by an immunoassay utilizing antigen-antibody reaction between a monoclonal antibody which specifically reacts with matrix protein (M1) of influenza A virus, or an antigen-binding fragment thereof, and influenza A virus in a sample. | 1. A method for measuring influenza A virus, said method comprising measuring influenza A virus by an immunoassay utilizing antigen-antibody reaction between a monoclonal antibody which specifically reacts with matrix protein (M1) of influenza A virus, or an antigen-binding fragment thereof, and influenza A virus in a sample. 2. The method according to claim 1, wherein said monoclonal antibody undergoes antigen-antibody reaction with each of the influenza A virus subtypes H1N1, H1N2, H2N2, H2N3, H3N2, H3N8, H4N6, H5N1, H5N2, H6N2, H7N1, H7N7, H7N9, H8N4, H9N2, H10N7, H11N6, H12N5, H13N6, H14N5, H15N8, and H16N3. 3. The method according to claim 1 or 2, wherein said monoclonal antibody binds to the region of the 127th to 252nd amino acids of matrix protein (M1) of influenza A virus. 4. The method according to claim 3, wherein said monoclonal antibody binds to the region of the 173rd to 186th amino acids of matrix protein (M1) of influenza A virus. 5. The method according to claim 3, wherein said monoclonal antibody binds to the region of the 232nd to 241st amino acids of matrix protein (M1) of influenza A virus. 6. The method according to claim 1, wherein said immunoassay is a sandwich method. 7. The method according to claim 6, which uses two kinds of monoclonal antibodies or antigen-binding fragments thereof which are capable of binding to matrix protein (M1) of influenza A virus at the same time. 8. The method according to claim 7, wherein both of said two kinds of monoclonal antibodies bind to the region of the 127th to 252nd amino acids of matrix protein (M1) of influenza A virus. 9. The method according to claim 8, using a first monoclonal antibody which binds to the region of the 173rd to 186th amino acids of matrix protein (M1) of influenza A virus, or an antigen-binding fragment thereof, and a second monoclonal antibody which binds to the region of the 232nd to 241st amino acids of matrix protein (M1) of influenza A virus, or an antigen-binding fragment thereof. 10. The method according to claim 6, wherein said immunoassay is immunochromatography. 11. The method according to claim 1, using a mixture of a monoclonal antibody which specifically reacts with matrix protein (M1) of influenza A virus, or an antigen-binding fragment thereof, and a monoclonal antibody which specifically reacts with nucleoprotein (NP) of influenza A virus, or an antigen-binding fragment thereof. 12. An immunoassay device comprising a detection area in which a first antibody or an antigen-binding fragment thereof is immobilized on a support, a label area in which a second antibody or an antigen-binding fragment thereof is supplied together with a sample, and a sample movement area, wherein at least one of said first antibody and said second antibody is a monoclonal antibody which specifically reacts with matrix protein (M1) of influenza A virus. 13. The immunoassay device according to claim 12, wherein said first and second antibodies are two kinds of monoclonal antibodies which are capable of binding to matrix protein (M1) of influenza A virus at the same time. 14. A monoclonal antibody which specifically reacts with matrix protein (M1) of influenza A virus, or an antigen-binding fragment thereof. 15. The monoclonal antibody according to claim 14, which undergoes antigen-antibody reaction with each of the influenza A virus subtypes H1N1, H1N2, H2N2, H2N3, H3N2, H3N8, H4N6, H5N1, H5N2, H6N2, H7N1, H7N7, H7N9, H8N4, H9N2, H10N7, H11N6, H12N5, H13N6, H14N5, H15N8, and H16N3, or an antigen-binding fragment thereof. 16. The monoclonal antibody according to claim 14 or 15, which binds to the region of the 127th to 252nd amino acids of matrix protein (M1) of influenza A virus, or an antigen-binding fragment thereof. 17. The monoclonal antibody according to claim 16, which binds to the region of the 173rd to 186th amino acids of matrix protein (M1) of influenza A virus, or an antigen-binding fragment thereof. 18. The monoclonal antibody according to claim 17, which binds to the region of the 232nd to 241st amino acids of matrix protein (M1) of influenza A virus, or an antigen-binding fragment thereof. | A method for measuring influenza A virus by an immunoassay using an anti-influenza A virus monoclonal antibody which is highly reactive with a wide range of subtypes is disclosed. The method for measuring influenza A virus includes measuring influenza A virus by an immunoassay utilizing antigen-antibody reaction between a monoclonal antibody which specifically reacts with matrix protein (M1) of influenza A virus, or an antigen-binding fragment thereof, and influenza A virus in a sample.1. A method for measuring influenza A virus, said method comprising measuring influenza A virus by an immunoassay utilizing antigen-antibody reaction between a monoclonal antibody which specifically reacts with matrix protein (M1) of influenza A virus, or an antigen-binding fragment thereof, and influenza A virus in a sample. 2. The method according to claim 1, wherein said monoclonal antibody undergoes antigen-antibody reaction with each of the influenza A virus subtypes H1N1, H1N2, H2N2, H2N3, H3N2, H3N8, H4N6, H5N1, H5N2, H6N2, H7N1, H7N7, H7N9, H8N4, H9N2, H10N7, H11N6, H12N5, H13N6, H14N5, H15N8, and H16N3. 3. The method according to claim 1 or 2, wherein said monoclonal antibody binds to the region of the 127th to 252nd amino acids of matrix protein (M1) of influenza A virus. 4. The method according to claim 3, wherein said monoclonal antibody binds to the region of the 173rd to 186th amino acids of matrix protein (M1) of influenza A virus. 5. The method according to claim 3, wherein said monoclonal antibody binds to the region of the 232nd to 241st amino acids of matrix protein (M1) of influenza A virus. 6. The method according to claim 1, wherein said immunoassay is a sandwich method. 7. The method according to claim 6, which uses two kinds of monoclonal antibodies or antigen-binding fragments thereof which are capable of binding to matrix protein (M1) of influenza A virus at the same time. 8. The method according to claim 7, wherein both of said two kinds of monoclonal antibodies bind to the region of the 127th to 252nd amino acids of matrix protein (M1) of influenza A virus. 9. The method according to claim 8, using a first monoclonal antibody which binds to the region of the 173rd to 186th amino acids of matrix protein (M1) of influenza A virus, or an antigen-binding fragment thereof, and a second monoclonal antibody which binds to the region of the 232nd to 241st amino acids of matrix protein (M1) of influenza A virus, or an antigen-binding fragment thereof. 10. The method according to claim 6, wherein said immunoassay is immunochromatography. 11. The method according to claim 1, using a mixture of a monoclonal antibody which specifically reacts with matrix protein (M1) of influenza A virus, or an antigen-binding fragment thereof, and a monoclonal antibody which specifically reacts with nucleoprotein (NP) of influenza A virus, or an antigen-binding fragment thereof. 12. An immunoassay device comprising a detection area in which a first antibody or an antigen-binding fragment thereof is immobilized on a support, a label area in which a second antibody or an antigen-binding fragment thereof is supplied together with a sample, and a sample movement area, wherein at least one of said first antibody and said second antibody is a monoclonal antibody which specifically reacts with matrix protein (M1) of influenza A virus. 13. The immunoassay device according to claim 12, wherein said first and second antibodies are two kinds of monoclonal antibodies which are capable of binding to matrix protein (M1) of influenza A virus at the same time. 14. A monoclonal antibody which specifically reacts with matrix protein (M1) of influenza A virus, or an antigen-binding fragment thereof. 15. The monoclonal antibody according to claim 14, which undergoes antigen-antibody reaction with each of the influenza A virus subtypes H1N1, H1N2, H2N2, H2N3, H3N2, H3N8, H4N6, H5N1, H5N2, H6N2, H7N1, H7N7, H7N9, H8N4, H9N2, H10N7, H11N6, H12N5, H13N6, H14N5, H15N8, and H16N3, or an antigen-binding fragment thereof. 16. The monoclonal antibody according to claim 14 or 15, which binds to the region of the 127th to 252nd amino acids of matrix protein (M1) of influenza A virus, or an antigen-binding fragment thereof. 17. The monoclonal antibody according to claim 16, which binds to the region of the 173rd to 186th amino acids of matrix protein (M1) of influenza A virus, or an antigen-binding fragment thereof. 18. The monoclonal antibody according to claim 17, which binds to the region of the 232nd to 241st amino acids of matrix protein (M1) of influenza A virus, or an antigen-binding fragment thereof. | 1,600 |
1,122 | 12,441,844 | 1,617 | A formulation having a slightly water soluble ingredient and method for preparing the same are disclosed. The millbase formulation comprises a slightly water soluble ingredient and a dispersant comprising a water soluble or water dispersible, derivative of an alternating copolymer or a salt thereof. The alternating copolymer comprises a residue of a first comonomer and a residue of a second comonomer. In addition, the first comonomer comprises an α,β-unsaturated oxyacid, or an anhydride or other derivative thereof. Moreover, the second comonomer comprises an olefinic compound containing one or more polymerizable double bonds, or a derivative thereof. Such formulations may be used to inhibit Ostwald ripening in agricultural as well as non-agricultural applications. | 1. A method of formulating a chemical formulation comprising:
providing a slightly water soluble ingredient and a dispersant comprising a water soluble derivative of an alternating copolymer or a salt thereof, wherein the alternating copolymer comprises a residue of a first comonomer and a residue of a second comonomer, and wherein the first comonomer comprises an α,β-unsaturated oxyacid, or an anhydride or other derivative thereof, and wherein the second comonomer comprises an olefinic compound containing one or more polymerizable double bonds, or a derivative thereof. 2. The method of claim 1, wherein the first comonomer is selected from the group consisting of fumaric acid and anhydride, and the esters, amides and imides derived thereof; maleic acid esters, amides and imides; itaconic acid and anhydride and the corresponding esters, amides and imides derived thereof; acrylic and methacrylic acids and the corresponding esters and amides derived thereof; vinylphosphonic acid and the corresponding esters and amides derived thereof; and ethylene sulphonic acid and the esters and amides derived thereof; acrylamido methyl propyl sulfonate; and combinations thereof. 3. The method of claim 1, wherein the slightly water soluble ingredient is an active ingredient used in agricultural formulations. 4. The method of claim 1, wherein the dispersant comprises a styrene/methacrylic acid copolymer. 5. The method of claim 1, wherein the alternating copolymer has a molecular weight from about 1,000 Daltons to about 90,000 Daltons. 6. The method of claim 1, wherein the chemical formulation comprises from about 0.5 w/wt. % to about 6.0 w/wt. % dispersant. 7. The method of claim 1, wherein the chemical formulation comprises more than one slightly water soluble ingredient. 8. The method of claim 1, wherein the chemical formulation comprises more than one dispersant. 9. A composition comprising:
a slightly water soluble ingredient; and a dispersant, wherein the dispersant comprises a water soluble derivative of an alternating copolymer or a salt thereof, wherein the alternating copolymer comprises a residue of a first comonomer and a residue of a second comonomer, and wherein the first comonomer comprises an α,β-unsaturated oxyacid, or an anhydride or other derivative thereof, and wherein the second comonomer comprises an olefinic compound containing one or more polymerizable double bonds, or a derivative thereof. 10. The composition of claim 9, further comprising at least a second slightly water soluble ingredient. 11. The composition of claim 9, wherein the composition is used in an application selected from the group consisting of: a dye, a pigment, a pharmaceutical, an ink, a coating, a resin, a fuel, gas treating, a lube, a detergent, and personal care. 12. The composition of claim 9, wherein the composition comprises from about 1 w/wt. % to about 65 w/wt. % slightly water soluble ingredient. 13. The composition of claim 9, wherein the composition comprises an aqueous suspension concentrate or suspoemulsion formulation. 14. The composition of claim 9, further comprising at least a second dispersant. 15. The composition of claim 9, further comprising a surfactant wetting agent, an adjuvant, a formulation aid, or combinations thereof. 16. A method of formulating an agricultural formulation comprising:
providing a slightly water soluble phenoxy herbicide and a dispersant comprising a water soluble, agriculturally acceptable derivative of an alternating copolymer or an agriculturally acceptable salt thereof, wherein the alternating copolymer comprises a residue of a first comonomer and a residue of a second comonomer, and wherein the first comonomer comprises an α,β-unsaturated oxyacid, or an anhydride or other derivative thereof, and wherein the second comonomer comprises an olefinic compound containing one or more polymerizable double bonds, or a derivative thereof. 17. The method of claim 16, wherein the slightly water soluble phenoxy herbicide is selected from the group consisting of 2,4-dichlorophenoxyacetic acid; 2,4-dichlorophenoxy propionic acid; 2,4-dichlorophenoxy butyric acid; 2,4,5-trichlorophenoxyacetic acid; 2-methyl-4-chlorophenoxyacetic acid; 2-methyl-4-chlorophenoxy propionic acid; 2-methyl-4-chlorophenoxy butyric acid; and combinations thereof. 18. The method of claim 16, further comprising dispersing the agricultural formulation in an aqueous medium to form a diluted suspension of the slightly water soluble phenoxy herbicide. 19. The method of claim 16, further comprising spraying the agricultural formulation. 20. An agricultural composition comprising:
a slightly water soluble phenoxy herbicide; and a dispersant, wherein the dispersant comprises a water soluble, agriculturally acceptable derivative of an alternating copolymer or an agriculturally acceptable salt thereof, wherein the alternating copolymer comprises a residue of a first comonomer and a residue of a second comonomer, and wherein the first comonomer comprises an α,β-unsaturated oxyacid, or an anhydride or other derivative thereof, and wherein the second comonomer comprises an olefinic compound containing one or more polymerizable double bonds, or a derivative thereof. | A formulation having a slightly water soluble ingredient and method for preparing the same are disclosed. The millbase formulation comprises a slightly water soluble ingredient and a dispersant comprising a water soluble or water dispersible, derivative of an alternating copolymer or a salt thereof. The alternating copolymer comprises a residue of a first comonomer and a residue of a second comonomer. In addition, the first comonomer comprises an α,β-unsaturated oxyacid, or an anhydride or other derivative thereof. Moreover, the second comonomer comprises an olefinic compound containing one or more polymerizable double bonds, or a derivative thereof. Such formulations may be used to inhibit Ostwald ripening in agricultural as well as non-agricultural applications.1. A method of formulating a chemical formulation comprising:
providing a slightly water soluble ingredient and a dispersant comprising a water soluble derivative of an alternating copolymer or a salt thereof, wherein the alternating copolymer comprises a residue of a first comonomer and a residue of a second comonomer, and wherein the first comonomer comprises an α,β-unsaturated oxyacid, or an anhydride or other derivative thereof, and wherein the second comonomer comprises an olefinic compound containing one or more polymerizable double bonds, or a derivative thereof. 2. The method of claim 1, wherein the first comonomer is selected from the group consisting of fumaric acid and anhydride, and the esters, amides and imides derived thereof; maleic acid esters, amides and imides; itaconic acid and anhydride and the corresponding esters, amides and imides derived thereof; acrylic and methacrylic acids and the corresponding esters and amides derived thereof; vinylphosphonic acid and the corresponding esters and amides derived thereof; and ethylene sulphonic acid and the esters and amides derived thereof; acrylamido methyl propyl sulfonate; and combinations thereof. 3. The method of claim 1, wherein the slightly water soluble ingredient is an active ingredient used in agricultural formulations. 4. The method of claim 1, wherein the dispersant comprises a styrene/methacrylic acid copolymer. 5. The method of claim 1, wherein the alternating copolymer has a molecular weight from about 1,000 Daltons to about 90,000 Daltons. 6. The method of claim 1, wherein the chemical formulation comprises from about 0.5 w/wt. % to about 6.0 w/wt. % dispersant. 7. The method of claim 1, wherein the chemical formulation comprises more than one slightly water soluble ingredient. 8. The method of claim 1, wherein the chemical formulation comprises more than one dispersant. 9. A composition comprising:
a slightly water soluble ingredient; and a dispersant, wherein the dispersant comprises a water soluble derivative of an alternating copolymer or a salt thereof, wherein the alternating copolymer comprises a residue of a first comonomer and a residue of a second comonomer, and wherein the first comonomer comprises an α,β-unsaturated oxyacid, or an anhydride or other derivative thereof, and wherein the second comonomer comprises an olefinic compound containing one or more polymerizable double bonds, or a derivative thereof. 10. The composition of claim 9, further comprising at least a second slightly water soluble ingredient. 11. The composition of claim 9, wherein the composition is used in an application selected from the group consisting of: a dye, a pigment, a pharmaceutical, an ink, a coating, a resin, a fuel, gas treating, a lube, a detergent, and personal care. 12. The composition of claim 9, wherein the composition comprises from about 1 w/wt. % to about 65 w/wt. % slightly water soluble ingredient. 13. The composition of claim 9, wherein the composition comprises an aqueous suspension concentrate or suspoemulsion formulation. 14. The composition of claim 9, further comprising at least a second dispersant. 15. The composition of claim 9, further comprising a surfactant wetting agent, an adjuvant, a formulation aid, or combinations thereof. 16. A method of formulating an agricultural formulation comprising:
providing a slightly water soluble phenoxy herbicide and a dispersant comprising a water soluble, agriculturally acceptable derivative of an alternating copolymer or an agriculturally acceptable salt thereof, wherein the alternating copolymer comprises a residue of a first comonomer and a residue of a second comonomer, and wherein the first comonomer comprises an α,β-unsaturated oxyacid, or an anhydride or other derivative thereof, and wherein the second comonomer comprises an olefinic compound containing one or more polymerizable double bonds, or a derivative thereof. 17. The method of claim 16, wherein the slightly water soluble phenoxy herbicide is selected from the group consisting of 2,4-dichlorophenoxyacetic acid; 2,4-dichlorophenoxy propionic acid; 2,4-dichlorophenoxy butyric acid; 2,4,5-trichlorophenoxyacetic acid; 2-methyl-4-chlorophenoxyacetic acid; 2-methyl-4-chlorophenoxy propionic acid; 2-methyl-4-chlorophenoxy butyric acid; and combinations thereof. 18. The method of claim 16, further comprising dispersing the agricultural formulation in an aqueous medium to form a diluted suspension of the slightly water soluble phenoxy herbicide. 19. The method of claim 16, further comprising spraying the agricultural formulation. 20. An agricultural composition comprising:
a slightly water soluble phenoxy herbicide; and a dispersant, wherein the dispersant comprises a water soluble, agriculturally acceptable derivative of an alternating copolymer or an agriculturally acceptable salt thereof, wherein the alternating copolymer comprises a residue of a first comonomer and a residue of a second comonomer, and wherein the first comonomer comprises an α,β-unsaturated oxyacid, or an anhydride or other derivative thereof, and wherein the second comonomer comprises an olefinic compound containing one or more polymerizable double bonds, or a derivative thereof. | 1,600 |
1,123 | 14,426,484 | 1,631 | Methods for diagnosing the status of periodontitis disease includes selecting a set of protein biomarkers including one or more biomarkers which have been shown to vary in abundance at particular stages of periodontitis. The set of protein biomarkers may be identified and quantified in expression in an acquired gingival crevicular fluid (GCF) or saliva oral fluid sample in order to distinguish between different states of periodontitis. Methods of diagnosing the status of periodontitis oral disease at varying levels of severity, e.g. gingivitis, mild periodontitis, or severe periodontitis, may include selecting a set of protein biomarkers which are capable distinguishing between different stages of periodontitis. | 1. A method for diagnosing the status of periodontitis disease, comprising:
providing a gingival crevicular fluid (GCF) sample and a saliva sample; generating a first protein profile by analyzing the proteome of the GCF sample; generating a second protein profile by analyzing the proteome of the saliva sample; determining an overlap region between the first protein profile and the second protein profile; selecting a set of protein biomarkers for identifying a particular state of periodontitis; and determining the expression levels in the selected set of protein biomarkers to diagnose the status of periodontitis disease; wherein selecting the set of protein biomarkers for distinguishing between states of periodontitis includes calculating a change in the abundance of proteins within the overlap region during different stages of periodontitis and selecting those proteins which are under or over expressed during a single state of periodontitis. 2. The method according to claim 1, wherein the set of protein biomarkers is selected for distinguishing between a gingivitis state and a periodontitis state. 3. The method according to claim 1, wherein the set of protein biomarkers is selected for distinguishing between a periodontal health and a disease state. 4. The method according to claim 1, wherein the set of protein biomarkers is selected for distinguishing between a mild periodontitis state and a severe periodontitis state. 5. The method according to claim 1, wherein the set of protein biomarkers includes at least one protein selected from the group consisting of haemoglobin chains alpha and beta, carbonic anhydrase 1 (International Protein Index or “IPI” #IPI00980674), and plastin-1. 6. The method according to claim 1, wherein the set of protein biomarkers includes at least one protein selected from the group consisting of S100-P, transaldolase, S100-A8 (calgranulin-A), myosin-9, Haemoglobin Alpha, and Haemoglobin Beta. 7. The method according to claim 1, wherein the set of protein biomarkers includes at least one protein selected from the group consisting of Alpha-1-acid glycoprotein 1 and 2, matrix metalloproteinase-9, Peptidyl-prolyl cis-trans isomerase A, and Haptoglobin-related protein (IPI00431645.1). 8. The method according to claim 1, wherein the set of protein biomarkers includes at least one protein selected from the group consisting of NADPH oxidase and Alpha-N-acetylgalactosaminidase. 9. The method according to claim 1, wherein the set of protein biomarkers includes Alpha-N-acetylgalactosaminidase. 10. The method according to claim 1, wherein the set of protein biomarkers includes at least one protein selected from the group consisting of Protein S100-A11 (IPI00013895.1), Protein IPI00037070.3, catalase (IPI00465436.4), Choline transporter-like protein 2 derivative (IPI00903245.1), and titin isoform N2-B (IPI00985334.2). 11. The method according to claim 5, wherein the set of protein biomarkers includes two or more biomarkers. 12. A kit for diagnosing the status of periodontitis disease, comprising a set of protein biomarkers selected to distinguish between stages of periodontitis; wherein the set of protein biomarkers for distinguishing between stages of periodontitis are selected by:
generating a first protein profile by analyzing the proteome of the GCF sample; generating a second protein profile by analyzing the proteome of the saliva sample; determining an overlap region between the first protein profile and the second protein profile; calculating a change in the abundance of proteins within the overlap region during different stages of periodontitis; and selecting those proteins which are under or over expressed during a single state of periodontitis. 13. The kit according to claim 12, wherein the set of protein biomarkers includes at least one protein selected from the group consisting of haemoglobin chains alpha and beta, carbonic anhydrase 1 (International Protein Index or “IPI” #IPI00980674), and plastin 1. 14. The kit according to claim 12, wherein the kit diagnoses gingivitis or mild periodontitis, and the set of protein biomarkers further includes at least one protein biomarker selected from coiled-coil domain-containing protein 86, zymogen granule protein 16 homolog B, isoform 2 of NADPH oxidase activator 1, salivary acidic proline-rich phosphoprotein 1/2, pituitary tumor transforming gene protein, isoform 2 of Guanine nucleotide exchange factor for Rab-3A, AngRem52, Alpha-N-acetylgalactosarninidase, Bardet-Biedl syndrome 10 protein, cDNA FU57374, 16 kDa protein, titin isoform N2-B, uncharacterized protein TP 0451 OS=Treponema pallidum (strain Nichols) GN=TP 0451 PE=4 SV=1-[Y451 TREPA], cDNA FU55140, Glutamate decarboxylase 2, protein having International Protein Index or “IPI” #IPI01.021118. Phosphocarrier protein HPr OS=Streptococcus salivarius GN=ptsH PE=1 SV=2 [PTHP STRSL], and salivary praline-rich protein 2. 15. (canceled) 16. The method according to claim 1, further including:
generating a protein profile by analyzing the proteome of the at least one oral fluid sample; and clustering the protein profile to determine a set of protein biomarkers. | Methods for diagnosing the status of periodontitis disease includes selecting a set of protein biomarkers including one or more biomarkers which have been shown to vary in abundance at particular stages of periodontitis. The set of protein biomarkers may be identified and quantified in expression in an acquired gingival crevicular fluid (GCF) or saliva oral fluid sample in order to distinguish between different states of periodontitis. Methods of diagnosing the status of periodontitis oral disease at varying levels of severity, e.g. gingivitis, mild periodontitis, or severe periodontitis, may include selecting a set of protein biomarkers which are capable distinguishing between different stages of periodontitis.1. A method for diagnosing the status of periodontitis disease, comprising:
providing a gingival crevicular fluid (GCF) sample and a saliva sample; generating a first protein profile by analyzing the proteome of the GCF sample; generating a second protein profile by analyzing the proteome of the saliva sample; determining an overlap region between the first protein profile and the second protein profile; selecting a set of protein biomarkers for identifying a particular state of periodontitis; and determining the expression levels in the selected set of protein biomarkers to diagnose the status of periodontitis disease; wherein selecting the set of protein biomarkers for distinguishing between states of periodontitis includes calculating a change in the abundance of proteins within the overlap region during different stages of periodontitis and selecting those proteins which are under or over expressed during a single state of periodontitis. 2. The method according to claim 1, wherein the set of protein biomarkers is selected for distinguishing between a gingivitis state and a periodontitis state. 3. The method according to claim 1, wherein the set of protein biomarkers is selected for distinguishing between a periodontal health and a disease state. 4. The method according to claim 1, wherein the set of protein biomarkers is selected for distinguishing between a mild periodontitis state and a severe periodontitis state. 5. The method according to claim 1, wherein the set of protein biomarkers includes at least one protein selected from the group consisting of haemoglobin chains alpha and beta, carbonic anhydrase 1 (International Protein Index or “IPI” #IPI00980674), and plastin-1. 6. The method according to claim 1, wherein the set of protein biomarkers includes at least one protein selected from the group consisting of S100-P, transaldolase, S100-A8 (calgranulin-A), myosin-9, Haemoglobin Alpha, and Haemoglobin Beta. 7. The method according to claim 1, wherein the set of protein biomarkers includes at least one protein selected from the group consisting of Alpha-1-acid glycoprotein 1 and 2, matrix metalloproteinase-9, Peptidyl-prolyl cis-trans isomerase A, and Haptoglobin-related protein (IPI00431645.1). 8. The method according to claim 1, wherein the set of protein biomarkers includes at least one protein selected from the group consisting of NADPH oxidase and Alpha-N-acetylgalactosaminidase. 9. The method according to claim 1, wherein the set of protein biomarkers includes Alpha-N-acetylgalactosaminidase. 10. The method according to claim 1, wherein the set of protein biomarkers includes at least one protein selected from the group consisting of Protein S100-A11 (IPI00013895.1), Protein IPI00037070.3, catalase (IPI00465436.4), Choline transporter-like protein 2 derivative (IPI00903245.1), and titin isoform N2-B (IPI00985334.2). 11. The method according to claim 5, wherein the set of protein biomarkers includes two or more biomarkers. 12. A kit for diagnosing the status of periodontitis disease, comprising a set of protein biomarkers selected to distinguish between stages of periodontitis; wherein the set of protein biomarkers for distinguishing between stages of periodontitis are selected by:
generating a first protein profile by analyzing the proteome of the GCF sample; generating a second protein profile by analyzing the proteome of the saliva sample; determining an overlap region between the first protein profile and the second protein profile; calculating a change in the abundance of proteins within the overlap region during different stages of periodontitis; and selecting those proteins which are under or over expressed during a single state of periodontitis. 13. The kit according to claim 12, wherein the set of protein biomarkers includes at least one protein selected from the group consisting of haemoglobin chains alpha and beta, carbonic anhydrase 1 (International Protein Index or “IPI” #IPI00980674), and plastin 1. 14. The kit according to claim 12, wherein the kit diagnoses gingivitis or mild periodontitis, and the set of protein biomarkers further includes at least one protein biomarker selected from coiled-coil domain-containing protein 86, zymogen granule protein 16 homolog B, isoform 2 of NADPH oxidase activator 1, salivary acidic proline-rich phosphoprotein 1/2, pituitary tumor transforming gene protein, isoform 2 of Guanine nucleotide exchange factor for Rab-3A, AngRem52, Alpha-N-acetylgalactosarninidase, Bardet-Biedl syndrome 10 protein, cDNA FU57374, 16 kDa protein, titin isoform N2-B, uncharacterized protein TP 0451 OS=Treponema pallidum (strain Nichols) GN=TP 0451 PE=4 SV=1-[Y451 TREPA], cDNA FU55140, Glutamate decarboxylase 2, protein having International Protein Index or “IPI” #IPI01.021118. Phosphocarrier protein HPr OS=Streptococcus salivarius GN=ptsH PE=1 SV=2 [PTHP STRSL], and salivary praline-rich protein 2. 15. (canceled) 16. The method according to claim 1, further including:
generating a protein profile by analyzing the proteome of the at least one oral fluid sample; and clustering the protein profile to determine a set of protein biomarkers. | 1,600 |
1,124 | 15,546,476 | 1,627 | Provided is an enema for rectal application containing budesonide as an active ingredient in order to treat inflammatory bowel disease, or to prevent a relapse. The enema for rectal application containing budesonide as the active ingredient, in which 1.5 to 2.5 mg of budesonide per dose is administered twice a day for 6 weeks in order to treat inflammatory bowel disease, or to prevent a relapse; the enema for rectal application described above, in which a dose of budesonide is 2.0 mg per dose; the enema for rectal application according to any one of the above, which is taken in order to treat ulcerative colitis or Crohn's disease, or to prevent a relapse; the enema for rectal application according to any one of the above, which has a foamy shape or a liquid shape. | 1. An enema for rectal application comprising budesonide as an active ingredient, wherein 1.5 to 2.5 mg of budesonide per dose is administered twice a day for 6 weeks in order to treat inflammatory bowel disease, or to prevent a relapse. 2. The enema for rectal application according to claim 1, wherein the dose of budesonide is 2 mg per dose. 3. The enema for rectal application according to claim 1, wherein the enema for rectal application is administered in order to treat ulcerative colitis or Crohn's disease, or to prevent a relapse. 4. The enema for rectal application according to claim 1, wherein the enema for rectal application has a foamy shape or a liquid shape. 5. A package of an enema for rectal application, wherein the enema for rectal application according to claim 1 containing 1.5 to 2.5 mg of budesonide per dose can be administered 14 times. 6. A manufacturing method of a package of an enema for rectal application, wherein the enema for rectal application according to claim 1 is adjusted such that the enema for rectal application containing 1.5 to 2.5 mg of budesonide per dose can be administered 14 times. 7. The enema for rectal application according to claim 2, wherein the enema for rectal application is administered in order to treat ulcerative colitis or Crohn's disease, or to prevent a relapse. 8. The enema for rectal application according to claim 2, wherein the enema for rectal application has a foamy shape or a liquid shape. 9. The enema for rectal application according to claim 3, wherein the enema for rectal application has a foamy shape or a liquid shape. 10. A package of an enema for rectal application, wherein the enema for rectal application according to claim 2 containing 1.5 to 2.5 mg of budesonide per dose can be administered 14 times. 11. A package of an enema for rectal application, wherein the enema for rectal application according to claim 3 containing 1.5 to 2.5 mg of budesonide per dose can be administered 14 times. 12. A package of an enema for rectal application, wherein the enema for rectal application according to claim 4 containing 1.5 to 2.5 mg of budesonide per dose can be administered 14 times. 13. A manufacturing method of a package of an enema for rectal application, wherein the enema for rectal application according to claim 2 is adjusted such that the enema for rectal application containing 1.5 to 2.5 mg of budesonide per dose can be administered 14 times. 14. A manufacturing method of a package of an enema for rectal application, wherein the enema for rectal application according to claim 3 is adjusted such that the enema for rectal application containing 1.5 to 2.5 mg of budesonide per dose can be administered 14 times. 15. A manufacturing method of a package of an enema for rectal application, wherein the enema for rectal application according to claim 4 is adjusted such that the enema for rectal application containing 1.5 to 2.5 mg of budesonide per dose can be administered 14 times. | Provided is an enema for rectal application containing budesonide as an active ingredient in order to treat inflammatory bowel disease, or to prevent a relapse. The enema for rectal application containing budesonide as the active ingredient, in which 1.5 to 2.5 mg of budesonide per dose is administered twice a day for 6 weeks in order to treat inflammatory bowel disease, or to prevent a relapse; the enema for rectal application described above, in which a dose of budesonide is 2.0 mg per dose; the enema for rectal application according to any one of the above, which is taken in order to treat ulcerative colitis or Crohn's disease, or to prevent a relapse; the enema for rectal application according to any one of the above, which has a foamy shape or a liquid shape.1. An enema for rectal application comprising budesonide as an active ingredient, wherein 1.5 to 2.5 mg of budesonide per dose is administered twice a day for 6 weeks in order to treat inflammatory bowel disease, or to prevent a relapse. 2. The enema for rectal application according to claim 1, wherein the dose of budesonide is 2 mg per dose. 3. The enema for rectal application according to claim 1, wherein the enema for rectal application is administered in order to treat ulcerative colitis or Crohn's disease, or to prevent a relapse. 4. The enema for rectal application according to claim 1, wherein the enema for rectal application has a foamy shape or a liquid shape. 5. A package of an enema for rectal application, wherein the enema for rectal application according to claim 1 containing 1.5 to 2.5 mg of budesonide per dose can be administered 14 times. 6. A manufacturing method of a package of an enema for rectal application, wherein the enema for rectal application according to claim 1 is adjusted such that the enema for rectal application containing 1.5 to 2.5 mg of budesonide per dose can be administered 14 times. 7. The enema for rectal application according to claim 2, wherein the enema for rectal application is administered in order to treat ulcerative colitis or Crohn's disease, or to prevent a relapse. 8. The enema for rectal application according to claim 2, wherein the enema for rectal application has a foamy shape or a liquid shape. 9. The enema for rectal application according to claim 3, wherein the enema for rectal application has a foamy shape or a liquid shape. 10. A package of an enema for rectal application, wherein the enema for rectal application according to claim 2 containing 1.5 to 2.5 mg of budesonide per dose can be administered 14 times. 11. A package of an enema for rectal application, wherein the enema for rectal application according to claim 3 containing 1.5 to 2.5 mg of budesonide per dose can be administered 14 times. 12. A package of an enema for rectal application, wherein the enema for rectal application according to claim 4 containing 1.5 to 2.5 mg of budesonide per dose can be administered 14 times. 13. A manufacturing method of a package of an enema for rectal application, wherein the enema for rectal application according to claim 2 is adjusted such that the enema for rectal application containing 1.5 to 2.5 mg of budesonide per dose can be administered 14 times. 14. A manufacturing method of a package of an enema for rectal application, wherein the enema for rectal application according to claim 3 is adjusted such that the enema for rectal application containing 1.5 to 2.5 mg of budesonide per dose can be administered 14 times. 15. A manufacturing method of a package of an enema for rectal application, wherein the enema for rectal application according to claim 4 is adjusted such that the enema for rectal application containing 1.5 to 2.5 mg of budesonide per dose can be administered 14 times. | 1,600 |
1,125 | 15,292,095 | 1,631 | Methods and compositions for preparation and use of recombinant viruses or other recombinant expression systems are presented in which neoepitopes are first identified in a patient- and cancer-specific manner and then further filtered by HLA-match to the patient. Selected neoepitopes are then expression using sequence elements that direct the expressed neoepitope to the HLA-type (MHC-I and/or MHC-II subtype) that has desirable affinity to the filtered neoepitope. | 1. A method of treating a cancer in a patient using immunotherapy, comprising:
generating a recombinant nucleic acid configured to express a cancer- and patient-specific neoepitope; wherein the neoepitope is a high-affinity binder to at least one MHC Class I sub-type or at least one MHC Class II sub-type of an HLA-type of the patient; wherein the recombinant nucleic acid comprises a sequence element that directs the expressed neoepitope toward presentation by the at least one MHC Class I sub-type or by at least one MHC Class II sub-type; transfecting a cell with the recombinant nucleic acid to thereby force the cell to express and present the cancer- and patient-specific neoepitope on the at least one MHC Class I sub-type or on the at least one MHC Class II sub-type of the cell; and wherein the step of transfecting is performed in the patient or wherein the transfected cell is administered to the patient. 2. The method of claim 1 wherein the cancer- and patient-specific neoepitope is identified by comparing omics data from diseased tissue and healthy tissue of the patient. 3. The method of claim 2 wherein the cancer- and patient-specific neoepitope is identified by filtering by at least one of mutation type, transcription strength, translation strength, and a priori known molecular variations. 4. The method of claim 1 wherein the recombinant nucleic acid is a viral expression vector, a bacterial expression vector, a yeast expression vector, or an RNA. 5. The method of claim 1 wherein the high-affinity binder has an affinity to the at least one MHC Class I sub-type or the at least one MHC Class II sub-type of less than 150 nM. 6. The method of claim 1 wherein the HLA-type of the patient is determined in silico using a de Bruijn graph. 7. The method of claim 1 wherein the sequence element is a lysosomal targeting sequence, an endosomal targeting sequence, a peroxisomal targeting sequence, or a cytoplasmic retention sequence. 8. The method of claim 1 wherein the recombinant nucleic acid further comprises at least one of a sequence encoding a co-stimulatory molecule and a sequence encoding a checkpoint inhibitor. 9. The method of claim 1 further comprising a step of verifying, in a proxy cell, presentation of the neoepitope by the at least one MHC Class I sub-type or by at least one MHC Class II sub-type. 10. The method of claim 1 further comprising a step of verifying, in a patient cancer cell or patient cancer tissue, presentation of the neoepitope by the at least one MHC Class I sub-type or by at least one MHC Class II sub-type. 11. The method of claim 10 wherein the step of verifying presentation is performed using a synthetic binder, antibody or fragment thereof, or a peptide obtained from phage display or RNA display, that binds to the neoepitope. 12. A method of generating a recombinant nucleic acid for immunotherapy, comprising:
comparing omics data from diseased tissue and healthy tissue of a patient to identify a disease-related patient-specific neoepitope of the patient; identifying at least one MHC Class I sub-type and at least one MHC Class II sub-type of an HLA-type of the patient; determining binding affinity of the neoepitope to the at least one MHC Class I sub-type and the at least one MHC Class II sub-type; selecting the neoepitope when the binding affinity is below a predetermined threshold value; generating a recombinant nucleic acid to include a nucleic acid sequence encoding the selected neoepitope, wherein the nucleic acid sequence encoding the selected neoepitope is under control of a promoter that drives expression of the selected neoepitope; and wherein the nucleic acid sequence further comprises a sequence element that directs the expressed selected neoepitope toward presentation by the at least one MHC Class I sub-type or by the at least one MHC Class II sub-type. 13. The method of claim 12 wherein the step of comparing omics data is performed by incremental synchronous alignment of the omics data. 14. The method of claim 12 wherein the at least one MHC Class I sub-type and the at least one MHC Class II sub-type is determined in silico using a de Bruijn graph. 15. The method of claim 12 wherein the binding affinity of the neoepitope to the at least one MHC Class I sub-type and the at least one MHC Class II sub-type is determined in silico, and wherein the predetermined threshold value is less than 150 nM. 16. A method of improving cancer neoantigen presentation, comprising:
comparing omics data from diseased tissue and healthy tissue of a patient to identify a plurality of disease-related patient-specific neoepitopes of the patient; filtering the disease-related patient-specific neoepitopes by at least one of mutation type, transcription strength, translation strength, and a priori known molecular variations to obtain filtered neoepitopes; selecting from the filtered neoepitopes a high-affinity binder to at least one MHC Class I sub-type and to at least one MHC Class II sub-type of an HLA-type of the patient; expressing in a patient cell or a cell with compatible HLA-type the high-affinity binder, and verifying presentation of the high-affinity binder by the at least one MHC Class I sub-type or by the at least one MHC Class II sub-type; and using the high-affinity binder in an immunotherapeutic modality upon verification of expression. 17. The method of claim 16 wherein the step of comparing omics data is performed by incremental synchronous alignment of the omics data, and wherein the diseased tissue is a cancer tissue. 18. The method of claim 16 wherein the mutation type is a missense mutation, wherein the transcription strength is measured by RNAseq, wherein the translation strength is measured by selective reaction monitoring mass spectroscopy, and wherein the a priori known molecular variations comprise at least one of single nucleotide polymorphisms, short deletion and insertion polymorphisms, microsatellite markers, short tandem repeats, heterozygous sequences, multinucleotide polymorphisms, and named variants. 19. The method of claim 16 wherein the high-affinity binder has an affinity to the at least one MHC Class I sub-type or the at least one MHC Class II sub-type of less than 150 nM. 20. The method of claim 16 wherein the patient cell or cell with compatible HLA-type is an antigen presenting cell. | Methods and compositions for preparation and use of recombinant viruses or other recombinant expression systems are presented in which neoepitopes are first identified in a patient- and cancer-specific manner and then further filtered by HLA-match to the patient. Selected neoepitopes are then expression using sequence elements that direct the expressed neoepitope to the HLA-type (MHC-I and/or MHC-II subtype) that has desirable affinity to the filtered neoepitope.1. A method of treating a cancer in a patient using immunotherapy, comprising:
generating a recombinant nucleic acid configured to express a cancer- and patient-specific neoepitope; wherein the neoepitope is a high-affinity binder to at least one MHC Class I sub-type or at least one MHC Class II sub-type of an HLA-type of the patient; wherein the recombinant nucleic acid comprises a sequence element that directs the expressed neoepitope toward presentation by the at least one MHC Class I sub-type or by at least one MHC Class II sub-type; transfecting a cell with the recombinant nucleic acid to thereby force the cell to express and present the cancer- and patient-specific neoepitope on the at least one MHC Class I sub-type or on the at least one MHC Class II sub-type of the cell; and wherein the step of transfecting is performed in the patient or wherein the transfected cell is administered to the patient. 2. The method of claim 1 wherein the cancer- and patient-specific neoepitope is identified by comparing omics data from diseased tissue and healthy tissue of the patient. 3. The method of claim 2 wherein the cancer- and patient-specific neoepitope is identified by filtering by at least one of mutation type, transcription strength, translation strength, and a priori known molecular variations. 4. The method of claim 1 wherein the recombinant nucleic acid is a viral expression vector, a bacterial expression vector, a yeast expression vector, or an RNA. 5. The method of claim 1 wherein the high-affinity binder has an affinity to the at least one MHC Class I sub-type or the at least one MHC Class II sub-type of less than 150 nM. 6. The method of claim 1 wherein the HLA-type of the patient is determined in silico using a de Bruijn graph. 7. The method of claim 1 wherein the sequence element is a lysosomal targeting sequence, an endosomal targeting sequence, a peroxisomal targeting sequence, or a cytoplasmic retention sequence. 8. The method of claim 1 wherein the recombinant nucleic acid further comprises at least one of a sequence encoding a co-stimulatory molecule and a sequence encoding a checkpoint inhibitor. 9. The method of claim 1 further comprising a step of verifying, in a proxy cell, presentation of the neoepitope by the at least one MHC Class I sub-type or by at least one MHC Class II sub-type. 10. The method of claim 1 further comprising a step of verifying, in a patient cancer cell or patient cancer tissue, presentation of the neoepitope by the at least one MHC Class I sub-type or by at least one MHC Class II sub-type. 11. The method of claim 10 wherein the step of verifying presentation is performed using a synthetic binder, antibody or fragment thereof, or a peptide obtained from phage display or RNA display, that binds to the neoepitope. 12. A method of generating a recombinant nucleic acid for immunotherapy, comprising:
comparing omics data from diseased tissue and healthy tissue of a patient to identify a disease-related patient-specific neoepitope of the patient; identifying at least one MHC Class I sub-type and at least one MHC Class II sub-type of an HLA-type of the patient; determining binding affinity of the neoepitope to the at least one MHC Class I sub-type and the at least one MHC Class II sub-type; selecting the neoepitope when the binding affinity is below a predetermined threshold value; generating a recombinant nucleic acid to include a nucleic acid sequence encoding the selected neoepitope, wherein the nucleic acid sequence encoding the selected neoepitope is under control of a promoter that drives expression of the selected neoepitope; and wherein the nucleic acid sequence further comprises a sequence element that directs the expressed selected neoepitope toward presentation by the at least one MHC Class I sub-type or by the at least one MHC Class II sub-type. 13. The method of claim 12 wherein the step of comparing omics data is performed by incremental synchronous alignment of the omics data. 14. The method of claim 12 wherein the at least one MHC Class I sub-type and the at least one MHC Class II sub-type is determined in silico using a de Bruijn graph. 15. The method of claim 12 wherein the binding affinity of the neoepitope to the at least one MHC Class I sub-type and the at least one MHC Class II sub-type is determined in silico, and wherein the predetermined threshold value is less than 150 nM. 16. A method of improving cancer neoantigen presentation, comprising:
comparing omics data from diseased tissue and healthy tissue of a patient to identify a plurality of disease-related patient-specific neoepitopes of the patient; filtering the disease-related patient-specific neoepitopes by at least one of mutation type, transcription strength, translation strength, and a priori known molecular variations to obtain filtered neoepitopes; selecting from the filtered neoepitopes a high-affinity binder to at least one MHC Class I sub-type and to at least one MHC Class II sub-type of an HLA-type of the patient; expressing in a patient cell or a cell with compatible HLA-type the high-affinity binder, and verifying presentation of the high-affinity binder by the at least one MHC Class I sub-type or by the at least one MHC Class II sub-type; and using the high-affinity binder in an immunotherapeutic modality upon verification of expression. 17. The method of claim 16 wherein the step of comparing omics data is performed by incremental synchronous alignment of the omics data, and wherein the diseased tissue is a cancer tissue. 18. The method of claim 16 wherein the mutation type is a missense mutation, wherein the transcription strength is measured by RNAseq, wherein the translation strength is measured by selective reaction monitoring mass spectroscopy, and wherein the a priori known molecular variations comprise at least one of single nucleotide polymorphisms, short deletion and insertion polymorphisms, microsatellite markers, short tandem repeats, heterozygous sequences, multinucleotide polymorphisms, and named variants. 19. The method of claim 16 wherein the high-affinity binder has an affinity to the at least one MHC Class I sub-type or the at least one MHC Class II sub-type of less than 150 nM. 20. The method of claim 16 wherein the patient cell or cell with compatible HLA-type is an antigen presenting cell. | 1,600 |
1,126 | 14,441,569 | 1,637 | The present invention relates to methods and kits which can be used to amplify nucleic acids with the advantage of decreasing user time and possible contamination. For easy processing and amplification of nucleic acid samples, the samples are bound to a solid support and used directly, without purification, in a nucleic acid amplification reaction such as the polymerase chain reaction (PCR). | 1. A method for amplification of nucleic acid comprising the steps:
i) contacting a solid support comprising a chaotropic salt with a cellular sample containing nucleic acid, ii) transferring said solid support to a reaction vessel, iii) incubating said nucleic acid on the solid support with a nucleic acid amplification reagent solution, iv) amplifying the nucleic acid to produce amplified nucleic acid, v) quantifying the amplified nucleic acid and optionally, vi) using Short Tandem Repeat (STR) profiling to produce an STR profile,
wherein steps i) to vi) are carried out in the presence of the solid support. 2. The method according to claim 1, wherein the solid support is in the reaction vessel prior to the addition of said cellular sample. 3. The method of claim 1, wherein the method of amplification is a polymerase chain reaction. 4. The method of claim 1, wherein the method of amplification comprises reverse transcription polymerase chain reaction, isothermal amplification or quantitative polymerase chain reaction. 5. The method of claim 1, wherein the nucleic acid amplification reagent solution comprises a polymerase, deoxyribonucleotide triphosphate (dNTP), a reaction buffer and at least one primer, wherein said primer is optionally labeled with a dye. 6. The method of claim 1, wherein the chaotropic salt is a guanidine salt. 7. The method of claim 6, wherein said guanidine salt is selected from the group consisting of guanidine thiocyanate, guandine chloride and guanidine hydrochloride. 8. The method of claims 1, wherein the chaotropic salt is a sodium salt such as sodium iodide. 9. The method of claim 1, wherein the solid support is washed with an aqueous solution following step i). 10. The method of claim 1, wherein the solid support is selected from the group consisting of a glass or silica-based solid phase medium, a plastics-based solid phase medium, a cellulose-based solid phase medium, glass fiber, glass microfiber, silica gel, silica oxide, nitrocellulose, carboxymethylcellulo se, polyester, polyamide, carbohydrate polymers, polypropylene, polytetraflurorethylene, polyvinylidinefluoride, wool and porous ceramics. 11. The method of claim 1, wherein the solid support is a cellulose based matrix. 12. The method of claim 11, wherein said cellulose based matrix is in the form of a pre punched disc. 13. The method of claim 11, wherein the cellulose based matrix is in the form of an FTA™ Elute card. 14. A method for amplification of nucleic acid comprising the steps:
i) contacting a solid support comprising a lysis reagent with a cellular sample containing nucleic acid, ii) transferring said solid support to a reaction vessel, iii) incubating said nucleic acid on the solid support with a nucleic acid amplification reagent solution, iv) amplifying the nucleic acid to produce amplified nucleic acid, v) quantifying the amplified nucleic acid,
wherein steps i) to v) are carried out in the presence of the solid support. 15. The method according to claim 14, wherein the solid support is in the reaction vessel prior to the addition of said cellular sample. 16. The method of claim 14, wherein the method of amplification is a polymerase chain reaction. 17. The method of claim 14, wherein said lysis reagent is selected from the group consisting of a surfactant, detergent and chaotropic salt. 18. The method of claim 14, wherein the lysis reagent is selected from the group consisting of sodium dodecyl sulfate, guanidine thiocynate, guanidine hydrochloride, guanidine chloride and sodium iodide. 19. The method of claim 14, wherein said solid support is impregnated with sodium dodecyl sulfate (SDS), ethylenediaminetetracetic acid (EDTA) and uric acid. 20. The method of claim 14, wherein the solid support is in the form of an FTA™ pre punched disc. 21. The methods of claims 14, wherein the solid support is selected from the group consisting of a glass or silica-based solid phase medium, a plastics-based solid phase medium, a cellulose-based solid phase medium, glass fiber, glass microfiber, silica gel, silica oxide, nitrocellulose, carboxymethylcellulose, polyester, polyamide, carbohydrate polymers, polypropylene, polytetraflurorethylene, polyvinylidinefluoride, wool and porous ceramics. 22. The method of claim 14, wherein the solid support is washed with an aqueous solution following step i). 23. The method of claim 14, wherein the amplified nucleic acid is quantified using a PCR imaging system. 24. The method according to claim 14, wherein the cellular sample is selected from a group consisting of eukaryotic cell, prokaryotic cell, virus, bacteria, plant and tissue culture cells. 25. The method according to claim 14, wherein said cellular sample is selected from the group consisting of blood, serum, semen, cerebral spinal fluid, synovial fluid, lymphatic fluid, saliva, buccal, cervical cell, vaginal cell, urine, faeces, hair, skin and muscle. 26. The method according to claim 14, for use as a tool selected from the group consisting of a molecular diagnostics tool, a human identification tool and a forensics tool. 27. The method according to claim 14, wherein the nucleic acid is stored on the solid support prior to step ii). 28. The method according to claim 14, wherein the nucleic acid is stored on the solid support for at least 30 minutes. 29. (canceled) | The present invention relates to methods and kits which can be used to amplify nucleic acids with the advantage of decreasing user time and possible contamination. For easy processing and amplification of nucleic acid samples, the samples are bound to a solid support and used directly, without purification, in a nucleic acid amplification reaction such as the polymerase chain reaction (PCR).1. A method for amplification of nucleic acid comprising the steps:
i) contacting a solid support comprising a chaotropic salt with a cellular sample containing nucleic acid, ii) transferring said solid support to a reaction vessel, iii) incubating said nucleic acid on the solid support with a nucleic acid amplification reagent solution, iv) amplifying the nucleic acid to produce amplified nucleic acid, v) quantifying the amplified nucleic acid and optionally, vi) using Short Tandem Repeat (STR) profiling to produce an STR profile,
wherein steps i) to vi) are carried out in the presence of the solid support. 2. The method according to claim 1, wherein the solid support is in the reaction vessel prior to the addition of said cellular sample. 3. The method of claim 1, wherein the method of amplification is a polymerase chain reaction. 4. The method of claim 1, wherein the method of amplification comprises reverse transcription polymerase chain reaction, isothermal amplification or quantitative polymerase chain reaction. 5. The method of claim 1, wherein the nucleic acid amplification reagent solution comprises a polymerase, deoxyribonucleotide triphosphate (dNTP), a reaction buffer and at least one primer, wherein said primer is optionally labeled with a dye. 6. The method of claim 1, wherein the chaotropic salt is a guanidine salt. 7. The method of claim 6, wherein said guanidine salt is selected from the group consisting of guanidine thiocyanate, guandine chloride and guanidine hydrochloride. 8. The method of claims 1, wherein the chaotropic salt is a sodium salt such as sodium iodide. 9. The method of claim 1, wherein the solid support is washed with an aqueous solution following step i). 10. The method of claim 1, wherein the solid support is selected from the group consisting of a glass or silica-based solid phase medium, a plastics-based solid phase medium, a cellulose-based solid phase medium, glass fiber, glass microfiber, silica gel, silica oxide, nitrocellulose, carboxymethylcellulo se, polyester, polyamide, carbohydrate polymers, polypropylene, polytetraflurorethylene, polyvinylidinefluoride, wool and porous ceramics. 11. The method of claim 1, wherein the solid support is a cellulose based matrix. 12. The method of claim 11, wherein said cellulose based matrix is in the form of a pre punched disc. 13. The method of claim 11, wherein the cellulose based matrix is in the form of an FTA™ Elute card. 14. A method for amplification of nucleic acid comprising the steps:
i) contacting a solid support comprising a lysis reagent with a cellular sample containing nucleic acid, ii) transferring said solid support to a reaction vessel, iii) incubating said nucleic acid on the solid support with a nucleic acid amplification reagent solution, iv) amplifying the nucleic acid to produce amplified nucleic acid, v) quantifying the amplified nucleic acid,
wherein steps i) to v) are carried out in the presence of the solid support. 15. The method according to claim 14, wherein the solid support is in the reaction vessel prior to the addition of said cellular sample. 16. The method of claim 14, wherein the method of amplification is a polymerase chain reaction. 17. The method of claim 14, wherein said lysis reagent is selected from the group consisting of a surfactant, detergent and chaotropic salt. 18. The method of claim 14, wherein the lysis reagent is selected from the group consisting of sodium dodecyl sulfate, guanidine thiocynate, guanidine hydrochloride, guanidine chloride and sodium iodide. 19. The method of claim 14, wherein said solid support is impregnated with sodium dodecyl sulfate (SDS), ethylenediaminetetracetic acid (EDTA) and uric acid. 20. The method of claim 14, wherein the solid support is in the form of an FTA™ pre punched disc. 21. The methods of claims 14, wherein the solid support is selected from the group consisting of a glass or silica-based solid phase medium, a plastics-based solid phase medium, a cellulose-based solid phase medium, glass fiber, glass microfiber, silica gel, silica oxide, nitrocellulose, carboxymethylcellulose, polyester, polyamide, carbohydrate polymers, polypropylene, polytetraflurorethylene, polyvinylidinefluoride, wool and porous ceramics. 22. The method of claim 14, wherein the solid support is washed with an aqueous solution following step i). 23. The method of claim 14, wherein the amplified nucleic acid is quantified using a PCR imaging system. 24. The method according to claim 14, wherein the cellular sample is selected from a group consisting of eukaryotic cell, prokaryotic cell, virus, bacteria, plant and tissue culture cells. 25. The method according to claim 14, wherein said cellular sample is selected from the group consisting of blood, serum, semen, cerebral spinal fluid, synovial fluid, lymphatic fluid, saliva, buccal, cervical cell, vaginal cell, urine, faeces, hair, skin and muscle. 26. The method according to claim 14, for use as a tool selected from the group consisting of a molecular diagnostics tool, a human identification tool and a forensics tool. 27. The method according to claim 14, wherein the nucleic acid is stored on the solid support prior to step ii). 28. The method according to claim 14, wherein the nucleic acid is stored on the solid support for at least 30 minutes. 29. (canceled) | 1,600 |
1,127 | 15,329,148 | 1,631 | Provided in the present disclosure are a method and a device for determining a fraction of cell free nucleic acids in a biological sample and use thereof, wherein the method comprises: (1) sequencing nucleic acids of a biological sample having free nucleic acids, in order to obtain sequencing results for a plurality of sequencing data; (2) based on the sequencing results, determining the number of nucleic acid molecules with a length falling within a preset range in the sample; and (3) based on the number of nucleic acid molecules with a length falling within the preset range, determining the ratio of free nucleic acids in the biological sample. | 1. A method for determining a fraction of cell-free nucleic acids from a predetermined source in a biological sample, comprising:
performing sequencing on cell-free nucleic acids contained in the biological sample, so as to obtain a sequencing result consisting of a plurality of sequencing data; determining the number of the cell-free nucleic acids in a length falling into a predetermined range in the biological sample based on the sequencing result; and determining the fraction of the cell-free nucleic acids from the predetermined source in the biological sample based on the number of the cell-free nucleic acids in the length falling into the predetermined range. 2. The method according to claim 1, wherein the biological sample is a peripheral blood sample. 3. The method according to claim 2, wherein the cell-free nucleic acid from the predetermined source is selected from one of the followings:
cell-free fetal nucleic acids or cell-free maternal nucleic acids in a peripheral blood sample obtained from a pregnant woman, or cell-free tumor derived nucleic acids or cell-free non-tumor derived nucleic acids in a peripheral blood sample obtained from a subject suffering from tumor, suspected to suffer from tumor or subjected to tumor screening. 4-5. (canceled) 6. The method according to of claim 1, wherein determining the number of the cell-free nucleic acids in the length falling into the predetermined range in the biological sample based on the sequencing result further comprises:
aligning the sequencing result to a reference genome, so as to construct a dataset consisting of a plurality of uniquely-mapped reads, where each read in the dataset can be mapped to a position of the reference genome only; determining a length of the cell-free nucleic acid corresponding to each uniquely-mapped read in the dataset; and determining the number of the cell-free nucleic acids in the length falling into the predetermined range. 7. The method according to claim 6, wherein determining the length of the cell-free nucleic acid corresponding to each uniquely-mapped read in the dataset further comprises:
determining the length of each read uniquely mapped to the reference genome as the length of the cell-free nucleic acid corresponding to the read. 8. The method according to claim 6, wherein in the case that the cell-free nucleic acids in the biological sample are sequenced by the paired-end sequencing, determining the length of the cell-free nucleic acid corresponding to each uniquely-mapped read in the dataset further comprises:
determining a position, corresponding to the reference genome, of 5′-end of the cell-free nucleic acid, based on sequencing data at one end of each uniquely-mapped read obtained in the paired-end sequencing; determining a position, corresponding to the reference genome, of 3′-end of the cell-free nucleic acid, based on sequencing data at the other end of same uniquely-mapped read obtained in the paired-end sequencing; and determining the length of the cell-free nucleic acid based on the position of 5′-end of the cell-free nucleic acid and the position of 3′-end of the cell-free nucleic acid. 9. The method according to claim 1, wherein the predetermined range is determined based on a plurality of control samples, in each of which the fraction of the cell-free nucleic acids from the predetermined source is known. 10. (canceled) 11. The method according to claim 9, wherein the predetermined range is determined by the following steps:
(a) determining lengths of the cell-free nucleic acids in the plurality of control samples; (b) setting a plurality of candidate length ranges, and determining a percentage of the cell-free nucleic acids, obtained from each of the plurality of control samples, present in each candidate length range; (c) determining a correlation coefficient between each candidate length range and the fraction of the cell-free nucleic acids from the predetermined source, based on the percentage of the cell-free nucleic acids, obtained from each of the plurality of control samples, present in each candidate length range and the fraction of the cell-free nucleic acids from the predetermined source in the control samples; and (d) determining at least one candidate length range or a combination of the candidate length ranges as the predetermined range based on the correlation coefficient. 12-13. (canceled) 14. The method according to claim 9, wherein determining the fraction of the cell-free nucleic acids from the predetermined source in the biological sample based on the number of the cell-free nucleic acids in the length falling into the predetermined range further comprises:
determining a percentage of the cell-free nucleic acids present in the predetermined range based on the number of cell-free nucleic acids in the length falling into the predetermined range; and determining the fraction of the cell-free nucleic acids from the predetermined source in the biological sample, based on the percentage of the cell-free nucleic acids present in the predetermined range, according to a predetermined function, wherein the predetermined function is determined based on the plurality of control samples. 15. The method according to claim 14, wherein the predetermined function is obtained by following steps:
(i) determining the percentage of the cell-free nucleic acids, obtained from each control sample, present in the predetermined range; and (ii) fitting the percentage of the cell-free nucleic acids, obtained from each control sample, present in the predetermined range with the known fraction of the cell-free nucleic acid from the predetermined source, to determine the predetermined function. 16. The method according to claim 15, wherein the percentage of the cell-free nucleic acids, obtained from each control sample, present in the predetermined range is fitted with the known fraction of the cell-free nucleic acid from the predetermined source by a linear fitting. 17. The method according to claim 1, wherein the cell-free nucleic acid from the predetermined source is cell-free fetal nucleic acid obtained from a peripheral blood sample of a pregnant woman, and the predetermined range is 185 bp to 204 bp. 18. The method according to claim 9, wherein the control sample is a peripheral blood sample obtained from a pregnant woman in which the fraction of the cell-free fetal nucleic acids is known. 19. The method according to claim 18, wherein the control sample is a peripheral blood sample obtained from a pregnant woman with a normal male fetus, in which the fraction of the cell-free fetal nucleic acids is known to be determined by chromosome Y. 20-37. (canceled) 38. A method for determining sexuality of twins, comprising:
performing sequencing on cell-free nucleic acids contained in a peripheral blood sample obtained from a pregnant woman with twins, so as to obtain a sequencing result consisting of a plurality of sequencing data; determining a first cell-free fetal DNA fraction based on the sequencing data, by the method according to claim 1; determining a second cell-free fetal DNA fraction based on a sequencing data derived from chromosome Y in the sequencing result; and determining the sexuality of the twins based on the first cell-free fetal DNA fraction and the second cell-free fetal DNA fraction. 39. The method according to claim 38, wherein the second cell-free fetal DNA fraction is determined according to the following formula:
fra.chry=(chry.ER %−Female.chry.ER %)/(Man.chry.ER %−Female.chry.ER %)*100%,
where fra.chry represents the second cell-free fetal DNA fraction, chry.ER % represents a percentage of the sequencing data derived from chromosome Y in the sequencing result to total sequencing data;
Female.chry.ER % represents an average percentage of sequencing data of cell-free nucleic acids derived from chromosome Y in a peripheral blood sample obtained from a pregnant woman predetermined to be with a normal female fetus to total sequencing data thereof; and
Man.chry.ER % represents an average percentage of sequencing data of cell-free nucleic acids derived from chromosome Y in a peripheral blood sample obtained from a healthy man to total sequencing data thereof. 40. The method according to claim 38, wherein determining the sexuality of the twins based on the first cell-free fetal DNA fraction and the second cell-free fetal DNA fraction further comprises:
(a) determining a ratio of the second cell-free fetal DNA fraction to the first cell-free fetal DNA fraction; and (b) determining the sexuality of the twins by comparing the ratio determined in (a) with a first threshold and a second threshold predetermined. 41. The method according to claim 40, wherein the first threshold is determined based on a plurality of control samples obtained from pregnant women known with female twins, and the second threshold is determined based on a plurality of control samples obtained from pregnant women known with male twins. 42. The method according to claim 41, wherein
both fetuses of the twins are female if the ratio of the second cell-free fetal DNA fraction to the first cell-free fetal DNA fraction is lower than the first threshold, both fetuses of the twins are male if the ratio of the second cell-free fetal DNA fraction to the first cell-free fetal DNA fraction is greater than the second threshold, and the twins include a male fetus and a female fetus if the ratio of the second cell-free fetal DNA fraction to the first cell-free fetal DNA fraction is equal to the first threshold or the second threshold, or between the first threshold and the second threshold. 43. The method according to claim 42, wherein the first threshold is 0.35 and the second threshold is 0.7. 44-49. (canceled) 50. A method for detecting a chromosome aneuploidy of twins, comprising:
performing sequencing on cell-free nucleic acids contained in a peripheral blood sample obtained from a pregnant woman with twins, so as to obtain a sequencing result consisting of a plurality of sequencing data; determining a first cell-free fetal DNA fraction, based on the sequencing data, by the method according to claim 1; determining a third cell-free fetal DNA fraction, based on a sequencing data derived from a predetermined chromosome in the sequencing result; and determining whether the twins under detection have aneuploidy with respect to the predetermined chromosome based on the first cell-free fetal DNA fraction and the third cell-free fetal DNA fraction. 51. The method according to claim 50, wherein the third cell-free fetal DNA fraction is determined according to the following formula:
fra.chri=2*(chri.ER %/adjust.chri.ER %−1)*100%,
where fra.chri represents the third cell-free fetal DNA fraction, i represents a serial number of the predetermined chromosome, and i is any integer in the range of 1 to 22; chri.ER % represents a percentage of the sequencing data derived from the predetermined chromosome in the sequencing result to total sequencing data; adjust.chri.ER % represents an average percentage of sequencing data of cell-free nucleic acids derived from the predetermined chromosome in a peripheral blood sample obtained from a pregnant woman predetermined to be with normal twins to total sequencing data thereof. 52. The method according to claim 51, wherein determining whether the twins under detection have aneuploidy with respect to the predetermined chromosome based on the first cell-free fetal DNA fraction and the third cell-free fetal DNA fraction further comprises:
(a) determining a ratio of the third cell-free fetal DNA fraction to the first cell-free fetal DNA fraction; and (b) determining whether the twins under detection have aneuploidy with respect to the predetermined chromosome by comparing the ratio determined in (a) with a third threshold and a fourth threshold predetermined. 53. The method according to claim 52, wherein the third threshold is determined based on a plurality of control samples obtained from pregnant women with twins known not to have aneuploidy with respect to the predetermined chromosome, and the fourth threshold is determined based on a plurality of control samples obtained from pregnant women with twins known to have aneuploidy with respect to the predetermined chromosome. 54. The method according to claim 53, wherein
both fetuses of the twins have no aneuploidy with respect to the predetermined chromosome if the ratio of the third cell-free fetal DNA fraction to the first cell-free fetal DNA fraction is lower than the third threshold, both fetuses of the twins have aneuploidy with respect to the predetermined chromosome if the ratio of the third cell-free fetal DNA fraction to the first cell-free fetal DNA fraction is greater than the fourth threshold, and one fetus of the twins has the aneuploidy with respect to the predetermined chromosome, while the other fetus of the twins has no aneuploidy with respect to the predetermined chromosome if the ratio of the third cell-free fetal DNA fraction to the first cell-free fetal DNA fraction is equal to the third threshold or the fourth threshold, or between the third threshold and the fourth threshold. 55. The method according to claim 54, wherein the third threshold is 0.35 and the fourth threshold is 0.7. 56. The method according to claim 50, wherein the predetermined chromosome is at least one selected from chromosomes 18, 21 and 23. 57-63. (canceled) 64. A method for determining a chromosome aneuploidy of twins, comprising:
performing sequencing on cell-free nucleic acids contained in a peripheral blood sample obtained from a pregnant woman with twins, so as to obtain a sequencing result consisting of a plurality of sequencing data; determining a fraction xi of the number of sequencing data derived from chromosome i in the sequencing result to total sequencing data, where i represents a serial number of the chromosome, and i is any integer in the range of 1 to 22; determining a T score of the chromosome i according to Ti=(xi−μi)/σi, where i represents the serial number of the chromosome and i is any integer in the range of 1 to 22, μi represents an average percentage of sequencing data of the chromosome i selected as a reference system in a reference database to total sequencing data thereof, σi represents a standard deviation of percentages of the sequencing data of the chromosome i selected as the reference system in the reference database to total sequencing data thereof, determining an L score of the chromosome i according to Li=log(d(Ti, a))/log(d(T2i, a)), where i represents the serial number of the chromosome and i is any integer in the range of 1 to 22, T2i=(xi−μi*(1+fra/2))/σi; d(Ti, a) and d(T2i, a) represent t distribution probability density function, where a represents degree of freedom, fra represents a first cell-free fetal DNA fraction determined by the method according to claim 1, plotting a four-quadrant diagram with T as vertical coordinate and L as horizontal coordinate by zoning with a first straight line where T=predetermined fifth threshold and a second straight line where L=predetermined sixth threshold, wherein both fetuses of the twins are determined to have trisome if a sample under detection is determined to be of the T score and the L score falling into a first quadrant; one fetus of the twins is determined to be of trisome and the other fetus of the twins is determined to be normal if a sample under detection is determined to be of the T score and the L score falling into a second quadrant; both fetuses of the twins are determined to be noirual if a sample under detection is determined to be of the T score and the L score falling into a third quadrant; the twins are determined to have a low fetal fraction if a sample under detection is determined to be of the T score and the L score falling into a fourth quadrant, such a result is not adopted. 65. A method for detecting fetal chimera, comprising:
performing sequencing on cell-free nucleic acids contained in a peripheral blood sample obtained from a pregnant woman with a fetus, optionally a male fetus, so as to obtain a sequencing result consisting of a plurality of sequencing data; determining a first cell-free fetal DNA fraction, based on the sequencing data, by the method according to claim 1, or estimating a fetal fraction by chromosome Y (fra.chrY %) as a first cell-free fetal DNA fraction according to the following formula:
fra.chry=(chry.ER %−Female.chry.ER %)/(Man.chry.ER %−Female.chry.ER %)*100%,
where fra.chry chry.ER % represents the first cell-free fetal DNA fraction, represents a percentage of sequencing data derived from chromosome Y in the sequencing result to total sequencing data; Female.chry.ER % represents an average percentage of sequencing data of cell-free nucleic acids derived from chromosome Y in a peripheral blood sample obtained from a pregnant woman predetermined to be with a normal female fetus to total sequencing data thereof; and Man.chry.ER % represents an average percentage of sequencing data of cell-free nucleic acids derived from chromosome Y in a peripheral blood sample obtained from a healthy man predetermined to total sequencing data thereof;
determining a third cell-free fetal DNA fraction based on sequencing data derived from a predetermined chromosome in the sequencing result; and
determining whether the fetus under detection has fetal chimera with respect to the predetermined chromosome based on the first cell-free fetal DNA fraction and the third cell-free fetal DNA fraction. 66. The method according to claim 65, wherein the third cell-free fetal DNA fraction is determined by the following formula:
fra.chri=2*(chri.ER %/adjust.chri.ER %−1)*100%,
where fra.chri represents the third cell-free fetal DNA fraction, i represents a serial number of the predetermined chromosome and i is any integer in the range of 1 to 22; chri.ER % represents a percentage of the sequencing data derived from the predetermined chromosome in the sequencing result to total sequencing data; adjust.chri.ER % represents an average percentage of sequencing data of cell-free nucleic acids derived from the predetermined chromosome in a peripheral blood sample obtained from a pregnant woman predetermined to be with a normal fetus to total sequencing data thereof. 67. The method according to claim 66, wherein determining whether the fetus under detection has fetal chimera with respect to the predetermined chromosome based on the first cell-free fetal DNA fraction and the third cell-free fetal DNA fraction further comprises:
(a) determining a ratio of the third cell-free fetal DNA fraction to the first cell-free fetal DNA fraction; and (b) determining whether the fetus under detection has chimera with respect to the predetermined chromosome by comparing the ratio determined in (a) with a plurality of predetermined thresholds. 68. The method according to claim 67, wherein the plurality of predetermined thresholds comprises at least one selected from:
a seventh threshold, determined based on a plurality of control samples with the predetermined chromosome known to be of complete monosome, an eighth threshold, determined based on a plurality of control samples with the predetermined chromosome known to be of monosome chimera, a ninth threshold, determined based on a plurality of control samples with the predetermined chromosome known to be normal, a tenth threshold, determined based on a plurality of control samples with the predetermined chromosome known to be of complete trisome, optionally, the predetermined chromosome of the fetus under detection is of complete monosome, if the ratio of the third cell-free fetal DNA fraction to the first cell-free fetal DNA fraction is lower than the seventh threshold; the predetermined chromosome of the fetus under detection is of monosome chimera, if the ratio of the third cell-free fetal DNA fraction to the first cell-free fetal DNA fraction is not lower than the seventh threshold and not greater than the eighth threshold; the predetermined chromosome of the fetus under detection is normal, if the ratio of the third cell-free fetal DNA fraction to the first cell-free fetal DNA fraction is greater than the eighth threshold and lower than the ninth threshold; the predetermined chromosome of the fetus under detection is of trisome chimera, if the ratio of the third cell-free fetal DNA fraction to the first cell-free fetal DNA fraction is not lower than the ninth threshold and not greater than the tenth threshold; and the predetermined chromosome of the fetus under detection is of complete trisome, if the ratio of the third cell-free fetal DNA fraction to the first cell-free fetal DNA fraction is greater than the tenth threshold. 69. The method according to claim 68, wherein the seventh threshold is greater than −1 and lower than 0, optionally is −0.85;
the eighth threshold is greater than the seventh threshold and lower than 0, optionally is −0.3;
the ninth threshold is greater than 0 and lower than 1, optionally is 0.3;
the tenth threshold is greater than the ninth threshold and lower than 1, optionally is 0.85. 70-74. (canceled) 75. A method for detecting fetal chimera, comprising:
performing sequencing on cell-free nucleic acids contained in a peripheral blood sample obtained from a pregnant woman with a fetus, so as to obtain a sequencing result consisting of a plurality of sequencing data; determining a fraction xi of the number of sequencing data derived from chromosome i in the sequencing result to total sequencing data, where i represents a serial number of the chromosome, and i is any integer in the range of 1 to 22; determining a T score of the chromosome i according to Ti=(xi−μi)/σi, where i represents the serial number of the chromosome and i is any integer in the range of 1 to 22, μi represents an average value of percentages of sequencing data of the chromosome i selected as a reference system in a reference database to total sequencing data thereof, σi represents a standard deviation of percentages of the sequencing data of the chromosome i selected as the reference system in the reference database to total sequencing data thereof,
determining an L score of the chromosome i according to Li=log(d(Ti,a))/log(d(T2i, a)) where i represents the serial number of the chromosome and i is any integer in the range of 1 to 22, T2i=(xi−μi*(1+fra/2))/σi; d(Ti, a) and d(T2i, a) represent t distribution probability density function, where a represents degree of freedom, fra represents a cell-free fetal DNA fraction determined by the method according to claim 1 or a fetal fraction estimated by chromosome Y (fra.chrY %),
fra.chry=(chry.ER %−Female.chry.ER %)/(Man.chry.ER %−Female.chry.ER %)*100%,
where fra.chry represents a cell-free fetal DNA fraction, chry.ER % represents a percentage of sequencing data derived from chromosome Y in the sequencing result to said total sequencing data; Female.chry.ER % represents an average percentage of sequencing data of cell-free nucleic acids derived from chromosome Y in a peripheral blood sample obtained from a pregnant woman predetermined to be with a normal female fetus to total sequencing data thereof; and Man.chry.ER % represents an average percentage of sequencing data of cell-free nucleic acids derived from chromosome Y in a peripheral blood sample obtained from a healthy man predetermined to total sequencing data thereof;
plotting a four-quadrant diagram with T as vertical coordinate and L as horizontal coordinate by zoning with a third straight line where T=predetermined eleventh threshold and a fourth straight line where L=predetermined twelfth threshold, when the T score is greater than 0,
wherein the fetus is determined to have complete monosome or monosome chimera with respect to the predetermined chromosome, if a sample under detection is determined to be of the T score and the L score falling into a first quadrant;
the fetus is determined to have monosome chimera with respect to the predetermined chromosome, if a sample under detection is determined to be of the T score and the L score falling into a second quadrant;
the fetus is determined to be normal with respect to the predetermined chromosome, if a sample under detection is determined to be of the T score and the L score falling into a third quadrant;
the fetus is determined to have a low fetal fraction if a sample under detection is determined to be of the T score and the L score falling into a fourth quadrant, such a result is not adopted,
plotting a four-quadrant diagram with T as vertical coordinate and L as horizontal coordinate by zoning with a first straight line where T=predetermined thirteenth threshold and a second straight line where L=predetermined fourteenth threshold, when the T score is greater than 0,
wherein the fetus is determined to have complete trisome or trisome chimera with respect to the predetermined chromosome, if a sample under detection is determined to be of the T score and the L score falling into a first quadrant;
the fetus is determined to have trisome chimera with respect to the predetermined chromosome, if a sample under detection is determined to be of the T score and the L score falling into a second quadrant;
the fetus is determined to be normal with respect to the predetermined chromosome, if a sample under detection is determined to be of the T score and the L score falling into a third quadrant;
the fetus is determined to have a low fetal fraction if a sample under detection is determined to be of the T score and the L score falling into a fourth quadrant, such a result is not adopted,
optionally, the eleventh threshold and the thirteenth threshold each independently is 3, and the twelfth threshold and the fourteenth threshold each independently is 1. 76. (canceled) 77. The method according to claim 14, wherein the predetermined function is d=0.0334*p+1.6657, where d represents a fraction of cell-free fetal nucleic acids, and p represents a percentage of cell-free nucleic acid present in the predetermined range. | Provided in the present disclosure are a method and a device for determining a fraction of cell free nucleic acids in a biological sample and use thereof, wherein the method comprises: (1) sequencing nucleic acids of a biological sample having free nucleic acids, in order to obtain sequencing results for a plurality of sequencing data; (2) based on the sequencing results, determining the number of nucleic acid molecules with a length falling within a preset range in the sample; and (3) based on the number of nucleic acid molecules with a length falling within the preset range, determining the ratio of free nucleic acids in the biological sample.1. A method for determining a fraction of cell-free nucleic acids from a predetermined source in a biological sample, comprising:
performing sequencing on cell-free nucleic acids contained in the biological sample, so as to obtain a sequencing result consisting of a plurality of sequencing data; determining the number of the cell-free nucleic acids in a length falling into a predetermined range in the biological sample based on the sequencing result; and determining the fraction of the cell-free nucleic acids from the predetermined source in the biological sample based on the number of the cell-free nucleic acids in the length falling into the predetermined range. 2. The method according to claim 1, wherein the biological sample is a peripheral blood sample. 3. The method according to claim 2, wherein the cell-free nucleic acid from the predetermined source is selected from one of the followings:
cell-free fetal nucleic acids or cell-free maternal nucleic acids in a peripheral blood sample obtained from a pregnant woman, or cell-free tumor derived nucleic acids or cell-free non-tumor derived nucleic acids in a peripheral blood sample obtained from a subject suffering from tumor, suspected to suffer from tumor or subjected to tumor screening. 4-5. (canceled) 6. The method according to of claim 1, wherein determining the number of the cell-free nucleic acids in the length falling into the predetermined range in the biological sample based on the sequencing result further comprises:
aligning the sequencing result to a reference genome, so as to construct a dataset consisting of a plurality of uniquely-mapped reads, where each read in the dataset can be mapped to a position of the reference genome only; determining a length of the cell-free nucleic acid corresponding to each uniquely-mapped read in the dataset; and determining the number of the cell-free nucleic acids in the length falling into the predetermined range. 7. The method according to claim 6, wherein determining the length of the cell-free nucleic acid corresponding to each uniquely-mapped read in the dataset further comprises:
determining the length of each read uniquely mapped to the reference genome as the length of the cell-free nucleic acid corresponding to the read. 8. The method according to claim 6, wherein in the case that the cell-free nucleic acids in the biological sample are sequenced by the paired-end sequencing, determining the length of the cell-free nucleic acid corresponding to each uniquely-mapped read in the dataset further comprises:
determining a position, corresponding to the reference genome, of 5′-end of the cell-free nucleic acid, based on sequencing data at one end of each uniquely-mapped read obtained in the paired-end sequencing; determining a position, corresponding to the reference genome, of 3′-end of the cell-free nucleic acid, based on sequencing data at the other end of same uniquely-mapped read obtained in the paired-end sequencing; and determining the length of the cell-free nucleic acid based on the position of 5′-end of the cell-free nucleic acid and the position of 3′-end of the cell-free nucleic acid. 9. The method according to claim 1, wherein the predetermined range is determined based on a plurality of control samples, in each of which the fraction of the cell-free nucleic acids from the predetermined source is known. 10. (canceled) 11. The method according to claim 9, wherein the predetermined range is determined by the following steps:
(a) determining lengths of the cell-free nucleic acids in the plurality of control samples; (b) setting a plurality of candidate length ranges, and determining a percentage of the cell-free nucleic acids, obtained from each of the plurality of control samples, present in each candidate length range; (c) determining a correlation coefficient between each candidate length range and the fraction of the cell-free nucleic acids from the predetermined source, based on the percentage of the cell-free nucleic acids, obtained from each of the plurality of control samples, present in each candidate length range and the fraction of the cell-free nucleic acids from the predetermined source in the control samples; and (d) determining at least one candidate length range or a combination of the candidate length ranges as the predetermined range based on the correlation coefficient. 12-13. (canceled) 14. The method according to claim 9, wherein determining the fraction of the cell-free nucleic acids from the predetermined source in the biological sample based on the number of the cell-free nucleic acids in the length falling into the predetermined range further comprises:
determining a percentage of the cell-free nucleic acids present in the predetermined range based on the number of cell-free nucleic acids in the length falling into the predetermined range; and determining the fraction of the cell-free nucleic acids from the predetermined source in the biological sample, based on the percentage of the cell-free nucleic acids present in the predetermined range, according to a predetermined function, wherein the predetermined function is determined based on the plurality of control samples. 15. The method according to claim 14, wherein the predetermined function is obtained by following steps:
(i) determining the percentage of the cell-free nucleic acids, obtained from each control sample, present in the predetermined range; and (ii) fitting the percentage of the cell-free nucleic acids, obtained from each control sample, present in the predetermined range with the known fraction of the cell-free nucleic acid from the predetermined source, to determine the predetermined function. 16. The method according to claim 15, wherein the percentage of the cell-free nucleic acids, obtained from each control sample, present in the predetermined range is fitted with the known fraction of the cell-free nucleic acid from the predetermined source by a linear fitting. 17. The method according to claim 1, wherein the cell-free nucleic acid from the predetermined source is cell-free fetal nucleic acid obtained from a peripheral blood sample of a pregnant woman, and the predetermined range is 185 bp to 204 bp. 18. The method according to claim 9, wherein the control sample is a peripheral blood sample obtained from a pregnant woman in which the fraction of the cell-free fetal nucleic acids is known. 19. The method according to claim 18, wherein the control sample is a peripheral blood sample obtained from a pregnant woman with a normal male fetus, in which the fraction of the cell-free fetal nucleic acids is known to be determined by chromosome Y. 20-37. (canceled) 38. A method for determining sexuality of twins, comprising:
performing sequencing on cell-free nucleic acids contained in a peripheral blood sample obtained from a pregnant woman with twins, so as to obtain a sequencing result consisting of a plurality of sequencing data; determining a first cell-free fetal DNA fraction based on the sequencing data, by the method according to claim 1; determining a second cell-free fetal DNA fraction based on a sequencing data derived from chromosome Y in the sequencing result; and determining the sexuality of the twins based on the first cell-free fetal DNA fraction and the second cell-free fetal DNA fraction. 39. The method according to claim 38, wherein the second cell-free fetal DNA fraction is determined according to the following formula:
fra.chry=(chry.ER %−Female.chry.ER %)/(Man.chry.ER %−Female.chry.ER %)*100%,
where fra.chry represents the second cell-free fetal DNA fraction, chry.ER % represents a percentage of the sequencing data derived from chromosome Y in the sequencing result to total sequencing data;
Female.chry.ER % represents an average percentage of sequencing data of cell-free nucleic acids derived from chromosome Y in a peripheral blood sample obtained from a pregnant woman predetermined to be with a normal female fetus to total sequencing data thereof; and
Man.chry.ER % represents an average percentage of sequencing data of cell-free nucleic acids derived from chromosome Y in a peripheral blood sample obtained from a healthy man to total sequencing data thereof. 40. The method according to claim 38, wherein determining the sexuality of the twins based on the first cell-free fetal DNA fraction and the second cell-free fetal DNA fraction further comprises:
(a) determining a ratio of the second cell-free fetal DNA fraction to the first cell-free fetal DNA fraction; and (b) determining the sexuality of the twins by comparing the ratio determined in (a) with a first threshold and a second threshold predetermined. 41. The method according to claim 40, wherein the first threshold is determined based on a plurality of control samples obtained from pregnant women known with female twins, and the second threshold is determined based on a plurality of control samples obtained from pregnant women known with male twins. 42. The method according to claim 41, wherein
both fetuses of the twins are female if the ratio of the second cell-free fetal DNA fraction to the first cell-free fetal DNA fraction is lower than the first threshold, both fetuses of the twins are male if the ratio of the second cell-free fetal DNA fraction to the first cell-free fetal DNA fraction is greater than the second threshold, and the twins include a male fetus and a female fetus if the ratio of the second cell-free fetal DNA fraction to the first cell-free fetal DNA fraction is equal to the first threshold or the second threshold, or between the first threshold and the second threshold. 43. The method according to claim 42, wherein the first threshold is 0.35 and the second threshold is 0.7. 44-49. (canceled) 50. A method for detecting a chromosome aneuploidy of twins, comprising:
performing sequencing on cell-free nucleic acids contained in a peripheral blood sample obtained from a pregnant woman with twins, so as to obtain a sequencing result consisting of a plurality of sequencing data; determining a first cell-free fetal DNA fraction, based on the sequencing data, by the method according to claim 1; determining a third cell-free fetal DNA fraction, based on a sequencing data derived from a predetermined chromosome in the sequencing result; and determining whether the twins under detection have aneuploidy with respect to the predetermined chromosome based on the first cell-free fetal DNA fraction and the third cell-free fetal DNA fraction. 51. The method according to claim 50, wherein the third cell-free fetal DNA fraction is determined according to the following formula:
fra.chri=2*(chri.ER %/adjust.chri.ER %−1)*100%,
where fra.chri represents the third cell-free fetal DNA fraction, i represents a serial number of the predetermined chromosome, and i is any integer in the range of 1 to 22; chri.ER % represents a percentage of the sequencing data derived from the predetermined chromosome in the sequencing result to total sequencing data; adjust.chri.ER % represents an average percentage of sequencing data of cell-free nucleic acids derived from the predetermined chromosome in a peripheral blood sample obtained from a pregnant woman predetermined to be with normal twins to total sequencing data thereof. 52. The method according to claim 51, wherein determining whether the twins under detection have aneuploidy with respect to the predetermined chromosome based on the first cell-free fetal DNA fraction and the third cell-free fetal DNA fraction further comprises:
(a) determining a ratio of the third cell-free fetal DNA fraction to the first cell-free fetal DNA fraction; and (b) determining whether the twins under detection have aneuploidy with respect to the predetermined chromosome by comparing the ratio determined in (a) with a third threshold and a fourth threshold predetermined. 53. The method according to claim 52, wherein the third threshold is determined based on a plurality of control samples obtained from pregnant women with twins known not to have aneuploidy with respect to the predetermined chromosome, and the fourth threshold is determined based on a plurality of control samples obtained from pregnant women with twins known to have aneuploidy with respect to the predetermined chromosome. 54. The method according to claim 53, wherein
both fetuses of the twins have no aneuploidy with respect to the predetermined chromosome if the ratio of the third cell-free fetal DNA fraction to the first cell-free fetal DNA fraction is lower than the third threshold, both fetuses of the twins have aneuploidy with respect to the predetermined chromosome if the ratio of the third cell-free fetal DNA fraction to the first cell-free fetal DNA fraction is greater than the fourth threshold, and one fetus of the twins has the aneuploidy with respect to the predetermined chromosome, while the other fetus of the twins has no aneuploidy with respect to the predetermined chromosome if the ratio of the third cell-free fetal DNA fraction to the first cell-free fetal DNA fraction is equal to the third threshold or the fourth threshold, or between the third threshold and the fourth threshold. 55. The method according to claim 54, wherein the third threshold is 0.35 and the fourth threshold is 0.7. 56. The method according to claim 50, wherein the predetermined chromosome is at least one selected from chromosomes 18, 21 and 23. 57-63. (canceled) 64. A method for determining a chromosome aneuploidy of twins, comprising:
performing sequencing on cell-free nucleic acids contained in a peripheral blood sample obtained from a pregnant woman with twins, so as to obtain a sequencing result consisting of a plurality of sequencing data; determining a fraction xi of the number of sequencing data derived from chromosome i in the sequencing result to total sequencing data, where i represents a serial number of the chromosome, and i is any integer in the range of 1 to 22; determining a T score of the chromosome i according to Ti=(xi−μi)/σi, where i represents the serial number of the chromosome and i is any integer in the range of 1 to 22, μi represents an average percentage of sequencing data of the chromosome i selected as a reference system in a reference database to total sequencing data thereof, σi represents a standard deviation of percentages of the sequencing data of the chromosome i selected as the reference system in the reference database to total sequencing data thereof, determining an L score of the chromosome i according to Li=log(d(Ti, a))/log(d(T2i, a)), where i represents the serial number of the chromosome and i is any integer in the range of 1 to 22, T2i=(xi−μi*(1+fra/2))/σi; d(Ti, a) and d(T2i, a) represent t distribution probability density function, where a represents degree of freedom, fra represents a first cell-free fetal DNA fraction determined by the method according to claim 1, plotting a four-quadrant diagram with T as vertical coordinate and L as horizontal coordinate by zoning with a first straight line where T=predetermined fifth threshold and a second straight line where L=predetermined sixth threshold, wherein both fetuses of the twins are determined to have trisome if a sample under detection is determined to be of the T score and the L score falling into a first quadrant; one fetus of the twins is determined to be of trisome and the other fetus of the twins is determined to be normal if a sample under detection is determined to be of the T score and the L score falling into a second quadrant; both fetuses of the twins are determined to be noirual if a sample under detection is determined to be of the T score and the L score falling into a third quadrant; the twins are determined to have a low fetal fraction if a sample under detection is determined to be of the T score and the L score falling into a fourth quadrant, such a result is not adopted. 65. A method for detecting fetal chimera, comprising:
performing sequencing on cell-free nucleic acids contained in a peripheral blood sample obtained from a pregnant woman with a fetus, optionally a male fetus, so as to obtain a sequencing result consisting of a plurality of sequencing data; determining a first cell-free fetal DNA fraction, based on the sequencing data, by the method according to claim 1, or estimating a fetal fraction by chromosome Y (fra.chrY %) as a first cell-free fetal DNA fraction according to the following formula:
fra.chry=(chry.ER %−Female.chry.ER %)/(Man.chry.ER %−Female.chry.ER %)*100%,
where fra.chry chry.ER % represents the first cell-free fetal DNA fraction, represents a percentage of sequencing data derived from chromosome Y in the sequencing result to total sequencing data; Female.chry.ER % represents an average percentage of sequencing data of cell-free nucleic acids derived from chromosome Y in a peripheral blood sample obtained from a pregnant woman predetermined to be with a normal female fetus to total sequencing data thereof; and Man.chry.ER % represents an average percentage of sequencing data of cell-free nucleic acids derived from chromosome Y in a peripheral blood sample obtained from a healthy man predetermined to total sequencing data thereof;
determining a third cell-free fetal DNA fraction based on sequencing data derived from a predetermined chromosome in the sequencing result; and
determining whether the fetus under detection has fetal chimera with respect to the predetermined chromosome based on the first cell-free fetal DNA fraction and the third cell-free fetal DNA fraction. 66. The method according to claim 65, wherein the third cell-free fetal DNA fraction is determined by the following formula:
fra.chri=2*(chri.ER %/adjust.chri.ER %−1)*100%,
where fra.chri represents the third cell-free fetal DNA fraction, i represents a serial number of the predetermined chromosome and i is any integer in the range of 1 to 22; chri.ER % represents a percentage of the sequencing data derived from the predetermined chromosome in the sequencing result to total sequencing data; adjust.chri.ER % represents an average percentage of sequencing data of cell-free nucleic acids derived from the predetermined chromosome in a peripheral blood sample obtained from a pregnant woman predetermined to be with a normal fetus to total sequencing data thereof. 67. The method according to claim 66, wherein determining whether the fetus under detection has fetal chimera with respect to the predetermined chromosome based on the first cell-free fetal DNA fraction and the third cell-free fetal DNA fraction further comprises:
(a) determining a ratio of the third cell-free fetal DNA fraction to the first cell-free fetal DNA fraction; and (b) determining whether the fetus under detection has chimera with respect to the predetermined chromosome by comparing the ratio determined in (a) with a plurality of predetermined thresholds. 68. The method according to claim 67, wherein the plurality of predetermined thresholds comprises at least one selected from:
a seventh threshold, determined based on a plurality of control samples with the predetermined chromosome known to be of complete monosome, an eighth threshold, determined based on a plurality of control samples with the predetermined chromosome known to be of monosome chimera, a ninth threshold, determined based on a plurality of control samples with the predetermined chromosome known to be normal, a tenth threshold, determined based on a plurality of control samples with the predetermined chromosome known to be of complete trisome, optionally, the predetermined chromosome of the fetus under detection is of complete monosome, if the ratio of the third cell-free fetal DNA fraction to the first cell-free fetal DNA fraction is lower than the seventh threshold; the predetermined chromosome of the fetus under detection is of monosome chimera, if the ratio of the third cell-free fetal DNA fraction to the first cell-free fetal DNA fraction is not lower than the seventh threshold and not greater than the eighth threshold; the predetermined chromosome of the fetus under detection is normal, if the ratio of the third cell-free fetal DNA fraction to the first cell-free fetal DNA fraction is greater than the eighth threshold and lower than the ninth threshold; the predetermined chromosome of the fetus under detection is of trisome chimera, if the ratio of the third cell-free fetal DNA fraction to the first cell-free fetal DNA fraction is not lower than the ninth threshold and not greater than the tenth threshold; and the predetermined chromosome of the fetus under detection is of complete trisome, if the ratio of the third cell-free fetal DNA fraction to the first cell-free fetal DNA fraction is greater than the tenth threshold. 69. The method according to claim 68, wherein the seventh threshold is greater than −1 and lower than 0, optionally is −0.85;
the eighth threshold is greater than the seventh threshold and lower than 0, optionally is −0.3;
the ninth threshold is greater than 0 and lower than 1, optionally is 0.3;
the tenth threshold is greater than the ninth threshold and lower than 1, optionally is 0.85. 70-74. (canceled) 75. A method for detecting fetal chimera, comprising:
performing sequencing on cell-free nucleic acids contained in a peripheral blood sample obtained from a pregnant woman with a fetus, so as to obtain a sequencing result consisting of a plurality of sequencing data; determining a fraction xi of the number of sequencing data derived from chromosome i in the sequencing result to total sequencing data, where i represents a serial number of the chromosome, and i is any integer in the range of 1 to 22; determining a T score of the chromosome i according to Ti=(xi−μi)/σi, where i represents the serial number of the chromosome and i is any integer in the range of 1 to 22, μi represents an average value of percentages of sequencing data of the chromosome i selected as a reference system in a reference database to total sequencing data thereof, σi represents a standard deviation of percentages of the sequencing data of the chromosome i selected as the reference system in the reference database to total sequencing data thereof,
determining an L score of the chromosome i according to Li=log(d(Ti,a))/log(d(T2i, a)) where i represents the serial number of the chromosome and i is any integer in the range of 1 to 22, T2i=(xi−μi*(1+fra/2))/σi; d(Ti, a) and d(T2i, a) represent t distribution probability density function, where a represents degree of freedom, fra represents a cell-free fetal DNA fraction determined by the method according to claim 1 or a fetal fraction estimated by chromosome Y (fra.chrY %),
fra.chry=(chry.ER %−Female.chry.ER %)/(Man.chry.ER %−Female.chry.ER %)*100%,
where fra.chry represents a cell-free fetal DNA fraction, chry.ER % represents a percentage of sequencing data derived from chromosome Y in the sequencing result to said total sequencing data; Female.chry.ER % represents an average percentage of sequencing data of cell-free nucleic acids derived from chromosome Y in a peripheral blood sample obtained from a pregnant woman predetermined to be with a normal female fetus to total sequencing data thereof; and Man.chry.ER % represents an average percentage of sequencing data of cell-free nucleic acids derived from chromosome Y in a peripheral blood sample obtained from a healthy man predetermined to total sequencing data thereof;
plotting a four-quadrant diagram with T as vertical coordinate and L as horizontal coordinate by zoning with a third straight line where T=predetermined eleventh threshold and a fourth straight line where L=predetermined twelfth threshold, when the T score is greater than 0,
wherein the fetus is determined to have complete monosome or monosome chimera with respect to the predetermined chromosome, if a sample under detection is determined to be of the T score and the L score falling into a first quadrant;
the fetus is determined to have monosome chimera with respect to the predetermined chromosome, if a sample under detection is determined to be of the T score and the L score falling into a second quadrant;
the fetus is determined to be normal with respect to the predetermined chromosome, if a sample under detection is determined to be of the T score and the L score falling into a third quadrant;
the fetus is determined to have a low fetal fraction if a sample under detection is determined to be of the T score and the L score falling into a fourth quadrant, such a result is not adopted,
plotting a four-quadrant diagram with T as vertical coordinate and L as horizontal coordinate by zoning with a first straight line where T=predetermined thirteenth threshold and a second straight line where L=predetermined fourteenth threshold, when the T score is greater than 0,
wherein the fetus is determined to have complete trisome or trisome chimera with respect to the predetermined chromosome, if a sample under detection is determined to be of the T score and the L score falling into a first quadrant;
the fetus is determined to have trisome chimera with respect to the predetermined chromosome, if a sample under detection is determined to be of the T score and the L score falling into a second quadrant;
the fetus is determined to be normal with respect to the predetermined chromosome, if a sample under detection is determined to be of the T score and the L score falling into a third quadrant;
the fetus is determined to have a low fetal fraction if a sample under detection is determined to be of the T score and the L score falling into a fourth quadrant, such a result is not adopted,
optionally, the eleventh threshold and the thirteenth threshold each independently is 3, and the twelfth threshold and the fourteenth threshold each independently is 1. 76. (canceled) 77. The method according to claim 14, wherein the predetermined function is d=0.0334*p+1.6657, where d represents a fraction of cell-free fetal nucleic acids, and p represents a percentage of cell-free nucleic acid present in the predetermined range. | 1,600 |
1,128 | 15,471,730 | 1,639 | An array including a solid support having a plurality of contours along its exterior surface. A first subset of contours is positioned along the exterior surface of the solid support to form a first pattern of features and a second subset of contours is positioned along the exterior surface to form a second pattern of features. The contours of the first subset are juxtaposed with the second subset along the exterior surface, whereby the first and second patterns form an interleaved pattern. The features of the first pattern occur at a first elevation z 1 and the features of the second pattern occur at a second elevation z 2 . The features of the first pattern are configured to attach analytes at a different elevation relative to analytes attached to the features of the second pattern. | 1. An array, comprising:
a solid support comprising a plurality of contours along an exterior surface of the solid support; wherein a first subset of the contours is positioned along the exterior surface of the solid support to form a first pattern of features and a second subset of the contours is positioned along the exterior surface of the solid support to form a second pattern of feature; wherein the contours of the first subset are juxtaposed with the contours of the second subset along the exterior surface, whereby the first and second patterns form an interleaved pattern along the exterior surface; wherein the features of the first pattern occur at a first elevation z1 and the features of the second pattern occur at a second elevation z2; and wherein the features comprise attachment points for analytes, whereby the features of the first pattern are configured to attach analytes at a different elevation relative to analytes attached to the features of the second pattern. 2. The array of claim 1, wherein the contours comprise depressions, wells, channels, projections, ridges or posts. 3. The array of claim 1, wherein the first pattern of features comprises a repeating pattern of features and wherein the second pattern comprises a repeating pattern of features. 4. The array of claim 1, wherein the contours of the first subset comprise wells having a bottom at elevation z1 and the contours of the second subset comprise wells having a bottom at elevation z2. 5. The array of claim 1, wherein the contours of the first subset comprise posts having a top at elevation z1 and the contours of the second subset comprise posts having a top at elevation z2. 6. The array of claim 1, wherein the contours of the first subset comprise wells having a bottom at elevation z1 and the contours of the second subset comprise posts having a top at elevation z2. 7. The array of claim 1, wherein the features each occupy an area that is smaller than about 1 μm2. 8. The array of claim 1, wherein nearest-neighbor features in the interleaved pattern have a pitch that is less than about 500 nm. 9. The array of claim 1, wherein z1 and z2 are at least about 2 μm apart. 10. The array of claim 1, wherein nearest-neighbor features in the first pattern have a pitch that is greater than about 500 nm. 11. The array of claim 1, wherein a material that is capable of attaching to the analytes is present at the features. 12. The array of claim 1, wherein the contours of the first subset intervene nearest-neighbor contours of the second subset and the contours of the second subset intervene nearest-neighbor contours of the first subset, whereby the first and second patterns form the interleaved pattern along the exterior surface. 13. The array of claim 12, wherein the first pattern has the same lattice pattern as the second pattern, and wherein the first pattern is offset from the second pattern along the exterior surface. 14. The array of claim 1, wherein the contours of the first subset are spaced from the contours of the second subset. 15. The array of claim 1, wherein the contours of the first subset are adjacent to the contours of the second subset. 16. An array, comprising:
a solid support; a first pattern of features positioned along an exterior surface of the solid support; a second pattern of features positioned along the exterior surface of the solid support and interleaved with the first pattern of features; wherein the features of the first pattern occur at a first elevation z1 and the features of the second pattern occur at a second elevation z2; and wherein the features of the first and second patterns comprise attachment points for analytes, the features of the first pattern being configured to attach analytes at a different elevation relative to analytes attached to the features of the second pattern. 17. The array of claim 16, wherein the contours of the first subset are spaced from the contours of the second subset. 18. The array of claim 16, wherein the contours of the first subset are adjacent to the contours of the second subset. 19. A method of detecting a plurality of analytes, comprising:
providing an array comprising a solid support comprising a first pattern of analyte features and a second pattern of analyte features along an exterior surface of the solid support, wherein the analyte features of the first pattern occur at a first elevation z1 and the analyte features of the second pattern occur at a second elevation z2 and, wherein the first and second patterns form an interleaved pattern along the exterior surface; detecting signals at the first elevation z1, whereby individual analyte features of the first pattern are distinguished from each other; and detecting signals at the second elevation z2, whereby individual analyte features of the second pattern are distinguished from each other, wherein analyte features in the first pattern are distinguished from nearest-neighbor analyte features in the second pattern by selectively detecting features at the first elevation z1 compared to features at the second elevation z2. 20. The method of claim 19, wherein analyte features in the first pattern are distinguished from nearest-neighbor analyte features in the second pattern by selectively focusing an optical detector to the first elevation z1 compared to the second elevation z2. | An array including a solid support having a plurality of contours along its exterior surface. A first subset of contours is positioned along the exterior surface of the solid support to form a first pattern of features and a second subset of contours is positioned along the exterior surface to form a second pattern of features. The contours of the first subset are juxtaposed with the second subset along the exterior surface, whereby the first and second patterns form an interleaved pattern. The features of the first pattern occur at a first elevation z 1 and the features of the second pattern occur at a second elevation z 2 . The features of the first pattern are configured to attach analytes at a different elevation relative to analytes attached to the features of the second pattern.1. An array, comprising:
a solid support comprising a plurality of contours along an exterior surface of the solid support; wherein a first subset of the contours is positioned along the exterior surface of the solid support to form a first pattern of features and a second subset of the contours is positioned along the exterior surface of the solid support to form a second pattern of feature; wherein the contours of the first subset are juxtaposed with the contours of the second subset along the exterior surface, whereby the first and second patterns form an interleaved pattern along the exterior surface; wherein the features of the first pattern occur at a first elevation z1 and the features of the second pattern occur at a second elevation z2; and wherein the features comprise attachment points for analytes, whereby the features of the first pattern are configured to attach analytes at a different elevation relative to analytes attached to the features of the second pattern. 2. The array of claim 1, wherein the contours comprise depressions, wells, channels, projections, ridges or posts. 3. The array of claim 1, wherein the first pattern of features comprises a repeating pattern of features and wherein the second pattern comprises a repeating pattern of features. 4. The array of claim 1, wherein the contours of the first subset comprise wells having a bottom at elevation z1 and the contours of the second subset comprise wells having a bottom at elevation z2. 5. The array of claim 1, wherein the contours of the first subset comprise posts having a top at elevation z1 and the contours of the second subset comprise posts having a top at elevation z2. 6. The array of claim 1, wherein the contours of the first subset comprise wells having a bottom at elevation z1 and the contours of the second subset comprise posts having a top at elevation z2. 7. The array of claim 1, wherein the features each occupy an area that is smaller than about 1 μm2. 8. The array of claim 1, wherein nearest-neighbor features in the interleaved pattern have a pitch that is less than about 500 nm. 9. The array of claim 1, wherein z1 and z2 are at least about 2 μm apart. 10. The array of claim 1, wherein nearest-neighbor features in the first pattern have a pitch that is greater than about 500 nm. 11. The array of claim 1, wherein a material that is capable of attaching to the analytes is present at the features. 12. The array of claim 1, wherein the contours of the first subset intervene nearest-neighbor contours of the second subset and the contours of the second subset intervene nearest-neighbor contours of the first subset, whereby the first and second patterns form the interleaved pattern along the exterior surface. 13. The array of claim 12, wherein the first pattern has the same lattice pattern as the second pattern, and wherein the first pattern is offset from the second pattern along the exterior surface. 14. The array of claim 1, wherein the contours of the first subset are spaced from the contours of the second subset. 15. The array of claim 1, wherein the contours of the first subset are adjacent to the contours of the second subset. 16. An array, comprising:
a solid support; a first pattern of features positioned along an exterior surface of the solid support; a second pattern of features positioned along the exterior surface of the solid support and interleaved with the first pattern of features; wherein the features of the first pattern occur at a first elevation z1 and the features of the second pattern occur at a second elevation z2; and wherein the features of the first and second patterns comprise attachment points for analytes, the features of the first pattern being configured to attach analytes at a different elevation relative to analytes attached to the features of the second pattern. 17. The array of claim 16, wherein the contours of the first subset are spaced from the contours of the second subset. 18. The array of claim 16, wherein the contours of the first subset are adjacent to the contours of the second subset. 19. A method of detecting a plurality of analytes, comprising:
providing an array comprising a solid support comprising a first pattern of analyte features and a second pattern of analyte features along an exterior surface of the solid support, wherein the analyte features of the first pattern occur at a first elevation z1 and the analyte features of the second pattern occur at a second elevation z2 and, wherein the first and second patterns form an interleaved pattern along the exterior surface; detecting signals at the first elevation z1, whereby individual analyte features of the first pattern are distinguished from each other; and detecting signals at the second elevation z2, whereby individual analyte features of the second pattern are distinguished from each other, wherein analyte features in the first pattern are distinguished from nearest-neighbor analyte features in the second pattern by selectively detecting features at the first elevation z1 compared to features at the second elevation z2. 20. The method of claim 19, wherein analyte features in the first pattern are distinguished from nearest-neighbor analyte features in the second pattern by selectively focusing an optical detector to the first elevation z1 compared to the second elevation z2. | 1,600 |
1,129 | 14,930,840 | 1,631 | Embodiments are directed to a computer-based system for analyzing genotype data of a set of multiple progeny to estimate information about unknown parents of the multiple progeny. The system includes a memory and a processor system communicatively coupled to the memory. The processor system is configured to receive data representing markers of each genotype of each of the multiple progeny, compare the data to identify compatible genotypes having compatible markers, and label the compatible genotypes as having at least one parent in common. | 1. A computer-based system for analyzing genotype data of a set of multiple progeny to estimate information about unknown parents of the multiple progeny, the system comprising:
a memory; and a processor system communicatively coupled to the memory; the processor system configured to: receive data representing markers of each genotype of each of the multiple progeny; compare the data to identify compatible genotypes having compatible markers; and label at least some of the compatible genotypes as having at least one parent in common. 2. The computer-based system of claim 1, wherein the processor system is further configured to label others of the compatible genotypes as having at least one parent not in common. 3. The computer-based system of claim 2, wherein the processor system is further configured to:
compare the data to identify incompatible genotypes having incompatible markers; and label the incompatible genotypes as not having any parent in common. 4. The computer-based system of claim 1, wherein the processor system is further configured to determine, based at least in part on the data, haploids contributed by the at least one parent in common. 5. The computer-based system of claim 2, wherein the processor system is further configured to determine, based at least in part on the data, haploids contributed by the at least one parent not in common. 6. The computer-based system of claim 2, wherein the processor system is further configured to:
receive first parent marker data representing markers of each genotype of the at least one parent in common; compare the first parent marker data to identify first parent compatible genotypes having compatible markers; and label the first parent compatible genotypes as being the same parent. 7. The computer-based system of claim 6, wherein the processor system is further configured to:
receive second parent marker data representing markers of each genotype of the at least one parent not in common; compare the second parent marker data to identify second parent compatible genotypes having compatible markers; and label the second parent compatible genotypes as being the same parent. 8-14. (canceled) 15. A computer program product for analyzing genotype data of a set of multiple progeny to estimate information about unknown parents of the multiple progeny, the computer program product comprising:
a computer readable storage medium having program instructions embodied therewith, wherein the computer readable storage medium is not a transitory signal per se, the program instructions readable by a processor system to cause the processor system to perform a method comprising: receiving, using the processor system, data representing markers of each genotype of each of the multiple progeny; comparing, using the processor system, the data to identify compatible genotypes having compatible markers; and labeling, using the processor system, at least some of the compatible genotypes as having at least one parent in common. 16. The computer-program product of claim 15 further comprising:
labeling others of the compatible genotypes as having at least one parent not in common;
comparing the data to identify incompatible genotypes having incompatible markers; and
labeling the incompatible genotypes as not having any parent in common. 17. The computer-program product of claim 15 further comprising determining, based at least in part on the data, haploids contributed by the at least one parent in common. 18. The computer-program product of claim 16 further comprising determining, based at least in part on the data, haploids contributed by the at least one parent not in common. 19. The computer-program product of claim 16 further comprising:
receiving, using the processor system, first parent marker data representing markers of each genotype of the at least one parent in common;
comparing the first parent marker data to identify first parent compatible genotypes having compatible markers; and
labeling the first parent compatible genotypes as being the same parent. 20. The computer-program product of claim 19 further comprising:
receiving, using the processor system, second parent marker data representing markers of each genotype of the at least one parent not in common;
comparing the second parent marker data to identify second parent compatible genotypes having compatible markers; and
labeling the second parent compatible genotypes as being the same parent. | Embodiments are directed to a computer-based system for analyzing genotype data of a set of multiple progeny to estimate information about unknown parents of the multiple progeny. The system includes a memory and a processor system communicatively coupled to the memory. The processor system is configured to receive data representing markers of each genotype of each of the multiple progeny, compare the data to identify compatible genotypes having compatible markers, and label the compatible genotypes as having at least one parent in common.1. A computer-based system for analyzing genotype data of a set of multiple progeny to estimate information about unknown parents of the multiple progeny, the system comprising:
a memory; and a processor system communicatively coupled to the memory; the processor system configured to: receive data representing markers of each genotype of each of the multiple progeny; compare the data to identify compatible genotypes having compatible markers; and label at least some of the compatible genotypes as having at least one parent in common. 2. The computer-based system of claim 1, wherein the processor system is further configured to label others of the compatible genotypes as having at least one parent not in common. 3. The computer-based system of claim 2, wherein the processor system is further configured to:
compare the data to identify incompatible genotypes having incompatible markers; and label the incompatible genotypes as not having any parent in common. 4. The computer-based system of claim 1, wherein the processor system is further configured to determine, based at least in part on the data, haploids contributed by the at least one parent in common. 5. The computer-based system of claim 2, wherein the processor system is further configured to determine, based at least in part on the data, haploids contributed by the at least one parent not in common. 6. The computer-based system of claim 2, wherein the processor system is further configured to:
receive first parent marker data representing markers of each genotype of the at least one parent in common; compare the first parent marker data to identify first parent compatible genotypes having compatible markers; and label the first parent compatible genotypes as being the same parent. 7. The computer-based system of claim 6, wherein the processor system is further configured to:
receive second parent marker data representing markers of each genotype of the at least one parent not in common; compare the second parent marker data to identify second parent compatible genotypes having compatible markers; and label the second parent compatible genotypes as being the same parent. 8-14. (canceled) 15. A computer program product for analyzing genotype data of a set of multiple progeny to estimate information about unknown parents of the multiple progeny, the computer program product comprising:
a computer readable storage medium having program instructions embodied therewith, wherein the computer readable storage medium is not a transitory signal per se, the program instructions readable by a processor system to cause the processor system to perform a method comprising: receiving, using the processor system, data representing markers of each genotype of each of the multiple progeny; comparing, using the processor system, the data to identify compatible genotypes having compatible markers; and labeling, using the processor system, at least some of the compatible genotypes as having at least one parent in common. 16. The computer-program product of claim 15 further comprising:
labeling others of the compatible genotypes as having at least one parent not in common;
comparing the data to identify incompatible genotypes having incompatible markers; and
labeling the incompatible genotypes as not having any parent in common. 17. The computer-program product of claim 15 further comprising determining, based at least in part on the data, haploids contributed by the at least one parent in common. 18. The computer-program product of claim 16 further comprising determining, based at least in part on the data, haploids contributed by the at least one parent not in common. 19. The computer-program product of claim 16 further comprising:
receiving, using the processor system, first parent marker data representing markers of each genotype of the at least one parent in common;
comparing the first parent marker data to identify first parent compatible genotypes having compatible markers; and
labeling the first parent compatible genotypes as being the same parent. 20. The computer-program product of claim 19 further comprising:
receiving, using the processor system, second parent marker data representing markers of each genotype of the at least one parent not in common;
comparing the second parent marker data to identify second parent compatible genotypes having compatible markers; and
labeling the second parent compatible genotypes as being the same parent. | 1,600 |
1,130 | 15,835,270 | 1,653 | The present disclosure relates to gastrointestinal (GI) tract detection methods, devices and systems. | 1. A method, comprising:
transferring a fluid sample from the gastrointestinal (GI) tract or from the reproductive tract of a subject into a first dilution chamber of a device in vivo; and combining the fluid sample and a first dilution fluid in the first dilution chamber to produce a first diluted sample. 2-165. (canceled) 266. The method of claim 1, wherein:
the device comprises a plurality of dilution chambers; and for each at least some of the plurality of dilution chambers, the method comprises:
transferring a fluid sample into the dilution chamber; and
combining the fluid sample and the first dilution fluid in the first dilution chamber to produce a diluted sample. 267. The method of claim 266, further comprising combining diluted samples from at least two different dilution chambers to provide a further diluted sample. 268. The method of claim 1, wherein the device is an ingestible device. 269. The method of claim 268, further comprising orally administering the device to the subject. 270. The method of claim 1, wherein the first dilution fluid comprises a sterile medium. 271. The method of claim 1, further comprising culturing the diluted sample to produce a cultured sample. 272. The method of claim 271, wherein the culturing is performed in vivo. 273. The method of claim 271, wherein the culturing is performed ex vivo. 274. The method of claim 1, further comprising detecting an analyte in the sample. 275. The method of claim 274, wherein the analyte comprises a cell. 276. The method of claim 1, wherein the first dilution fluid comprises an anti-fungal agent. 277. The method of claim 1, wherein the first dilution fluid comprises sterile media, and the sterile media comprise an antibiotic. 278. The method of claim 1, wherein the first dilution fluid comprises an indicator media. 279. The method of claim 1, further comprising culturing the one or more diluted samples to produce one or more cultured samples, and detecting the presence or absence of an analyte in the one or more cultured samples. 280. The method of claim 1, further comprising detecting a level of bacteria in the one or more diluted or cultured samples, wherein the fluid sample is jejunal fluid and a bacterial concentration of 105 CFU/mL or greater in the jejunal fluid is indicative that the subject has SIBO. 281. The method of claim 1, wherein the analyte comprises a bacterium, and the method comprises detecting the presence or absence of bacterial growth in the one or more cultured samples. 282. The method of claim 281, wherein the volume of the fluid sample is about 5 μL, the dilution of the fluid sample is a dilution of about 1:10000 and detecting the presence of bacterial growth in the dilution is indicative of a bacterial concentration of 105 or greater colony forming units (CFU)/mL in the fluid sample. 283. The method of claim 281, wherein the fluid sample is jejunal fluid and a bacterial concentration of 105 CFU/mL or greater in the jejunal fluid is indicative that the subject has Small Intestinal Bacterial Overgrowth (SIBO). 284. A device, comprising:
a chamber configured to dilute a fluid sample from the GI tract or the reproductive tract of a subject; and a dilution chamber configured to house dilution fluid to dilute the fluid sample in the dilution chamber, wherein the device is an ingestible device. | The present disclosure relates to gastrointestinal (GI) tract detection methods, devices and systems.1. A method, comprising:
transferring a fluid sample from the gastrointestinal (GI) tract or from the reproductive tract of a subject into a first dilution chamber of a device in vivo; and combining the fluid sample and a first dilution fluid in the first dilution chamber to produce a first diluted sample. 2-165. (canceled) 266. The method of claim 1, wherein:
the device comprises a plurality of dilution chambers; and for each at least some of the plurality of dilution chambers, the method comprises:
transferring a fluid sample into the dilution chamber; and
combining the fluid sample and the first dilution fluid in the first dilution chamber to produce a diluted sample. 267. The method of claim 266, further comprising combining diluted samples from at least two different dilution chambers to provide a further diluted sample. 268. The method of claim 1, wherein the device is an ingestible device. 269. The method of claim 268, further comprising orally administering the device to the subject. 270. The method of claim 1, wherein the first dilution fluid comprises a sterile medium. 271. The method of claim 1, further comprising culturing the diluted sample to produce a cultured sample. 272. The method of claim 271, wherein the culturing is performed in vivo. 273. The method of claim 271, wherein the culturing is performed ex vivo. 274. The method of claim 1, further comprising detecting an analyte in the sample. 275. The method of claim 274, wherein the analyte comprises a cell. 276. The method of claim 1, wherein the first dilution fluid comprises an anti-fungal agent. 277. The method of claim 1, wherein the first dilution fluid comprises sterile media, and the sterile media comprise an antibiotic. 278. The method of claim 1, wherein the first dilution fluid comprises an indicator media. 279. The method of claim 1, further comprising culturing the one or more diluted samples to produce one or more cultured samples, and detecting the presence or absence of an analyte in the one or more cultured samples. 280. The method of claim 1, further comprising detecting a level of bacteria in the one or more diluted or cultured samples, wherein the fluid sample is jejunal fluid and a bacterial concentration of 105 CFU/mL or greater in the jejunal fluid is indicative that the subject has SIBO. 281. The method of claim 1, wherein the analyte comprises a bacterium, and the method comprises detecting the presence or absence of bacterial growth in the one or more cultured samples. 282. The method of claim 281, wherein the volume of the fluid sample is about 5 μL, the dilution of the fluid sample is a dilution of about 1:10000 and detecting the presence of bacterial growth in the dilution is indicative of a bacterial concentration of 105 or greater colony forming units (CFU)/mL in the fluid sample. 283. The method of claim 281, wherein the fluid sample is jejunal fluid and a bacterial concentration of 105 CFU/mL or greater in the jejunal fluid is indicative that the subject has Small Intestinal Bacterial Overgrowth (SIBO). 284. A device, comprising:
a chamber configured to dilute a fluid sample from the GI tract or the reproductive tract of a subject; and a dilution chamber configured to house dilution fluid to dilute the fluid sample in the dilution chamber, wherein the device is an ingestible device. | 1,600 |
1,131 | 15,327,671 | 1,616 | The application relates to compositions for enhancing plant growth, comprising at least one lipo-chitooligosaccharide (LCO) compound; and one beneficial microorganism selected from Streptomyces, Trichoderma or Bacillus and optionally further pesticide and to the methods for enhancing plant growth and treating seeds with said compositions. | 1. A method for synergistically enhancing the growth of a plant or plant part, comprising contacting said plant or plant part with at least one lipo-chitooligosaccharide (LCO) and at least one agriculturally beneficial microorganism, said at least one agriculturally beneficial microorganism comprising Bacillus sp., isolat AQ175, ATCC 55608; Bacillus sp., isolate AQ177, ATCC 55609; Bacillus amyloliquefaciens FZB24; Baccillus amyloliquefaciens isolate NRRL B-50349; Bacillus amyloliquefaciens SB3778; Bacillus amyloliquefaciens TJ1000; Bacillus pumilus isolate AQ717, NRRL B-21662; Bacillus Punilus isolate NRRL B-30087; Bacillus subtilis isolate AQ713, NRRL V-21661; Bacillus subtilis isolate AQ743, NRRL B-21665; Bacillus thuringiensis isolate AQ52, NRRL B-21619; Streptomyces sp. isolate NRRL No. B-30145, Striptomyces sp. isolate M1064, Streptomyces WYE 53, Streptomyces galbus isolate NRRL 30232, Streptomyces lydicus WYEC 108, Streptomyces violaceusniger YCED 9, Trichoderma asperelium SKT-1, Trichoderma atroviride LC52, Trichoderma harzianum T-22, Trichoderma harzianum TJ-35, Trichoderma harzianum T-39, Trichoderma harzianum ICC012, Trichoderma virens GL-21, Trichoderma virens GI-3, Trichoderma virens GI-21, Trichoderma viride TV1, and/or Trichoderma viride ICC080. 2. The method of claim 1, wherein said at least one LCO comprises one or more LCOs represented by the structure (I):
in which G is selected from the group consisting of hexosamine, acetyl-substituted hexosamine, sulfated-substituted hexosamine, and ether-subsititued hexosamine; R1, R2, R3, R5, R6 and R7, which are identical or different, are selected from the group consisting of H, CH3CO—, CxHyCO—, a carbamoyl, and a carbamic acid, wherein x is an integer between 0 and 17, and y is an integer between 1 and 35; R4 is selected from the group consisting of a saturated, monounsaturated, diunsaturated or triunsaturated aliphatic chain containing at least 12 carbon atoms; and n is equal to 1, 2, 3, or 4. 3. The method of claim 1, wherein said at least one LCO comprises one or more LCOs represented by the structure (II):
in which R is H or CH3CO—; and n is equal to 2 or 3. 4. The method of claim 1, wherein said at least one LCO comprises one or more LCOs represented by the structure (III):
in which R1 is selected from the group consisting of C14:0, 3OH-C14:0, iso-C15:0, C16:0, 3-OH-016:0, iso-C15:0, C16:1, C16:2, C16:3, iso-C17:0, iso-C17:1, C18:0, 3OH-C18:0, 018:0/3-OH, C18:1, OH-C18:1, C18:2, C18:3, C18:4, C19:1 carbamoyl, C20:0, C20:1, 3-OH-C20:1, 020:1/3-OH, C20:2, C20:3, C22:1, and C18-26(ω-1)-OH (including the C18, C20, C22, C24 and C26 hydroxylated species thereof, and C16:1Δ9, C16:2 (Δ2,9) and C16:3 (Δ2,4,9)); R2 hydrogen or methyl; R3 is selected from the group consisting of hydrogen, acetyl or carbamoyl; R4 hydrogen, acetyl or carbamoyl; R5 represents hydrogen, acetyl or carbamoyl; R6 is selected from the group consisting of hydrogen, arabinosyl, fucosyl, acetyl, sulfate ester, SO3H, 3-0-S-2-0-MeFuc, 2-0-MeFuc, and 4-0-AcFuc; R7 is selected from the group consisting of hydrogen, mannosyl or glycerol; R8 is selected from the group consisting of hydrogen, methyl, or —CH2OH; R9 is selected from the group consisting of hydrogen, arabinosyl, or fucosyl; R10 is selected from the group consisting of hydrogen, acetyl or fucosyl; and n is equal to 0, 1, 2 or 3. 5. The method of claim 1, wherein said at least one LCO comprises one or more LCOs represented by the structure (IV):
in which R1 is selected from the group consisting of C16, C16:0, C16:1, C16:2, C18:0, C18:1Δ9Z or C18:1Δ11Z; R2 represents hydrogen or SO3H; and n is equal to 1 or 2. 6. The composition of claim 1, wherein said at least one LCO comprises:
an LCO represented by the structure (V):
an LCO represented by the structure (VI):
an LCO represented by the structure (VII):
an LCO represented by the structure (VIII):
an LCO represented by the structure (IX):
an LCO represented by the structure (X):
an LCO represented by the structure (XI):
an LCO represented by the structure (XII):
an LCO represented by the structure (XIII):
an LCO represented by the structure (XIV):
an LCO represented by the structure (XV):
an LCO represented by the structure (XVI):
an LCO represented by the structure (XVII):
an LCO represented by the structure (XVIII):
an LCO represented by the structure (XIX):
an LCO represented by the structure (XX):
an LCO represented by the structure (XXI):
an LCO represented by the structure (XXII):
an LCO represented by the structure (XXIII):
an LCO represented by the structure (XXIV):
an LCO represented by the structure ( )W):
an LCO represented by the structure (XXVI):
an LCO represented by the structure (XXVII):
an LCO represented by the structure (XXVIII):
an LCO represented by the structure (XXIX):
an LCO represented by the structure (XXX):
an LCO represented by the structure (XXXI):
an LCO represented by the structure (XXXII):
and/or an LCO represented by the structure (XXXIII): 7. The method of claim 1, wherein said at least one agriculturally beneficial microorganism comprises Bacillus amyloliquefaciens FZB24. 8. The method of claim 1, wherein said at least one agriculturally beneficial microorganism comprises Bacillus amyloliquefaciens SB3778. 9. The method of claim 1, wherein said at least one agriculturally beneficial microorganism comprises Bacillus amyloliquefaciens TJ1000. 10. The method of claim 1, wherein said at least one agriculturally beneficial microorganism comprises Streptomyces lydicus WYEC 108. 11. The method of claim 1, wherein said at least one agriculturally beneficial microorganism comprises Trichoderma harzianum ICC012. 12. The method of claim 1, wherein said at least one agriculturally beneficial microorganism comprises Trichoderma virens GI-3. 13. The method of claim 1, wherein said at least one agriculturally beneficial microorganism comprises Trichoderma virens GI-21. 14. The method of claim 1, wherein said at least one agriculturally beneficial microorganism comprises Trichoderma viride ICC080. 15. The method of claim 1, further comprising contacting said plant or plant part with at least one fungicide, herbicie, insecticide, acaricide, and/or nematicide. 16. The method of claim 1, further comprising contacting said plant or plant part with azoxystrobin, pyraoxystrobin, penflufen, sedaxane, dimethomorph and/or ipconazole. 17. The method of any claim 1, further comprising contacting said plant or plant part with lambda-cyhalothrin, gamma-cyhalothrin, imidacloprid, thiamethoxam, pyriprole, chlorantraniliprole, clothianidin, cyazypyr, abamectin, and/or pyrimidifen 18. (canceled) | The application relates to compositions for enhancing plant growth, comprising at least one lipo-chitooligosaccharide (LCO) compound; and one beneficial microorganism selected from Streptomyces, Trichoderma or Bacillus and optionally further pesticide and to the methods for enhancing plant growth and treating seeds with said compositions.1. A method for synergistically enhancing the growth of a plant or plant part, comprising contacting said plant or plant part with at least one lipo-chitooligosaccharide (LCO) and at least one agriculturally beneficial microorganism, said at least one agriculturally beneficial microorganism comprising Bacillus sp., isolat AQ175, ATCC 55608; Bacillus sp., isolate AQ177, ATCC 55609; Bacillus amyloliquefaciens FZB24; Baccillus amyloliquefaciens isolate NRRL B-50349; Bacillus amyloliquefaciens SB3778; Bacillus amyloliquefaciens TJ1000; Bacillus pumilus isolate AQ717, NRRL B-21662; Bacillus Punilus isolate NRRL B-30087; Bacillus subtilis isolate AQ713, NRRL V-21661; Bacillus subtilis isolate AQ743, NRRL B-21665; Bacillus thuringiensis isolate AQ52, NRRL B-21619; Streptomyces sp. isolate NRRL No. B-30145, Striptomyces sp. isolate M1064, Streptomyces WYE 53, Streptomyces galbus isolate NRRL 30232, Streptomyces lydicus WYEC 108, Streptomyces violaceusniger YCED 9, Trichoderma asperelium SKT-1, Trichoderma atroviride LC52, Trichoderma harzianum T-22, Trichoderma harzianum TJ-35, Trichoderma harzianum T-39, Trichoderma harzianum ICC012, Trichoderma virens GL-21, Trichoderma virens GI-3, Trichoderma virens GI-21, Trichoderma viride TV1, and/or Trichoderma viride ICC080. 2. The method of claim 1, wherein said at least one LCO comprises one or more LCOs represented by the structure (I):
in which G is selected from the group consisting of hexosamine, acetyl-substituted hexosamine, sulfated-substituted hexosamine, and ether-subsititued hexosamine; R1, R2, R3, R5, R6 and R7, which are identical or different, are selected from the group consisting of H, CH3CO—, CxHyCO—, a carbamoyl, and a carbamic acid, wherein x is an integer between 0 and 17, and y is an integer between 1 and 35; R4 is selected from the group consisting of a saturated, monounsaturated, diunsaturated or triunsaturated aliphatic chain containing at least 12 carbon atoms; and n is equal to 1, 2, 3, or 4. 3. The method of claim 1, wherein said at least one LCO comprises one or more LCOs represented by the structure (II):
in which R is H or CH3CO—; and n is equal to 2 or 3. 4. The method of claim 1, wherein said at least one LCO comprises one or more LCOs represented by the structure (III):
in which R1 is selected from the group consisting of C14:0, 3OH-C14:0, iso-C15:0, C16:0, 3-OH-016:0, iso-C15:0, C16:1, C16:2, C16:3, iso-C17:0, iso-C17:1, C18:0, 3OH-C18:0, 018:0/3-OH, C18:1, OH-C18:1, C18:2, C18:3, C18:4, C19:1 carbamoyl, C20:0, C20:1, 3-OH-C20:1, 020:1/3-OH, C20:2, C20:3, C22:1, and C18-26(ω-1)-OH (including the C18, C20, C22, C24 and C26 hydroxylated species thereof, and C16:1Δ9, C16:2 (Δ2,9) and C16:3 (Δ2,4,9)); R2 hydrogen or methyl; R3 is selected from the group consisting of hydrogen, acetyl or carbamoyl; R4 hydrogen, acetyl or carbamoyl; R5 represents hydrogen, acetyl or carbamoyl; R6 is selected from the group consisting of hydrogen, arabinosyl, fucosyl, acetyl, sulfate ester, SO3H, 3-0-S-2-0-MeFuc, 2-0-MeFuc, and 4-0-AcFuc; R7 is selected from the group consisting of hydrogen, mannosyl or glycerol; R8 is selected from the group consisting of hydrogen, methyl, or —CH2OH; R9 is selected from the group consisting of hydrogen, arabinosyl, or fucosyl; R10 is selected from the group consisting of hydrogen, acetyl or fucosyl; and n is equal to 0, 1, 2 or 3. 5. The method of claim 1, wherein said at least one LCO comprises one or more LCOs represented by the structure (IV):
in which R1 is selected from the group consisting of C16, C16:0, C16:1, C16:2, C18:0, C18:1Δ9Z or C18:1Δ11Z; R2 represents hydrogen or SO3H; and n is equal to 1 or 2. 6. The composition of claim 1, wherein said at least one LCO comprises:
an LCO represented by the structure (V):
an LCO represented by the structure (VI):
an LCO represented by the structure (VII):
an LCO represented by the structure (VIII):
an LCO represented by the structure (IX):
an LCO represented by the structure (X):
an LCO represented by the structure (XI):
an LCO represented by the structure (XII):
an LCO represented by the structure (XIII):
an LCO represented by the structure (XIV):
an LCO represented by the structure (XV):
an LCO represented by the structure (XVI):
an LCO represented by the structure (XVII):
an LCO represented by the structure (XVIII):
an LCO represented by the structure (XIX):
an LCO represented by the structure (XX):
an LCO represented by the structure (XXI):
an LCO represented by the structure (XXII):
an LCO represented by the structure (XXIII):
an LCO represented by the structure (XXIV):
an LCO represented by the structure ( )W):
an LCO represented by the structure (XXVI):
an LCO represented by the structure (XXVII):
an LCO represented by the structure (XXVIII):
an LCO represented by the structure (XXIX):
an LCO represented by the structure (XXX):
an LCO represented by the structure (XXXI):
an LCO represented by the structure (XXXII):
and/or an LCO represented by the structure (XXXIII): 7. The method of claim 1, wherein said at least one agriculturally beneficial microorganism comprises Bacillus amyloliquefaciens FZB24. 8. The method of claim 1, wherein said at least one agriculturally beneficial microorganism comprises Bacillus amyloliquefaciens SB3778. 9. The method of claim 1, wherein said at least one agriculturally beneficial microorganism comprises Bacillus amyloliquefaciens TJ1000. 10. The method of claim 1, wherein said at least one agriculturally beneficial microorganism comprises Streptomyces lydicus WYEC 108. 11. The method of claim 1, wherein said at least one agriculturally beneficial microorganism comprises Trichoderma harzianum ICC012. 12. The method of claim 1, wherein said at least one agriculturally beneficial microorganism comprises Trichoderma virens GI-3. 13. The method of claim 1, wherein said at least one agriculturally beneficial microorganism comprises Trichoderma virens GI-21. 14. The method of claim 1, wherein said at least one agriculturally beneficial microorganism comprises Trichoderma viride ICC080. 15. The method of claim 1, further comprising contacting said plant or plant part with at least one fungicide, herbicie, insecticide, acaricide, and/or nematicide. 16. The method of claim 1, further comprising contacting said plant or plant part with azoxystrobin, pyraoxystrobin, penflufen, sedaxane, dimethomorph and/or ipconazole. 17. The method of any claim 1, further comprising contacting said plant or plant part with lambda-cyhalothrin, gamma-cyhalothrin, imidacloprid, thiamethoxam, pyriprole, chlorantraniliprole, clothianidin, cyazypyr, abamectin, and/or pyrimidifen 18. (canceled) | 1,600 |
1,132 | 16,096,493 | 1,626 | In a process for the synthesis of a nitrile by endothermic catalyzed reaction of ammonia with a hydrocarbon using heating obtained by passing an alternating current through a metallic coil, the endothermic reaction between ammonia and the hydrocarbon takes place in a reactor with direct inductive heating in the reaction zone. The heating is extremely fast, which makes the reaction practically instantaneous. | 1. A process for the synthesis of a nitrile by catalyzed reaction of ammonia with a hydrocarbon using heating obtained by passing an alternating current through a metallic coil, wherein the endothermic reaction between ammonia and the hydrocarbon takes place in a reactor with direct inductive heating in the reaction zone. 2. Process according to claim 1, wherein the coil is mounted within the synthesis reactor, and the catalyst is placed inside the coil. 3. Process according to claim 2, wherein the coil is made of Kanthal-type (Fe—Cr—Al alloy) wire. 4. Process according to claim 1, wherein the inductive heating is carried out using an induction heater which is a ferromagnetic metal structure provided with a suitable coating, and wherein the heating is generated by magnetic hysteresis losses. 5. Process according to claim 4, wherein the induction heater consists of a ferromagnetic catalyst with a high electric coercivity. 6. Process according to claim 5, wherein the catalyst is diluted with a magnetic material. 7. Process according to claim 4, wherein the metal structure is a metal selected from Fe—Cr and Al—Ni—Co alloys. 8. Process according to claim 7, wherein the metal structure is coated with a porous oxide surface impregnated with a catalytic phase. 9. Process according to claim 8, wherein the catalytic phase contains a catalyst based on Co or Sn. 10. Process according to claim 1, wherein the hydrocarbon is methane, ethane, propane, iso-butane and olefins. | In a process for the synthesis of a nitrile by endothermic catalyzed reaction of ammonia with a hydrocarbon using heating obtained by passing an alternating current through a metallic coil, the endothermic reaction between ammonia and the hydrocarbon takes place in a reactor with direct inductive heating in the reaction zone. The heating is extremely fast, which makes the reaction practically instantaneous.1. A process for the synthesis of a nitrile by catalyzed reaction of ammonia with a hydrocarbon using heating obtained by passing an alternating current through a metallic coil, wherein the endothermic reaction between ammonia and the hydrocarbon takes place in a reactor with direct inductive heating in the reaction zone. 2. Process according to claim 1, wherein the coil is mounted within the synthesis reactor, and the catalyst is placed inside the coil. 3. Process according to claim 2, wherein the coil is made of Kanthal-type (Fe—Cr—Al alloy) wire. 4. Process according to claim 1, wherein the inductive heating is carried out using an induction heater which is a ferromagnetic metal structure provided with a suitable coating, and wherein the heating is generated by magnetic hysteresis losses. 5. Process according to claim 4, wherein the induction heater consists of a ferromagnetic catalyst with a high electric coercivity. 6. Process according to claim 5, wherein the catalyst is diluted with a magnetic material. 7. Process according to claim 4, wherein the metal structure is a metal selected from Fe—Cr and Al—Ni—Co alloys. 8. Process according to claim 7, wherein the metal structure is coated with a porous oxide surface impregnated with a catalytic phase. 9. Process according to claim 8, wherein the catalytic phase contains a catalyst based on Co or Sn. 10. Process according to claim 1, wherein the hydrocarbon is methane, ethane, propane, iso-butane and olefins. | 1,600 |
1,133 | 15,609,564 | 1,612 | The present invention relates to compositions and methods for mineralizing a dental surface or subsurface including providing a composition including stabilized ACP and a source of fluoride ions. | 1-12. (canceled) 13. A method of mineralizing a dental surface or subsurface comprising providing a composition to contact the dental surface or subsurface, wherein the composition, prior to contacting the dental surface or subsurface, comprises (i) about 0.01% to 50% by weight casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate, and, separately, (ii) free fluoride ions in an amount of from at least 400 ppm to about 3,000 ppm. 14. A method according to claim 13, wherein the composition is selected from the group consisting of toothpaste; tooth gel; tooth powder; dental creme; liquid dentifrice; mouthwash; troche; chewing gum; gingival massage creme; gargle tablet and dental restorative. 15. A method according to claim 13, wherein the composition comprises sodium fluoride. 16. A method for remineralizing a subsurface enamel lesion comprising providing a composition to contact the subsurface enamel lesion, wherein the composition, prior to contacting the subsurface enamel lesion, comprises (i) about 0.01% to 50% by weight casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate, and, separately, (ii) free fluoride ions in an amount of from at least 400 ppm to about 3,000 ppm. 17. A method according to claim 16, wherein the composition is selected from the groups consisting of toothpaste; tooth gel; tooth powder; dental creme; liquid dentifrice; mouthwash; troche; chewing gum; gingival massage creme; gargle tablet and dental restorative. 18. A method of treating and/or preventing dental caries in tooth enamel comprising providing a composition to contact the tooth enamel, wherein the composition, prior to contacting the tooth enamel, comprises (i) about 0.01% to 50% by weight casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate, and, separately, (ii) free fluoride ions in an amount of from at least 400 ppm to about 3,000 ppm. 19. A method of increasing fluoride uptake into a dental surface or subsurface from an oral composition, the method comprising incorporating about 0.01% to 50% by weight casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate into the oral composition prior to treatment of the dental surface or subsurface, wherein the oral composition separately comprises free fluoride ions in an amount of from at least 400 ppm to about 3,000 ppm. 20. A method of mineralizing a dental surface or subsurface according to claim 16, wherein the composition further comprises a dentally acceptable polishing material and a surfactant prior to contacting the dental surface or subsurface, wherein the composition does not contain a calcium chelator or a phosphate buffer. 21. A method for manufacturing a composition for mineralizing a dental surface or subsurface comprising preparing a composition comprising (i) about 0.01% to 50% by weight casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate, and, separately, (ii) free fluoride ions in an amount of from at least 400 ppm to about 3,000 ppm. 22. A method according to claim 13, wherein the composition comprises free fluoride ions in a range of about 400 ppm to 1500 ppm. 23. A method according to claim 13, wherein the composition comprises about 900 ppm free fluoride. 24. A method according to claim 16, wherein the composition comprises free fluoride ions in a range of about 400 ppm to 1500 ppm. 25. A method according to claim 16, wherein the composition comprises about 900 ppm free fluoride. 26. A method according to claim 18, wherein the composition comprises free fluoride ions in a range of about 400 ppm to 1500 ppm. 27. A method according to claim 18, wherein the composition comprises about 900 ppm free fluoride. 28. A method according to claim 13, wherein the composition comprises about 1% to 10% by weight casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate. 29. A method according to claim 13, wherein the composition comprises about 20% casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate. 30. A method according to claim 13, wherein the composition comprises about 5% casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate. 31. A method according to claim 13, wherein the composition comprises about 3% casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate. 32. A method according to claim 16, wherein the composition comprises about 1% to 10% h weight casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate. 33. A method according to claim 16, wherein the composition comprises about 20% casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate. 34. A method according to claim 16, wherein the composition comprises about 5% casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate. 35. A method according to claim 16, wherein the composition comprises about 3% casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate. | The present invention relates to compositions and methods for mineralizing a dental surface or subsurface including providing a composition including stabilized ACP and a source of fluoride ions.1-12. (canceled) 13. A method of mineralizing a dental surface or subsurface comprising providing a composition to contact the dental surface or subsurface, wherein the composition, prior to contacting the dental surface or subsurface, comprises (i) about 0.01% to 50% by weight casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate, and, separately, (ii) free fluoride ions in an amount of from at least 400 ppm to about 3,000 ppm. 14. A method according to claim 13, wherein the composition is selected from the group consisting of toothpaste; tooth gel; tooth powder; dental creme; liquid dentifrice; mouthwash; troche; chewing gum; gingival massage creme; gargle tablet and dental restorative. 15. A method according to claim 13, wherein the composition comprises sodium fluoride. 16. A method for remineralizing a subsurface enamel lesion comprising providing a composition to contact the subsurface enamel lesion, wherein the composition, prior to contacting the subsurface enamel lesion, comprises (i) about 0.01% to 50% by weight casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate, and, separately, (ii) free fluoride ions in an amount of from at least 400 ppm to about 3,000 ppm. 17. A method according to claim 16, wherein the composition is selected from the groups consisting of toothpaste; tooth gel; tooth powder; dental creme; liquid dentifrice; mouthwash; troche; chewing gum; gingival massage creme; gargle tablet and dental restorative. 18. A method of treating and/or preventing dental caries in tooth enamel comprising providing a composition to contact the tooth enamel, wherein the composition, prior to contacting the tooth enamel, comprises (i) about 0.01% to 50% by weight casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate, and, separately, (ii) free fluoride ions in an amount of from at least 400 ppm to about 3,000 ppm. 19. A method of increasing fluoride uptake into a dental surface or subsurface from an oral composition, the method comprising incorporating about 0.01% to 50% by weight casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate into the oral composition prior to treatment of the dental surface or subsurface, wherein the oral composition separately comprises free fluoride ions in an amount of from at least 400 ppm to about 3,000 ppm. 20. A method of mineralizing a dental surface or subsurface according to claim 16, wherein the composition further comprises a dentally acceptable polishing material and a surfactant prior to contacting the dental surface or subsurface, wherein the composition does not contain a calcium chelator or a phosphate buffer. 21. A method for manufacturing a composition for mineralizing a dental surface or subsurface comprising preparing a composition comprising (i) about 0.01% to 50% by weight casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate, and, separately, (ii) free fluoride ions in an amount of from at least 400 ppm to about 3,000 ppm. 22. A method according to claim 13, wherein the composition comprises free fluoride ions in a range of about 400 ppm to 1500 ppm. 23. A method according to claim 13, wherein the composition comprises about 900 ppm free fluoride. 24. A method according to claim 16, wherein the composition comprises free fluoride ions in a range of about 400 ppm to 1500 ppm. 25. A method according to claim 16, wherein the composition comprises about 900 ppm free fluoride. 26. A method according to claim 18, wherein the composition comprises free fluoride ions in a range of about 400 ppm to 1500 ppm. 27. A method according to claim 18, wherein the composition comprises about 900 ppm free fluoride. 28. A method according to claim 13, wherein the composition comprises about 1% to 10% by weight casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate. 29. A method according to claim 13, wherein the composition comprises about 20% casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate. 30. A method according to claim 13, wherein the composition comprises about 5% casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate. 31. A method according to claim 13, wherein the composition comprises about 3% casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate. 32. A method according to claim 16, wherein the composition comprises about 1% to 10% h weight casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate. 33. A method according to claim 16, wherein the composition comprises about 20% casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate. 34. A method according to claim 16, wherein the composition comprises about 5% casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate. 35. A method according to claim 16, wherein the composition comprises about 3% casein phosphopeptide-stabilized amorphous calcium phosphate or casein phosphopeptide-stabilized amorphous calcium fluoride phosphate. | 1,600 |
1,134 | 14,124,429 | 1,619 | The invention relates to the use of, and methods of use employing, certain glycolipid compounds as defined in detail below and having preservative or antimicrobial properties, novel compounds of the glycolipid class, and related invention embodiments.
The compounds have the formula I
wherein m is 3 to 5, n is 2 to 5, o is 0 or 1 and p is 3 to 17, with the proviso that the sum m+n+o+p is not less than 14; and
R is a carbohydrate moiety bound via one of its carbon atoms to the binding oxygen,
and/or a physiologically, especially pharmaceutically or nutraceutically or cosmetically, acceptable salt thereof, or an ester thereof,
as such or in the form of a composition,
where the compound may be present in open chain form and/or in the form of a lactone (FIG. 1 ). | 1. Method of preservating a material or imparting antimicrobial properties to said material, said method comprising adding to said material an effective amount therefor of a compound of the formula I, or a mixture of two or more such compounds of the formula I,
wherein m is 3 to 5, n is 2 to 5, o is 0 or 1 and p is 3 to 17, with the proviso that the sum m+n+o+p is not less than 14; and
R is a carbohydrate moiety bound via one of its carbon atoms to the binding oxygen,
and/or a physiologically, especially pharmaceutically or nutraceutically or cosmetically, acceptable salt thereof, or an ester thereof,
where the compound may be present in open chain form and/or in the form of a lactone,
where said material is selected from the group consisting of a cosmetic, a food, a beverage, a pharmaceutical, a medical device, and an active packaging material. 2. Method according to claim 1, where the material to which the compound is added is a cosmetic, a food or a beverage. 3. Method according to claim 1, where in the compound of the formula I m is 3 to 5, n is 2 to 5, o is 0 or 1, p is 5 to 15 and R is a moiety of the subformula
wherein the rings A, B and C are monosaccharide moieties each independently from the others with 5 or 6 ring members, wherein one or more of the hydroxyl groups may be acylated. 4. Method according to claim 1, wherein the compound or mixture of compounds of the formula I comprises at least one compound selected from the group of compounds with the following formulae:
or a physiologically acceptable salt thereof. 5. Method according to claim 1, where at least one additional preservative is added. 6. Method according to claim 1, where the compound or compounds of the formula I, a physiologically acceptable salt thereof, and/or an ester thereof, is added in the form of an extract from a natural source or obtained from such an extract. 7. Method according to claim 6, where the source of the extract is Dacryopinax spathularia strain FU50088, Ditiola radicata strain MUCL 53180, Ditiola nuda strain CBS 173.60 or Femsjonia luteo-alba (=Ditiola pezizaeformis) strain MUCL 53500. 8. A compound or a mixture of compounds of the formula I:
wherein m is 3 to 5, n is 2 to 5, o is 0 or 1 and p is 3 to 17, with the proviso that the sum m+n+o+p is not less than 14; and
R is a carbohydrate moiety bound via one of its carbon atoms to the binding oxygen,
and/or a physiologically, especially pharmaceutically or nutraceutically or cosmetically, acceptable salt thereof, or an ester thereof,
where the moiety R carries at least one hydroxyl group esterified with an acid with 3 or more carbon atoms,
where the compound may be present in open chain form and/or in the form of a lactone, or a physiologically acceptable salt, and/or an ester thereof. 9. A compound of the formula I according to claim 8, which is selected from the group consisting of compounds represented in the following table:
and physiologically acceptable salts and esters thereof. 10. A preservative or antimicrobial composition, comprising as active agent a compound or a mixture of compounds of the formula I, a physiologically acceptable salt thereof, and/or an ester thereof, as shown or defined in claim 8, alone or with another additive, optionally a carrier material. 11. The composition according to claim 10, which is a precursor of a beverage. 12. An extract comprising one or more compounds of the formula I, a physiologically acceptable salt thereof, and/or an ester thereof, as shown or defined in claim 8. 13. A method of enhancing microbial stability of a material, comprising adding one or more compounds of the formula I, a physiologically acceptable salt thereof, and/or an ester thereof, as shown or defined in claim 8 to a material, selected from the group consisting of a cosmetic, a food, a beverage, a pharmaceutical, a medical device, and an active packaging material. 14. A material comprising, as or within a coating and/or as admixture, an additive in the form of a compound or a mixture of compounds of the formula I, a physiologically acceptable salt thereof and/or an ester thereof, as defined in claim 8, which material is a cosmetic, a food, a beverage, a pharmaceutical, a medical device, or an active packaging material. 15. The material according to claim 14, where the beverage is selected from the group consisting of water, flavoured water, fortified water, a flavoured beverage, carbonated water, a juice, cola, lemon-lime, ginger ale, root beer beverages which are carbonated in the manner of soft drinks, a syrup, a diet beverages, a carbonated soft drink, a fruit juice, other fruit containing beverages which provide the flavor of fruit juices and contain greater than 0% fruit juice but less than 100% fruit juice, fruit flavored beverages, vegetable juices, vegetable containing beverages, which provide the flavor of any of the aforementioned vegetable juices and contain greater than 0% vegetable juice but less than 100% vegetable juice, isotonic beverages, non-isotonic beverages, soft drinks containing a fruit juice, coffee, tea, tea beverages prepared from tea concentrate, extracts, or powders, drinkable dairy products, hot chocolate, chocolate powders/mixes, drinkable soy products, non-diary milks, alcoholic beverages, fruit smoothies, horchata, sport drinks, energy drinks, health drinks, wellness drinks, shakes, protein drinks, drinkable soy yogurts, low acid beverages, acidified beverages, nectars, tonics, frozen carbonated beverages, frozen uncarbonated beverages, liquid meal replacements, infant formulations, and combinations or mixtures thereof; or the material is a cosmetic selected from a cream, emulsion, lotion, gel or oil for the skin; a face masks, a tinted base, a make-up powder, an after-bath powder, a hygienic powder, a toilet soap, a deodorant soap, a perfumes, a toilet water, an eau de Cologne, a bath or shower preparation; a depilatory; a deodorant, an anti-perspirant, a hair care product; a setting product; a cleansing product; a conditioning product; a hairdressing product; a shaving products; a product for making up and removing make-up from the face and the eyes, a product intended for application to the lips, a products for care of the teeth and/or the mouth; a product for nail care and/or make-up, a product for external intimate hygiene, a sunbathing product, a product for tanning without sun, a skin-whitening product, an anti-wrinkle product, a tampon, a sanitary towel, a diaper and a handkerchief. 16. A material obtained by the method according to claim 1. | The invention relates to the use of, and methods of use employing, certain glycolipid compounds as defined in detail below and having preservative or antimicrobial properties, novel compounds of the glycolipid class, and related invention embodiments.
The compounds have the formula I
wherein m is 3 to 5, n is 2 to 5, o is 0 or 1 and p is 3 to 17, with the proviso that the sum m+n+o+p is not less than 14; and
R is a carbohydrate moiety bound via one of its carbon atoms to the binding oxygen,
and/or a physiologically, especially pharmaceutically or nutraceutically or cosmetically, acceptable salt thereof, or an ester thereof,
as such or in the form of a composition,
where the compound may be present in open chain form and/or in the form of a lactone (FIG. 1 ).1. Method of preservating a material or imparting antimicrobial properties to said material, said method comprising adding to said material an effective amount therefor of a compound of the formula I, or a mixture of two or more such compounds of the formula I,
wherein m is 3 to 5, n is 2 to 5, o is 0 or 1 and p is 3 to 17, with the proviso that the sum m+n+o+p is not less than 14; and
R is a carbohydrate moiety bound via one of its carbon atoms to the binding oxygen,
and/or a physiologically, especially pharmaceutically or nutraceutically or cosmetically, acceptable salt thereof, or an ester thereof,
where the compound may be present in open chain form and/or in the form of a lactone,
where said material is selected from the group consisting of a cosmetic, a food, a beverage, a pharmaceutical, a medical device, and an active packaging material. 2. Method according to claim 1, where the material to which the compound is added is a cosmetic, a food or a beverage. 3. Method according to claim 1, where in the compound of the formula I m is 3 to 5, n is 2 to 5, o is 0 or 1, p is 5 to 15 and R is a moiety of the subformula
wherein the rings A, B and C are monosaccharide moieties each independently from the others with 5 or 6 ring members, wherein one or more of the hydroxyl groups may be acylated. 4. Method according to claim 1, wherein the compound or mixture of compounds of the formula I comprises at least one compound selected from the group of compounds with the following formulae:
or a physiologically acceptable salt thereof. 5. Method according to claim 1, where at least one additional preservative is added. 6. Method according to claim 1, where the compound or compounds of the formula I, a physiologically acceptable salt thereof, and/or an ester thereof, is added in the form of an extract from a natural source or obtained from such an extract. 7. Method according to claim 6, where the source of the extract is Dacryopinax spathularia strain FU50088, Ditiola radicata strain MUCL 53180, Ditiola nuda strain CBS 173.60 or Femsjonia luteo-alba (=Ditiola pezizaeformis) strain MUCL 53500. 8. A compound or a mixture of compounds of the formula I:
wherein m is 3 to 5, n is 2 to 5, o is 0 or 1 and p is 3 to 17, with the proviso that the sum m+n+o+p is not less than 14; and
R is a carbohydrate moiety bound via one of its carbon atoms to the binding oxygen,
and/or a physiologically, especially pharmaceutically or nutraceutically or cosmetically, acceptable salt thereof, or an ester thereof,
where the moiety R carries at least one hydroxyl group esterified with an acid with 3 or more carbon atoms,
where the compound may be present in open chain form and/or in the form of a lactone, or a physiologically acceptable salt, and/or an ester thereof. 9. A compound of the formula I according to claim 8, which is selected from the group consisting of compounds represented in the following table:
and physiologically acceptable salts and esters thereof. 10. A preservative or antimicrobial composition, comprising as active agent a compound or a mixture of compounds of the formula I, a physiologically acceptable salt thereof, and/or an ester thereof, as shown or defined in claim 8, alone or with another additive, optionally a carrier material. 11. The composition according to claim 10, which is a precursor of a beverage. 12. An extract comprising one or more compounds of the formula I, a physiologically acceptable salt thereof, and/or an ester thereof, as shown or defined in claim 8. 13. A method of enhancing microbial stability of a material, comprising adding one or more compounds of the formula I, a physiologically acceptable salt thereof, and/or an ester thereof, as shown or defined in claim 8 to a material, selected from the group consisting of a cosmetic, a food, a beverage, a pharmaceutical, a medical device, and an active packaging material. 14. A material comprising, as or within a coating and/or as admixture, an additive in the form of a compound or a mixture of compounds of the formula I, a physiologically acceptable salt thereof and/or an ester thereof, as defined in claim 8, which material is a cosmetic, a food, a beverage, a pharmaceutical, a medical device, or an active packaging material. 15. The material according to claim 14, where the beverage is selected from the group consisting of water, flavoured water, fortified water, a flavoured beverage, carbonated water, a juice, cola, lemon-lime, ginger ale, root beer beverages which are carbonated in the manner of soft drinks, a syrup, a diet beverages, a carbonated soft drink, a fruit juice, other fruit containing beverages which provide the flavor of fruit juices and contain greater than 0% fruit juice but less than 100% fruit juice, fruit flavored beverages, vegetable juices, vegetable containing beverages, which provide the flavor of any of the aforementioned vegetable juices and contain greater than 0% vegetable juice but less than 100% vegetable juice, isotonic beverages, non-isotonic beverages, soft drinks containing a fruit juice, coffee, tea, tea beverages prepared from tea concentrate, extracts, or powders, drinkable dairy products, hot chocolate, chocolate powders/mixes, drinkable soy products, non-diary milks, alcoholic beverages, fruit smoothies, horchata, sport drinks, energy drinks, health drinks, wellness drinks, shakes, protein drinks, drinkable soy yogurts, low acid beverages, acidified beverages, nectars, tonics, frozen carbonated beverages, frozen uncarbonated beverages, liquid meal replacements, infant formulations, and combinations or mixtures thereof; or the material is a cosmetic selected from a cream, emulsion, lotion, gel or oil for the skin; a face masks, a tinted base, a make-up powder, an after-bath powder, a hygienic powder, a toilet soap, a deodorant soap, a perfumes, a toilet water, an eau de Cologne, a bath or shower preparation; a depilatory; a deodorant, an anti-perspirant, a hair care product; a setting product; a cleansing product; a conditioning product; a hairdressing product; a shaving products; a product for making up and removing make-up from the face and the eyes, a product intended for application to the lips, a products for care of the teeth and/or the mouth; a product for nail care and/or make-up, a product for external intimate hygiene, a sunbathing product, a product for tanning without sun, a skin-whitening product, an anti-wrinkle product, a tampon, a sanitary towel, a diaper and a handkerchief. 16. A material obtained by the method according to claim 1. | 1,600 |
1,135 | 15,306,163 | 1,633 | Disclosed are AAV viral-based vector compositions useful in delivering a variety of nucleic acid segments, including those encoding therapeutic polypeptides to selected mammalian host cells for use in therapeutic autoimmune modalities, including, for example, the in vivo induction of immunological tolerance via a liver-directed AAV-based gene therapeutic regimen for treating and/or ameliorating autoimmune disorders such as multiple sclerosis. | 1. A recombinant adeno-associated viral (rAAV) nucleic acid vector comprising:
a polynucleotide that includes a nucleic acid segment that encodes a first autoimmune disease therapeutic molecule operably linked to a promoter that is capable of expressing the nucleic acid segment in one or more cells of a mammalian liver. 2. The rAAV nucleic acid vector of claim 1, wherein the nucleic acid segment encodes a mammalian myelin basis protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG). 3. The rAAV nucleic acid vector of claim 1, wherein the nucleic acid segment encodes a human myelin basis protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG). 4. The rAAV nucleic acid vector of claim 2 or 3, wherein the nucleic acid segment encodes a biologically-active myelin basis protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG), that comprises an at least 20 amino acid contiguous sequence as set forth in SEQ ID NOs: 1, 2, 3, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, or 35. 5. The rAAV nucleic acid vector of claim 4, wherein the nucleic acid segment encodes a biologically-active myelin basis protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG), comprises an amino acid sequence that is at least 95% identical to the sequence of SEQ ID NOs: 1, 2, 3, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, or 35. 6. The rAAV nucleic acid vector of claim 2, wherein the nucleic acid segment encodes a biologically-active myelin basis protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG), that comprises an at least 20 amino acid contiguous sequence as set forth in SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3, respectively. 7. The rAAV nucleic acid vector of claim 6, wherein the nucleic acid segment encodes a biologically-active myelin basis protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG) that comprises an amino acid sequence that is at least 95% identical to the sequence of SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3. 8. The rAAV nucleic acid vector of any one of claims 1 to 7, wherein the nucleic acid segment further comprises an enhancer, a post-transcriptional regulatory sequence, a polyadenylation signal, or any combination thereof, operably linked to the nucleic acid segment encoding the therapeutic molecule. 9. The rAAV nucleic acid vector of any one of claims 1 to 8, wherein the promoter is a mammalian cell-specific or a mammalian tissue-specific promoter. 10. The rAAV nucleic acid vector of any one of claims 1 to 9, wherein the nucleic acid segment further encodes or further expresses a polypeptide, a peptide, a ribozyme, a peptide nucleic acid, an siRNA, an RNAi, an antisense oligonucleotide, an antisense polynucleotide, an antibody, an antigen binding fragment, or any combination thereof. 11. The rAAV nucleic acid vector of claim 10, wherein the nucleic acid segment further encodes a second distinct therapeutic molecule that is effective in treating or ameliorating one or more symptoms of autoimmune disease in the mammal. 12. The rAAV nucleic acid vector of claim 11, wherein the autoimmune disease is multiple sclerosis. 13. A rAAV particle comprising the rAAV nucleic acid vector of any one of claims 1 to 12. 13. A method for providing a mammal in need thereof with a therapeutically-effective amount of a selected therapeutic agent, the method comprising systemically administering to the mammal, an amount of the rAAV nucleic acid vector of any one of claims 1 to 12 or the rAAV particle of claim 13; and for a time effective to provide the mammal with a therapeutically-effective amount of the encoded therapeutic molecule. 14. A method for treating or ameliorating one or more symptoms of an inflammatory disease in a mammal, the method comprising: systemically administering to the mammal, the rAAV nucleic acid vector of any one of claims 1 to 12 or the rAAV particle of claim 13, in an amount and for a time sufficient to treat or ameliorate the one or more symptoms of autoimmune disease in the mammal. 15. The method of claim 14, wherein the mammal has, is suspected of having, is at risk for developing, or has been diagnosed with at least a first autoimmune disorder. 16. The method of claim 15, wherein the autoimmune disease is multiple sclerosis, disseminated sclerosis, or encephalomyelitis disseminata. 17. The method of claim 16, wherein the mammal is a newborn, an infant, a juvenile, or a young adult. 18. The method of any one of claims 14 to 17, wherein production of the therapeutic molecule in the mammal reduces CNS inflammation, inhibits demyelination, re-establishes immune tolerance to one or more neuroproteins, stimulates the production of endogenous antigen-specific regulatory T cells, or any combination thereof. 19. The method of any one of claims 14 to 18, wherein the rAAV vector encodes a second distinct therapeutic molecule selected from the group consisting of an agonist, an antagonist, an anti-apoptosis factor, an inhibitor, a receptor, a cytokine, a cytotoxin, an erythropoietic agent, a glycoprotein, a growth factor, a growth factor receptor, a hormone, a hormone receptor, an interferon, an interleukin, an interleukin receptor, a nerve growth factor, a neuroactive peptide, a neuroactive peptide receptor, a protease, a protease inhibitor, a protein decarboxylase, a protein kinase, a protein kinase inhibitor, an enzyme, a receptor binding protein, a transport protein or an inhibitor thereof, a serotonin receptor, or an uptake inhibitor thereof, a serpin, a serpin receptor, a tumor suppressor, a chemotherapeutic, or any combination thereof. | Disclosed are AAV viral-based vector compositions useful in delivering a variety of nucleic acid segments, including those encoding therapeutic polypeptides to selected mammalian host cells for use in therapeutic autoimmune modalities, including, for example, the in vivo induction of immunological tolerance via a liver-directed AAV-based gene therapeutic regimen for treating and/or ameliorating autoimmune disorders such as multiple sclerosis.1. A recombinant adeno-associated viral (rAAV) nucleic acid vector comprising:
a polynucleotide that includes a nucleic acid segment that encodes a first autoimmune disease therapeutic molecule operably linked to a promoter that is capable of expressing the nucleic acid segment in one or more cells of a mammalian liver. 2. The rAAV nucleic acid vector of claim 1, wherein the nucleic acid segment encodes a mammalian myelin basis protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG). 3. The rAAV nucleic acid vector of claim 1, wherein the nucleic acid segment encodes a human myelin basis protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG). 4. The rAAV nucleic acid vector of claim 2 or 3, wherein the nucleic acid segment encodes a biologically-active myelin basis protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG), that comprises an at least 20 amino acid contiguous sequence as set forth in SEQ ID NOs: 1, 2, 3, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, or 35. 5. The rAAV nucleic acid vector of claim 4, wherein the nucleic acid segment encodes a biologically-active myelin basis protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG), comprises an amino acid sequence that is at least 95% identical to the sequence of SEQ ID NOs: 1, 2, 3, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, or 35. 6. The rAAV nucleic acid vector of claim 2, wherein the nucleic acid segment encodes a biologically-active myelin basis protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG), that comprises an at least 20 amino acid contiguous sequence as set forth in SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3, respectively. 7. The rAAV nucleic acid vector of claim 6, wherein the nucleic acid segment encodes a biologically-active myelin basis protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG) that comprises an amino acid sequence that is at least 95% identical to the sequence of SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3. 8. The rAAV nucleic acid vector of any one of claims 1 to 7, wherein the nucleic acid segment further comprises an enhancer, a post-transcriptional regulatory sequence, a polyadenylation signal, or any combination thereof, operably linked to the nucleic acid segment encoding the therapeutic molecule. 9. The rAAV nucleic acid vector of any one of claims 1 to 8, wherein the promoter is a mammalian cell-specific or a mammalian tissue-specific promoter. 10. The rAAV nucleic acid vector of any one of claims 1 to 9, wherein the nucleic acid segment further encodes or further expresses a polypeptide, a peptide, a ribozyme, a peptide nucleic acid, an siRNA, an RNAi, an antisense oligonucleotide, an antisense polynucleotide, an antibody, an antigen binding fragment, or any combination thereof. 11. The rAAV nucleic acid vector of claim 10, wherein the nucleic acid segment further encodes a second distinct therapeutic molecule that is effective in treating or ameliorating one or more symptoms of autoimmune disease in the mammal. 12. The rAAV nucleic acid vector of claim 11, wherein the autoimmune disease is multiple sclerosis. 13. A rAAV particle comprising the rAAV nucleic acid vector of any one of claims 1 to 12. 13. A method for providing a mammal in need thereof with a therapeutically-effective amount of a selected therapeutic agent, the method comprising systemically administering to the mammal, an amount of the rAAV nucleic acid vector of any one of claims 1 to 12 or the rAAV particle of claim 13; and for a time effective to provide the mammal with a therapeutically-effective amount of the encoded therapeutic molecule. 14. A method for treating or ameliorating one or more symptoms of an inflammatory disease in a mammal, the method comprising: systemically administering to the mammal, the rAAV nucleic acid vector of any one of claims 1 to 12 or the rAAV particle of claim 13, in an amount and for a time sufficient to treat or ameliorate the one or more symptoms of autoimmune disease in the mammal. 15. The method of claim 14, wherein the mammal has, is suspected of having, is at risk for developing, or has been diagnosed with at least a first autoimmune disorder. 16. The method of claim 15, wherein the autoimmune disease is multiple sclerosis, disseminated sclerosis, or encephalomyelitis disseminata. 17. The method of claim 16, wherein the mammal is a newborn, an infant, a juvenile, or a young adult. 18. The method of any one of claims 14 to 17, wherein production of the therapeutic molecule in the mammal reduces CNS inflammation, inhibits demyelination, re-establishes immune tolerance to one or more neuroproteins, stimulates the production of endogenous antigen-specific regulatory T cells, or any combination thereof. 19. The method of any one of claims 14 to 18, wherein the rAAV vector encodes a second distinct therapeutic molecule selected from the group consisting of an agonist, an antagonist, an anti-apoptosis factor, an inhibitor, a receptor, a cytokine, a cytotoxin, an erythropoietic agent, a glycoprotein, a growth factor, a growth factor receptor, a hormone, a hormone receptor, an interferon, an interleukin, an interleukin receptor, a nerve growth factor, a neuroactive peptide, a neuroactive peptide receptor, a protease, a protease inhibitor, a protein decarboxylase, a protein kinase, a protein kinase inhibitor, an enzyme, a receptor binding protein, a transport protein or an inhibitor thereof, a serotonin receptor, or an uptake inhibitor thereof, a serpin, a serpin receptor, a tumor suppressor, a chemotherapeutic, or any combination thereof. | 1,600 |
1,136 | 16,322,571 | 1,627 | The present invention relates to a pharmaceutical composition comprising pomalidomide, maltodextrin and a filler, wherein the weight ratio of maltodextrin to filler ranges from 1:1 to 1:2. The invention further relates to the use of said pharmaceutical composition as medicament in the treatment of multiple myeloma. | 1. A pharmaceutical composition comprising pomalidomide, maltodextrin and a filler, wherein the weight ratio of maltodextrin to filler ranges from 1:1 to 1:2. 2. The composition according to claim 1, wherein the maltodextrin has a dextrose equivalent (DE) of 11 to 14. 3. The composition according to claim 1, wherein the filler is selected from microcrystalline cellulose and calcium lactate. 4. The composition according to claim 3, wherein the filler is microcrystalline cellulose. 5. The composition according to claim 1, wherein pomalidomide is present in an amount of more than 2% by weight based on the total weight of the composition. 6. The composition according to claim 1, wherein the pomalidomide has a particle size distribution D90 equal to or less than 15 μm. 7. The composition according to claim 1, further comprising a lubricant and optionally a disintegrant. 8. The composition according to claim 7, wherein the lubricant is sodium stearyl fumarate. 9. The composition according to claim 7, wherein the disintegrant is croscarmellose sodium. 10. The composition according to claim 1, which exhibits a dissolution rate of at least 65% in 15 minutes and at least 90% in 45 minutes when tested in aqueous hydrochloric acid 0.1 N in a USP apparatus II at 50-100 rpm, 37° C. 11. The composition according to claim 1, wherein the composition is in the form of a capsule. 12. A process to prepare the composition according to claim 11 comprising blending pomalidomide and excipients followed by encapsulation. 13. A method of treating multiple myeloma, which comprises administering the composition according to claim 1 to a patient in need thereof. 14. The composition according to claim 2, wherein the filler is selected from microcrystalline cellulose and calcium lactate. 15. The composition according to claim 14, further comprising a lubricant and optionally a disintegrant. 16. The composition according to claim 15, wherein the lubricant is sodium stearyl fumarate. 17. The composition according to claim 16, wherein said filler is microcrystalline cellulose. 18. The composition according to claim 15, wherein said filler is calcium lactate. 19. The composition according to claim 18, wherein said disintegrant is present and said disintegrant is croscarmellose sodium. 20. The composition according to claim 1, wherein said weight ratio of maltodextrin to filler is within the range of 1:1.2 to 1:1.5. | The present invention relates to a pharmaceutical composition comprising pomalidomide, maltodextrin and a filler, wherein the weight ratio of maltodextrin to filler ranges from 1:1 to 1:2. The invention further relates to the use of said pharmaceutical composition as medicament in the treatment of multiple myeloma.1. A pharmaceutical composition comprising pomalidomide, maltodextrin and a filler, wherein the weight ratio of maltodextrin to filler ranges from 1:1 to 1:2. 2. The composition according to claim 1, wherein the maltodextrin has a dextrose equivalent (DE) of 11 to 14. 3. The composition according to claim 1, wherein the filler is selected from microcrystalline cellulose and calcium lactate. 4. The composition according to claim 3, wherein the filler is microcrystalline cellulose. 5. The composition according to claim 1, wherein pomalidomide is present in an amount of more than 2% by weight based on the total weight of the composition. 6. The composition according to claim 1, wherein the pomalidomide has a particle size distribution D90 equal to or less than 15 μm. 7. The composition according to claim 1, further comprising a lubricant and optionally a disintegrant. 8. The composition according to claim 7, wherein the lubricant is sodium stearyl fumarate. 9. The composition according to claim 7, wherein the disintegrant is croscarmellose sodium. 10. The composition according to claim 1, which exhibits a dissolution rate of at least 65% in 15 minutes and at least 90% in 45 minutes when tested in aqueous hydrochloric acid 0.1 N in a USP apparatus II at 50-100 rpm, 37° C. 11. The composition according to claim 1, wherein the composition is in the form of a capsule. 12. A process to prepare the composition according to claim 11 comprising blending pomalidomide and excipients followed by encapsulation. 13. A method of treating multiple myeloma, which comprises administering the composition according to claim 1 to a patient in need thereof. 14. The composition according to claim 2, wherein the filler is selected from microcrystalline cellulose and calcium lactate. 15. The composition according to claim 14, further comprising a lubricant and optionally a disintegrant. 16. The composition according to claim 15, wherein the lubricant is sodium stearyl fumarate. 17. The composition according to claim 16, wherein said filler is microcrystalline cellulose. 18. The composition according to claim 15, wherein said filler is calcium lactate. 19. The composition according to claim 18, wherein said disintegrant is present and said disintegrant is croscarmellose sodium. 20. The composition according to claim 1, wherein said weight ratio of maltodextrin to filler is within the range of 1:1.2 to 1:1.5. | 1,600 |
1,137 | 15,758,828 | 1,616 | The present disclosure provides stable inoculant compositions and methods for enhancing the survival and/or stability of microorganisms in an inoculant composition. In some embodiments, the microorganisms in an inoculant compositions are stabilized by the presence of one or more maltodextrins having a dextrose equivalent value of about 15 to about 20. | 1. An aqueous inoculant composition comprising:
one or more maltodextrins having a dextrose equivalent value of about 15 to about 20; maltose; and one or more strains of Gram-negative bacteria, said one or more maltodextrins and said maltose comprising about 35 to about 65% of said inoculant composition (w/w, based upon the total weight of said inoculant composition). 2. The aqueous inoculant composition of claim 1, in which said one or more maltodextrins and said maltose are present in a maltodextrin:maltose ratio of about 15:85 to about 85:15. 3. The aqueous inoculant composition of claim 1, in which said one or more maltodextrins and said maltose are present in a maltodextrin:maltose ratio of about 35:65 to about 65:35. 4. The aqueous inoculant composition of claim 1, in which said one or more strains of Gram-negative bacteria is/are present in a concentration ranging from about 1×101 to about 1×1015 colony-forming units per gram of said inoculant composition. 5. The aqueous inoculant composition of claim 1, in which said one or more strains of Gram-negative bacteria is/are present in a concentration ranging from about 1×104 to about 1×1011 colony-forming units per gram of said inoculant composition. 6. The aqueous inoculant composition of claim 1, in which said one or more Gram-negative bacteria is/are present at a concentration of at least 1×107 colony-forming units per gram of said inoculant composition. 7. A method comprising drying the aqueous inoculant composition of claim 1 to produce a non-aqueous inoculant powder or granule. 8. The method of claim 7, in which said aqueous inoculant composition is spray-dried, freeze-dried or spray-freeze-dried to produce said non-aqueous inoculant powder or granule. 9. A method comprising applying the aqueous inoculation composition of claim 1 to a plant or plant part. 10. A method comprising applying the non-aqueous inoculant powder or granule of claim 7 to a plant or plant part. 11. A method comprising applying the aqueous inoculation composition of claim 1 to a plant growth medium. 12. A method comprising applying the non-aqueous inoculant powder or granule of claim 7 to a plant growth medium. 13. A coated plant seed, comprising:
a plant seed; and a coating that covers at least a portion of an outer surface of said plant seed, said coating comprising the aqueous inoculant composition of claim 1. 14. A coated plant seed, comprising:
a plant seed; and a coating that covers at least a portion of an outer surface of said plant seed, said coating comprising the non-aqueous inoculant powder or granule of claim 7. 15. A kit comprising a plurality of plant seeds that have been treated with the aqueous inoculant composition of claim 1. 16. A kit comprising a plurality of plant seeds that have been treated with the non-aqueous inoculant powder or granule of claim 7. | The present disclosure provides stable inoculant compositions and methods for enhancing the survival and/or stability of microorganisms in an inoculant composition. In some embodiments, the microorganisms in an inoculant compositions are stabilized by the presence of one or more maltodextrins having a dextrose equivalent value of about 15 to about 20.1. An aqueous inoculant composition comprising:
one or more maltodextrins having a dextrose equivalent value of about 15 to about 20; maltose; and one or more strains of Gram-negative bacteria, said one or more maltodextrins and said maltose comprising about 35 to about 65% of said inoculant composition (w/w, based upon the total weight of said inoculant composition). 2. The aqueous inoculant composition of claim 1, in which said one or more maltodextrins and said maltose are present in a maltodextrin:maltose ratio of about 15:85 to about 85:15. 3. The aqueous inoculant composition of claim 1, in which said one or more maltodextrins and said maltose are present in a maltodextrin:maltose ratio of about 35:65 to about 65:35. 4. The aqueous inoculant composition of claim 1, in which said one or more strains of Gram-negative bacteria is/are present in a concentration ranging from about 1×101 to about 1×1015 colony-forming units per gram of said inoculant composition. 5. The aqueous inoculant composition of claim 1, in which said one or more strains of Gram-negative bacteria is/are present in a concentration ranging from about 1×104 to about 1×1011 colony-forming units per gram of said inoculant composition. 6. The aqueous inoculant composition of claim 1, in which said one or more Gram-negative bacteria is/are present at a concentration of at least 1×107 colony-forming units per gram of said inoculant composition. 7. A method comprising drying the aqueous inoculant composition of claim 1 to produce a non-aqueous inoculant powder or granule. 8. The method of claim 7, in which said aqueous inoculant composition is spray-dried, freeze-dried or spray-freeze-dried to produce said non-aqueous inoculant powder or granule. 9. A method comprising applying the aqueous inoculation composition of claim 1 to a plant or plant part. 10. A method comprising applying the non-aqueous inoculant powder or granule of claim 7 to a plant or plant part. 11. A method comprising applying the aqueous inoculation composition of claim 1 to a plant growth medium. 12. A method comprising applying the non-aqueous inoculant powder or granule of claim 7 to a plant growth medium. 13. A coated plant seed, comprising:
a plant seed; and a coating that covers at least a portion of an outer surface of said plant seed, said coating comprising the aqueous inoculant composition of claim 1. 14. A coated plant seed, comprising:
a plant seed; and a coating that covers at least a portion of an outer surface of said plant seed, said coating comprising the non-aqueous inoculant powder or granule of claim 7. 15. A kit comprising a plurality of plant seeds that have been treated with the aqueous inoculant composition of claim 1. 16. A kit comprising a plurality of plant seeds that have been treated with the non-aqueous inoculant powder or granule of claim 7. | 1,600 |
1,138 | 13,391,590 | 1,619 | A composition comprising a pigment particle that is coated with Polyquaternium-67. The pigment particle can be included in a cleansing composition for deposition on a surface, such as skin. | 1. A composition comprising a pigment particle that is coated with Polyquaternium-67. 2. The composition of claim 1, wherein the particle is at least one material chosen from mica/titanium dioxide, mica/iron oxide, mica, titanium dioxide, zinc oxides, iron oxides, chromium oxides, silica, talc, and kaolin. 3. The composition of claim 1, wherein the particle is mica/titanium dioxide. 4. The composition of claim 1, wherein the pigment particle further comprises isopropyl titanium triisostearate. 5. The composition of claim 1 further comprising a surfactant. 6. The composition of claim 5, wherein the composition is a body wash. 7. The composition of claim 5 further comprising at least one material chosen from an oil and petrolatum. 8. A method of increasing gloss on a surface comprising, applying the composition of claim 1 to the surface. 9. The method of claim 8 further comprising rinsing the composition from the surface. 10. The method of claim 8, wherein the particle is at least one material chosen from mica/titanium dioxide, mica/iron oxide, mica, titanium dioxide, zinc oxides, iron oxides, chromium oxides silica, talc, and kaolin. 11. The method of claim 8, wherein the pigment particle is mica/titanium dioxide. 12. The method of claim 8, wherein the composition further comprises a surfactant. 13. The method of claim 12, wherein the composition further comprises at least one material chosen from an oil and petrolatum. 14. The method of claim 12, wherein the pigment particle is mica/titanium dioxide. | A composition comprising a pigment particle that is coated with Polyquaternium-67. The pigment particle can be included in a cleansing composition for deposition on a surface, such as skin.1. A composition comprising a pigment particle that is coated with Polyquaternium-67. 2. The composition of claim 1, wherein the particle is at least one material chosen from mica/titanium dioxide, mica/iron oxide, mica, titanium dioxide, zinc oxides, iron oxides, chromium oxides, silica, talc, and kaolin. 3. The composition of claim 1, wherein the particle is mica/titanium dioxide. 4. The composition of claim 1, wherein the pigment particle further comprises isopropyl titanium triisostearate. 5. The composition of claim 1 further comprising a surfactant. 6. The composition of claim 5, wherein the composition is a body wash. 7. The composition of claim 5 further comprising at least one material chosen from an oil and petrolatum. 8. A method of increasing gloss on a surface comprising, applying the composition of claim 1 to the surface. 9. The method of claim 8 further comprising rinsing the composition from the surface. 10. The method of claim 8, wherein the particle is at least one material chosen from mica/titanium dioxide, mica/iron oxide, mica, titanium dioxide, zinc oxides, iron oxides, chromium oxides silica, talc, and kaolin. 11. The method of claim 8, wherein the pigment particle is mica/titanium dioxide. 12. The method of claim 8, wherein the composition further comprises a surfactant. 13. The method of claim 12, wherein the composition further comprises at least one material chosen from an oil and petrolatum. 14. The method of claim 12, wherein the pigment particle is mica/titanium dioxide. | 1,600 |
1,139 | 16,284,800 | 1,616 | The present invention relates to the use of LCOs in initiating earlier flowering, increased number of buds and flower buds and earlier fruit development in non legume and legume plants, as compared to flowering and fruit development under conditions without use of LCOs, and the enhancement of plant growth and yield associated therewith; to compositions comprising an effective amount of at least one LCO and agriculturally acceptable carriers, associated with earlier flowering, increased bud and flower numbers and earlier initiation of fruit development as compared to conditions without use of LCOs, and with increased growth and plant; and to methods using LCOs and compositions of one or more LCOs and agriculturally acceptable carriers, associated with earlier flowering, increased bud and flower numbers and earlier fruit development in both legume and non-legume crop plants as compared to conditions without use of LCOs and associated enhancement of growth and yield. | 1. A composition comprising a lipo-chitooligosaccharide (LCO) in an amount effective to initiate early flowering of a non-leguminous plant when said composition is foliarly applied to said non-leguminous plant prior to flowering of said non-leguminous plant. 2. The composition of claim 1, wherein said LCO is present in an amount effective to initiate flowering of said non-leguminous plant at least two days prior to that of an untreated control plant. 3. The composition of claim 1, wherein said LCO is present in an amount effective to initiate flowering of said non-leguminous plant at least three days prior to that of an untreated control plant. 4. The composition of claim 1, wherein said LCO is present in an amount effective to initiate flowering of said non-leguminous plant at least four days prior to that of an untreated control plant. 5. The composition of claim 1, wherein said plant is of the family Solonaceae. 6. The composition of claim 1, wherein said plant is a tomato plant. 7. The composition of claim 1, wherein said plant is a pepper plant. 8. The composition of claim 1, wherein said plant is of the family Asteraceae, Malvaceae, or Cucurbitaceae. 9. The composition of claim 1, wherein said plant is of the family Poaceae. 10. The composition of claim 1, wherein said plant is a corn plant. 11. The composition of claim 1, wherein said plant is a strawberry plant. 12. A composition comprising a lipo-chitooligosaccharide (LCO) in an amount effective to initiate early fruiting of a non-leguminous plant when said composition is foliarly applied to said non-leguminous plant prior to fruiting of said non-leguminous plant. 13. The composition of claim 12, wherein said LCO is present in an amount effective to initiate fruiting of said non-leguminous plant at least ten days prior to that of an untreated control plant. 14. The composition of claim 1, wherein said plant is of the family Solonaceae. 15. The composition of claim 1, wherein said plant is a tomato plant. 16. The composition of claim 1, wherein said plant is a pepper plant. 17. The composition of claim 1, wherein said plant is of the family Asteraceae, Malvaceae, or Cucurbitaceae. 18. The composition of claim 1, wherein said plant is of the family Poaceae. 19. The composition of claim 1, wherein said plant is a corn plant. 20. The composition of claim 1, wherein said plant is a strawberry plant. | The present invention relates to the use of LCOs in initiating earlier flowering, increased number of buds and flower buds and earlier fruit development in non legume and legume plants, as compared to flowering and fruit development under conditions without use of LCOs, and the enhancement of plant growth and yield associated therewith; to compositions comprising an effective amount of at least one LCO and agriculturally acceptable carriers, associated with earlier flowering, increased bud and flower numbers and earlier initiation of fruit development as compared to conditions without use of LCOs, and with increased growth and plant; and to methods using LCOs and compositions of one or more LCOs and agriculturally acceptable carriers, associated with earlier flowering, increased bud and flower numbers and earlier fruit development in both legume and non-legume crop plants as compared to conditions without use of LCOs and associated enhancement of growth and yield.1. A composition comprising a lipo-chitooligosaccharide (LCO) in an amount effective to initiate early flowering of a non-leguminous plant when said composition is foliarly applied to said non-leguminous plant prior to flowering of said non-leguminous plant. 2. The composition of claim 1, wherein said LCO is present in an amount effective to initiate flowering of said non-leguminous plant at least two days prior to that of an untreated control plant. 3. The composition of claim 1, wherein said LCO is present in an amount effective to initiate flowering of said non-leguminous plant at least three days prior to that of an untreated control plant. 4. The composition of claim 1, wherein said LCO is present in an amount effective to initiate flowering of said non-leguminous plant at least four days prior to that of an untreated control plant. 5. The composition of claim 1, wherein said plant is of the family Solonaceae. 6. The composition of claim 1, wherein said plant is a tomato plant. 7. The composition of claim 1, wherein said plant is a pepper plant. 8. The composition of claim 1, wherein said plant is of the family Asteraceae, Malvaceae, or Cucurbitaceae. 9. The composition of claim 1, wherein said plant is of the family Poaceae. 10. The composition of claim 1, wherein said plant is a corn plant. 11. The composition of claim 1, wherein said plant is a strawberry plant. 12. A composition comprising a lipo-chitooligosaccharide (LCO) in an amount effective to initiate early fruiting of a non-leguminous plant when said composition is foliarly applied to said non-leguminous plant prior to fruiting of said non-leguminous plant. 13. The composition of claim 12, wherein said LCO is present in an amount effective to initiate fruiting of said non-leguminous plant at least ten days prior to that of an untreated control plant. 14. The composition of claim 1, wherein said plant is of the family Solonaceae. 15. The composition of claim 1, wherein said plant is a tomato plant. 16. The composition of claim 1, wherein said plant is a pepper plant. 17. The composition of claim 1, wherein said plant is of the family Asteraceae, Malvaceae, or Cucurbitaceae. 18. The composition of claim 1, wherein said plant is of the family Poaceae. 19. The composition of claim 1, wherein said plant is a corn plant. 20. The composition of claim 1, wherein said plant is a strawberry plant. | 1,600 |
1,140 | 13,805,578 | 1,637 | Gene-based diagnostics capable of rapidly discriminating selected strains of a selected pathogen from other populations within the same species are disclosed. Sequence-specific, real-time monitoring of LAMP of DNA may be accomplished through the use of oglionucleotide probes, referred to as “assimilating probes.” The assimilating probes include two oglionucleotide strands, one which includes a quencher (referred to as the quenching probe) and another which includes a fluorophore (referred to as the fluorescent probe). A fluorescent signal results when the two strands are displaced from one another during the LAMP reaction. By monitoring the emitted fluorescence, sequence specific amplification may be detected. | 1. A method of monitoring LOOP-mediated isothermal amplification (LAMP) of a target DNA, comprising:
contacting an assimilating probe and a DNA polymerase with a LAMP reaction mixture, wherein the LAMP reaction mixture comprises the target DNA and one or more LAMP primers that hybridize with the target DNA, wherein the assimilating probe comprises a first and second oligonucleotide strands, wherein the first oligonucleotide strand comprises a quencher probe at a 3′ end and wherein the second oligonucleotide strand of the assimilating probe comprises a fluorophore at a 5′ end; wherein the ratio of the amount of the second oligonucleotide strand to the amount of the first oligonucleotide strand is less than 1:1; and measuring fluorescence emitted by the LAMP reaction mixture that has been contacted with the assimilating probe and the DNA polymerase. 2. The method of claim 1, wherein the quencher comprises DABCYL, TAMRA, or a Black Hole Quencher. 3. The method of claim 1, wherein the fluorophore comprises fluorescein, cy3, cy5, or one or more quantum dots. 4. The method of claim 1, wherein the first oligonucleotide strand and the second oligonucleotide strand are not hybridized with each other. 5. The method of claim 1, wherein the concentration of the DNA polymerase is greater than or equal to 8 U. 6. The method of claim 1, wherein the amount of the first oligonucleotide strand is within the range between 0.02 to 0.8 μM. 7. The method of claim 1, wherein the amount of the second oligonucleotide strand is within the range between 0.01 μM to 0.4 μM. 8. (canceled) 9. The method of claim 1, wherein the target DNA comprises DNA from bacteriophage lambda, race 3 biovar 2 strains of Ralstonia solanacearum, Ralstonia solanacearum, Salmonella enterica, or Staphylococcus aureus. 10. An assimilating probe for monitoring LOOP-mediated isothermal amplification (LAMP) of a target DNA comprising:
a first oligonucleotide strand comprising a quencher probe at a 3′ end of the first oligonucleotide strand; and a second oligonucleotide strand comprising a fluorophore at a 5′ end of the second oligonucleotide strand; wherein the ratio of the amount of the second oligonucleotide strand to the first oligonucleotide strand is less than 1:1. 11. The probe of claim 10, wherein the fluorophore comprises fluorescein, cy3, cy5, or one or more quantum dots. 12. The probe of claim 10, wherein the quencher comprises DABCYL, TAMRA, or a Black Hole Quencher. 13. The probe of claim 10, wherein the first oligonucleotide strand and the second oligonucleotide strand are not hybridized with each other. 14. The probe of claim 10, wherein the amount of the first oligonucleotide strand is within the range between 0.02 to 0.8 μM. 15. The probe of claim 10, wherein the amount of the second oligonucleotide strand is within the range between 0.01 μM to 0.4 μM. 16. The probe of claim 10, wherein the second oligonucleotide strand comprises an overhanging unmatched segment that is not complementary to the first oligonucleotide strand. 17. The method of claim 1, wherein the assimilating probe is contacted with the LAMP reaction mixture before the DNA polymerase is contacted with the LAMP reaction mixture. 18. The method of claim 1, wherein the DNA polymerase is contacted with a LAMP reaction mixture comprising an assimilating probe. 19. A method of detecting the presence or absence of a target DNA
contacting an assimilating probe and a DNA polymerase with a LAMP reaction mixture, wherein the LAMP reaction mixture comprises a sample to be tested for the presence of a target DNA and one or more LAMP primers capable of amplifying the target DNA, wherein the assimilating probe comprises a first and second oligonucleotide strands, wherein the first oligonucleotide strand comprises a quencher probe at a 3′ end and wherein the second oligonucleotide strand of the assimilating probe comprises a fluorophore at a 5′ end; wherein the ratio of the amount of the second oligonucleotide strand to the amount of the first oligonucleotide strand is less than 1:1; and detecting the presence or absence of the target DNA. 20. The method of claim 19, wherein detecting comprises measuring fluorescence emitted by the LAMP reaction mixture that has been contacted with the assimilating probe and the DNA polymerase. 21. The method of claim 19 comprises:
simultaneously detecting the presence or absence of different target DNAs,
wherein the one or more LAMP primers capable of amplifying the target DNA are capable of amplifying different target DNAs,
wherein multiple assimilating probes are contacted with the LAMP reaction mixture. | Gene-based diagnostics capable of rapidly discriminating selected strains of a selected pathogen from other populations within the same species are disclosed. Sequence-specific, real-time monitoring of LAMP of DNA may be accomplished through the use of oglionucleotide probes, referred to as “assimilating probes.” The assimilating probes include two oglionucleotide strands, one which includes a quencher (referred to as the quenching probe) and another which includes a fluorophore (referred to as the fluorescent probe). A fluorescent signal results when the two strands are displaced from one another during the LAMP reaction. By monitoring the emitted fluorescence, sequence specific amplification may be detected.1. A method of monitoring LOOP-mediated isothermal amplification (LAMP) of a target DNA, comprising:
contacting an assimilating probe and a DNA polymerase with a LAMP reaction mixture, wherein the LAMP reaction mixture comprises the target DNA and one or more LAMP primers that hybridize with the target DNA, wherein the assimilating probe comprises a first and second oligonucleotide strands, wherein the first oligonucleotide strand comprises a quencher probe at a 3′ end and wherein the second oligonucleotide strand of the assimilating probe comprises a fluorophore at a 5′ end; wherein the ratio of the amount of the second oligonucleotide strand to the amount of the first oligonucleotide strand is less than 1:1; and measuring fluorescence emitted by the LAMP reaction mixture that has been contacted with the assimilating probe and the DNA polymerase. 2. The method of claim 1, wherein the quencher comprises DABCYL, TAMRA, or a Black Hole Quencher. 3. The method of claim 1, wherein the fluorophore comprises fluorescein, cy3, cy5, or one or more quantum dots. 4. The method of claim 1, wherein the first oligonucleotide strand and the second oligonucleotide strand are not hybridized with each other. 5. The method of claim 1, wherein the concentration of the DNA polymerase is greater than or equal to 8 U. 6. The method of claim 1, wherein the amount of the first oligonucleotide strand is within the range between 0.02 to 0.8 μM. 7. The method of claim 1, wherein the amount of the second oligonucleotide strand is within the range between 0.01 μM to 0.4 μM. 8. (canceled) 9. The method of claim 1, wherein the target DNA comprises DNA from bacteriophage lambda, race 3 biovar 2 strains of Ralstonia solanacearum, Ralstonia solanacearum, Salmonella enterica, or Staphylococcus aureus. 10. An assimilating probe for monitoring LOOP-mediated isothermal amplification (LAMP) of a target DNA comprising:
a first oligonucleotide strand comprising a quencher probe at a 3′ end of the first oligonucleotide strand; and a second oligonucleotide strand comprising a fluorophore at a 5′ end of the second oligonucleotide strand; wherein the ratio of the amount of the second oligonucleotide strand to the first oligonucleotide strand is less than 1:1. 11. The probe of claim 10, wherein the fluorophore comprises fluorescein, cy3, cy5, or one or more quantum dots. 12. The probe of claim 10, wherein the quencher comprises DABCYL, TAMRA, or a Black Hole Quencher. 13. The probe of claim 10, wherein the first oligonucleotide strand and the second oligonucleotide strand are not hybridized with each other. 14. The probe of claim 10, wherein the amount of the first oligonucleotide strand is within the range between 0.02 to 0.8 μM. 15. The probe of claim 10, wherein the amount of the second oligonucleotide strand is within the range between 0.01 μM to 0.4 μM. 16. The probe of claim 10, wherein the second oligonucleotide strand comprises an overhanging unmatched segment that is not complementary to the first oligonucleotide strand. 17. The method of claim 1, wherein the assimilating probe is contacted with the LAMP reaction mixture before the DNA polymerase is contacted with the LAMP reaction mixture. 18. The method of claim 1, wherein the DNA polymerase is contacted with a LAMP reaction mixture comprising an assimilating probe. 19. A method of detecting the presence or absence of a target DNA
contacting an assimilating probe and a DNA polymerase with a LAMP reaction mixture, wherein the LAMP reaction mixture comprises a sample to be tested for the presence of a target DNA and one or more LAMP primers capable of amplifying the target DNA, wherein the assimilating probe comprises a first and second oligonucleotide strands, wherein the first oligonucleotide strand comprises a quencher probe at a 3′ end and wherein the second oligonucleotide strand of the assimilating probe comprises a fluorophore at a 5′ end; wherein the ratio of the amount of the second oligonucleotide strand to the amount of the first oligonucleotide strand is less than 1:1; and detecting the presence or absence of the target DNA. 20. The method of claim 19, wherein detecting comprises measuring fluorescence emitted by the LAMP reaction mixture that has been contacted with the assimilating probe and the DNA polymerase. 21. The method of claim 19 comprises:
simultaneously detecting the presence or absence of different target DNAs,
wherein the one or more LAMP primers capable of amplifying the target DNA are capable of amplifying different target DNAs,
wherein multiple assimilating probes are contacted with the LAMP reaction mixture. | 1,600 |
1,141 | 15,833,127 | 1,617 | The present disclosure provides lubricant compositions suitable for use on human tissue and effective to provide multiple sensations sequentially and/or in varying intensities. The lubricants can include a lubricating base and at least two different sensorial agents effective to impart different sensations, such as warming, cooling, tingling, refreshing, and numbing. The lubricants particularly can be suitable for use in sexual experiences so that the imparted sensations can increase and/or improve such experiences. The present disclosure further provides condoms incorporating such lubricant compositions. | 1. A lubricant comprising:
a lubricating base; a first sensorial agent effective to impart a first sensation to contacted human tissue; and a second sensorial agent effective to impart a second sensation to the contacted human tissue, the second sensation being different from the first sensation; wherein onset of the first sensation and onset of the second sensation are sequential and are temporally separated. 2. The lubricant of claim 1, further comprising a third sensorial agent effective to impart a third sensation to the contacted human tissue, the third sensation being different from the first sensation and the second sensation, wherein onset of the third sensation and onset of the second sensation are sequential and temporally separated. 3. The lubricant of claim 1, wherein intensity of one or both of the first sensation and the second sensation varies over the time of contact with the human tissue. 4. The lubricant of claim 3, wherein intensity of one or both of the first sensation and the second sensation gradually increases to a maximum intensity and then gradually decreases. 5. The lubricant of claim 1, wherein the onset of the first sensation and onset of the second sensation are temporally separated by a time of about 5 seconds or greater. 6. The lubricant of claim 5, wherein the onset of the first sensation and onset of the second sensation are temporally separated by a time of about 5 seconds to about 5 minutes. 7. The lubricant of claim 2, wherein the onset of the second sensation and the onset of the third sensation are temporally separated by a time of about 5 seconds or greater. 8. The lubricant of claim 2, wherein the onset of the second sensation and onset of the third sensation are temporally separated by a time of about 5 seconds to about 5 minutes. 9. The lubricant of claim 1, wherein the first sensation and the second sensation are each independently imparted for a duration of about 30 seconds to about 15 minutes. 10. The lubricant of claim 2, wherein the third sensation is independently imparted for a duration of about 30 seconds to about 15 minutes. 11. The lubricant of claim 1, wherein the first sensation substantially ceases before the onset of the second sensation. 12. The lubricant of claim 2, wherein the second sensation substantially ceases before the onset of the third sensation. 13. The lubricant of claim 1, wherein the imparting of the first sensation overlaps with the imparting of the second sensation by a time of no more than 3 minutes. 14. The lubricant of claim 2, wherein the imparting of the second sensation overlaps with the imparting of the third sensation by a time of no more than 3 minutes. 15. The lubricant of claim 1, wherein the first sensation and the second sensation are independently selected from the group consisting of warming, cooling, tingling, numbing, and refreshing. 16. The lubricant of claim 2, wherein the third sensation is selected from the group consisting of warming, cooling, tingling, numbing, and refreshing. 17. The lubricant of claim 1, wherein one of the first sensorial agent and the second sensorial agent is a warming sensorial agent, and the other of the first sensorial agent and the second sensorial agent is a cooling sensorial agent. 18. The lubricant of claim 2, wherein one of the first sensorial agent, the second sensorial agent, and the third sensorial agent is a warming sensorial agent, and another of the first sensorial agent, the second sensorial agent, and the third sensorial agent is a cooling sensorial agent, and the remaining of the first sensorial agent, the second sensorial agent, and the third sensorial agent is a tingling sensorial agent. 19. The lubricant of claim 1, wherein the onset of the first sensation occurs within 30 seconds of initial contact to the human skin, and the onset of the second sensation is delayed for at least 1 minute after initial contact to the human skin. 20. A method of providing lubrication and varying sensations to human tissue, the method comprising applying a lubricant to the human tissue, wherein the lubricant comprises:
a lubricating base; a first sensorial agent effective to impart a first sensation to contacted human tissue; and a second sensorial agent effective to impart a second sensation to the contacted human tissue, the second sensation being different from the first sensation; wherein onset of the first sensation and onset of the second sensation are sequential and are temporally separated. 21. A packaged condom comprising:
a male genital engaging tubular sheath having an inner surface and an outer surface; and a lubricant applied to at least a portion of one or both of the inner surface and the outer surface of the tubular sheath, the lubricant comprising:
a lubricating base;
a first sensorial agent effective to impart a first sensation to contacted human tissue; and
a second sensorial agent effective to impart a second sensation to the contacted human tissue, the second sensation being different from the first sensation;
wherein onset of the first sensation and onset of the second sensation are sequential and are temporally separated. | The present disclosure provides lubricant compositions suitable for use on human tissue and effective to provide multiple sensations sequentially and/or in varying intensities. The lubricants can include a lubricating base and at least two different sensorial agents effective to impart different sensations, such as warming, cooling, tingling, refreshing, and numbing. The lubricants particularly can be suitable for use in sexual experiences so that the imparted sensations can increase and/or improve such experiences. The present disclosure further provides condoms incorporating such lubricant compositions.1. A lubricant comprising:
a lubricating base; a first sensorial agent effective to impart a first sensation to contacted human tissue; and a second sensorial agent effective to impart a second sensation to the contacted human tissue, the second sensation being different from the first sensation; wherein onset of the first sensation and onset of the second sensation are sequential and are temporally separated. 2. The lubricant of claim 1, further comprising a third sensorial agent effective to impart a third sensation to the contacted human tissue, the third sensation being different from the first sensation and the second sensation, wherein onset of the third sensation and onset of the second sensation are sequential and temporally separated. 3. The lubricant of claim 1, wherein intensity of one or both of the first sensation and the second sensation varies over the time of contact with the human tissue. 4. The lubricant of claim 3, wherein intensity of one or both of the first sensation and the second sensation gradually increases to a maximum intensity and then gradually decreases. 5. The lubricant of claim 1, wherein the onset of the first sensation and onset of the second sensation are temporally separated by a time of about 5 seconds or greater. 6. The lubricant of claim 5, wherein the onset of the first sensation and onset of the second sensation are temporally separated by a time of about 5 seconds to about 5 minutes. 7. The lubricant of claim 2, wherein the onset of the second sensation and the onset of the third sensation are temporally separated by a time of about 5 seconds or greater. 8. The lubricant of claim 2, wherein the onset of the second sensation and onset of the third sensation are temporally separated by a time of about 5 seconds to about 5 minutes. 9. The lubricant of claim 1, wherein the first sensation and the second sensation are each independently imparted for a duration of about 30 seconds to about 15 minutes. 10. The lubricant of claim 2, wherein the third sensation is independently imparted for a duration of about 30 seconds to about 15 minutes. 11. The lubricant of claim 1, wherein the first sensation substantially ceases before the onset of the second sensation. 12. The lubricant of claim 2, wherein the second sensation substantially ceases before the onset of the third sensation. 13. The lubricant of claim 1, wherein the imparting of the first sensation overlaps with the imparting of the second sensation by a time of no more than 3 minutes. 14. The lubricant of claim 2, wherein the imparting of the second sensation overlaps with the imparting of the third sensation by a time of no more than 3 minutes. 15. The lubricant of claim 1, wherein the first sensation and the second sensation are independently selected from the group consisting of warming, cooling, tingling, numbing, and refreshing. 16. The lubricant of claim 2, wherein the third sensation is selected from the group consisting of warming, cooling, tingling, numbing, and refreshing. 17. The lubricant of claim 1, wherein one of the first sensorial agent and the second sensorial agent is a warming sensorial agent, and the other of the first sensorial agent and the second sensorial agent is a cooling sensorial agent. 18. The lubricant of claim 2, wherein one of the first sensorial agent, the second sensorial agent, and the third sensorial agent is a warming sensorial agent, and another of the first sensorial agent, the second sensorial agent, and the third sensorial agent is a cooling sensorial agent, and the remaining of the first sensorial agent, the second sensorial agent, and the third sensorial agent is a tingling sensorial agent. 19. The lubricant of claim 1, wherein the onset of the first sensation occurs within 30 seconds of initial contact to the human skin, and the onset of the second sensation is delayed for at least 1 minute after initial contact to the human skin. 20. A method of providing lubrication and varying sensations to human tissue, the method comprising applying a lubricant to the human tissue, wherein the lubricant comprises:
a lubricating base; a first sensorial agent effective to impart a first sensation to contacted human tissue; and a second sensorial agent effective to impart a second sensation to the contacted human tissue, the second sensation being different from the first sensation; wherein onset of the first sensation and onset of the second sensation are sequential and are temporally separated. 21. A packaged condom comprising:
a male genital engaging tubular sheath having an inner surface and an outer surface; and a lubricant applied to at least a portion of one or both of the inner surface and the outer surface of the tubular sheath, the lubricant comprising:
a lubricating base;
a first sensorial agent effective to impart a first sensation to contacted human tissue; and
a second sensorial agent effective to impart a second sensation to the contacted human tissue, the second sensation being different from the first sensation;
wherein onset of the first sensation and onset of the second sensation are sequential and are temporally separated. | 1,600 |
1,142 | 14,888,259 | 1,615 | The invention relates to an antiseptic material, in particular as a wound dressing, containing a carrier material and at least one antiseptic together with a surfactant, wherein the carrier material is equipped with a cyclodextrin or cyclodextrin derivative that is loaded in the antiseptic or antiseptics. | 1. Antiseptic material, especially wound dressing, containing a carrier material and at least one antiseptic together with a surfactant, wherein the carrier material is finished with a cyclodextrin or cyclodextrin derivative, which is loaded with the antiseptic. 2. Antiseptic material according to claim 1, wherein the carrier material is a polymeric foam, especially a porous polyurethane foam. 3. Antiseptic material according to claim 1, wherein the carrier material is a textile carrier material, especially a polyester or cotton. 4. Antiseptic material according to claim 1, wherein the carrier material is finished with a β-cyclodextrin or a β-cyclodextrin derivative. 5. Antiseptic material according to claim 1, wherein the cyclodextrin or cyclodextrin derivative is bound to the carrier material via an anchor group chemically and/or mechanically and/or by physical interactions. 6. Antiseptic material according to claim 1, wherein the cyclodextrin or cyclodextrin derivative is bound chemically to a polysaccharide, a polyvinylamine or a polyethylenimine, which for its part is bound to the carrier material via physical interactions. 7. Antiseptic material according to claim 1, comprising a content of 1 to 5 wt % of cyclodextrin or cyclodextrin derivative, relative to the weight of the carrier material. 8. Antiseptic material according to claim 1, wherein the antiseptic is one from the group of polyamines or biguanides. 9. Antiseptic material according to claim 8, wherein the cyclodextrin or cyclodextrin derivative is loaded with chlorhexidine or polyhexanide. 10. Antiseptic material according to claim 1, wherein the molecular ratio of cyclodextrin or cyclodextrin derivative to antiseptic lies in the range of 0.1 to 1.0. 11. Antiseptic material according to claim 1, wherein it contains a betaine. 12. Antiseptic material according to claim 11, wherein the betaine is undecylenic amidopropyl betaine or trimethylammonium acetate. 13. Antiseptic material according to claim 11, wherein it contains antiseptic and betaine in approximately equimolar amounts. 14. Antiseptic material according to claim 1 as wound dressing or plaster. 15. Antiseptic material according to claim 1 as everyday textile for the health care. 16. Antiseptic material according to claim 1 as an antimicrobial functional patch for the cosmetics. 17. Antiseptic material according to claim 1 as protective garments finished with biocide. 18. Use of a polyvinylamine-β-cyclodextrin with polyhexanide loading in aqueous solution together with a betaine for the preparation of antiseptically finished materials. | The invention relates to an antiseptic material, in particular as a wound dressing, containing a carrier material and at least one antiseptic together with a surfactant, wherein the carrier material is equipped with a cyclodextrin or cyclodextrin derivative that is loaded in the antiseptic or antiseptics.1. Antiseptic material, especially wound dressing, containing a carrier material and at least one antiseptic together with a surfactant, wherein the carrier material is finished with a cyclodextrin or cyclodextrin derivative, which is loaded with the antiseptic. 2. Antiseptic material according to claim 1, wherein the carrier material is a polymeric foam, especially a porous polyurethane foam. 3. Antiseptic material according to claim 1, wherein the carrier material is a textile carrier material, especially a polyester or cotton. 4. Antiseptic material according to claim 1, wherein the carrier material is finished with a β-cyclodextrin or a β-cyclodextrin derivative. 5. Antiseptic material according to claim 1, wherein the cyclodextrin or cyclodextrin derivative is bound to the carrier material via an anchor group chemically and/or mechanically and/or by physical interactions. 6. Antiseptic material according to claim 1, wherein the cyclodextrin or cyclodextrin derivative is bound chemically to a polysaccharide, a polyvinylamine or a polyethylenimine, which for its part is bound to the carrier material via physical interactions. 7. Antiseptic material according to claim 1, comprising a content of 1 to 5 wt % of cyclodextrin or cyclodextrin derivative, relative to the weight of the carrier material. 8. Antiseptic material according to claim 1, wherein the antiseptic is one from the group of polyamines or biguanides. 9. Antiseptic material according to claim 8, wherein the cyclodextrin or cyclodextrin derivative is loaded with chlorhexidine or polyhexanide. 10. Antiseptic material according to claim 1, wherein the molecular ratio of cyclodextrin or cyclodextrin derivative to antiseptic lies in the range of 0.1 to 1.0. 11. Antiseptic material according to claim 1, wherein it contains a betaine. 12. Antiseptic material according to claim 11, wherein the betaine is undecylenic amidopropyl betaine or trimethylammonium acetate. 13. Antiseptic material according to claim 11, wherein it contains antiseptic and betaine in approximately equimolar amounts. 14. Antiseptic material according to claim 1 as wound dressing or plaster. 15. Antiseptic material according to claim 1 as everyday textile for the health care. 16. Antiseptic material according to claim 1 as an antimicrobial functional patch for the cosmetics. 17. Antiseptic material according to claim 1 as protective garments finished with biocide. 18. Use of a polyvinylamine-β-cyclodextrin with polyhexanide loading in aqueous solution together with a betaine for the preparation of antiseptically finished materials. | 1,600 |
1,143 | 16,859,490 | 1,645 | Methods for generating immune responses using adenovirus vectors that allow multiple vaccinations with the same adenovirus vector and vaccinations in individuals with preexisting immunity to adenovirus are provided. | 1.-36. (canceled) 37. A composition comprising:
a replication defective adenovirus vector comprising:
(a) a deletion in the E2b region; and
(b) a nucleic acid sequence encoding an antigen, wherein the antigen is a viral protein, and wherein the virus is a single stranded RNA virus. 38. The composition of claim 37, wherein the replication defective adenovirus vector further comprises a deletion in the E1 region. 39. The composition of claim 37, wherein the nucleic acid sequence encoding the antigen is located in the E1 region. 40. The composition of claim 37, wherein the replication defective adenovirus vector further comprises a deletion in the E3 region. 41. The composition of claim 37, wherein the nucleic acid sequence encoding the antigen is located in the E3 region. 42. The composition of claim 37, wherein the replication defective adenovirus vector is derived from Adenovirus serotype 5. 43. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 1010 virus particles/ml. 44. The composition of claim 37, wherein the replication defective adenovirus vector is not helper-adenovirus dependent. 45. The composition of claim 37, wherein the virus is a human coronavirus. 46. The composition of claim 45, wherein the virus is a severe acute respiratory syndrome (SARS) coronavirus. 47. The composition of claim 46, wherein the antigen is SARS coat protein. 48. The composition of claim 37, further comprising an adjuvant. 49. The composition of claim 48, wherein the adjuvant is granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF), interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin-2 (IL-2), IL-7, IL-12, IL-4, IL-5, IL-6, IL-10, IL-12, or a combination thereof. 50. The composition of claim 37, wherein the composition is formulated for intramuscular, subcutaneous, or intradermal administration. 51. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 109 virus particles/ml. 52. The composition of claim 37, wherein the antigen has been modified to increase immunogenicity. 53. A cell comprising the composition of claim 37. 54. The cell of claim 53, wherein the cell constitutively expresses DNA polymerase and preterminal protein. 55. The cell of claim 54, wherein the cell is an antigen-presenting cell. 56. The composition of claim 37, further comprising a second replication defective adenovirus vector comprising a deletion in the E2b region and a nucleic acid sequence encoding an adjuvant. | Methods for generating immune responses using adenovirus vectors that allow multiple vaccinations with the same adenovirus vector and vaccinations in individuals with preexisting immunity to adenovirus are provided.1.-36. (canceled) 37. A composition comprising:
a replication defective adenovirus vector comprising:
(a) a deletion in the E2b region; and
(b) a nucleic acid sequence encoding an antigen, wherein the antigen is a viral protein, and wherein the virus is a single stranded RNA virus. 38. The composition of claim 37, wherein the replication defective adenovirus vector further comprises a deletion in the E1 region. 39. The composition of claim 37, wherein the nucleic acid sequence encoding the antigen is located in the E1 region. 40. The composition of claim 37, wherein the replication defective adenovirus vector further comprises a deletion in the E3 region. 41. The composition of claim 37, wherein the nucleic acid sequence encoding the antigen is located in the E3 region. 42. The composition of claim 37, wherein the replication defective adenovirus vector is derived from Adenovirus serotype 5. 43. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 1010 virus particles/ml. 44. The composition of claim 37, wherein the replication defective adenovirus vector is not helper-adenovirus dependent. 45. The composition of claim 37, wherein the virus is a human coronavirus. 46. The composition of claim 45, wherein the virus is a severe acute respiratory syndrome (SARS) coronavirus. 47. The composition of claim 46, wherein the antigen is SARS coat protein. 48. The composition of claim 37, further comprising an adjuvant. 49. The composition of claim 48, wherein the adjuvant is granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF), interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin-2 (IL-2), IL-7, IL-12, IL-4, IL-5, IL-6, IL-10, IL-12, or a combination thereof. 50. The composition of claim 37, wherein the composition is formulated for intramuscular, subcutaneous, or intradermal administration. 51. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 109 virus particles/ml. 52. The composition of claim 37, wherein the antigen has been modified to increase immunogenicity. 53. A cell comprising the composition of claim 37. 54. The cell of claim 53, wherein the cell constitutively expresses DNA polymerase and preterminal protein. 55. The cell of claim 54, wherein the cell is an antigen-presenting cell. 56. The composition of claim 37, further comprising a second replication defective adenovirus vector comprising a deletion in the E2b region and a nucleic acid sequence encoding an adjuvant. | 1,600 |
1,144 | 15,265,709 | 1,645 | Methods for generating immune responses using adenovirus vectors that allow multiple vaccinations with the same adenovirus vector and vaccinations in individuals with preexisting immunity to adenovirus are provided. | 1-36. (canceled) 37. A composition comprising a replication defective adenovirus vector comprising:
a deletion in the E2b region; and a nucleic acid sequence encoding Her2/neu. 38. The composition of claim 37, further comprising a replication defective adenovirus vector comprising a nucleic acid sequence encoding a tumor protein, a viral coat protein, a bacterial surface protein, or a combination thereof. 39. The composition of claim 37, wherein the replication defective adenovirus vector further comprises a deletion in the E1 region, a deletion in the E3 region, a deletion in the E4 region, or a combination thereof. 40. The composition of claim 37, wherein the replication defective adenovirus vector is not a gutted vector. 41. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 106 virus particles/ml. 42. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 107 virus particles/ml. 43. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 108 virus particles/ml. 44. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 109 virus particles/ml. 45. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 1010 virus particles/ml. 46. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 1011 virus particles/ml. 47. The composition of claim 37, further comprising a second replication defective adenovirus vector comprising a deletion in the E2b region. 48. The composition of claim 47, wherein the second replication defective adenovirus vector further comprises a deletion in the E1 region, a deletion in the E3 region, a deletion in the E4 region, or a combination thereof. 49. The composition of claim 37, further comprising an immune adjuvant. 50. The composition of claim 37, wherein the composition is formulated in a liposome. 51. The composition of claim 37, wherein the composition is formulated for parenteral, intravenous, intramuscular, intradermal, subcutaneous or intraperitoneal administration. 52. The composition of claim 37, wherein the replication defective adenovirus vector further encodes a protein that increases the immunogenicity of Her2/neu. 53. The composition of claim 52, wherein the protein that increases the immunogenicity of Her2/neu is a Mycobacterium tuberculosis-derived Ra12 fragment, a protein D derivative, LYTA, or any combinations thereof. 54. The composition of claim 37, wherein the Her2/neu is non-oncogenic. 55. A cell for producing the replication defective adenovirus vector comprising the composition of claim 37. 56. The cell of claim 55, wherein the cell constitutively expresses DNA polymerase and preterminal protein. 57. A method of inducing an antigen-specific immune, immunoprotective, or immunotherapeutic response in a subject in need thereof, the method comprising administering to the subject the composition of claim 37. 58. The method of claim 57, wherein the subject has preexisting immunity to adenovirus. 59. The method of claim 57, wherein the composition is administered to the subject at least twice. 60. The method of claim 57, wherein the composition is administered to the subject at least three times. 61. The method of claim 57, wherein the composition is administered at 2, 3, or 4 week intervals. 62. The method of claim 57, wherein the composition is administered at 4 months for booster immunizations after the priming immunization. 63. The method of claim 57, wherein the composition is administered parenterally, intravenously, intramuscularly, intradermally, subcutaneously or intraperitoneally. 64. A method of preventing or treating a Her2/neu-expressing tumor in a subject in need thereof, comprising administering to the subject the composition of claim 37. | Methods for generating immune responses using adenovirus vectors that allow multiple vaccinations with the same adenovirus vector and vaccinations in individuals with preexisting immunity to adenovirus are provided.1-36. (canceled) 37. A composition comprising a replication defective adenovirus vector comprising:
a deletion in the E2b region; and a nucleic acid sequence encoding Her2/neu. 38. The composition of claim 37, further comprising a replication defective adenovirus vector comprising a nucleic acid sequence encoding a tumor protein, a viral coat protein, a bacterial surface protein, or a combination thereof. 39. The composition of claim 37, wherein the replication defective adenovirus vector further comprises a deletion in the E1 region, a deletion in the E3 region, a deletion in the E4 region, or a combination thereof. 40. The composition of claim 37, wherein the replication defective adenovirus vector is not a gutted vector. 41. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 106 virus particles/ml. 42. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 107 virus particles/ml. 43. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 108 virus particles/ml. 44. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 109 virus particles/ml. 45. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 1010 virus particles/ml. 46. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 1011 virus particles/ml. 47. The composition of claim 37, further comprising a second replication defective adenovirus vector comprising a deletion in the E2b region. 48. The composition of claim 47, wherein the second replication defective adenovirus vector further comprises a deletion in the E1 region, a deletion in the E3 region, a deletion in the E4 region, or a combination thereof. 49. The composition of claim 37, further comprising an immune adjuvant. 50. The composition of claim 37, wherein the composition is formulated in a liposome. 51. The composition of claim 37, wherein the composition is formulated for parenteral, intravenous, intramuscular, intradermal, subcutaneous or intraperitoneal administration. 52. The composition of claim 37, wherein the replication defective adenovirus vector further encodes a protein that increases the immunogenicity of Her2/neu. 53. The composition of claim 52, wherein the protein that increases the immunogenicity of Her2/neu is a Mycobacterium tuberculosis-derived Ra12 fragment, a protein D derivative, LYTA, or any combinations thereof. 54. The composition of claim 37, wherein the Her2/neu is non-oncogenic. 55. A cell for producing the replication defective adenovirus vector comprising the composition of claim 37. 56. The cell of claim 55, wherein the cell constitutively expresses DNA polymerase and preterminal protein. 57. A method of inducing an antigen-specific immune, immunoprotective, or immunotherapeutic response in a subject in need thereof, the method comprising administering to the subject the composition of claim 37. 58. The method of claim 57, wherein the subject has preexisting immunity to adenovirus. 59. The method of claim 57, wherein the composition is administered to the subject at least twice. 60. The method of claim 57, wherein the composition is administered to the subject at least three times. 61. The method of claim 57, wherein the composition is administered at 2, 3, or 4 week intervals. 62. The method of claim 57, wherein the composition is administered at 4 months for booster immunizations after the priming immunization. 63. The method of claim 57, wherein the composition is administered parenterally, intravenously, intramuscularly, intradermally, subcutaneously or intraperitoneally. 64. A method of preventing or treating a Her2/neu-expressing tumor in a subject in need thereof, comprising administering to the subject the composition of claim 37. | 1,600 |
1,145 | 15,265,723 | 1,645 | Methods for generating immune responses using adenovirus vectors that allow multiple vaccinations with the same adenovirus vector and vaccinations in individuals with preexisting immunity to adenovirus are provided. | 1-36. (canceled) 37. A composition comprising a replication defective adenovirus vector comprising:
a deletion in the E2b region; and a nucleic acid sequence encoding HPV E6, HPV E7 or a combination thereof. 38. The composition of claim 37, further comprising a replication defective adenovirus vector comprising a nucleic acid sequence encoding a tumor protein, a viral coat protein, a bacterial surface protein, or a combination thereof. 39. The composition of claim 37, wherein the replication defective adenovirus vector further comprises a deletion in the E1 region, a deletion in the E3 region, a deletion in the E4 region, or a combination thereof. 40. The composition of claim 37, wherein the replication defective adenovirus vector is not a gutted vector. 41. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 106 virus particles/ml. 42. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 107 virus particles/ml. 43. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 108 virus particles/ml. 44. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 109 virus particles/ml. 45. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 1010 virus particles/ml. 46. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 1011 virus particles/ml. 47. The composition of claim 37, further comprising a second replication defective adenovirus vector comprising a deletion in the E2b region. 48. The composition of claim 47, wherein the second replication defective adenovirus vector further comprises a deletion in the E1 region, a deletion in the E3 region, a deletion in the E4 region, or a combination thereof. 49. The composition of claim 37, further comprising an immune adjuvant. 50. The composition of claim 37, wherein the composition is formulated in a liposome. 51. The composition of claim 37, wherein the composition is formulated for parenteral, intravenous, intramuscular, intradermal, subcutaneous or intraperitoneal administration. 52. The composition of claim 37, wherein the replication defective adenovirus vector further encodes a protein that increases the immunogenicity of the target antigen. 53. The composition of claim 52, wherein the protein that increases the immunogenicity of target antigen is a Mycobacterium tuberculosis-derived Ra12 fragment, a protein D derivative, LYTA, or any combinations thereof. 54. The composition of claim 37, wherein the HPV E6 or HPV E7 is non-oncogenic. 55. The composition of claim 37, wherein the HPV E6 has a deletion of its p53 binding site. 56. The composition of claim 37, wherein the composition comprises:
a first replication defective adenovirus vector comprising:
a deletion in the E2b region; and
a nucleic acid sequence encoding HPV E6; and
a second replication defective adenovirus vector comprising:
a deletion in the E2b region; and
a nucleic acid sequence encoding HPV E7. 57. A cell for producing the replication defective adenovirus vector comprising the composition of claim 37. 58. The cell of claim 57, wherein the cell constitutively expresses DNA polymerase and preterminal protein. 59. A method of inducing an antigen-specific immune, immunoprotective, or immunotherapeutic response in a subject in need thereof, the method comprising administering to the subject the composition of claim 37. 60. The method of claim 59, wherein the subject has preexisting immunity to adenovirus. 61. The method of claim 59, wherein the composition is administered to the subject at least twice. 62. The method of claim 59, wherein the composition is administered at 2, 3, or 4 week intervals. 63. The method of claim 59, wherein the composition is administered at 4 months for booster immunizations after the priming immunization. 64. The method of claim 59, wherein the method comprises administering:
a first replication defective adenovirus vector comprising:
a deletion in the E2b region; and
a nucleic acid sequence encoding HPV E6; and
a second replication defective adenovirus vector comprising:
a deletion in the E2b region; and
a nucleic acid sequence encoding HPV E7,
wherein the first replication defective adenovirus vector and second replication defective adenovirus vector are administered simultaneously or sequentially. 65. A method of treating an HPV-expressing cell and/or tumor in a subject in need thereof, comprising administering to the subject the composition of claim 37. | Methods for generating immune responses using adenovirus vectors that allow multiple vaccinations with the same adenovirus vector and vaccinations in individuals with preexisting immunity to adenovirus are provided.1-36. (canceled) 37. A composition comprising a replication defective adenovirus vector comprising:
a deletion in the E2b region; and a nucleic acid sequence encoding HPV E6, HPV E7 or a combination thereof. 38. The composition of claim 37, further comprising a replication defective adenovirus vector comprising a nucleic acid sequence encoding a tumor protein, a viral coat protein, a bacterial surface protein, or a combination thereof. 39. The composition of claim 37, wherein the replication defective adenovirus vector further comprises a deletion in the E1 region, a deletion in the E3 region, a deletion in the E4 region, or a combination thereof. 40. The composition of claim 37, wherein the replication defective adenovirus vector is not a gutted vector. 41. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 106 virus particles/ml. 42. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 107 virus particles/ml. 43. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 108 virus particles/ml. 44. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 109 virus particles/ml. 45. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 1010 virus particles/ml. 46. The composition of claim 37, wherein the composition comprises the replication defective adenovirus vector at a concentration of at least 1011 virus particles/ml. 47. The composition of claim 37, further comprising a second replication defective adenovirus vector comprising a deletion in the E2b region. 48. The composition of claim 47, wherein the second replication defective adenovirus vector further comprises a deletion in the E1 region, a deletion in the E3 region, a deletion in the E4 region, or a combination thereof. 49. The composition of claim 37, further comprising an immune adjuvant. 50. The composition of claim 37, wherein the composition is formulated in a liposome. 51. The composition of claim 37, wherein the composition is formulated for parenteral, intravenous, intramuscular, intradermal, subcutaneous or intraperitoneal administration. 52. The composition of claim 37, wherein the replication defective adenovirus vector further encodes a protein that increases the immunogenicity of the target antigen. 53. The composition of claim 52, wherein the protein that increases the immunogenicity of target antigen is a Mycobacterium tuberculosis-derived Ra12 fragment, a protein D derivative, LYTA, or any combinations thereof. 54. The composition of claim 37, wherein the HPV E6 or HPV E7 is non-oncogenic. 55. The composition of claim 37, wherein the HPV E6 has a deletion of its p53 binding site. 56. The composition of claim 37, wherein the composition comprises:
a first replication defective adenovirus vector comprising:
a deletion in the E2b region; and
a nucleic acid sequence encoding HPV E6; and
a second replication defective adenovirus vector comprising:
a deletion in the E2b region; and
a nucleic acid sequence encoding HPV E7. 57. A cell for producing the replication defective adenovirus vector comprising the composition of claim 37. 58. The cell of claim 57, wherein the cell constitutively expresses DNA polymerase and preterminal protein. 59. A method of inducing an antigen-specific immune, immunoprotective, or immunotherapeutic response in a subject in need thereof, the method comprising administering to the subject the composition of claim 37. 60. The method of claim 59, wherein the subject has preexisting immunity to adenovirus. 61. The method of claim 59, wherein the composition is administered to the subject at least twice. 62. The method of claim 59, wherein the composition is administered at 2, 3, or 4 week intervals. 63. The method of claim 59, wherein the composition is administered at 4 months for booster immunizations after the priming immunization. 64. The method of claim 59, wherein the method comprises administering:
a first replication defective adenovirus vector comprising:
a deletion in the E2b region; and
a nucleic acid sequence encoding HPV E6; and
a second replication defective adenovirus vector comprising:
a deletion in the E2b region; and
a nucleic acid sequence encoding HPV E7,
wherein the first replication defective adenovirus vector and second replication defective adenovirus vector are administered simultaneously or sequentially. 65. A method of treating an HPV-expressing cell and/or tumor in a subject in need thereof, comprising administering to the subject the composition of claim 37. | 1,600 |
1,146 | 15,568,487 | 1,631 | Contemplated compositions and methods are directed to cancer neoepitopes and uses of such neoepitopes, especially to generate synthetic antibodies against neoepitopes that may then be employed in the manufacture of a therapeutic agent. Preferred therapeutic agents will comprise a synthetic antibody against a neoepitope, and most preferably in combination with a cellular or non-cellular component for use as a diagnostic or therapeutic agent. | 1. A method of generating a pharmaceutical agent for cancer immune therapy, comprising:
using matched normal omics data of a tumor to generate in silico a plurality of n-mers that contain at least one patient- and cancer-specific cancer neoepitope; filtering in silico the n-mers to so obtain a subset of neoepitope sequences; preparing at least one synthetic n-mer peptide using sequence information from the subset of neoepitope sequences; using the synthetic n-mer peptide to isolate a recombinant antibody; obtaining sequence information of the complementarity determining region of the recombinant antibody; generating a synthetic antibody using the sequence information of the complementarity determining region of the recombinant antibody; and coupling the synthetic antibody to a therapeutic or diagnostic agent to so obtain the pharmaceutical agent. 2. The method of claim 1 wherein the matched normal omics data are at least one of whole genomic sequencing data, exome sequencing data, and transcriptome data. 3. The method of claim 1 wherein the matched normal omics data are matched against normal before treatment of the patient. 4. The method of claim 1 wherein each of the plurality of n-mer peptides has a length of between 7 and 11 amino acids. 5. The method of claim 1 wherein the plurality of n-mer peptides is at least 1,000 n-mer peptides. 6. The method of claim 1 wherein different of the plurality of n-mer peptides have different neoepitopes. 7. The method of claim 1 wherein the step of filtering includes at least one of filtering by type of mutation, filtering by strength of expression, filtering by sub-cellular location, and filtering by binding affinity towards an HLA-type of the patient. 8. The method of claim 1 wherein the step of filtering includes at least two of filtering by type of mutation, filtering by strength of expression, filtering by sub-cellular location, and filtering by binding affinity towards an HLA-type of the patient. 9. The method of claim 1 wherein the step of filtering includes at least three of filtering by type of mutation, filtering by strength of expression, filtering by sub-cellular location, and filtering by binding affinity towards an HLA-type of the patient. 10. The method of claim 1 wherein the step of using the synthetic n-mer peptide to isolate the recombinant antibody comprises phage panning. 11. The method of claim 10 wherein the step of phage panning further comprises affinity maturation. 12. The method of claim 1 wherein the sequence information of the complementarity determining region of the recombinant antibody comprises CDR1-H, CDR2-H, and CDR3-H. 13. The method of claim 1 wherein the synthetic antibody is generated using CDR or SDR grafting onto a human antibody scaffold. 14. The method of claim 1 wherein the synthetic antibody is generated via recombinant expression as a IgG, a F(ab′)2, a Fab′, a Fab, or a scFv. 15. The method of claim 1 wherein the therapeutic or diagnostic agent is a non-cellular agent. 16. The method of claim 15 wherein the non-cellular agent is a chemotherapeutic drug, a radio isotope, a PET detectable isotope, a SPECT detectable isotope, or an affinity agent. 17. The method of claim 1 wherein the therapeutic agent is a cell. 18. The method of claim 17 wherein the cell is a T-cell or an NK cell. 19. The method of claim 18 wherein the cell is a T-cell expressing a chimeric receptor having a scFv as ectodomain and wherein the synthetic antibody is the scFv. 20. The method of claim 18 wherein the cell is an NK cell expressing a high-affinity Fcγ receptor (CD16) and wherein the synthetic antibody is an IgG and is bound to the NK cell via the high-affinity Fcγ receptor. 21. The method of claim 1 wherein the pharmaceutical agent is obtained in therapeutically effective quantities within less than 6 weeks from using the matched normal omics data. 22. A method of generating a synthetic antibody to a cancer neoepitope of a patient where the cancer neoepitope failed to elicit a protective immune response, comprising:
using the cancer neoepitope to select a binding recombinant antibody from a library of recombinant antibodies, wherein the cancer neoepitope is patient- and cancer-specific; analyzing hypervariable loops in the binding recombinant antibody to thereby obtain specificity information for the binding recombinant antibody; modifying a gene coding for at least a portion of a human antibody using the specificity information; and recombinantly expressing the modified gene to produce the synthetic antibody. 23. The method of claim 22 wherein the cancer neoepitope is an HLA matched cancer neoepitope. 24. The method of claim 22 wherein the library of recombinant antibodies is a phage display library. 25. The method of claim 22 further comprising a step of affinity maturing the binding recombinant antibody to derive an optimized binding recombinant antibody. 26. The method of claim 22 wherein the step of analyzing the analyzing hypervariable loops comprises sequencing DNA encoding the hypervariable loops. 27. The method of claim 22 wherein the step of modifying comprises CDR or SDR grafting. 28. The method of claim 22 wherein the at least portion of the human antibody is a scFv. 29. The method of claim 22 wherein the step of recombinantly expressing the gene produces the synthetic antibody in form of a IgG, a F(ab′)2, a Fab′, a Fab, or a scFv. 30. The method of claim 22 wherein the cancer neoepitope is expressed in the cancer of the patient. 31. The method of claim 22 wherein the neoepitope is unique to the patient and cancer in the patient. 32. A composition comprising a synthetic antibody having binding affinity against a patient- and cancer-specific HLA-matched cancer neoepitope wherein the neoepitope is unique to the patient and cancer in the patient. 33. The composition of claim 32 wherein the HLA-matched cancer neoepitope is matched for MHC-I presentation. 34. The composition of claim 32 wherein the synthetic antibody is selected from the group consisting of an IgG, a F(ab′)2, a Fab′, a Fab, and a scFv. 35. The composition of claim 32 wherein a therapeutic agent is coupled to the synthetic antibody. 36. The composition of claim 35 wherein the therapeutic agent is a non-cellular agent. 37. The composition of claim 36 wherein the non-cellular agent is a chemotherapeutic drug, a radio isotope, a PET detectable isotope, a SPECT detectable isotope, or an affinity agent. 38. The composition of claim 35 wherein the therapeutic agent is a cell. 39. The composition of claim 38 wherein the cell is a T-cell or an NK cell that optionally expresses a genetically modified CD16 receptor. 40. The composition of claim 39 wherein the cell is a T-cell expressing a chimeric receptor having a scFv as ectodomain and wherein the synthetic antibody is the scFv. 41. The composition of claim 39 wherein the cell is an NK cell expressing a high-affinity Fcγ receptor (CD16) and wherein the synthetic antibody is an IgG and is bound to the NK cell via the high-affinity Fcγ receptor. 42. The composition of claim 32 wherein the cancer neoepitope has a sequence selected from the group consisting of SEQ ID NO 1 to SEQ ID NO 1,408,729. 43. A composition comprising a solid phase to which is bound a patient- and cancer-specific HLA-matched cancer neoepitope, wherein the cancer neoepitope is unique to the patient and cancer in the patient. 44. The composition of claim 43 wherein the solid phase comprises a wall of a reagent container, a magnetic bead, or an individually addressable element. 45. The composition of claim 43 wherein the cancer neoepitope has a length of between 7 and 9 amino acids. 46. The composition of claim 43 further comprising a synthetic antibody bound to the cancer neoepitope. 47. The composition of claim 46 wherein the synthetic antibody bound is selected from the group consisting of an IgG, a F(ab′)2, a Fab′, a Fab, and a scFv. 48. The composition of claim 46 wherein the synthetic antibody is coupled to a virus particle. 49. The composition of claim 46 wherein the cancer neoepitope has a sequence selected from the group consisting of SEQ ID NO 1 to SEQ ID NO 1,408,729. | Contemplated compositions and methods are directed to cancer neoepitopes and uses of such neoepitopes, especially to generate synthetic antibodies against neoepitopes that may then be employed in the manufacture of a therapeutic agent. Preferred therapeutic agents will comprise a synthetic antibody against a neoepitope, and most preferably in combination with a cellular or non-cellular component for use as a diagnostic or therapeutic agent.1. A method of generating a pharmaceutical agent for cancer immune therapy, comprising:
using matched normal omics data of a tumor to generate in silico a plurality of n-mers that contain at least one patient- and cancer-specific cancer neoepitope; filtering in silico the n-mers to so obtain a subset of neoepitope sequences; preparing at least one synthetic n-mer peptide using sequence information from the subset of neoepitope sequences; using the synthetic n-mer peptide to isolate a recombinant antibody; obtaining sequence information of the complementarity determining region of the recombinant antibody; generating a synthetic antibody using the sequence information of the complementarity determining region of the recombinant antibody; and coupling the synthetic antibody to a therapeutic or diagnostic agent to so obtain the pharmaceutical agent. 2. The method of claim 1 wherein the matched normal omics data are at least one of whole genomic sequencing data, exome sequencing data, and transcriptome data. 3. The method of claim 1 wherein the matched normal omics data are matched against normal before treatment of the patient. 4. The method of claim 1 wherein each of the plurality of n-mer peptides has a length of between 7 and 11 amino acids. 5. The method of claim 1 wherein the plurality of n-mer peptides is at least 1,000 n-mer peptides. 6. The method of claim 1 wherein different of the plurality of n-mer peptides have different neoepitopes. 7. The method of claim 1 wherein the step of filtering includes at least one of filtering by type of mutation, filtering by strength of expression, filtering by sub-cellular location, and filtering by binding affinity towards an HLA-type of the patient. 8. The method of claim 1 wherein the step of filtering includes at least two of filtering by type of mutation, filtering by strength of expression, filtering by sub-cellular location, and filtering by binding affinity towards an HLA-type of the patient. 9. The method of claim 1 wherein the step of filtering includes at least three of filtering by type of mutation, filtering by strength of expression, filtering by sub-cellular location, and filtering by binding affinity towards an HLA-type of the patient. 10. The method of claim 1 wherein the step of using the synthetic n-mer peptide to isolate the recombinant antibody comprises phage panning. 11. The method of claim 10 wherein the step of phage panning further comprises affinity maturation. 12. The method of claim 1 wherein the sequence information of the complementarity determining region of the recombinant antibody comprises CDR1-H, CDR2-H, and CDR3-H. 13. The method of claim 1 wherein the synthetic antibody is generated using CDR or SDR grafting onto a human antibody scaffold. 14. The method of claim 1 wherein the synthetic antibody is generated via recombinant expression as a IgG, a F(ab′)2, a Fab′, a Fab, or a scFv. 15. The method of claim 1 wherein the therapeutic or diagnostic agent is a non-cellular agent. 16. The method of claim 15 wherein the non-cellular agent is a chemotherapeutic drug, a radio isotope, a PET detectable isotope, a SPECT detectable isotope, or an affinity agent. 17. The method of claim 1 wherein the therapeutic agent is a cell. 18. The method of claim 17 wherein the cell is a T-cell or an NK cell. 19. The method of claim 18 wherein the cell is a T-cell expressing a chimeric receptor having a scFv as ectodomain and wherein the synthetic antibody is the scFv. 20. The method of claim 18 wherein the cell is an NK cell expressing a high-affinity Fcγ receptor (CD16) and wherein the synthetic antibody is an IgG and is bound to the NK cell via the high-affinity Fcγ receptor. 21. The method of claim 1 wherein the pharmaceutical agent is obtained in therapeutically effective quantities within less than 6 weeks from using the matched normal omics data. 22. A method of generating a synthetic antibody to a cancer neoepitope of a patient where the cancer neoepitope failed to elicit a protective immune response, comprising:
using the cancer neoepitope to select a binding recombinant antibody from a library of recombinant antibodies, wherein the cancer neoepitope is patient- and cancer-specific; analyzing hypervariable loops in the binding recombinant antibody to thereby obtain specificity information for the binding recombinant antibody; modifying a gene coding for at least a portion of a human antibody using the specificity information; and recombinantly expressing the modified gene to produce the synthetic antibody. 23. The method of claim 22 wherein the cancer neoepitope is an HLA matched cancer neoepitope. 24. The method of claim 22 wherein the library of recombinant antibodies is a phage display library. 25. The method of claim 22 further comprising a step of affinity maturing the binding recombinant antibody to derive an optimized binding recombinant antibody. 26. The method of claim 22 wherein the step of analyzing the analyzing hypervariable loops comprises sequencing DNA encoding the hypervariable loops. 27. The method of claim 22 wherein the step of modifying comprises CDR or SDR grafting. 28. The method of claim 22 wherein the at least portion of the human antibody is a scFv. 29. The method of claim 22 wherein the step of recombinantly expressing the gene produces the synthetic antibody in form of a IgG, a F(ab′)2, a Fab′, a Fab, or a scFv. 30. The method of claim 22 wherein the cancer neoepitope is expressed in the cancer of the patient. 31. The method of claim 22 wherein the neoepitope is unique to the patient and cancer in the patient. 32. A composition comprising a synthetic antibody having binding affinity against a patient- and cancer-specific HLA-matched cancer neoepitope wherein the neoepitope is unique to the patient and cancer in the patient. 33. The composition of claim 32 wherein the HLA-matched cancer neoepitope is matched for MHC-I presentation. 34. The composition of claim 32 wherein the synthetic antibody is selected from the group consisting of an IgG, a F(ab′)2, a Fab′, a Fab, and a scFv. 35. The composition of claim 32 wherein a therapeutic agent is coupled to the synthetic antibody. 36. The composition of claim 35 wherein the therapeutic agent is a non-cellular agent. 37. The composition of claim 36 wherein the non-cellular agent is a chemotherapeutic drug, a radio isotope, a PET detectable isotope, a SPECT detectable isotope, or an affinity agent. 38. The composition of claim 35 wherein the therapeutic agent is a cell. 39. The composition of claim 38 wherein the cell is a T-cell or an NK cell that optionally expresses a genetically modified CD16 receptor. 40. The composition of claim 39 wherein the cell is a T-cell expressing a chimeric receptor having a scFv as ectodomain and wherein the synthetic antibody is the scFv. 41. The composition of claim 39 wherein the cell is an NK cell expressing a high-affinity Fcγ receptor (CD16) and wherein the synthetic antibody is an IgG and is bound to the NK cell via the high-affinity Fcγ receptor. 42. The composition of claim 32 wherein the cancer neoepitope has a sequence selected from the group consisting of SEQ ID NO 1 to SEQ ID NO 1,408,729. 43. A composition comprising a solid phase to which is bound a patient- and cancer-specific HLA-matched cancer neoepitope, wherein the cancer neoepitope is unique to the patient and cancer in the patient. 44. The composition of claim 43 wherein the solid phase comprises a wall of a reagent container, a magnetic bead, or an individually addressable element. 45. The composition of claim 43 wherein the cancer neoepitope has a length of between 7 and 9 amino acids. 46. The composition of claim 43 further comprising a synthetic antibody bound to the cancer neoepitope. 47. The composition of claim 46 wherein the synthetic antibody bound is selected from the group consisting of an IgG, a F(ab′)2, a Fab′, a Fab, and a scFv. 48. The composition of claim 46 wherein the synthetic antibody is coupled to a virus particle. 49. The composition of claim 46 wherein the cancer neoepitope has a sequence selected from the group consisting of SEQ ID NO 1 to SEQ ID NO 1,408,729. | 1,600 |
1,147 | 15,744,593 | 1,653 | The invention is in the field of cultures of microalgae, in particular thraustochytrids. The invention relates to a protein-rich biomass of thraustochytrids, to a method of obtaining said biomass, and to the uses thereof. | 1. A thraustochytrid biomass comprising at least 35% by weight of proteins relative to the weight of dry matter. 2. The biomass according to claim 1, wherein it comprises at least 45% proteins. 3. The biomass according to claim 1, wherein it comprises at least 60% proteins. 4. The biomass according to claim 1, wherein it comprises less than 20% fat by weight relative to the weight of dry matter. 5. The biomass according to claim 4, wherein it comprises less than 10% fat. 6. The biomass according to claim 1, wherein said thraustochytrids are of a genus selected from the group consisting of Aurantiochytrium, Aplanochytrium, Botryochytrium, Japonochytrium, Oblongichytrium, Parietichytrium, Schizochytrium, Sicyoidochytrium, Thraustochytrium and Ulkenia. 7. The biomass according to claim 6, wherein said thraustochytrids are selected from the species Aurantiochytrium mangrovei CCAP 4062/2; Aurantiochytrium mangrovei CCAP 4062/3; Aurantiochytrium mangrovei CCAP 4062/4; Aurantiochytrium mangrovei, CCAP 4062/5; Aurantiochytrium mangrovei CCAP 4062/6; Aurantiochytrium mangrovei CCAP 4062/1; Schizochytrium sp. 4087/3; Schizochytrium sp. CCAP 4087/1; Schizochytrium sp. CCAP 4087/4; Schizochytrium sp. CCAP 4087/5. 8. The biomass according to claim 1, wherein it has a moisture content of 1% to 95%. 9. The biomass according to claim 8, wherein it has a moisture content of 70% to 90%. 10. The biomass according to claim 8, wherein it has a moisture content of 1% to 10%. 11. A process for producing a biomass as defined in claim 1, wherein it comprises:
a. a first step of culturing thraustochytrids in a defined culture medium comprising a carbon source, a nitrogen source, a phosphorus source and salts, said first step a) being divided into two sub-steps, a first sub-step: a1) of growth in the suitable culture medium until carbon source contents in the medium lower than 20 g/L are obtained, followed by a second sub-step: a2) of production wherein one or more carbon source, nitrogen source and/or phosphorus source enrichment solutions are added to the culture medium, simultaneously or successively, until a culture density of at least 40 g/L dry matter is obtained; b. a second step of recovering the biomass obtained in the first step by separating said biomass from the culture medium. 12. The process according to claim 11, wherein in step a2) the carbon source content is maintained between 0 and 50 g/L, the nitrogen source content is maintained between 0.5 and 5 g/L and the phosphorous source content is maintained between 0.5 and 5 g/L. 13. The process according to claim 11, wherein it comprises a third step:
c. of drying the biomass recovered in the second step. 14-15. (canceled) 16. A method for improving animal performance comprising administering to the animal the thraustochytrid biomass as described in claim 1. 17. The method according to claim 16, wherein the improvement in performance is evaluated by measuring consumption, weight gain or feed conversion ratio. 18. A cosmetic or pharmaceutical composition for humans or animals comprising a biomass as described in claim 1. 19. A food product, wherein it comprises a biomass as described in claim 1. 20. A livestock feed, wherein it comprises 1% to 60% of a biomass as described according to claim 1. 21. The feed according to claim 20, wherein it comprises 1% to 20% of the said biomass. 22. The feed according to claim 21, wherein it comprises 3% to 8% of the said biomass. 23. A livestock feed, wherein it comprises 1% to 40% of a biomass according to claim 1. 24. The feed according to claim 23, wherein it comprises 5% to 10% of the said biomass. 25. (canceled) | The invention is in the field of cultures of microalgae, in particular thraustochytrids. The invention relates to a protein-rich biomass of thraustochytrids, to a method of obtaining said biomass, and to the uses thereof.1. A thraustochytrid biomass comprising at least 35% by weight of proteins relative to the weight of dry matter. 2. The biomass according to claim 1, wherein it comprises at least 45% proteins. 3. The biomass according to claim 1, wherein it comprises at least 60% proteins. 4. The biomass according to claim 1, wherein it comprises less than 20% fat by weight relative to the weight of dry matter. 5. The biomass according to claim 4, wherein it comprises less than 10% fat. 6. The biomass according to claim 1, wherein said thraustochytrids are of a genus selected from the group consisting of Aurantiochytrium, Aplanochytrium, Botryochytrium, Japonochytrium, Oblongichytrium, Parietichytrium, Schizochytrium, Sicyoidochytrium, Thraustochytrium and Ulkenia. 7. The biomass according to claim 6, wherein said thraustochytrids are selected from the species Aurantiochytrium mangrovei CCAP 4062/2; Aurantiochytrium mangrovei CCAP 4062/3; Aurantiochytrium mangrovei CCAP 4062/4; Aurantiochytrium mangrovei, CCAP 4062/5; Aurantiochytrium mangrovei CCAP 4062/6; Aurantiochytrium mangrovei CCAP 4062/1; Schizochytrium sp. 4087/3; Schizochytrium sp. CCAP 4087/1; Schizochytrium sp. CCAP 4087/4; Schizochytrium sp. CCAP 4087/5. 8. The biomass according to claim 1, wherein it has a moisture content of 1% to 95%. 9. The biomass according to claim 8, wherein it has a moisture content of 70% to 90%. 10. The biomass according to claim 8, wherein it has a moisture content of 1% to 10%. 11. A process for producing a biomass as defined in claim 1, wherein it comprises:
a. a first step of culturing thraustochytrids in a defined culture medium comprising a carbon source, a nitrogen source, a phosphorus source and salts, said first step a) being divided into two sub-steps, a first sub-step: a1) of growth in the suitable culture medium until carbon source contents in the medium lower than 20 g/L are obtained, followed by a second sub-step: a2) of production wherein one or more carbon source, nitrogen source and/or phosphorus source enrichment solutions are added to the culture medium, simultaneously or successively, until a culture density of at least 40 g/L dry matter is obtained; b. a second step of recovering the biomass obtained in the first step by separating said biomass from the culture medium. 12. The process according to claim 11, wherein in step a2) the carbon source content is maintained between 0 and 50 g/L, the nitrogen source content is maintained between 0.5 and 5 g/L and the phosphorous source content is maintained between 0.5 and 5 g/L. 13. The process according to claim 11, wherein it comprises a third step:
c. of drying the biomass recovered in the second step. 14-15. (canceled) 16. A method for improving animal performance comprising administering to the animal the thraustochytrid biomass as described in claim 1. 17. The method according to claim 16, wherein the improvement in performance is evaluated by measuring consumption, weight gain or feed conversion ratio. 18. A cosmetic or pharmaceutical composition for humans or animals comprising a biomass as described in claim 1. 19. A food product, wherein it comprises a biomass as described in claim 1. 20. A livestock feed, wherein it comprises 1% to 60% of a biomass as described according to claim 1. 21. The feed according to claim 20, wherein it comprises 1% to 20% of the said biomass. 22. The feed according to claim 21, wherein it comprises 3% to 8% of the said biomass. 23. A livestock feed, wherein it comprises 1% to 40% of a biomass according to claim 1. 24. The feed according to claim 23, wherein it comprises 5% to 10% of the said biomass. 25. (canceled) | 1,600 |
1,148 | 15,306,585 | 1,699 | Cosmetic products, comprising a container having a tubular body, the wall of which has a transmission for visible light of from 25 to about 100%, and on the top end of which a dispenser head is attached, the dispenser head being bounded below by a movable trailing piston, and a cosmetic preparation in the interior of the container which preparation comprises an outer flowable water-based gel-type phase having a transmission for light of 700 nm wavelength of from 30 to 100% and/or a viscosity of 1000-10,000 mPas at a temperature of 25° C. and a shear rate of approximately 10, and an inner solid particulate phase which comprises substantially spherical particles having an average diameter of from 0.1 to 10 mm, the volume ratio of the inner particulate phase to the outer aqueous gel ranging from about 20%:80% to 74%:26%. | 1.-9. (canceled) 10. A cosmetic product, wherein the product comprises a container and a cosmetic preparation inside the container, the container comprising a tubular body whose walls have a transmittance for visible light of from 25% to about 100% and on whose top end a dispenser head is mounted and which is bounded at its bottom by a movable drawing plunger, and the cosmetic preparation comprising (i) an external fluid gel phase on aqueous basis having a transmittance for light of a wavelength of 700 nm of from 30% to 100% and/or having a viscosity at 25° C. and a shear rate of about 10 of from 1,000 to 10,000 mPas, and optionally comprising customary auxiliaries and or adjuvants which are dispersible or soluble in water, and (ii) an internal solid particulate phase comprising substantially spherical particles whose average diameter is from 0.1 mm to 10 mm, a volume ratio (ii) (i) ranging from about 20%:80% to 74%:26%. 11. The product of claim 10, wherein the volume ratio (ii):(i) ranges from about 30%:70% to 65%: 35%. 12. The product of claim 10, wherein the volume ratio (ii):(i) ranges from about 40%:60% to 60%:40%. 13. The product of claim 10, wherein (i) has a viscosity at 25° C. and a shear rate of about 10 of from 3,000 to 9,000 mPas. 14. The product of claim 10, wherein (i) has a viscosity at 25° C. and a shear rate of about 10 of from 5,000 to 8,000 mPas. 15. The product of claim 10, wherein the average diameter of the substantially spherical particles is from 2 mm to 7.5 mm. 16. The product of claim 10, wherein the dispenser head comprises
an outer actuating element having a dispensing aperture which is sealed by a nonreturn valve, a base unit lying on the tubular body and having an opening to the tubular body, and a flexible inner, substantially cylindrically shaped hollow body having bellows-like walls,
elements of the dispenser head being designed such that
the hollow body has openings and at each of its two end faces,
the hollow body lies by a bottom end face on the base unit, with an opening thereof and a bottom opening of the hollow body lying over one another,
such that if
the actuating element as a result of external pressure compresses the inner hollow body in a direction of its longitudinal axis,
a substance inside the hollow body is conveyed through the nonretum valve and the dispenser head out of the container, and
when an external pressure subsides, a recovery force of the flexible inner hollow body draws substance from the tubular body into the flexible inner hollow body. 17. The product of claim 16, wherein the inner hollow body is designed such that its bottom opening at a bottom end face comprises a device which cuts up a flow of substance from an interior of the tubular body into the hollow body into a plurality of substreams. 18. The product of claim 10, wherein (i) comprises one or more hydrocolloids selected from celluloses, methylcelluloses, and polyacrylates. 19. The product of claim 10, wherein (i) comprises one or more hydrocolloids selected from carrageen, xanthan, “Acrylates/C 10-30 Alkyl Acrylate Crosspolymers”, and ammonium acryloyldimethyltaurate/vinylpyrrolidone copolymers. 20. The product of claim 18, wherein a total concentration of the one or more hydrocolloids is less than 1.5 wt %, based on a total weight of the preparation. 21. The product of claim 20, wherein the total concentration of the one or more hydrocolloids is from 0.1 wt % to 1.0 wt %. 22. The product of claim 10, wherein (ii) comprises (A) a polymer matrix which is substantially insoluble in water, (B) one or more substances selected from ubiquinones and/or plastoquinones, (C) one or more light filter substances selected from metal oxide pigments, and, optionally, (D) one or more light filter substances selected from customary cosmetic light protection filter substances. 23. The product of claim 22, wherein (A) is selected from algin, carrageenan, agar, gellan gum, chitosan, and alginates. 24. The product of claim 22, wherein (A) comprises sodium alginate. 25. The product of claim 22, wherein (C) is selected from one or more of TiO2, ZnO oxides of iron, ZrO2, SiO2, oxides of manganese, Al2O3, oxides of cerium, mixed oxides of the corresponding metals, and BaSO4. 26. The product of claim 22, wherein (B) comprises ubiquinone 10 (coenzyme Q10). 27. The product of claim 22, wherein (D) is selected from one or more of octyl methoxycinnamate, octocrylene, Tinosorb M, Tinosorb S, Mexoryl XL, benzophenone-3, benzophenone-4. 28. A cosmetic product, wherein the product comprises a container and a cosmetic preparation inside the container, the container comprising a tubular body whose walls have a transmittance for visible light of from 25% to about 100% and on whose top end a dispenser head is mounted and which is bounded at its bottom by a movable drawing plunger, and the cosmetic preparation comprising (i) an external fluid gel phase on aqueous basis comprising one or more hydrocolloids selected from celluloses, methylcelluloses and polyacrylates and having a transmittance for light of a wavelength of 700 nm of from 30% to 100% and a viscosity at 25° C. and a shear rate of about 10 of from 5,000 to 8,000 mPas, and optionally comprising customary auxiliaries and or adjuvants which are dispersible or soluble in water, and (ii) an internal solid particulate phase comprising substantially spherical particles whose average diameter is from 2 mm to 7.5 mm and comprising (A) a polymer matrix which is substantially insoluble in water, (B) one or more substances selected from ubiquinones and/or plastoquinones, (C) one or more light filter substances selected from metal oxide pigments, and, optionally, (D) one or more light filter substances selected from customary cosmetic light protection filter substances, a volume ratio (ii):(i) ranging from about 60%:40% to 40%:60%. 29. The product of claim 28, wherein the dispenser head comprises
an outer actuating element having a dispensing aperture which is sealed by a nonreturn valve, a base unit lying on the tubular body and having an opening to the tubular body, and a flexible inner, substantially cylindrically shaped hollow body having bellows-like walls,
elements of the dispenser head being designed such that
the hollow body has openings and at each of its two end faces,
the hollow body lies by a bottom end face on the base unit, with an opening thereof and a bottom opening of the hollow body lying over one another,
such that if
the actuating element as a result of external pressure compresses the inner hollow body in a direction of its longitudinal axis,
a substance inside the hollow body (H) is conveyed through the nonretum valve and the dispenser head out of the container, and
when an external pressure subsides, a recovery force of the flexible inner hollow body draws substance from the tubular body into the flexible inner hollow body. | Cosmetic products, comprising a container having a tubular body, the wall of which has a transmission for visible light of from 25 to about 100%, and on the top end of which a dispenser head is attached, the dispenser head being bounded below by a movable trailing piston, and a cosmetic preparation in the interior of the container which preparation comprises an outer flowable water-based gel-type phase having a transmission for light of 700 nm wavelength of from 30 to 100% and/or a viscosity of 1000-10,000 mPas at a temperature of 25° C. and a shear rate of approximately 10, and an inner solid particulate phase which comprises substantially spherical particles having an average diameter of from 0.1 to 10 mm, the volume ratio of the inner particulate phase to the outer aqueous gel ranging from about 20%:80% to 74%:26%.1.-9. (canceled) 10. A cosmetic product, wherein the product comprises a container and a cosmetic preparation inside the container, the container comprising a tubular body whose walls have a transmittance for visible light of from 25% to about 100% and on whose top end a dispenser head is mounted and which is bounded at its bottom by a movable drawing plunger, and the cosmetic preparation comprising (i) an external fluid gel phase on aqueous basis having a transmittance for light of a wavelength of 700 nm of from 30% to 100% and/or having a viscosity at 25° C. and a shear rate of about 10 of from 1,000 to 10,000 mPas, and optionally comprising customary auxiliaries and or adjuvants which are dispersible or soluble in water, and (ii) an internal solid particulate phase comprising substantially spherical particles whose average diameter is from 0.1 mm to 10 mm, a volume ratio (ii) (i) ranging from about 20%:80% to 74%:26%. 11. The product of claim 10, wherein the volume ratio (ii):(i) ranges from about 30%:70% to 65%: 35%. 12. The product of claim 10, wherein the volume ratio (ii):(i) ranges from about 40%:60% to 60%:40%. 13. The product of claim 10, wherein (i) has a viscosity at 25° C. and a shear rate of about 10 of from 3,000 to 9,000 mPas. 14. The product of claim 10, wherein (i) has a viscosity at 25° C. and a shear rate of about 10 of from 5,000 to 8,000 mPas. 15. The product of claim 10, wherein the average diameter of the substantially spherical particles is from 2 mm to 7.5 mm. 16. The product of claim 10, wherein the dispenser head comprises
an outer actuating element having a dispensing aperture which is sealed by a nonreturn valve, a base unit lying on the tubular body and having an opening to the tubular body, and a flexible inner, substantially cylindrically shaped hollow body having bellows-like walls,
elements of the dispenser head being designed such that
the hollow body has openings and at each of its two end faces,
the hollow body lies by a bottom end face on the base unit, with an opening thereof and a bottom opening of the hollow body lying over one another,
such that if
the actuating element as a result of external pressure compresses the inner hollow body in a direction of its longitudinal axis,
a substance inside the hollow body is conveyed through the nonretum valve and the dispenser head out of the container, and
when an external pressure subsides, a recovery force of the flexible inner hollow body draws substance from the tubular body into the flexible inner hollow body. 17. The product of claim 16, wherein the inner hollow body is designed such that its bottom opening at a bottom end face comprises a device which cuts up a flow of substance from an interior of the tubular body into the hollow body into a plurality of substreams. 18. The product of claim 10, wherein (i) comprises one or more hydrocolloids selected from celluloses, methylcelluloses, and polyacrylates. 19. The product of claim 10, wherein (i) comprises one or more hydrocolloids selected from carrageen, xanthan, “Acrylates/C 10-30 Alkyl Acrylate Crosspolymers”, and ammonium acryloyldimethyltaurate/vinylpyrrolidone copolymers. 20. The product of claim 18, wherein a total concentration of the one or more hydrocolloids is less than 1.5 wt %, based on a total weight of the preparation. 21. The product of claim 20, wherein the total concentration of the one or more hydrocolloids is from 0.1 wt % to 1.0 wt %. 22. The product of claim 10, wherein (ii) comprises (A) a polymer matrix which is substantially insoluble in water, (B) one or more substances selected from ubiquinones and/or plastoquinones, (C) one or more light filter substances selected from metal oxide pigments, and, optionally, (D) one or more light filter substances selected from customary cosmetic light protection filter substances. 23. The product of claim 22, wherein (A) is selected from algin, carrageenan, agar, gellan gum, chitosan, and alginates. 24. The product of claim 22, wherein (A) comprises sodium alginate. 25. The product of claim 22, wherein (C) is selected from one or more of TiO2, ZnO oxides of iron, ZrO2, SiO2, oxides of manganese, Al2O3, oxides of cerium, mixed oxides of the corresponding metals, and BaSO4. 26. The product of claim 22, wherein (B) comprises ubiquinone 10 (coenzyme Q10). 27. The product of claim 22, wherein (D) is selected from one or more of octyl methoxycinnamate, octocrylene, Tinosorb M, Tinosorb S, Mexoryl XL, benzophenone-3, benzophenone-4. 28. A cosmetic product, wherein the product comprises a container and a cosmetic preparation inside the container, the container comprising a tubular body whose walls have a transmittance for visible light of from 25% to about 100% and on whose top end a dispenser head is mounted and which is bounded at its bottom by a movable drawing plunger, and the cosmetic preparation comprising (i) an external fluid gel phase on aqueous basis comprising one or more hydrocolloids selected from celluloses, methylcelluloses and polyacrylates and having a transmittance for light of a wavelength of 700 nm of from 30% to 100% and a viscosity at 25° C. and a shear rate of about 10 of from 5,000 to 8,000 mPas, and optionally comprising customary auxiliaries and or adjuvants which are dispersible or soluble in water, and (ii) an internal solid particulate phase comprising substantially spherical particles whose average diameter is from 2 mm to 7.5 mm and comprising (A) a polymer matrix which is substantially insoluble in water, (B) one or more substances selected from ubiquinones and/or plastoquinones, (C) one or more light filter substances selected from metal oxide pigments, and, optionally, (D) one or more light filter substances selected from customary cosmetic light protection filter substances, a volume ratio (ii):(i) ranging from about 60%:40% to 40%:60%. 29. The product of claim 28, wherein the dispenser head comprises
an outer actuating element having a dispensing aperture which is sealed by a nonreturn valve, a base unit lying on the tubular body and having an opening to the tubular body, and a flexible inner, substantially cylindrically shaped hollow body having bellows-like walls,
elements of the dispenser head being designed such that
the hollow body has openings and at each of its two end faces,
the hollow body lies by a bottom end face on the base unit, with an opening thereof and a bottom opening of the hollow body lying over one another,
such that if
the actuating element as a result of external pressure compresses the inner hollow body in a direction of its longitudinal axis,
a substance inside the hollow body (H) is conveyed through the nonretum valve and the dispenser head out of the container, and
when an external pressure subsides, a recovery force of the flexible inner hollow body draws substance from the tubular body into the flexible inner hollow body. | 1,600 |
1,149 | 15,538,326 | 1,627 | The present invention relates to the use of the anti-megakaryocytic agent anagrelide, or a therapeutically active metabolite thereof, in the prevention or treatment of metastatic disease in cancer patients displaying paraneoplastic thrombocytosis. | 1. A compound, wherein the compound is anagrelide, a pharmaceutically acceptable salt, solvate or active metabolite thereof, for use in treating or preventing metastatic disease in a thrombocytotic cancer patient. 2. A compound, wherein the compound is anagrelide, a pharmaceutically acceptable salt, solvate or active metabolite thereof, for use in inhibiting the migratory attraction between circulating cancer cells and bone marrow megakaryocytes. 3. The compound for use of claim 2, wherein the inhibition of the migratory attraction between circulating cancer cells and bone marrow megakaryocytes reduces the likelihood of metastases, e.g. bone or lung metastases. 4. A compound, wherein the compound is anagrelide, a pharmaceutically acceptable salt, solvate or active metabolite thereof, for use in inhibiting the stimulatory effect of cancer cells on the process of megakaryocytopoiesis and platelet formation in a patient. 5. The compound for use of any preceding claim, wherein the patient is a thrombocytotic individual at risk of developing cancer 6. The compound for use of any preceding claim, wherein the patient being treated is a thrombocytotic individual. 7. The compound for use of any preceding claim, wherein the cancer to be treated is selected from the group consisting of brain, oral cavity, the head and neck (e.g. the nasopharanygeal region), thyroid carcinoma, gastrointestinal cancers (e.g. oesophageal or gastric cancers), pancreatic, hepatocellular cancer, colorectal cancer, cancer of the lungs and bronchus, cancer of the ovaries, endometrium, cervix, breast, prostate, kidneys, skin mesothelioma, melanoma, gallbladder and multiple myeloma. 8. The compound for use of any preceding claim, formulated as a cardio-sparing/side effect reducing formulation selected from the group consisting of: sublingual tablets, buccal spray, mucoadhesive buccal tablets, mucoadhesive buccal films, buccal lozenges/lollipops, rectal suppositories, rectal gels, nasal spray, pulmonary delivery devices, transdermal patches gels ointments or creams, injectable formulations including those given intravenously, intramuscularly or subcutaneously as immediate and sustained release preparations. 9. The compound for use of any preceding claim, wherein the platelet count is reduced to an upper limit of 400×103/μL but above a lower limit of 150×103/μL. 10. The compound for use of any preceding claim, wherein the platelet count is reduced to an upper limit of 350×103/μL but above a lower limit of 150×103/μL. 11. The compound for use of any preceding claim, wherein the platelet count is reduced to an upper limit of 300×103/μL but above a lower limit of 150×103/μL 12. The compound for use of any preceding claim, wherein the platelet count is reduced to an upper limit of 250×103/μL but above a lower limit of 150×103/μL | The present invention relates to the use of the anti-megakaryocytic agent anagrelide, or a therapeutically active metabolite thereof, in the prevention or treatment of metastatic disease in cancer patients displaying paraneoplastic thrombocytosis.1. A compound, wherein the compound is anagrelide, a pharmaceutically acceptable salt, solvate or active metabolite thereof, for use in treating or preventing metastatic disease in a thrombocytotic cancer patient. 2. A compound, wherein the compound is anagrelide, a pharmaceutically acceptable salt, solvate or active metabolite thereof, for use in inhibiting the migratory attraction between circulating cancer cells and bone marrow megakaryocytes. 3. The compound for use of claim 2, wherein the inhibition of the migratory attraction between circulating cancer cells and bone marrow megakaryocytes reduces the likelihood of metastases, e.g. bone or lung metastases. 4. A compound, wherein the compound is anagrelide, a pharmaceutically acceptable salt, solvate or active metabolite thereof, for use in inhibiting the stimulatory effect of cancer cells on the process of megakaryocytopoiesis and platelet formation in a patient. 5. The compound for use of any preceding claim, wherein the patient is a thrombocytotic individual at risk of developing cancer 6. The compound for use of any preceding claim, wherein the patient being treated is a thrombocytotic individual. 7. The compound for use of any preceding claim, wherein the cancer to be treated is selected from the group consisting of brain, oral cavity, the head and neck (e.g. the nasopharanygeal region), thyroid carcinoma, gastrointestinal cancers (e.g. oesophageal or gastric cancers), pancreatic, hepatocellular cancer, colorectal cancer, cancer of the lungs and bronchus, cancer of the ovaries, endometrium, cervix, breast, prostate, kidneys, skin mesothelioma, melanoma, gallbladder and multiple myeloma. 8. The compound for use of any preceding claim, formulated as a cardio-sparing/side effect reducing formulation selected from the group consisting of: sublingual tablets, buccal spray, mucoadhesive buccal tablets, mucoadhesive buccal films, buccal lozenges/lollipops, rectal suppositories, rectal gels, nasal spray, pulmonary delivery devices, transdermal patches gels ointments or creams, injectable formulations including those given intravenously, intramuscularly or subcutaneously as immediate and sustained release preparations. 9. The compound for use of any preceding claim, wherein the platelet count is reduced to an upper limit of 400×103/μL but above a lower limit of 150×103/μL. 10. The compound for use of any preceding claim, wherein the platelet count is reduced to an upper limit of 350×103/μL but above a lower limit of 150×103/μL. 11. The compound for use of any preceding claim, wherein the platelet count is reduced to an upper limit of 300×103/μL but above a lower limit of 150×103/μL 12. The compound for use of any preceding claim, wherein the platelet count is reduced to an upper limit of 250×103/μL but above a lower limit of 150×103/μL | 1,600 |
1,150 | 16,859,826 | 1,631 | Contemplated panomic systems and methods significantly improve accuracy of genetic testing by taking into account matched normal data and expression levels of various genes in diseased tissue. Analysis and physician guidance is further improved by combining so identified clinically relevant changes with pathway analysis to thereby allow for classification of a tumor and/or identification of potentially druggable targets within affected pathways. | 1-14. (canceled) 15. A high throughput computer-based genomic analysis system for reducing false positives and negatives, comprising:
at least one multi-lane sequencing device configured to sequence at least one patient's normal tissue and diseased tissue in a common run;
wherein the at least one sequencing device is further configured to generate a genome sequence, an exome sequence and an RNA sequence of the normal and disease tissues by sequencing a genome, an exome, and RNA of the tissues; and
wherein the exome sequence and RNA sequence are enriched relative to the genome sequence by at least a factor of five; and
a modeling computer system comprising:
at least one processor;
at least one memory; and
a modeling and reporting engine executable on the at least one processor:
according to software instructions store in the at least one memory and configured to:
store the genome sequence, the exome sequence, and the RNA sequence of the normal tissue and the diseased tissue of at least one patient in the at least one memory;
store at least one sequence-based treatment model in the at least one memory, wherein the at least one sequence-based treatment model is programmed to generate clinical report data as a function of sequence data;
generate patient-specific clinical report data in the at least one memory by executing the at least one sequence-based treatment model on at least one of the genome sequence, the exome sequence and the RNA sequence of the at least one patient, wherein the clinical report data comprises RNA transcription level for the genomic sequences;
generate a clinical report from the patient-specific clinical report data; and
cause an output device to present the clinical report, wherein the clinical report is annotated as
(a) false positive upon determination that the transcription level is below a threshold level or
(b) true positive upon determination that the transcription level is above the threshold level or
(c) false negative upon determination that the tumor and matched normal have no difference for a specific sequence, and where the transcription level is above the threshold level. 16. The system of claim 15 wherein the at least one multi-lane sequencing device is further configured to sequence at least eight patient's normal tissue and diseased in the common run, or wherein the at least one multi-lane sequencing device includes at least ten one multi-lane sequencing devices. 17. The system of claim 15 wherein the genome sequence comprises less than 20× reads, wherein the exome sequence comprises at least 150× reads, and wherein the RNA sequence comprises at least 150× reads. 18. The system of claim 15 wherein the exome sequence or the RNA sequence is enriched by at least a factor of 10 relative to the genome sequence. 19. The system of claim 15 wherein the at least one treatment model comprises an ensemble of treatment models, a trained treatment outcome prediction model, pathway expression model, a pathway recognition algorithm using data integration on genomic models (PARADIGM), or a drug response model. 20. The system of claim 15 wherein the at least one of the genome sequence, the exome sequence, and the RNA sequence is stored in the at least one memory according to a BAMBAM format. | Contemplated panomic systems and methods significantly improve accuracy of genetic testing by taking into account matched normal data and expression levels of various genes in diseased tissue. Analysis and physician guidance is further improved by combining so identified clinically relevant changes with pathway analysis to thereby allow for classification of a tumor and/or identification of potentially druggable targets within affected pathways.1-14. (canceled) 15. A high throughput computer-based genomic analysis system for reducing false positives and negatives, comprising:
at least one multi-lane sequencing device configured to sequence at least one patient's normal tissue and diseased tissue in a common run;
wherein the at least one sequencing device is further configured to generate a genome sequence, an exome sequence and an RNA sequence of the normal and disease tissues by sequencing a genome, an exome, and RNA of the tissues; and
wherein the exome sequence and RNA sequence are enriched relative to the genome sequence by at least a factor of five; and
a modeling computer system comprising:
at least one processor;
at least one memory; and
a modeling and reporting engine executable on the at least one processor:
according to software instructions store in the at least one memory and configured to:
store the genome sequence, the exome sequence, and the RNA sequence of the normal tissue and the diseased tissue of at least one patient in the at least one memory;
store at least one sequence-based treatment model in the at least one memory, wherein the at least one sequence-based treatment model is programmed to generate clinical report data as a function of sequence data;
generate patient-specific clinical report data in the at least one memory by executing the at least one sequence-based treatment model on at least one of the genome sequence, the exome sequence and the RNA sequence of the at least one patient, wherein the clinical report data comprises RNA transcription level for the genomic sequences;
generate a clinical report from the patient-specific clinical report data; and
cause an output device to present the clinical report, wherein the clinical report is annotated as
(a) false positive upon determination that the transcription level is below a threshold level or
(b) true positive upon determination that the transcription level is above the threshold level or
(c) false negative upon determination that the tumor and matched normal have no difference for a specific sequence, and where the transcription level is above the threshold level. 16. The system of claim 15 wherein the at least one multi-lane sequencing device is further configured to sequence at least eight patient's normal tissue and diseased in the common run, or wherein the at least one multi-lane sequencing device includes at least ten one multi-lane sequencing devices. 17. The system of claim 15 wherein the genome sequence comprises less than 20× reads, wherein the exome sequence comprises at least 150× reads, and wherein the RNA sequence comprises at least 150× reads. 18. The system of claim 15 wherein the exome sequence or the RNA sequence is enriched by at least a factor of 10 relative to the genome sequence. 19. The system of claim 15 wherein the at least one treatment model comprises an ensemble of treatment models, a trained treatment outcome prediction model, pathway expression model, a pathway recognition algorithm using data integration on genomic models (PARADIGM), or a drug response model. 20. The system of claim 15 wherein the at least one of the genome sequence, the exome sequence, and the RNA sequence is stored in the at least one memory according to a BAMBAM format. | 1,600 |
1,151 | 15,585,697 | 1,653 | Methods of treating osteoarthritis using protocatechuic acid (PCA) injected into an osteoarthritis joint are provided. | 1. A method of inhibiting interleukin-1 (IL-1) induced glycosaminoglycoside (GAG) release in an arthritic joint of a subject, comprising administering into the arthritic joint of the subject by an intra-articular injection, a composition that is a solution consisting of protocatechuic acid (“PCA”), glucose and a pharmaceutically acceptable carrier, wherein the concentration of said glucose in said solution is 5%, and wherein the PCA is administered at a dose of 0.002 mg to 100 mg per joint. 2. The method according to claim 1, wherein the composition increases gene expression of IGF-1 in the arthritic joint. 3. The method according to claim 1, wherein the composition is provided in a biodegradable microsphere. 4. The method according to claim 3, wherein the microsphere comprises a slow release bioadsorbable material. 5. The method according to claim 4, wherein the bioadsorbable material is 50/50 D, L lactide/glycolide or 85/15 D, L lactide/glycolide. 6. The method according to claim 1, wherein inhibiting interleukin-1 (IL-1) induced glycosaminoglycoside (GAG) release in the arthritic joint of a subject is associated with a chondroprotective effect in the joint of a subject. 7. The method according to claim 1, wherein inhibiting interleukin-1 (IL-1) induced glycosaminoglycoside release in the arthritic joint of a subject is associated with a chondronutritive effect in the joint of a subject. 8. A method for treating damaged cartilage in an arthritic joint in a subject, comprising administering into the arthritic joint of the subject, by an intra-articular injection of a composition that is a solution consisting of PCA, glucose and a pharmaceutically acceptable carrier, wherein the concentration of said glucose in said solution is 5%, and wherein the PCA is administered at a dose of 0.002 mg to 100 mg per joint. 9. The method according to claim 11, wherein the composition stimulates the production of insulin-like growth factor-1 (IGF-1) in a joint to regenerate the damaged cartilage. 10. The method of claim 1 wherein the joint is a synovial joint. 11. The method of claim 8 wherein the joint is a synovial joint. | Methods of treating osteoarthritis using protocatechuic acid (PCA) injected into an osteoarthritis joint are provided.1. A method of inhibiting interleukin-1 (IL-1) induced glycosaminoglycoside (GAG) release in an arthritic joint of a subject, comprising administering into the arthritic joint of the subject by an intra-articular injection, a composition that is a solution consisting of protocatechuic acid (“PCA”), glucose and a pharmaceutically acceptable carrier, wherein the concentration of said glucose in said solution is 5%, and wherein the PCA is administered at a dose of 0.002 mg to 100 mg per joint. 2. The method according to claim 1, wherein the composition increases gene expression of IGF-1 in the arthritic joint. 3. The method according to claim 1, wherein the composition is provided in a biodegradable microsphere. 4. The method according to claim 3, wherein the microsphere comprises a slow release bioadsorbable material. 5. The method according to claim 4, wherein the bioadsorbable material is 50/50 D, L lactide/glycolide or 85/15 D, L lactide/glycolide. 6. The method according to claim 1, wherein inhibiting interleukin-1 (IL-1) induced glycosaminoglycoside (GAG) release in the arthritic joint of a subject is associated with a chondroprotective effect in the joint of a subject. 7. The method according to claim 1, wherein inhibiting interleukin-1 (IL-1) induced glycosaminoglycoside release in the arthritic joint of a subject is associated with a chondronutritive effect in the joint of a subject. 8. A method for treating damaged cartilage in an arthritic joint in a subject, comprising administering into the arthritic joint of the subject, by an intra-articular injection of a composition that is a solution consisting of PCA, glucose and a pharmaceutically acceptable carrier, wherein the concentration of said glucose in said solution is 5%, and wherein the PCA is administered at a dose of 0.002 mg to 100 mg per joint. 9. The method according to claim 11, wherein the composition stimulates the production of insulin-like growth factor-1 (IGF-1) in a joint to regenerate the damaged cartilage. 10. The method of claim 1 wherein the joint is a synovial joint. 11. The method of claim 8 wherein the joint is a synovial joint. | 1,600 |
1,152 | 15,302,796 | 1,619 | Disclosed are cosmetic or pharmaceutical composition comprising a UV filter combination of
(a) an aqueous dispersion of 5,6,5′,6′-tetraphenyl-3,3′-(1,4-Phenylene)bis(1,2,4-Triazine) corresponding to the formula
in particulate form; and
(b) the UV filters selected from
(b 1 ) Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine; (b 2 ) Butyl Methoxydibenzoylmethane; (b 3 ) Diethylhexyl Butamido Triazone; (b 4 ) Ethylhexyl Triazone; (b 5 ) Diethylamino Hydroxy Benzoyl Hexyl Benzoate; (b 6 ) Ethyhexyl Methoxycinnamate; (b 7 ) Ethylhexyl Salicylate; (b 8 ) Homosalate; (b 9 ) Octocrylene; (b 10 ) Methylene Bis-Benzotriazolyl Tetramethylbutylphenol; (b 11 ) Phenylbenzimidazole Sulfonic Acid; (b 12 ) Titanium Dioxide; (b 13 ) Tris-Biphenyl Triazine; and (b 14 ) (2-{4-[2-(4-Diethylamino-2-hydroxy-benzoyl)-benzoyl]-piperazine-1- carbonyl}-phenyl)-(4- diethylami- no-2-hydroxy-phenyl)-methanone; (b 15 ) BBDAPT; Benzoic acid, 4,4′-[[6-[[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]-1 disiloxanyl]propyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-, dibutyl ester; (b 16 ) benzylidene malonates; and (b 17 ) merocyanine derivatives; (b 18 ) Bis(butylbenzoate) diaminotriazine aminopropylsiloxane; (b 19 ) Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine) encapsulated in a polymer matrix; (b 20 ) 2-(2H-Benzotriazol-2-yl)-6-[(2-ethylhexyloxy)methyl]-4-methylphenol; and (b 21 ) 2-Propenoic acid, 3-(4-methoxyphenyl)-, 2-methylphenyl ester. | 1.-22. (canceled) 23. A cosmetic or pharmaceutical composition comprising a UV filter combination of
(a) an aqueous dispersion of 5,6,5′,6′-tetraphenyl-3,3′-(1,4-Phenylene)bis(1,2,4-Triazine) corresponding to the formula
in particulate form; and
(b) the UV filters selected from the group consisting of
(b1) Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine;
(b2) Butyl Methoxydibenzoylmethane;
(b3) Diethylhexyl Butamido Triazone;
(b4) Ethylhexyl Triazone;
(b5) Diethylamino Hydroxy Benzoyl Hexyl Benzoate;
(b6) Ethylhexyl Methoxycinnamate;
(b7) Ethylhexyl Salicylate;
(b8) Homosalate;
(b9) Octocrylene;
(b10) Methylene Bis-Benzotriazolyl Tetramethylbutylphenol;
(b11) Phenylbenzimidazole Sulfonic Acid;
(b12) Titanium Dioxide;
(b13) Tris-Biphenyl Triazine;
(b14) (2-{4-[2-(4-Diethylamino-2-hydroxy-benzoyl)-benzoyl]-piperazine-1-carbonyl}-phenyl)-(4-diethylamino-2-hydroxy-phenyl)-methanone;
(b15) BBDAPT; Benzoic acid, 4,4′-[[6-[[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]-1 disiloxanyl]propyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-, dibutyl ester;
(b16) benzylidene malonates;
(b17) merocyanine derivatives;
(b18) Bis(butylbenzoate) diaminotriazine aminopropylsiloxane;
(b19) Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine) encapsulated in a polymer matrix;
(b20) 2-(2H-Benzotriazol-2-yl)-6-[(2-ethylhexyloxy)methyl]-4-methylphenol; and
(b21) 2-Propenoic acid, 3-(4-methoxyphenyl)-, 2-methylphenyl ester.
wherein said composition contains at least two of the UV filters (b1)-(b17); and
wherein said composition also contains a pharmaceutically or cosmetically acceptable excipient. 24. The cosmetic or pharmaceutical composition according to claim 23, wherein component (a) represents an aqueous dispersion comprising the UV filter of formula (1) in a concentration range from 40 to 50% b.w. 25. The cosmetic or pharmaceutical composition according to claim 23, wherein the aqueous dispersion according to component (a) contains a dispersing agent selected from PPG-1-PEG-9 Lauryl Glycol Ether. 26. The cosmetic or pharmaceutical composition according to claim 23, wherein the compound of formula (1) is present in the micronized state. 27. The cosmetic or pharmaceutical composition according to claim 23, wherein the average particle size of component (a) is in the range from 0.02 to 2 micrometres. 28. The cosmetic or pharmaceutical composition according to claim 23, wherein component (a) represents an aqueous dispersion comprising the UV filter of formula (1) encapsulated in a polymer carrier in a concentration range from 20 to 50% b.w. 29. The cosmetic or pharmaceutical composition according to claim 23, comprising
(UV1) Phenylene Bis-Diphenyltriazine (a) of formula (1); (UV2) Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine (b1); and (UV3) filters selected from the group consisting of
(UV31) Diethylamino Hydroxy Benzoyl Hexyl Benzoate (b5);
(UV32) Butyl Methoxydibenzoylmethane (b2); and
(UV33) Benzoic acid, 4,4′-[[6-[[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]-1 disiloxanyl]propyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-, dibutyl ester (b15). 30. The cosmetic or pharmaceutical composition according to claim 23, comprising
(UV1) Phenylene Bis-Diphenyltriazine (a) of formula (1); (UV2) Methylene Bis-Benzotriazolyl Tetramethylbutylphenol (b10); and (UV3) filters selected from the group consisting of
(UV31) Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine (b1);
(UV32) Diethylamino Hydroxy Benzoyl Hexyl Benzoate (b5);
(UV33) Butyl Methoxydibenzoylmethane (b2); and
(UV34) Benzoic acid, 4,4′-[[6-[[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]-1 disiloxanyl]propyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-, dibutyl ester. 31. The cosmetic or pharmaceutical composition according to claim 23, comprising
(UV1) Phenylene Bis-Diphenyltriazine (a) of formula (1); (UV2) Diethylamino Hydroxy Benzoyl Hexyl Benzoate (b5); and (UV3) Butyl Methoxydibenzoylmethane (b2). 32. The cosmetic or pharmaceutical composition according to claim 23, comprising
(UV1) Phenylene Bis-Diphenyltriazine (a) of formula (1); (UV2) Ethylhexyl Triazone (b4); and UV filters (UV3) selected from the group consisting of
(UV31) Methylene Bis-Benzotriazolyl Tetramethylbutylphenol (b10);
(UV32) Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine (b1);
(UV33) Diethylamino Hydroxy Benzoyl Hexyl Benzoate (b5);
(UV34) Butyl Methoxydibenzoylmethane (b2); and
(UV35) Benzoic acid, 4,4′-[[6-[[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]-1 disiloxanyl]propyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-, dibutyl ester (b15). 33. The cosmetic or pharmaceutical composition according to claim 23, comprising
(UV1) Phenylene Bis-Diphenyltriazine (a) of formula (1); (UV2) Benzoic acid, 4,4′-[[6-[[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]-1 disiloxanyl]-propyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-, dibutyl ester (b15); and UV filters (UV3) selected from the group consisting of
(UV31) Methylene Bis-Benzotriazolyl Tetramethylbutylphenol (b10);
(UV32) Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine (b1);
(UV33) Diethylamino Hydroxy Benzoyl Hexyl Benzoate (b5); and
(UV34) Butyl Methoxydibenzoylmethane (b2). 34. The cosmetic or pharmaceutical composition according to claim 23, comprising
(UV1) Phenylene Bis-Diphenyltriazine (a) of formula (1); (UV2) Methylene Bis-Benzotriazolyl Tetramethylbutylphenol (b10); (UV3) Ethylhexyl Triazone (b4); and UV filters (UV4) selected from the group consisting of
(UV41) Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine (b1);
(UV42) Diethylamino Hydroxy Benzoyl Hexyl Benzoate (b5);
(UV43) Butyl Methoxydibenzoylmethane (b2); and
(UV44) Benzoic acid, 4,4′-[[6-[[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]-1 disiloxanyl]propyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-, dibutyl ester (b15). 35. The cosmetic or pharmaceutical composition according to claim 23, comprising
(UV1) Phenylene Bis-Diphenyltriazine (a) of formula (1); (UV2) Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine (b1); (UV3) Ethylhexyl Triazone (b4); and the UV filters (UV4) selected from the group consisting of
(UV41) Diethylamino Hydroxy Benzoyl Hexyl Benzoate (b5);
(UV42) Butyl Methoxydibenzoylmethane (b2); and
(UV43) Benzoic acid, 4,4′-[[6-[[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]-1 disiloxanyl]propyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-, dibutyl ester (b15). 36. The cosmetic or pharmaceutical composition according to claim 23, comprising
(UV1) Phenylene Bis-Diphenyltriazine (a) of formula (1); (UV2) Diethylamino Hydroxy Benzoyl Hexyl Benzoate (b5); (UV3) Butyl Methoxydibenzoylmethane (b2); and (UV4) Ethylhexyl Triazone (b4). 37. The cosmetic or pharmaceutical composition according to claim 23, comprising
(UV1) Phenylene Bis-Diphenyltriazine (a) of formula (1); (UV2) Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine (b1); (UV3) Ethylhexyl Triazone (b4); the UV filters (UV4) selected from the group consisting of
(UV41) Methylene Bis-Benzotriazolyl Tatramethylbutylphenyl (b10
(UV42) Diethylamino Hydroxy Benzoyl Hexyl Benzoate (b5); and
(UV43) Butyl Methoxydibenzoylmethane (b2); and
the UV filters (UV5) selected from the group consisting of
(UV51) Ethylhexyl Salicylate (b7);
(UV52) Tris-Biphenyl Triazine (b13);
(UV53) Octocrylene (b9);
(UV54) Diethylhexyl Butamido Triazone (b3);
(UV55) Phenylbenzimidazole Sulfonic Acid (b11);
(UV56) Titanium Dioxide (b12)
(UV57) Homosalate (b8);
(UV58) (2-{4-[2-(4-Diethylamino-2-hydroxy-benzoyl)-benzoyl]-piperazine-1-carbonyl}-phenyl)-(4-diethylamino-2-hydroxy-phenyl)-methanone (b14); and
(UV59) Benzoic acid, 4,4′-[[6-[[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]-1 disiloxanyl]propyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-, dibutyl ester (b15). 38. The cosmetic or pharmaceutical composition according to claim 23, comprising
(UV1) Phenylene Bis-Diphenyltriazine (a) of formula (1); (UV2) Methylene Bis-Benzotriazolyl Tetramethylbutylphenol (b10); (UV3) Ethylhexyl Triazone (b4); the UV filters (UV4) selected from the group consisting of
(UV41) Diethylamino Hydroxy Benzoyl Hexyl Benzoate (b5)
(UV42) Butyl Methoxydibenzoylmethane (b2);
and the UV filters (UV5) selected from the group consisting of
(UV51) Ethylhexyl Salicylate (b7)
(UV52) Tris-Biphenyl Triazine (b13)
(UV53) Octocrylene (b9)
(UV54) Diethylhexyl Butamido Triazone (b3)
(UV55) Phenylbenzimidazole Sulfonic Acid (b11)
(UV56) Titanium Dioxide (b12)
(UV57) Homosalate (b5)
(UV58) (2-{4-[2-(4-Diethylamino-2-hydroxy-benzoyl)-benzoyl]-piperazine-1-carbonyl}-phenyl)-(4-diethylamino-2-hydroxy-phenyl)-methanone (b14); and
(UV59) Benzoic acid, 4,4′-[[6-[[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]-1 disiloxanyl]propyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-, dibutyl ester (b15). 39. The cosmetic or pharmaceutical composition according to claim 23, wherein the UV filters (b10) Methylene Bis-Benzotriazolyl Tetramethylbutylphenol, (b13) Tris-Biphenyl Triazine and (b14) (2-{4-[2-(4-Diethylamino-2-hydroxy-benzoyl)-benzoyl]-piperazine-1-carbonyl}-phenyl)-(4-diethylamino-2-hydroxy-phenyl)-methanone are present in the cosmetic or pharmaceutical composition in their micronized state. 40. A method for the preparation of an aqueous dispersion comprising the micronized insoluble organic UV absorber of formula (1),
which method comprises grinding the insoluble organic UV absorber, in coarse particle form, in a grinding apparatus in the presence of 1 to 50% by weight of a grinding aid. 41. The method according to claim 40, wherein the grinding apparatus is selected from jet mills, ball mills, vibratory mills and hammer mills. 42. The method according to claim 40, wherein the grinding aid is selected from anionic, non-ionic or amphoteric surfactants, emulsifiers and polymeric grinding aids. 43. The method according to claim 42, wherein the grinding aid is PPG-1-PEG-9 Lauryl Glycol Ether. 44. The method according to claim 40, wherein the compound of formula (1) exhibits a particle size from 0.02 to 2 μm. | Disclosed are cosmetic or pharmaceutical composition comprising a UV filter combination of
(a) an aqueous dispersion of 5,6,5′,6′-tetraphenyl-3,3′-(1,4-Phenylene)bis(1,2,4-Triazine) corresponding to the formula
in particulate form; and
(b) the UV filters selected from
(b 1 ) Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine; (b 2 ) Butyl Methoxydibenzoylmethane; (b 3 ) Diethylhexyl Butamido Triazone; (b 4 ) Ethylhexyl Triazone; (b 5 ) Diethylamino Hydroxy Benzoyl Hexyl Benzoate; (b 6 ) Ethyhexyl Methoxycinnamate; (b 7 ) Ethylhexyl Salicylate; (b 8 ) Homosalate; (b 9 ) Octocrylene; (b 10 ) Methylene Bis-Benzotriazolyl Tetramethylbutylphenol; (b 11 ) Phenylbenzimidazole Sulfonic Acid; (b 12 ) Titanium Dioxide; (b 13 ) Tris-Biphenyl Triazine; and (b 14 ) (2-{4-[2-(4-Diethylamino-2-hydroxy-benzoyl)-benzoyl]-piperazine-1- carbonyl}-phenyl)-(4- diethylami- no-2-hydroxy-phenyl)-methanone; (b 15 ) BBDAPT; Benzoic acid, 4,4′-[[6-[[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]-1 disiloxanyl]propyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-, dibutyl ester; (b 16 ) benzylidene malonates; and (b 17 ) merocyanine derivatives; (b 18 ) Bis(butylbenzoate) diaminotriazine aminopropylsiloxane; (b 19 ) Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine) encapsulated in a polymer matrix; (b 20 ) 2-(2H-Benzotriazol-2-yl)-6-[(2-ethylhexyloxy)methyl]-4-methylphenol; and (b 21 ) 2-Propenoic acid, 3-(4-methoxyphenyl)-, 2-methylphenyl ester.1.-22. (canceled) 23. A cosmetic or pharmaceutical composition comprising a UV filter combination of
(a) an aqueous dispersion of 5,6,5′,6′-tetraphenyl-3,3′-(1,4-Phenylene)bis(1,2,4-Triazine) corresponding to the formula
in particulate form; and
(b) the UV filters selected from the group consisting of
(b1) Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine;
(b2) Butyl Methoxydibenzoylmethane;
(b3) Diethylhexyl Butamido Triazone;
(b4) Ethylhexyl Triazone;
(b5) Diethylamino Hydroxy Benzoyl Hexyl Benzoate;
(b6) Ethylhexyl Methoxycinnamate;
(b7) Ethylhexyl Salicylate;
(b8) Homosalate;
(b9) Octocrylene;
(b10) Methylene Bis-Benzotriazolyl Tetramethylbutylphenol;
(b11) Phenylbenzimidazole Sulfonic Acid;
(b12) Titanium Dioxide;
(b13) Tris-Biphenyl Triazine;
(b14) (2-{4-[2-(4-Diethylamino-2-hydroxy-benzoyl)-benzoyl]-piperazine-1-carbonyl}-phenyl)-(4-diethylamino-2-hydroxy-phenyl)-methanone;
(b15) BBDAPT; Benzoic acid, 4,4′-[[6-[[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]-1 disiloxanyl]propyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-, dibutyl ester;
(b16) benzylidene malonates;
(b17) merocyanine derivatives;
(b18) Bis(butylbenzoate) diaminotriazine aminopropylsiloxane;
(b19) Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine) encapsulated in a polymer matrix;
(b20) 2-(2H-Benzotriazol-2-yl)-6-[(2-ethylhexyloxy)methyl]-4-methylphenol; and
(b21) 2-Propenoic acid, 3-(4-methoxyphenyl)-, 2-methylphenyl ester.
wherein said composition contains at least two of the UV filters (b1)-(b17); and
wherein said composition also contains a pharmaceutically or cosmetically acceptable excipient. 24. The cosmetic or pharmaceutical composition according to claim 23, wherein component (a) represents an aqueous dispersion comprising the UV filter of formula (1) in a concentration range from 40 to 50% b.w. 25. The cosmetic or pharmaceutical composition according to claim 23, wherein the aqueous dispersion according to component (a) contains a dispersing agent selected from PPG-1-PEG-9 Lauryl Glycol Ether. 26. The cosmetic or pharmaceutical composition according to claim 23, wherein the compound of formula (1) is present in the micronized state. 27. The cosmetic or pharmaceutical composition according to claim 23, wherein the average particle size of component (a) is in the range from 0.02 to 2 micrometres. 28. The cosmetic or pharmaceutical composition according to claim 23, wherein component (a) represents an aqueous dispersion comprising the UV filter of formula (1) encapsulated in a polymer carrier in a concentration range from 20 to 50% b.w. 29. The cosmetic or pharmaceutical composition according to claim 23, comprising
(UV1) Phenylene Bis-Diphenyltriazine (a) of formula (1); (UV2) Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine (b1); and (UV3) filters selected from the group consisting of
(UV31) Diethylamino Hydroxy Benzoyl Hexyl Benzoate (b5);
(UV32) Butyl Methoxydibenzoylmethane (b2); and
(UV33) Benzoic acid, 4,4′-[[6-[[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]-1 disiloxanyl]propyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-, dibutyl ester (b15). 30. The cosmetic or pharmaceutical composition according to claim 23, comprising
(UV1) Phenylene Bis-Diphenyltriazine (a) of formula (1); (UV2) Methylene Bis-Benzotriazolyl Tetramethylbutylphenol (b10); and (UV3) filters selected from the group consisting of
(UV31) Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine (b1);
(UV32) Diethylamino Hydroxy Benzoyl Hexyl Benzoate (b5);
(UV33) Butyl Methoxydibenzoylmethane (b2); and
(UV34) Benzoic acid, 4,4′-[[6-[[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]-1 disiloxanyl]propyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-, dibutyl ester. 31. The cosmetic or pharmaceutical composition according to claim 23, comprising
(UV1) Phenylene Bis-Diphenyltriazine (a) of formula (1); (UV2) Diethylamino Hydroxy Benzoyl Hexyl Benzoate (b5); and (UV3) Butyl Methoxydibenzoylmethane (b2). 32. The cosmetic or pharmaceutical composition according to claim 23, comprising
(UV1) Phenylene Bis-Diphenyltriazine (a) of formula (1); (UV2) Ethylhexyl Triazone (b4); and UV filters (UV3) selected from the group consisting of
(UV31) Methylene Bis-Benzotriazolyl Tetramethylbutylphenol (b10);
(UV32) Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine (b1);
(UV33) Diethylamino Hydroxy Benzoyl Hexyl Benzoate (b5);
(UV34) Butyl Methoxydibenzoylmethane (b2); and
(UV35) Benzoic acid, 4,4′-[[6-[[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]-1 disiloxanyl]propyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-, dibutyl ester (b15). 33. The cosmetic or pharmaceutical composition according to claim 23, comprising
(UV1) Phenylene Bis-Diphenyltriazine (a) of formula (1); (UV2) Benzoic acid, 4,4′-[[6-[[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]-1 disiloxanyl]-propyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-, dibutyl ester (b15); and UV filters (UV3) selected from the group consisting of
(UV31) Methylene Bis-Benzotriazolyl Tetramethylbutylphenol (b10);
(UV32) Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine (b1);
(UV33) Diethylamino Hydroxy Benzoyl Hexyl Benzoate (b5); and
(UV34) Butyl Methoxydibenzoylmethane (b2). 34. The cosmetic or pharmaceutical composition according to claim 23, comprising
(UV1) Phenylene Bis-Diphenyltriazine (a) of formula (1); (UV2) Methylene Bis-Benzotriazolyl Tetramethylbutylphenol (b10); (UV3) Ethylhexyl Triazone (b4); and UV filters (UV4) selected from the group consisting of
(UV41) Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine (b1);
(UV42) Diethylamino Hydroxy Benzoyl Hexyl Benzoate (b5);
(UV43) Butyl Methoxydibenzoylmethane (b2); and
(UV44) Benzoic acid, 4,4′-[[6-[[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]-1 disiloxanyl]propyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-, dibutyl ester (b15). 35. The cosmetic or pharmaceutical composition according to claim 23, comprising
(UV1) Phenylene Bis-Diphenyltriazine (a) of formula (1); (UV2) Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine (b1); (UV3) Ethylhexyl Triazone (b4); and the UV filters (UV4) selected from the group consisting of
(UV41) Diethylamino Hydroxy Benzoyl Hexyl Benzoate (b5);
(UV42) Butyl Methoxydibenzoylmethane (b2); and
(UV43) Benzoic acid, 4,4′-[[6-[[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]-1 disiloxanyl]propyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-, dibutyl ester (b15). 36. The cosmetic or pharmaceutical composition according to claim 23, comprising
(UV1) Phenylene Bis-Diphenyltriazine (a) of formula (1); (UV2) Diethylamino Hydroxy Benzoyl Hexyl Benzoate (b5); (UV3) Butyl Methoxydibenzoylmethane (b2); and (UV4) Ethylhexyl Triazone (b4). 37. The cosmetic or pharmaceutical composition according to claim 23, comprising
(UV1) Phenylene Bis-Diphenyltriazine (a) of formula (1); (UV2) Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine (b1); (UV3) Ethylhexyl Triazone (b4); the UV filters (UV4) selected from the group consisting of
(UV41) Methylene Bis-Benzotriazolyl Tatramethylbutylphenyl (b10
(UV42) Diethylamino Hydroxy Benzoyl Hexyl Benzoate (b5); and
(UV43) Butyl Methoxydibenzoylmethane (b2); and
the UV filters (UV5) selected from the group consisting of
(UV51) Ethylhexyl Salicylate (b7);
(UV52) Tris-Biphenyl Triazine (b13);
(UV53) Octocrylene (b9);
(UV54) Diethylhexyl Butamido Triazone (b3);
(UV55) Phenylbenzimidazole Sulfonic Acid (b11);
(UV56) Titanium Dioxide (b12)
(UV57) Homosalate (b8);
(UV58) (2-{4-[2-(4-Diethylamino-2-hydroxy-benzoyl)-benzoyl]-piperazine-1-carbonyl}-phenyl)-(4-diethylamino-2-hydroxy-phenyl)-methanone (b14); and
(UV59) Benzoic acid, 4,4′-[[6-[[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]-1 disiloxanyl]propyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-, dibutyl ester (b15). 38. The cosmetic or pharmaceutical composition according to claim 23, comprising
(UV1) Phenylene Bis-Diphenyltriazine (a) of formula (1); (UV2) Methylene Bis-Benzotriazolyl Tetramethylbutylphenol (b10); (UV3) Ethylhexyl Triazone (b4); the UV filters (UV4) selected from the group consisting of
(UV41) Diethylamino Hydroxy Benzoyl Hexyl Benzoate (b5)
(UV42) Butyl Methoxydibenzoylmethane (b2);
and the UV filters (UV5) selected from the group consisting of
(UV51) Ethylhexyl Salicylate (b7)
(UV52) Tris-Biphenyl Triazine (b13)
(UV53) Octocrylene (b9)
(UV54) Diethylhexyl Butamido Triazone (b3)
(UV55) Phenylbenzimidazole Sulfonic Acid (b11)
(UV56) Titanium Dioxide (b12)
(UV57) Homosalate (b5)
(UV58) (2-{4-[2-(4-Diethylamino-2-hydroxy-benzoyl)-benzoyl]-piperazine-1-carbonyl}-phenyl)-(4-diethylamino-2-hydroxy-phenyl)-methanone (b14); and
(UV59) Benzoic acid, 4,4′-[[6-[[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]-1 disiloxanyl]propyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-, dibutyl ester (b15). 39. The cosmetic or pharmaceutical composition according to claim 23, wherein the UV filters (b10) Methylene Bis-Benzotriazolyl Tetramethylbutylphenol, (b13) Tris-Biphenyl Triazine and (b14) (2-{4-[2-(4-Diethylamino-2-hydroxy-benzoyl)-benzoyl]-piperazine-1-carbonyl}-phenyl)-(4-diethylamino-2-hydroxy-phenyl)-methanone are present in the cosmetic or pharmaceutical composition in their micronized state. 40. A method for the preparation of an aqueous dispersion comprising the micronized insoluble organic UV absorber of formula (1),
which method comprises grinding the insoluble organic UV absorber, in coarse particle form, in a grinding apparatus in the presence of 1 to 50% by weight of a grinding aid. 41. The method according to claim 40, wherein the grinding apparatus is selected from jet mills, ball mills, vibratory mills and hammer mills. 42. The method according to claim 40, wherein the grinding aid is selected from anionic, non-ionic or amphoteric surfactants, emulsifiers and polymeric grinding aids. 43. The method according to claim 42, wherein the grinding aid is PPG-1-PEG-9 Lauryl Glycol Ether. 44. The method according to claim 40, wherein the compound of formula (1) exhibits a particle size from 0.02 to 2 μm. | 1,600 |
1,153 | 13,709,897 | 1,633 | The present application describes an antibody-coding, non-modified or modified RNA and the use thereof for expression of this antibody, for the preparation of a pharmaceutical composition, in particular a passive vaccine, for treatment of tumours and cancer diseases, cardiovascular diseases, infectious diseases, auto-immune diseases, virus diseases and monogenetic diseases, e.g. also in gene therapy. The present invention furthermore describes and in vitro transcription method, in vitro methods for expression of this antibody using the RNA according to the invention and an in vivo method. | 1-37. (canceled) 38. A method of treating a cancer disease, cardiovascular disease, infectious disease or autoimmune disease, the method comprising administering a pharmaceutical composition, the pharmaceutical composition comprising a RNA for intracellular expression of an antibody, wherein the RNA contains at least one coding region, wherein at least one coding region codes for at least one antibody. 39. The method of claim 38, wherein the pharmaceutical composition is a passive vaccine for treatment of tumour or infectious diseases. 40. The method of claim 38, wherein the cancer disease or tumour disease is selected from the group consisting of a melanoma, malignant melanoma, colon carcinoma, lymphoma, sarcoma, blastoma, kidney carcinoma, gastrointestinal tumour, glioma, prostate tumour, bladder cancer, rectal tumour, stomach cancer, oesophageal cancer, pancreatic cancer, liver cancer, mammary carcinoma, uterine cancer, cervical cancer, acute myeloid leukaemia (AML), acute lymphoid leukaemia (ALL), chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL), hepatomas, diverse virus-induced tumour, adenocarcinoma, herpes virus-induced tumour, hepatitis B-induced tumour, HTLV-1- and HTLV-2-induced lymphoma, acusticus neurinoma, lung carcinoma, small cell lung carcinoma, throat cancer, anal carcinoma, glioblastoma, rectum carcinoma, astrocytoma, brain tumour, retinoblastoma, basalioma, brain metastasis, medulloblastoma, vaginal cancer, testicular cancer, thyroid carcinoma, Hodgkin's syndrome, meningeomas, Schneeberger's disease, pituitary tumour, mycosis fungoide, carcinoid, neurinoma, spinalioma, Burkitt's lymphoma, laryngeal cancer. kidney cancer, thymoma, corpus carcinoma, bone cancer, non-Hodgkin's lymphoma, urethral cancer, CUP syndrome, head/neck tumour, oligodendroglioma, vulval cancer, intestinal cancer, colon carcinoma, oesophageal carcinoma, wart condition, small intestine tumour, craniopharyngeomas, ovarian carcinoma, soft tissue tumour, ovarian cancer, pancreatic carcinoma, endometrium carcinoma, liver metastasis, penis cancer, tongue cancer, gallbladder cancer, leukaemia, plasmocytoma, lid tumour and prostate cancer. 41. The method of claim 38, wherein the infectious disease is selected from the group consisting of influenza, malaria, SARS, yellow fever, AIDS, Lyme borreliosis, leishmaniasis, anthrax, meningitis, viral infectious diseases, such as AIDS, condyloma acuminate, molluscum contagiosum, dengue fever, three-day fever, Ebola virus, colds, early summer meningoencephalitis (ESME), influenza, shingles, hepatitis, herpes simplex type I, herpes simplex type II, herpes zoster, influenza, Japanese encephalitis, Lassa fever, Marburg virus, measles, foot and mouth disease, mononucleosis, mumps, Norwalk virus infection, Pfeiffer's glandular fever, smallpox, polio, pseuodcroup, infectious erythema, rabies, warts, West Nile fever, chicken-pox, cytomegalovirus (CMV), bacterial infectious diseases, anthrax, appendicitis, borreliosis, botulism, Campylobacter, Chlamydia trachomatis (inflammation of the urethra, conjunctiva), cholera, diphtheria, donavonosis, epiglottitis, louse-borne typhus, typhoid fever, gas gangrene, gonorrhoea, hare plague, Helicobacter pylori, whooping cough, climatic bubo, osteomyelitis, legionnaires' disease, leprosy, listeriosis, pneumonia, meningitis, bacterial meningitis, anthrax, inflammation of the middle ear, Mycoplasma hominis, neonatal sepsis, noma, paratyphoid fever, plague, Reiter's syndrome, Rocky Mountain spotted fever, Salmonella paratyphoid fever, Salmonella typhoid fever, scarlet fever, syphilis, tetanus, gonorrhoea, tsutsugamushi fever, tuberculosis, typhus, vaginitis, soft chancre, and infectious diseases caused by parasites, protozoa or fungi, such as amoebic dysentery, bilharziosis, Chagas' disease, Echinococcus, fish tapeworm, ichthyotoxism, fox tapeworm, mycosis pedis, dog tapeworm, candiosis, ptyriasis, scabies, cutaneous leishmaniasis, lamblian dysentery, lice, malaria, onchocercosis, fungal diseases, beef tapeworm, schistosomiasis, sleeping sickness, pork tapeworm, toxoplasmosis, trichomoniasis, trypanosomiasis, visceral leishmaniasis, nappy dermatitis, or infections caused by the dwarf tapeworm. 42. The method of claim 38, wherein the cardiovascular disease is selected from the group consisting of coronary heart disease, arteriosclerosis, apoplexy and hypertension, and neuronal disease. 43. The method of claim 42, wherein the neuronal disease is selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis, dystonia, epilepsy, multiple sclerosis and Parkinson's disease. 44. The method of claim 38, wherein the autoimmune disease is selected from the group consisting of autoimmune type I disease, autoimmune type H disease, autoimmune type III disease and autoimmune type IV disease. 45. The method of claim 38, wherein the autoimmune disease is selected from the group consisting of multiple sclerosis (MS), rheumatoid arthritis, diabetes, diabetes type I, systemic lupus erythematosus (SLE), chronic polyarthritis, Basedow's disease, autoimmune forms of chronic hepatitis, colitis ulcerosa, allergy type I diseases, allergy type II diseases, allergy type III diseases, allergy type IV diseases, fibromyalgia, hair loss, Bechterew's disease, Crohn's disease, myasthenia gravis, neurodermatitis, polymyalgia rheumatica, progressive systemic sclerosis (PSS), psoriasis, Reiter's syndrome, rheumatic arthritis, psoriasis and vasculitis. 46. The method of claim 38, wherein the RNA is single-stranded or double-stranded. 47. The method of claim 38, wherein the RNA Is linear or circular, 48. The method of claim 38, wherein the RNA is rRNA, tRNA or mRNA. 49. The method of claim 48, wherein the RNA is an mRNA. 50. The method of claim 38, wherein the antibody coded is chosen from monoclonal and polyclonal antibodies, chimeric antibodies, human antibodies, humanized antibodies, bispecific antibodies, intrabodies and fragments of these antibodies. 51. The method of claim 38, wherein the coded antibody fragments are chosen from Fab, Fab′, F(ab′)2, Fe, Facb, pFc′, Fd, and FIT or scFv fragments of these antibodies. 52. The method of claim 38, wherein the coded antibodies or antibody fragments specifically recognize and bind tumour-specific surface antigens chosen from (TSSA), 5T4, a5β1-integrin, 707-AP, AFP, ART-4, B7H4, BAGE, β-catenin/m, Bcr-abl, MN/C IX-antigen, CA125, CAMEL, CAP-1, CASP-8, β-catenin/m, CB4, CD19, CD20, CD22, CD25, CDC27/m, CD 30, CD33, CD52, CD56, CD80, CDK4/m, CEA, CT, Cyp-B, DAM, EGFR, ErbB3, ELF2M, EMMPRIN, EpCam, ETV6-AML1, G250, GAGE, GnT-V, Gp100, HAGE, HER-2/neu, HLAA*0201-R170I, HPV-E7, HSP70-2M, HAST-2, hTERT (or hTRT), iCE, IGF-1R, IL2R, IL-5, KIAA0205, LAGE, LDLR/FUT, MAGE, MART-1 /Melan-A, MART-2/Ski, MC1R, myosin/m, MUC1, MUM-1, -2, -3, NA88-A, PAP, proteinase-3, p190 minor bcr-abl, Pm1/RARα, FRAME, PSA, PSM, PSMA, RAGE, RU1 or RU2, SAGE, SART-1 or SART-3, survivin, TEL/AML1, TGFβ, TPI/m, TRP-1, TRP-2, TRP-2/INT2, VEGF and WT1, NY-Eso-1 and NY-Eso-B. 53. The method of claim 38, wherein the RNA is modified. 54. The method of claim 53, wherein the modification is chosen from modifications of the nucleotide sequence compared with a precursor RNA sequence by introduction of non-native nucleotides and/or by covalent coupling of the RNA with another group. 55. The method of claim 54, wherein the RNA has a G/C content in the coding region of the base-modified RNA which is greater than the G/C content of the coding region of the native RNA sequence, the coded amino acid sequence being unchanged with respect to the wild-type or, respectively, the precursor RNA. 56. The method of claim 54, wherein the coding region of the modified RNA is modified compared with the coding region of the native RNA such that at least one codon of the native RNA which codes for a tRNA which is relatively rare in the ceil is exchanged for a codon which codes for a tRNA which is relatively frequent in the cell and which carries the same amino acid as the relatively rare tRNA. 57. The method of claim 54, wherein the RNA has a lipid modification. 58. The method of claim 54, wherein the RNA contains on at least one nucleotide of the RNA a modification of a nucleotide, wherein the nucleotides are chosen from 1-methyl-adenine, 2-methyl-adenine, 2-methylthio-N-6-isopentenyl-adenine, N6-methyl-adenine, N6-isopentenyl-adenine, 2-thio-cytosine, 3-methyl-cytosine, 4-acetyl-cytosine, 5-methyl-cytosine, 2,6-diaminopurine, 1-methyl-guanine, 2-methyl-guanine, 2,2-dimethyl-guanine, 7-methyl-guanine, inosine, 1 -methyl-inosine, dihydro-uracil, 2-thio-uracil, 4-thio-uracil, 5-carboxymethylaminomethyl-2-thio-uracil, 5-(carboxyhydroxymethyl)-uracil, 5-fluoro-uracil, 5-bromo-uracil, 5-carboxymethylaminomethyl-uracil, 5-methyl-2-thio-uracil, 5-methyl-uracil, N-uracil-5-oxyacetic acid methyl ester, 5-methylaminomethyl-uracil, 5-methoxyaminomethyl-2-thio-uracil, 5-methoxycarbonylmethyl-uracil, 5-methoxy-uracil, uracil-5-oxyacetic acid methyl ester, uracil-5-oxyacetic acid (v), pseudouracil, 1-methyl-pseudouracil, queosine, β-D-mannosyl-queosine, wybutoxosine, and phosphoramidates, phosphorothioates, peptide nucleotides, methylphosphonates, 7-deazagnanosines 5-methylcytosine and inosine. 59. The method of claim 54, wherein the RNA contains on at least one nucleotide of the RNA a modification of a nucleotide, wherein the nucleotides are base-modified nucleotides chosen from the group consisting of 2-amino-6-chloropurine riboside 5′-triphosphate, 2-aminoadenosine 5′-triphosphate, 2-thiocytidine 5′-triphosphate, 2-thiouridine 5′-triphosphate, 4-thiouridine 5′-triphosphate, 5-aminoallylcytidine 5′-triphosphate, 5-aminoallyluridine 5′-triphosphate, 5-bromocytidine 5′-triphosphate, 5-bromouridine 5′-triphosphate, 5-iodocytidine 5-triphosphate, 5-iodouridine 5′-triphosphate, 5-methylcytidine 51-triphosphate, 5-methyluridine 5′-triphosphate, 6-azacytidine 5′-triphosphate, 6-azauridine 5′-triphosphate, 6-cholorpurine riboside 5′-triphosphate, 7-deazaadenosine 5′-triphosphate, 7-deazaguanosine 5′-triphosphate, 8-azaadenosine 5′-triphosphate, 8-azidoadenosine 5′-triphosphate, benzimidazole riboside 5′-triphosphate, N1-methyladenosine 5′-triphosphate, N1-methylguanosine 5′-triphosphate, N6-methyladenosine 5′-triphosphate, O6-methylguanosine 5′-triphosphate, pseudouridine 5′-triphosphate, puromycin 5′-triphosphate or xanthosine 5′-triphosphate. 60. The method of claim 59, wherein the base-modified nucleotides are chosen from the group consisting of 5-methylcytidine 5′-triphosphate and pseudouridine 5′-triphosphate. 61. The method of claim 38, wherein the RNA additionally has a 5′ cap structure chosen from the group consisting of m7G(5′)ppp (5′(A,G(5′)ppp(5′)A and G(5′)ppp(5′)G. 62. The method of claim 38, wherein the RNA additionally has a poly-A tail of from about 10 to 200 adenosine nucleotides (SEQ ID NO: 62). 63. The method of claim 38, wherein the RNA additionally has a poly-C tail of from about 10 to 200 cytosine nucleotides (SEQ ID NO: 54). 64. The method of claim 38, wherein the RNA additionally codes a tag for purification chosen from the group consisting of a hexahistidine tag (SEQ ID NO: 59) (HIS tag, polyhistidine tag), a streptavidin tag (Strep tag), an SBP tag (streptavidin-binding tag) or a GST (glutathione S-transferase) tag, or codes for a tag for purification via an antibody epitope chosen from the group consisting of antibody-binding tags, a Mye tag, a Swa11 epitope, a FLAG tag or an HA tag. 65. The method of claim 38, wherein the RNA additionally codes a signal peptide and/or a localization sequence, in particular a secretion sequence. 66. The method of claim 65, wherein the localization sequence is chosen from one of the sequences according to SEQ ID NO: 18 to 50. 67. The method of claim 38, wherein the RNA contains an antibody-coding sequence which codes for the heavy chains according to SEQ ID NO: 2 and the light chains according to SEQ ID NO: 4. 68. The method of claim 38, wherein the RNA contains an antibody-coding sequence according to SEQ ID NO: 5. 69. The method of claim 38, wherein the RNA contains an antibody-coding sequence which codes for the heavy chains according to SEQ ID NO: 7 and the light chains according to SEQ ID NO: 9. 70. The method of claim 38, wherein the RNA contains an antibody-coding sequence according to SEQ ID NO: 10. 71. The method of claim 38, wherein the modified RNA contains an antibody-coding sequence which codes for the heavy chains according to SEQ ID NO: 12 and the light chains according to SEQ ID NO: 14. 72. The method of claim 38, wherein the RNA contains an antibody-coding sequence according to SEQ ID NO: 15. 73. The method of claim 38, wherein the modified RNA contains an antibody-coding sequence which has a sequence identity of at least 70% to the sequence SEQ ID NO: 5,10 or 15 over the total length of the nucleic acid sequence of SEQ ID NO: 5, 10 or 15. 74. In vitro transcription method for the preparation of an antibody-coding, optionally modified RNA, comprising the following steps:
a. provision of a nucleic acid which codes for an antibody, as defined in claim 13; b. addition of the nucleic acid to an in vitro transcription medium comprising an RNA polymerase, a suitable buffer, a nucleic acid mix comprising one or more modified nucleotides in exchange for one or more of the naturally occurring nucleotides A, G, C or U, and optionally one or more naturally occurring nucleotides A, G, C or U, if not ail the naturally occurring nucleotides A, G, C or U are to be exchanged, or optionally only naturally occurring nucleotides and optionally an RNase inhibitor; c. incubation of the nucleic acid in the in vitro transcription medium and in vitro transcription of the nucleic acid to give an antibody-coding, optionally modified RNA according to claim 38; d. optionally purification of the antibody-coding, optionally modified RNA and removal of the non-incorporated nucleotides from the in vitro transcription medium. 75. In vitro transcription and translation method for expression of an antibody, comprising the following steps:
a. provision of a nucleic acid which codes for an antibody, as defined in claim 13; b. addition of the nucleic acid to an in vitro transcription medium comprising an RNA polymerase, a suitable buffer, a nucleic acid mix comprising one or more modified nucleotides in exchange for one or more of the naturally occurring nucleotides A, O, C or U, and optionally one or more naturally occurring nucleotides A, G, C or U, if not ail the naturally occurring nucleotides A, G, C or U are to be exchanged, or optionally only naturally occurring nucleotides and optionally an RNase inhibitor; c. incubation of the nucleic acid in the in vitro transcription medium and in vitro transcription of the nucleic acid to give an antibody-coding, optionally modified RNA according to claim 38; d. optionally purification of the antibody-coding, optionally modified RNA and removal of the non-incorporated nucleotides from the in vitro transcription medium, e. addition of the optionally modified RNA obtained in step c) (and optionally in step d) to an in vitro translation medium; f. incubation of the optionally modified RNA in the in vitro translation medium and in vitro translation of the antibody coded by the optionally modified RNA; g. optionally purification of the antibody translated in step f). 76. In vitro transcription and translation method for expression of an antibody in a host cell, comprising the following steps:
a. provision of a nucleic acid which codes for an antibody, as defined in claim 13; b. addition of the nucleic acid to an in vitro transcription medium comprising an RNA polymerase, a suitable buffer, one or more modified nucleotides in exchange for one or more of the naturally occurring nucleotides A, G, C or U and optionally one or more naturally occurring nucleotides A, G, C or U, if not all the naturally occurring nucleotides A, G, C or U are to be exchanged, or only naturally occurring nucleotides and optionally an RNase inhibitor; c. incubation of the nucleic acid in the in vitro transcription medium and in vitro transcription of the nucleic acid to give an antibody-coding, optionally modified RNA according to claim 38; d. optionally purification of the antibody-coding, optionally modified RNA according to the invention and removal of the non-incorporated nucleotides from the in vitro transcription medium, e. transfection of the optionally modified RNA obtained in step c) (and optionally d)) into a host cell; f. incubation of the optionally modified nucleic acid in the host cell and translation of the antibody coded by the optionally modified RNA in the host cell; g. optionally isolation and/or purification of the antibody translated in step f). | The present application describes an antibody-coding, non-modified or modified RNA and the use thereof for expression of this antibody, for the preparation of a pharmaceutical composition, in particular a passive vaccine, for treatment of tumours and cancer diseases, cardiovascular diseases, infectious diseases, auto-immune diseases, virus diseases and monogenetic diseases, e.g. also in gene therapy. The present invention furthermore describes and in vitro transcription method, in vitro methods for expression of this antibody using the RNA according to the invention and an in vivo method.1-37. (canceled) 38. A method of treating a cancer disease, cardiovascular disease, infectious disease or autoimmune disease, the method comprising administering a pharmaceutical composition, the pharmaceutical composition comprising a RNA for intracellular expression of an antibody, wherein the RNA contains at least one coding region, wherein at least one coding region codes for at least one antibody. 39. The method of claim 38, wherein the pharmaceutical composition is a passive vaccine for treatment of tumour or infectious diseases. 40. The method of claim 38, wherein the cancer disease or tumour disease is selected from the group consisting of a melanoma, malignant melanoma, colon carcinoma, lymphoma, sarcoma, blastoma, kidney carcinoma, gastrointestinal tumour, glioma, prostate tumour, bladder cancer, rectal tumour, stomach cancer, oesophageal cancer, pancreatic cancer, liver cancer, mammary carcinoma, uterine cancer, cervical cancer, acute myeloid leukaemia (AML), acute lymphoid leukaemia (ALL), chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL), hepatomas, diverse virus-induced tumour, adenocarcinoma, herpes virus-induced tumour, hepatitis B-induced tumour, HTLV-1- and HTLV-2-induced lymphoma, acusticus neurinoma, lung carcinoma, small cell lung carcinoma, throat cancer, anal carcinoma, glioblastoma, rectum carcinoma, astrocytoma, brain tumour, retinoblastoma, basalioma, brain metastasis, medulloblastoma, vaginal cancer, testicular cancer, thyroid carcinoma, Hodgkin's syndrome, meningeomas, Schneeberger's disease, pituitary tumour, mycosis fungoide, carcinoid, neurinoma, spinalioma, Burkitt's lymphoma, laryngeal cancer. kidney cancer, thymoma, corpus carcinoma, bone cancer, non-Hodgkin's lymphoma, urethral cancer, CUP syndrome, head/neck tumour, oligodendroglioma, vulval cancer, intestinal cancer, colon carcinoma, oesophageal carcinoma, wart condition, small intestine tumour, craniopharyngeomas, ovarian carcinoma, soft tissue tumour, ovarian cancer, pancreatic carcinoma, endometrium carcinoma, liver metastasis, penis cancer, tongue cancer, gallbladder cancer, leukaemia, plasmocytoma, lid tumour and prostate cancer. 41. The method of claim 38, wherein the infectious disease is selected from the group consisting of influenza, malaria, SARS, yellow fever, AIDS, Lyme borreliosis, leishmaniasis, anthrax, meningitis, viral infectious diseases, such as AIDS, condyloma acuminate, molluscum contagiosum, dengue fever, three-day fever, Ebola virus, colds, early summer meningoencephalitis (ESME), influenza, shingles, hepatitis, herpes simplex type I, herpes simplex type II, herpes zoster, influenza, Japanese encephalitis, Lassa fever, Marburg virus, measles, foot and mouth disease, mononucleosis, mumps, Norwalk virus infection, Pfeiffer's glandular fever, smallpox, polio, pseuodcroup, infectious erythema, rabies, warts, West Nile fever, chicken-pox, cytomegalovirus (CMV), bacterial infectious diseases, anthrax, appendicitis, borreliosis, botulism, Campylobacter, Chlamydia trachomatis (inflammation of the urethra, conjunctiva), cholera, diphtheria, donavonosis, epiglottitis, louse-borne typhus, typhoid fever, gas gangrene, gonorrhoea, hare plague, Helicobacter pylori, whooping cough, climatic bubo, osteomyelitis, legionnaires' disease, leprosy, listeriosis, pneumonia, meningitis, bacterial meningitis, anthrax, inflammation of the middle ear, Mycoplasma hominis, neonatal sepsis, noma, paratyphoid fever, plague, Reiter's syndrome, Rocky Mountain spotted fever, Salmonella paratyphoid fever, Salmonella typhoid fever, scarlet fever, syphilis, tetanus, gonorrhoea, tsutsugamushi fever, tuberculosis, typhus, vaginitis, soft chancre, and infectious diseases caused by parasites, protozoa or fungi, such as amoebic dysentery, bilharziosis, Chagas' disease, Echinococcus, fish tapeworm, ichthyotoxism, fox tapeworm, mycosis pedis, dog tapeworm, candiosis, ptyriasis, scabies, cutaneous leishmaniasis, lamblian dysentery, lice, malaria, onchocercosis, fungal diseases, beef tapeworm, schistosomiasis, sleeping sickness, pork tapeworm, toxoplasmosis, trichomoniasis, trypanosomiasis, visceral leishmaniasis, nappy dermatitis, or infections caused by the dwarf tapeworm. 42. The method of claim 38, wherein the cardiovascular disease is selected from the group consisting of coronary heart disease, arteriosclerosis, apoplexy and hypertension, and neuronal disease. 43. The method of claim 42, wherein the neuronal disease is selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis, dystonia, epilepsy, multiple sclerosis and Parkinson's disease. 44. The method of claim 38, wherein the autoimmune disease is selected from the group consisting of autoimmune type I disease, autoimmune type H disease, autoimmune type III disease and autoimmune type IV disease. 45. The method of claim 38, wherein the autoimmune disease is selected from the group consisting of multiple sclerosis (MS), rheumatoid arthritis, diabetes, diabetes type I, systemic lupus erythematosus (SLE), chronic polyarthritis, Basedow's disease, autoimmune forms of chronic hepatitis, colitis ulcerosa, allergy type I diseases, allergy type II diseases, allergy type III diseases, allergy type IV diseases, fibromyalgia, hair loss, Bechterew's disease, Crohn's disease, myasthenia gravis, neurodermatitis, polymyalgia rheumatica, progressive systemic sclerosis (PSS), psoriasis, Reiter's syndrome, rheumatic arthritis, psoriasis and vasculitis. 46. The method of claim 38, wherein the RNA is single-stranded or double-stranded. 47. The method of claim 38, wherein the RNA Is linear or circular, 48. The method of claim 38, wherein the RNA is rRNA, tRNA or mRNA. 49. The method of claim 48, wherein the RNA is an mRNA. 50. The method of claim 38, wherein the antibody coded is chosen from monoclonal and polyclonal antibodies, chimeric antibodies, human antibodies, humanized antibodies, bispecific antibodies, intrabodies and fragments of these antibodies. 51. The method of claim 38, wherein the coded antibody fragments are chosen from Fab, Fab′, F(ab′)2, Fe, Facb, pFc′, Fd, and FIT or scFv fragments of these antibodies. 52. The method of claim 38, wherein the coded antibodies or antibody fragments specifically recognize and bind tumour-specific surface antigens chosen from (TSSA), 5T4, a5β1-integrin, 707-AP, AFP, ART-4, B7H4, BAGE, β-catenin/m, Bcr-abl, MN/C IX-antigen, CA125, CAMEL, CAP-1, CASP-8, β-catenin/m, CB4, CD19, CD20, CD22, CD25, CDC27/m, CD 30, CD33, CD52, CD56, CD80, CDK4/m, CEA, CT, Cyp-B, DAM, EGFR, ErbB3, ELF2M, EMMPRIN, EpCam, ETV6-AML1, G250, GAGE, GnT-V, Gp100, HAGE, HER-2/neu, HLAA*0201-R170I, HPV-E7, HSP70-2M, HAST-2, hTERT (or hTRT), iCE, IGF-1R, IL2R, IL-5, KIAA0205, LAGE, LDLR/FUT, MAGE, MART-1 /Melan-A, MART-2/Ski, MC1R, myosin/m, MUC1, MUM-1, -2, -3, NA88-A, PAP, proteinase-3, p190 minor bcr-abl, Pm1/RARα, FRAME, PSA, PSM, PSMA, RAGE, RU1 or RU2, SAGE, SART-1 or SART-3, survivin, TEL/AML1, TGFβ, TPI/m, TRP-1, TRP-2, TRP-2/INT2, VEGF and WT1, NY-Eso-1 and NY-Eso-B. 53. The method of claim 38, wherein the RNA is modified. 54. The method of claim 53, wherein the modification is chosen from modifications of the nucleotide sequence compared with a precursor RNA sequence by introduction of non-native nucleotides and/or by covalent coupling of the RNA with another group. 55. The method of claim 54, wherein the RNA has a G/C content in the coding region of the base-modified RNA which is greater than the G/C content of the coding region of the native RNA sequence, the coded amino acid sequence being unchanged with respect to the wild-type or, respectively, the precursor RNA. 56. The method of claim 54, wherein the coding region of the modified RNA is modified compared with the coding region of the native RNA such that at least one codon of the native RNA which codes for a tRNA which is relatively rare in the ceil is exchanged for a codon which codes for a tRNA which is relatively frequent in the cell and which carries the same amino acid as the relatively rare tRNA. 57. The method of claim 54, wherein the RNA has a lipid modification. 58. The method of claim 54, wherein the RNA contains on at least one nucleotide of the RNA a modification of a nucleotide, wherein the nucleotides are chosen from 1-methyl-adenine, 2-methyl-adenine, 2-methylthio-N-6-isopentenyl-adenine, N6-methyl-adenine, N6-isopentenyl-adenine, 2-thio-cytosine, 3-methyl-cytosine, 4-acetyl-cytosine, 5-methyl-cytosine, 2,6-diaminopurine, 1-methyl-guanine, 2-methyl-guanine, 2,2-dimethyl-guanine, 7-methyl-guanine, inosine, 1 -methyl-inosine, dihydro-uracil, 2-thio-uracil, 4-thio-uracil, 5-carboxymethylaminomethyl-2-thio-uracil, 5-(carboxyhydroxymethyl)-uracil, 5-fluoro-uracil, 5-bromo-uracil, 5-carboxymethylaminomethyl-uracil, 5-methyl-2-thio-uracil, 5-methyl-uracil, N-uracil-5-oxyacetic acid methyl ester, 5-methylaminomethyl-uracil, 5-methoxyaminomethyl-2-thio-uracil, 5-methoxycarbonylmethyl-uracil, 5-methoxy-uracil, uracil-5-oxyacetic acid methyl ester, uracil-5-oxyacetic acid (v), pseudouracil, 1-methyl-pseudouracil, queosine, β-D-mannosyl-queosine, wybutoxosine, and phosphoramidates, phosphorothioates, peptide nucleotides, methylphosphonates, 7-deazagnanosines 5-methylcytosine and inosine. 59. The method of claim 54, wherein the RNA contains on at least one nucleotide of the RNA a modification of a nucleotide, wherein the nucleotides are base-modified nucleotides chosen from the group consisting of 2-amino-6-chloropurine riboside 5′-triphosphate, 2-aminoadenosine 5′-triphosphate, 2-thiocytidine 5′-triphosphate, 2-thiouridine 5′-triphosphate, 4-thiouridine 5′-triphosphate, 5-aminoallylcytidine 5′-triphosphate, 5-aminoallyluridine 5′-triphosphate, 5-bromocytidine 5′-triphosphate, 5-bromouridine 5′-triphosphate, 5-iodocytidine 5-triphosphate, 5-iodouridine 5′-triphosphate, 5-methylcytidine 51-triphosphate, 5-methyluridine 5′-triphosphate, 6-azacytidine 5′-triphosphate, 6-azauridine 5′-triphosphate, 6-cholorpurine riboside 5′-triphosphate, 7-deazaadenosine 5′-triphosphate, 7-deazaguanosine 5′-triphosphate, 8-azaadenosine 5′-triphosphate, 8-azidoadenosine 5′-triphosphate, benzimidazole riboside 5′-triphosphate, N1-methyladenosine 5′-triphosphate, N1-methylguanosine 5′-triphosphate, N6-methyladenosine 5′-triphosphate, O6-methylguanosine 5′-triphosphate, pseudouridine 5′-triphosphate, puromycin 5′-triphosphate or xanthosine 5′-triphosphate. 60. The method of claim 59, wherein the base-modified nucleotides are chosen from the group consisting of 5-methylcytidine 5′-triphosphate and pseudouridine 5′-triphosphate. 61. The method of claim 38, wherein the RNA additionally has a 5′ cap structure chosen from the group consisting of m7G(5′)ppp (5′(A,G(5′)ppp(5′)A and G(5′)ppp(5′)G. 62. The method of claim 38, wherein the RNA additionally has a poly-A tail of from about 10 to 200 adenosine nucleotides (SEQ ID NO: 62). 63. The method of claim 38, wherein the RNA additionally has a poly-C tail of from about 10 to 200 cytosine nucleotides (SEQ ID NO: 54). 64. The method of claim 38, wherein the RNA additionally codes a tag for purification chosen from the group consisting of a hexahistidine tag (SEQ ID NO: 59) (HIS tag, polyhistidine tag), a streptavidin tag (Strep tag), an SBP tag (streptavidin-binding tag) or a GST (glutathione S-transferase) tag, or codes for a tag for purification via an antibody epitope chosen from the group consisting of antibody-binding tags, a Mye tag, a Swa11 epitope, a FLAG tag or an HA tag. 65. The method of claim 38, wherein the RNA additionally codes a signal peptide and/or a localization sequence, in particular a secretion sequence. 66. The method of claim 65, wherein the localization sequence is chosen from one of the sequences according to SEQ ID NO: 18 to 50. 67. The method of claim 38, wherein the RNA contains an antibody-coding sequence which codes for the heavy chains according to SEQ ID NO: 2 and the light chains according to SEQ ID NO: 4. 68. The method of claim 38, wherein the RNA contains an antibody-coding sequence according to SEQ ID NO: 5. 69. The method of claim 38, wherein the RNA contains an antibody-coding sequence which codes for the heavy chains according to SEQ ID NO: 7 and the light chains according to SEQ ID NO: 9. 70. The method of claim 38, wherein the RNA contains an antibody-coding sequence according to SEQ ID NO: 10. 71. The method of claim 38, wherein the modified RNA contains an antibody-coding sequence which codes for the heavy chains according to SEQ ID NO: 12 and the light chains according to SEQ ID NO: 14. 72. The method of claim 38, wherein the RNA contains an antibody-coding sequence according to SEQ ID NO: 15. 73. The method of claim 38, wherein the modified RNA contains an antibody-coding sequence which has a sequence identity of at least 70% to the sequence SEQ ID NO: 5,10 or 15 over the total length of the nucleic acid sequence of SEQ ID NO: 5, 10 or 15. 74. In vitro transcription method for the preparation of an antibody-coding, optionally modified RNA, comprising the following steps:
a. provision of a nucleic acid which codes for an antibody, as defined in claim 13; b. addition of the nucleic acid to an in vitro transcription medium comprising an RNA polymerase, a suitable buffer, a nucleic acid mix comprising one or more modified nucleotides in exchange for one or more of the naturally occurring nucleotides A, G, C or U, and optionally one or more naturally occurring nucleotides A, G, C or U, if not ail the naturally occurring nucleotides A, G, C or U are to be exchanged, or optionally only naturally occurring nucleotides and optionally an RNase inhibitor; c. incubation of the nucleic acid in the in vitro transcription medium and in vitro transcription of the nucleic acid to give an antibody-coding, optionally modified RNA according to claim 38; d. optionally purification of the antibody-coding, optionally modified RNA and removal of the non-incorporated nucleotides from the in vitro transcription medium. 75. In vitro transcription and translation method for expression of an antibody, comprising the following steps:
a. provision of a nucleic acid which codes for an antibody, as defined in claim 13; b. addition of the nucleic acid to an in vitro transcription medium comprising an RNA polymerase, a suitable buffer, a nucleic acid mix comprising one or more modified nucleotides in exchange for one or more of the naturally occurring nucleotides A, O, C or U, and optionally one or more naturally occurring nucleotides A, G, C or U, if not ail the naturally occurring nucleotides A, G, C or U are to be exchanged, or optionally only naturally occurring nucleotides and optionally an RNase inhibitor; c. incubation of the nucleic acid in the in vitro transcription medium and in vitro transcription of the nucleic acid to give an antibody-coding, optionally modified RNA according to claim 38; d. optionally purification of the antibody-coding, optionally modified RNA and removal of the non-incorporated nucleotides from the in vitro transcription medium, e. addition of the optionally modified RNA obtained in step c) (and optionally in step d) to an in vitro translation medium; f. incubation of the optionally modified RNA in the in vitro translation medium and in vitro translation of the antibody coded by the optionally modified RNA; g. optionally purification of the antibody translated in step f). 76. In vitro transcription and translation method for expression of an antibody in a host cell, comprising the following steps:
a. provision of a nucleic acid which codes for an antibody, as defined in claim 13; b. addition of the nucleic acid to an in vitro transcription medium comprising an RNA polymerase, a suitable buffer, one or more modified nucleotides in exchange for one or more of the naturally occurring nucleotides A, G, C or U and optionally one or more naturally occurring nucleotides A, G, C or U, if not all the naturally occurring nucleotides A, G, C or U are to be exchanged, or only naturally occurring nucleotides and optionally an RNase inhibitor; c. incubation of the nucleic acid in the in vitro transcription medium and in vitro transcription of the nucleic acid to give an antibody-coding, optionally modified RNA according to claim 38; d. optionally purification of the antibody-coding, optionally modified RNA according to the invention and removal of the non-incorporated nucleotides from the in vitro transcription medium, e. transfection of the optionally modified RNA obtained in step c) (and optionally d)) into a host cell; f. incubation of the optionally modified nucleic acid in the host cell and translation of the antibody coded by the optionally modified RNA in the host cell; g. optionally isolation and/or purification of the antibody translated in step f). | 1,600 |
1,154 | 16,157,225 | 1,628 | The present invention concerns methods for treating and preventing endothelial dysfunction and related disorders, including, for example, pulmonary arterial hypertension, using bardoxolone methyl or analogs thereof. | 1. A method of treating or preventing endothelial dysfunction in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of a compound of the formula:
or a pharmaceutically acceptable salt or tautomer thereof,
wherein the patient has been identified as not having at least one of the following characteristics:
(a) a history of left-sided myocardial disease;
(b) an elevated B-type natriuretic peptide (BNP) level; and
(c) an elevated albumin/creatinine ratio (ACR). 2-62. (canceled) 63. A method of treating or preventing pulmonary hypertension in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of a compound of the formula:
or a pharmaceutically acceptable salt or tautomer thereof. 64-112. (canceled) 113. The method of claim 63, wherein the pulmonary hypertension is pulmonary arterial hypertension. 114-172. (canceled) 173. A method of treating or preventing a cardiovascular disease in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of a compound of the formula:
or a pharmaceutically acceptable salt or tautomer thereof,
wherein the patient has been identified as not having at least one of the following characteristics:
(a) a history of left-sided myocardial disease;
(b) an elevated B-type natriuretic peptide (BNP) level; and
(c) an elevated albumin/creatinine ratio (ACR). 174. The method of claim 173, wherein the cardiovascular disease is atherosclerosis, restenosis, or thrombosis. 175-272. (canceled) 273. A method of treating or preventing chronic kidney disease in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of a compound of the formula:
or a pharmaceutically acceptable salt or tautomer thereof,
wherein the patient has been identified as not having at least one of the following characteristics:
(a) a history of left-sided myocardial disease;
(b) an elevated B-type natriuretic peptide (BNP) level; and
(c) an elevated albumin/creatinine ratio (ACR). 274. The method of claim 273, wherein the patient does not have stage 4 CKD. 275. The method of claim 273, wherein the patient does not have a history of left-sided myocardial disease. 276. The method of claim 273, wherein the patient does not have a history of heart failure. 277. The method of claim 273, wherein the patient does not have an elevated BNP level. 278. The method of claim 277, wherein the patient does not have a BNP level greater than 200 pg/mL. 279. The method of claim 273, wherein the patient does not have an elevated ACR. 280. The method of claim 279, wherein the patient does not have an ACR greater than 300 mg/g. 281. The method of claim 273, wherein the patient's estimated glomerular filtration rate (eGFR) is greater than or equal to 30 mL/min/1.73 m2. 282. The method of claim 281, wherein the patient's eGFR is greater than or equal to 45 mL/min/1.73 m2. 283. The method of claim 282, wherein the patient's eGFR is greater than or equal to 60 mL/min/1.73 m2. 284. The method of claim 273, wherein at least a portion of the compound is present as an amorphous form having an X-ray diffraction pattern (CuKα) with a halo peak at approximately 13.5° 2θ, substantially as shown in FIG. 1C, and a transition glass temperature (Tg). 285. The method of claim 284, wherein the Tg value is in the range of about 120° C. to about 135° C. 286. The method of claim 285, wherein the Tg value is in the range of about 125° C. to about 130° C. 287. The method of claim 273, wherein the pharmaceutically effective amount is a daily dose from about 0.1 mg to about 300 mg of the compound. 288. The method of claim 287, wherein the daily dose is from about 0.5 mg to about 200 mg of the compound. 289. The method of claim 273, wherein the compound is administered orally, intraarterially or intravenously. 290. The method of claim 273, wherein the compound is formulated as a hard or soft capsule or a tablet. 291. The method of claim 273, wherein the compound is formulated as a solid dispersion comprising (i) the compound and (ii) an excipient. 292. The method of claim 291, wherein the excipient is a methacrylic acid ethyl acrylate copolymer. 293. The method of claim 292, wherein the copolymer comprises methacrylic acid and ethyl acrylate at a 1:1 ratio. 294. A method for treating or preventing a disorder for which endothelial dysfunction is a significant contributing factor in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of a compound of the formula:
or a pharmaceutically acceptable salt or tautomer thereof,
wherein the patient has been identified as not having at least one of the following characteristics:
(a) a history of left-sided myocardial disease;
(b) an elevated B-type natriuretic peptide (BNP) level; and
(c) an elevated albumin/creatinine ratio (ACR). | The present invention concerns methods for treating and preventing endothelial dysfunction and related disorders, including, for example, pulmonary arterial hypertension, using bardoxolone methyl or analogs thereof.1. A method of treating or preventing endothelial dysfunction in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of a compound of the formula:
or a pharmaceutically acceptable salt or tautomer thereof,
wherein the patient has been identified as not having at least one of the following characteristics:
(a) a history of left-sided myocardial disease;
(b) an elevated B-type natriuretic peptide (BNP) level; and
(c) an elevated albumin/creatinine ratio (ACR). 2-62. (canceled) 63. A method of treating or preventing pulmonary hypertension in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of a compound of the formula:
or a pharmaceutically acceptable salt or tautomer thereof. 64-112. (canceled) 113. The method of claim 63, wherein the pulmonary hypertension is pulmonary arterial hypertension. 114-172. (canceled) 173. A method of treating or preventing a cardiovascular disease in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of a compound of the formula:
or a pharmaceutically acceptable salt or tautomer thereof,
wherein the patient has been identified as not having at least one of the following characteristics:
(a) a history of left-sided myocardial disease;
(b) an elevated B-type natriuretic peptide (BNP) level; and
(c) an elevated albumin/creatinine ratio (ACR). 174. The method of claim 173, wherein the cardiovascular disease is atherosclerosis, restenosis, or thrombosis. 175-272. (canceled) 273. A method of treating or preventing chronic kidney disease in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of a compound of the formula:
or a pharmaceutically acceptable salt or tautomer thereof,
wherein the patient has been identified as not having at least one of the following characteristics:
(a) a history of left-sided myocardial disease;
(b) an elevated B-type natriuretic peptide (BNP) level; and
(c) an elevated albumin/creatinine ratio (ACR). 274. The method of claim 273, wherein the patient does not have stage 4 CKD. 275. The method of claim 273, wherein the patient does not have a history of left-sided myocardial disease. 276. The method of claim 273, wherein the patient does not have a history of heart failure. 277. The method of claim 273, wherein the patient does not have an elevated BNP level. 278. The method of claim 277, wherein the patient does not have a BNP level greater than 200 pg/mL. 279. The method of claim 273, wherein the patient does not have an elevated ACR. 280. The method of claim 279, wherein the patient does not have an ACR greater than 300 mg/g. 281. The method of claim 273, wherein the patient's estimated glomerular filtration rate (eGFR) is greater than or equal to 30 mL/min/1.73 m2. 282. The method of claim 281, wherein the patient's eGFR is greater than or equal to 45 mL/min/1.73 m2. 283. The method of claim 282, wherein the patient's eGFR is greater than or equal to 60 mL/min/1.73 m2. 284. The method of claim 273, wherein at least a portion of the compound is present as an amorphous form having an X-ray diffraction pattern (CuKα) with a halo peak at approximately 13.5° 2θ, substantially as shown in FIG. 1C, and a transition glass temperature (Tg). 285. The method of claim 284, wherein the Tg value is in the range of about 120° C. to about 135° C. 286. The method of claim 285, wherein the Tg value is in the range of about 125° C. to about 130° C. 287. The method of claim 273, wherein the pharmaceutically effective amount is a daily dose from about 0.1 mg to about 300 mg of the compound. 288. The method of claim 287, wherein the daily dose is from about 0.5 mg to about 200 mg of the compound. 289. The method of claim 273, wherein the compound is administered orally, intraarterially or intravenously. 290. The method of claim 273, wherein the compound is formulated as a hard or soft capsule or a tablet. 291. The method of claim 273, wherein the compound is formulated as a solid dispersion comprising (i) the compound and (ii) an excipient. 292. The method of claim 291, wherein the excipient is a methacrylic acid ethyl acrylate copolymer. 293. The method of claim 292, wherein the copolymer comprises methacrylic acid and ethyl acrylate at a 1:1 ratio. 294. A method for treating or preventing a disorder for which endothelial dysfunction is a significant contributing factor in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of a compound of the formula:
or a pharmaceutically acceptable salt or tautomer thereof,
wherein the patient has been identified as not having at least one of the following characteristics:
(a) a history of left-sided myocardial disease;
(b) an elevated B-type natriuretic peptide (BNP) level; and
(c) an elevated albumin/creatinine ratio (ACR). | 1,600 |
1,155 | 15,765,756 | 1,628 | The present invention relates to methods and pharmaceutical compositions for the treatment of choroidal neovascularisation. In particular, the present invention relates to a method of treating choroidal neovascularisation in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a mineralocorticoid receptor antagonist. | 1. A method of treating choroidal neovascularisation in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a mineralocorticoid receptor antagonist. 2. The method of claim 1 wherein the subject suffers from a disease selected from the group consisting of age-related macular degeneration, myopic choroidal neovascularization, idiopathic choroidal neovascularization, polypoidal chorioretinopathy associated or not to central serous chorioretinoapthy and some inflammatory conditions such as such uveitis posterior, traumatic choroidal rupture, angioid streaks, and ocular histoplasmosis syndrome. 3. The method of claim 1 wherein the choroidal neovascularisation is secondary to age-related macular degeneration. 4. The method of claim 1 wherein the choroidal neovascularisation is secondary to pathological myopia. 5. The method of claim 1 wherein the choroidal neovascularisation is an idiopathic choroidal neovascularisation. 6. The method of claim 1 wherein the subject suffers from polypoidal choroidal vasculopathy. 7. The method of claim 1 wherein the MR antagonist is an epoxy-steroidal mineralocorticoid receptor antagonist or a non-epoxy-steroidal mineralocorticoid receptor antagonist. 8. The method of claim 1 wherein the MR antagonist is administered to the subject in combination with an anti-VEGF agent. 9. The method of claim 1 wherein the subject is refractory to an anti-VEGF treatment. 10. The method of claim 1 wherein the MR antagonist is administered to the subject by intraocular or periocular administration, either directly injected into the vitreous or in a peri-ocular space. 11. The method of claim 1 wherein the MR antagonist is administered to the subject in the form of microspheres that are injected into the subconjunctival space or into the vitreous. 12. The method of claim 10, wherein the peri-ocular space is a sub conjunctival space, a sub tenon space, a peri bulbar space, a reto bular space, an intra scleral space or a supra choroidal space. | The present invention relates to methods and pharmaceutical compositions for the treatment of choroidal neovascularisation. In particular, the present invention relates to a method of treating choroidal neovascularisation in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a mineralocorticoid receptor antagonist.1. A method of treating choroidal neovascularisation in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a mineralocorticoid receptor antagonist. 2. The method of claim 1 wherein the subject suffers from a disease selected from the group consisting of age-related macular degeneration, myopic choroidal neovascularization, idiopathic choroidal neovascularization, polypoidal chorioretinopathy associated or not to central serous chorioretinoapthy and some inflammatory conditions such as such uveitis posterior, traumatic choroidal rupture, angioid streaks, and ocular histoplasmosis syndrome. 3. The method of claim 1 wherein the choroidal neovascularisation is secondary to age-related macular degeneration. 4. The method of claim 1 wherein the choroidal neovascularisation is secondary to pathological myopia. 5. The method of claim 1 wherein the choroidal neovascularisation is an idiopathic choroidal neovascularisation. 6. The method of claim 1 wherein the subject suffers from polypoidal choroidal vasculopathy. 7. The method of claim 1 wherein the MR antagonist is an epoxy-steroidal mineralocorticoid receptor antagonist or a non-epoxy-steroidal mineralocorticoid receptor antagonist. 8. The method of claim 1 wherein the MR antagonist is administered to the subject in combination with an anti-VEGF agent. 9. The method of claim 1 wherein the subject is refractory to an anti-VEGF treatment. 10. The method of claim 1 wherein the MR antagonist is administered to the subject by intraocular or periocular administration, either directly injected into the vitreous or in a peri-ocular space. 11. The method of claim 1 wherein the MR antagonist is administered to the subject in the form of microspheres that are injected into the subconjunctival space or into the vitreous. 12. The method of claim 10, wherein the peri-ocular space is a sub conjunctival space, a sub tenon space, a peri bulbar space, a reto bular space, an intra scleral space or a supra choroidal space. | 1,600 |
1,156 | 16,045,338 | 1,613 | A composition for transdermal delivery of a progestin for progestin hormone therapy is disclosed. Also disclosed is a transdermal delivery device comprising the composition. For progestin-only hormone therapy, the composition contains an anti-oxidant and does not contain an estrogen. For therapy involving a progestin and an estrogen, the composition contains the progestin, the estrogen and an additional anti-oxidant. Methods of improving the stability of progestin-containing compositions comprising oxidative agents are also disclosed. The methods comprise including one or more anti-oxidants in the compositions. | 1. An adhesive polymer matrix composition for transdermal delivery of levonorgestrel, wherein:
(a) the composition comprises the levonorgestrel, an anti-oxidant, and a skin permeation enhancer in a polyacrylate pressure sensitive adhesive (PSA); (b) the composition comprises at least one component that contributes to oxidative degradation of the levonorgestrel, wherein the at least one component is one or more of (i) the polyacrylate PSA, (ii) the skin permeation enhancer wherein the enhancer comprises dimethyl sulfoxide (DMSO), and (iii) polyvinyl pyrrolidone (PVP) or a PVP copolymer; (c) (i) the anti-oxidant is not an estrogen; (ii) the anti-oxidant is not a sulfoxide or a fatty acid; and (iii) the anti-oxidant protects against oxidative degradation of the levonorgestrel by the one or more of the PSA, the DMSO and the PVP or PVP copolymer; and (d) the stability of the composition is improved over the stability of such composition lacking the anti-oxidant. 2. The composition of claim 1 that lacks an estrogen. 3. The composition of claim 1, wherein the anti-oxidant is selected from Vitamins A, C, D, and E, carotenoids, flavanoids, isoflavanoids, beta-carotene, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), glutathione, lycopene, gallic acid and esters thereof, salicylic acid and esters thereof, sulfites, or any combination thereof. 4. The composition of claim 3 that lacks an estrogen. 5. The composition of claim 1 wherein the anti-oxidant is selected from sodium bisulfite, sodium sulfite, isopropyl gallate, Vitamin C, Vitamin E, BHA, BHT, pentaerythritoltetrakis(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate), tris(2,4-di-tert-butylphenyl)phosphite or any combination thereof. 6. The composition of claim 5 that lacks an estrogen. 7. The composition of claim 1, wherein the polyacrylate PSA contributes to oxidative degradation of the levonorgestrel. 8. The composition of claim 1, wherein the skin permeation enhancer is DMSO and the DMSO contributes to the oxidative degradation of the levonorgestrel. 9. The composition of claim 8 that lacks an estrogen. 10. The composition of claim 1, wherein the PVP or PVP copolymer contributes to the oxidative degradation of the levonorgestrel and the PVP copolymer is PVP/vinyl acetate (PVP/VA). 11. The composition of claim 10 that lacks an estrogen. 12. The composition of claim 1, further comprising one or more other skin permeation enhancers selected from a fatty (C8-C20) alcohol ester of a hydroxyl acid, a lower (C1-C4) alkyl ester of a hydroxyl acid, and a C6-C18 fatty acid. 13. The composition of claim 12 that lacks an estrogen. 14. The composition of claim 1, disposed within a transdermal delivery device that comprises a skin contacting surface and a non-skin contacting surface, a release liner adjacent the skin contacting surface and a backing layer adjacent the non-skin contacting surface. 15. A method of improving the stability of a transdermal delivery composition comprising levonorgestrel, the method comprising adding an anti-oxidant other than an estrogen to the composition; wherein
(a) the composition comprises the levonorgestrel and a skin permeation enhancer in a polyacrylate pressure sensitive adhesive (PSA); (b) the composition comprises at least one component that contributes to oxidative degradation of the levonorgestrel, wherein the at least one component is one or more of (i) the polyacrylate PSA, (ii) the skin permeation enhancer wherein the enhancer comprises DMSO, and (iii) polyvinyl pyrrolidone (PVP) or a PVP copolymer; and (c) (i) the anti-oxidant is not a sulfoxide or a fatty acid; and (iii) the anti-oxidant protects against oxidative degradation of the levonorgestrel by the one or more of the PSA, the DMSO and the PVP or PVP copolymer. 16. The method of claim 15, comprising adding an anti-oxidant selected from Vitamins A, C, D, and E, carotenoids, flavanoids, isoflavanoids, beta-carotene, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), glutathione, lycopene, gallic acid and esters thereof, salicylic acid and esters thereof, sulfites, or any combination thereof. 17. The method of claim 15, comprising adding an anti-oxidant selected from sodium bisulfite, sodium sulfite, isopropyl gallate, Vitamin C, Vitamin E, BHA, BHT, pentaerythritoltetrakis(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate), tris(2,4-di-tert-butylphenyl)phosphite or any combination thereof. 18. The method of claim 15, wherein the composition lacks an estrogen. 19. The method of claim 15, wherein the composition comprises a PVP copolymer that is PVP/VA. 20. The method of claim 15, wherein the composition further comprises one or more other skin permeation enhancers selected from a fatty (C8-C20) alcohol ester of a hydroxyl acid, a lower (C1-C4) alkyl ester of a hydroxyl acid, and a C6-C18 fatty acid. | A composition for transdermal delivery of a progestin for progestin hormone therapy is disclosed. Also disclosed is a transdermal delivery device comprising the composition. For progestin-only hormone therapy, the composition contains an anti-oxidant and does not contain an estrogen. For therapy involving a progestin and an estrogen, the composition contains the progestin, the estrogen and an additional anti-oxidant. Methods of improving the stability of progestin-containing compositions comprising oxidative agents are also disclosed. The methods comprise including one or more anti-oxidants in the compositions.1. An adhesive polymer matrix composition for transdermal delivery of levonorgestrel, wherein:
(a) the composition comprises the levonorgestrel, an anti-oxidant, and a skin permeation enhancer in a polyacrylate pressure sensitive adhesive (PSA); (b) the composition comprises at least one component that contributes to oxidative degradation of the levonorgestrel, wherein the at least one component is one or more of (i) the polyacrylate PSA, (ii) the skin permeation enhancer wherein the enhancer comprises dimethyl sulfoxide (DMSO), and (iii) polyvinyl pyrrolidone (PVP) or a PVP copolymer; (c) (i) the anti-oxidant is not an estrogen; (ii) the anti-oxidant is not a sulfoxide or a fatty acid; and (iii) the anti-oxidant protects against oxidative degradation of the levonorgestrel by the one or more of the PSA, the DMSO and the PVP or PVP copolymer; and (d) the stability of the composition is improved over the stability of such composition lacking the anti-oxidant. 2. The composition of claim 1 that lacks an estrogen. 3. The composition of claim 1, wherein the anti-oxidant is selected from Vitamins A, C, D, and E, carotenoids, flavanoids, isoflavanoids, beta-carotene, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), glutathione, lycopene, gallic acid and esters thereof, salicylic acid and esters thereof, sulfites, or any combination thereof. 4. The composition of claim 3 that lacks an estrogen. 5. The composition of claim 1 wherein the anti-oxidant is selected from sodium bisulfite, sodium sulfite, isopropyl gallate, Vitamin C, Vitamin E, BHA, BHT, pentaerythritoltetrakis(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate), tris(2,4-di-tert-butylphenyl)phosphite or any combination thereof. 6. The composition of claim 5 that lacks an estrogen. 7. The composition of claim 1, wherein the polyacrylate PSA contributes to oxidative degradation of the levonorgestrel. 8. The composition of claim 1, wherein the skin permeation enhancer is DMSO and the DMSO contributes to the oxidative degradation of the levonorgestrel. 9. The composition of claim 8 that lacks an estrogen. 10. The composition of claim 1, wherein the PVP or PVP copolymer contributes to the oxidative degradation of the levonorgestrel and the PVP copolymer is PVP/vinyl acetate (PVP/VA). 11. The composition of claim 10 that lacks an estrogen. 12. The composition of claim 1, further comprising one or more other skin permeation enhancers selected from a fatty (C8-C20) alcohol ester of a hydroxyl acid, a lower (C1-C4) alkyl ester of a hydroxyl acid, and a C6-C18 fatty acid. 13. The composition of claim 12 that lacks an estrogen. 14. The composition of claim 1, disposed within a transdermal delivery device that comprises a skin contacting surface and a non-skin contacting surface, a release liner adjacent the skin contacting surface and a backing layer adjacent the non-skin contacting surface. 15. A method of improving the stability of a transdermal delivery composition comprising levonorgestrel, the method comprising adding an anti-oxidant other than an estrogen to the composition; wherein
(a) the composition comprises the levonorgestrel and a skin permeation enhancer in a polyacrylate pressure sensitive adhesive (PSA); (b) the composition comprises at least one component that contributes to oxidative degradation of the levonorgestrel, wherein the at least one component is one or more of (i) the polyacrylate PSA, (ii) the skin permeation enhancer wherein the enhancer comprises DMSO, and (iii) polyvinyl pyrrolidone (PVP) or a PVP copolymer; and (c) (i) the anti-oxidant is not a sulfoxide or a fatty acid; and (iii) the anti-oxidant protects against oxidative degradation of the levonorgestrel by the one or more of the PSA, the DMSO and the PVP or PVP copolymer. 16. The method of claim 15, comprising adding an anti-oxidant selected from Vitamins A, C, D, and E, carotenoids, flavanoids, isoflavanoids, beta-carotene, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), glutathione, lycopene, gallic acid and esters thereof, salicylic acid and esters thereof, sulfites, or any combination thereof. 17. The method of claim 15, comprising adding an anti-oxidant selected from sodium bisulfite, sodium sulfite, isopropyl gallate, Vitamin C, Vitamin E, BHA, BHT, pentaerythritoltetrakis(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate), tris(2,4-di-tert-butylphenyl)phosphite or any combination thereof. 18. The method of claim 15, wherein the composition lacks an estrogen. 19. The method of claim 15, wherein the composition comprises a PVP copolymer that is PVP/VA. 20. The method of claim 15, wherein the composition further comprises one or more other skin permeation enhancers selected from a fatty (C8-C20) alcohol ester of a hydroxyl acid, a lower (C1-C4) alkyl ester of a hydroxyl acid, and a C6-C18 fatty acid. | 1,600 |
1,157 | 15,542,500 | 1,615 | This invention relates to the use of the combination of 25-hydroxyvitamin D3 (“25-OH D3”) and antioxidants/anti-inflammatories (ascorbic acid vitamin E and canthaxanthin) to make a premix or feed which can ameliorate various problems observed in companion animals which have been subject to overfeeding. Foods containing the 25-OH D3 and antioxidants/anti-inflammatories and premixes are also provided. | 1. A food suitable for a companion animal comprising the combination comprising 25-Hydroxy vitamin D (25-OH D), Vitamin C, Vitamin E and a carotenoid selected from the group consisting of: lycopene, astaxanthin, cryptoxanthin, beta-carotene, lutein, zeaxanthin and canthaxanthin. 2. A food according to claim 1 comprising: 25-OH D, beta carotene, vitamin C and Vitamin E and
optionally further comprises at least one further bio-active ingredient selected from the group consisting of: Vitamin D, Vitamin B2, Vitamin B6, Niacin, Zinc, Copper, Manganese, and Selenium. 3. A combination according to claim 1 wherein the amount of Vitamin E or Vitamin C to beta carotene may range from 40:1 to 1:1; preferably from 20:1 to 1:1; and more preferably from 10:1 to 1:1 4. A combination according to claim 1 wherein the 25-hydroxy vitamin D is 25-hydroxy vitamin D3 (25-OH D3). 5. A feed comprising the combination or according to claim 1 wherein:
the amount of 25-OH D3 is from 15-200 μm/kg
the amount of Vitamin E is from 40-400 mg/kg
the amount of ascorbic acid is from 40-400 mg/kg; and
the amount of beta carotene is from 1-15 mg/kg 6. A feed according to claim 1 wherein:
the amount of 25-OH D3 is from 80-150 μm/kg;
the amount of Vitamin E is from 30-300 mg/kg;
the amount of ascorbic acid is from 80-300 mg/kg; and
the amount of beta-carotene is from 1-15 mg/kg. 7. A feed according to claim 1 comprising:
25-OH D3: 35-150 m/kg;
Vitamin E: 80-300 mg/kg;
Beta carotene: 3-12 mg/kg; and
Ascorbic acid: 100-300 mg/kg. 8. A feed according to claim 1 comprising:
25-0H D3: 35 μg/kg
Vitamin E: 80 mg/kg
Beta-Carotene: 3 mg/kg; and
Ascorbic acid: 100 mg/kg. 9. A feed according to claim 1 comprising:
25-0H D3: 69 μg/kg
Vitamin E: 150 mg/kg
Beta Carotene: 6 mg/kg; and
Ascorbic acid: 150 mg/kg. 10. A feed according to claim 1 comprising:
25-0H D3: 150 m/kg
Vitamin E: 300 mg/kg
Beta Carotene: 12 mg/kg, and
Ascorbic acid: 300 mg/kg. 11. A method of ameliorating the amount of weight gained by a companion animal which is fed ad libitum comprising: administering the combination of 25-OH D, a carotenoid, Vitamin C and Vitamin E to the animal. 12. A method according to claim 11 further comprising administering at least one further bio-active ingredient selected from the group consisting of:
Vitamin D, Vitamin B2, Vitamin B6, Niacin, Zinc, Copper, Manganese, Selenium and combinations thereof. | This invention relates to the use of the combination of 25-hydroxyvitamin D3 (“25-OH D3”) and antioxidants/anti-inflammatories (ascorbic acid vitamin E and canthaxanthin) to make a premix or feed which can ameliorate various problems observed in companion animals which have been subject to overfeeding. Foods containing the 25-OH D3 and antioxidants/anti-inflammatories and premixes are also provided.1. A food suitable for a companion animal comprising the combination comprising 25-Hydroxy vitamin D (25-OH D), Vitamin C, Vitamin E and a carotenoid selected from the group consisting of: lycopene, astaxanthin, cryptoxanthin, beta-carotene, lutein, zeaxanthin and canthaxanthin. 2. A food according to claim 1 comprising: 25-OH D, beta carotene, vitamin C and Vitamin E and
optionally further comprises at least one further bio-active ingredient selected from the group consisting of: Vitamin D, Vitamin B2, Vitamin B6, Niacin, Zinc, Copper, Manganese, and Selenium. 3. A combination according to claim 1 wherein the amount of Vitamin E or Vitamin C to beta carotene may range from 40:1 to 1:1; preferably from 20:1 to 1:1; and more preferably from 10:1 to 1:1 4. A combination according to claim 1 wherein the 25-hydroxy vitamin D is 25-hydroxy vitamin D3 (25-OH D3). 5. A feed comprising the combination or according to claim 1 wherein:
the amount of 25-OH D3 is from 15-200 μm/kg
the amount of Vitamin E is from 40-400 mg/kg
the amount of ascorbic acid is from 40-400 mg/kg; and
the amount of beta carotene is from 1-15 mg/kg 6. A feed according to claim 1 wherein:
the amount of 25-OH D3 is from 80-150 μm/kg;
the amount of Vitamin E is from 30-300 mg/kg;
the amount of ascorbic acid is from 80-300 mg/kg; and
the amount of beta-carotene is from 1-15 mg/kg. 7. A feed according to claim 1 comprising:
25-OH D3: 35-150 m/kg;
Vitamin E: 80-300 mg/kg;
Beta carotene: 3-12 mg/kg; and
Ascorbic acid: 100-300 mg/kg. 8. A feed according to claim 1 comprising:
25-0H D3: 35 μg/kg
Vitamin E: 80 mg/kg
Beta-Carotene: 3 mg/kg; and
Ascorbic acid: 100 mg/kg. 9. A feed according to claim 1 comprising:
25-0H D3: 69 μg/kg
Vitamin E: 150 mg/kg
Beta Carotene: 6 mg/kg; and
Ascorbic acid: 150 mg/kg. 10. A feed according to claim 1 comprising:
25-0H D3: 150 m/kg
Vitamin E: 300 mg/kg
Beta Carotene: 12 mg/kg, and
Ascorbic acid: 300 mg/kg. 11. A method of ameliorating the amount of weight gained by a companion animal which is fed ad libitum comprising: administering the combination of 25-OH D, a carotenoid, Vitamin C and Vitamin E to the animal. 12. A method according to claim 11 further comprising administering at least one further bio-active ingredient selected from the group consisting of:
Vitamin D, Vitamin B2, Vitamin B6, Niacin, Zinc, Copper, Manganese, Selenium and combinations thereof. | 1,600 |
1,158 | 15,542,091 | 1,615 | This invention relates to the use of the combination of 25-hydroxyvitamin D3 (“25-OH D3”) and antioxidants/anti-inflammatories (ascorbic acid vitamin E and canthaxanthin) to make a premix or feed which can ameliorate various problems observed in poultry which have been subject to overfeeding. Feeds containing the 25-OH D3 and antioxidants/anti-inflammatories and premixes are also provided. | 1. A combination comprising 25-Hydroxy vitamin D, ascorbic acid, Vitamin E and canthaxanthin for use in a poultry feed promoting ovarian health, wherein ovarian health is indicated by at least one indicia of ovarian health selected from the group consisting of:
a) reduced ovarian degeneration, occurrence of ovarian degeneration at a later onset, or no occurrence of ovarian degeneration; and b) reduction in the amount of ovarian tumors, reduction in size of ovarian tumors, reduction in both size and number of ovarian tumors, occurrence at a later onset, or no occurrence of ovarian tumors. 2. A combination according to claim 1 wherein ovarian health comprises at least one of the following conditions:
a) ovarian degeneration is lessened, occurs at a later onset, or does not occur
b) ovarian tumors are reduced in number, reduced in size, reduced in both size and number, occur at a later onset, or do not occur. 3. A combination according to claim 1 further comprising at least one further bio-active ingredient selected from the group consisting of:
Vitamin D, Vitamin B2, Vitamin B6, Niacin, Zinc, Copper, Manganese, and Selenium. 4. A combination according to claim 1 further comprising at least one bio-active ingredient selected from the group consisting of Vitamin D, Vitamin B2, Vitamin B6, Niacin, Pantothenic Acid, Folic Acid Biotin, Zinc, Copper, Manganese, and Selenium. 5. A feed or premix comprising a combination according to claim 1. 6. A combination, feed, or premix according to claim 1 wherein the 25-hydroxy vitamin D is 25-hydroxy vitamin D3 (25-OH D3). 7. A method of promoting ovarian health in poultry, wherein ovarian health is indicated by at least one indicia of ovarian health selected from the group consisting of:
a) reduced ovarian degeneration, occurrence of ovarian degeneration at a later onset, or no occurrence of ovarian degeneration; and b) reduction in the amount of ovarian tumors, reduction in size of ovarian tumors, reduction in both size and number of ovarian tumors, occurrence at a later onset, or no occurrence of ovarian tumors;
comprising feeding poultry a feed comprising the combination of 25-Hydroxy vitamin D, ascorbic acid, Vitamin E and canthaxanthin. 8. A method according to claim 7, wherein the feeding is ad libitum. | This invention relates to the use of the combination of 25-hydroxyvitamin D3 (“25-OH D3”) and antioxidants/anti-inflammatories (ascorbic acid vitamin E and canthaxanthin) to make a premix or feed which can ameliorate various problems observed in poultry which have been subject to overfeeding. Feeds containing the 25-OH D3 and antioxidants/anti-inflammatories and premixes are also provided.1. A combination comprising 25-Hydroxy vitamin D, ascorbic acid, Vitamin E and canthaxanthin for use in a poultry feed promoting ovarian health, wherein ovarian health is indicated by at least one indicia of ovarian health selected from the group consisting of:
a) reduced ovarian degeneration, occurrence of ovarian degeneration at a later onset, or no occurrence of ovarian degeneration; and b) reduction in the amount of ovarian tumors, reduction in size of ovarian tumors, reduction in both size and number of ovarian tumors, occurrence at a later onset, or no occurrence of ovarian tumors. 2. A combination according to claim 1 wherein ovarian health comprises at least one of the following conditions:
a) ovarian degeneration is lessened, occurs at a later onset, or does not occur
b) ovarian tumors are reduced in number, reduced in size, reduced in both size and number, occur at a later onset, or do not occur. 3. A combination according to claim 1 further comprising at least one further bio-active ingredient selected from the group consisting of:
Vitamin D, Vitamin B2, Vitamin B6, Niacin, Zinc, Copper, Manganese, and Selenium. 4. A combination according to claim 1 further comprising at least one bio-active ingredient selected from the group consisting of Vitamin D, Vitamin B2, Vitamin B6, Niacin, Pantothenic Acid, Folic Acid Biotin, Zinc, Copper, Manganese, and Selenium. 5. A feed or premix comprising a combination according to claim 1. 6. A combination, feed, or premix according to claim 1 wherein the 25-hydroxy vitamin D is 25-hydroxy vitamin D3 (25-OH D3). 7. A method of promoting ovarian health in poultry, wherein ovarian health is indicated by at least one indicia of ovarian health selected from the group consisting of:
a) reduced ovarian degeneration, occurrence of ovarian degeneration at a later onset, or no occurrence of ovarian degeneration; and b) reduction in the amount of ovarian tumors, reduction in size of ovarian tumors, reduction in both size and number of ovarian tumors, occurrence at a later onset, or no occurrence of ovarian tumors;
comprising feeding poultry a feed comprising the combination of 25-Hydroxy vitamin D, ascorbic acid, Vitamin E and canthaxanthin. 8. A method according to claim 7, wherein the feeding is ad libitum. | 1,600 |
1,159 | 14,783,699 | 1,648 | The present disclosure provides immunogenic compositions comprising HCV E1, E2, or E1/E2 polypeptides from two or more different HCV genotypes. The present disclosure provides immunogenic compositions comprising HCV E2 or E1/E2 polypeptides from two or more different HCV genotypes. The immunogenic compositions are useful in carrying out methods of inducing an immune response to HCV. The present disclosure further provides methods of stimulating an immune response to HCV in an individual. | 1. An immunogenic composition comprising:
a) an hepatitis C virus (HCV) E1 polypeptide, E2 polypeptide or E1E2 polypeptide from a first HCV genotype; b) an HCV E1 polypeptide, E2 polypeptide, or E1E2 polypeptide from a second HCV genotype; and c) a pharmaceutically acceptable excipient, with the proviso that the composition comprises at least one E1 polypeptide and at least one E2 polypeptide. 2. The composition of claim 1, wherein the first HCV genotype is genotype 1; and
the second HCV genotype is genotype 2. 3. The composition of claim 1, wherein the first HCV genotype is genotype 1; and
the second HCV genotype is genotype 3. 4. The composition of claim 1, wherein composition comprises:
i) an E1/E2 heterodimeric polypeptide complex of HCV genotype 1; and E1/E2 polypeptide of HCV genotype 3; ii) an E1/E2 heterodimeric polypeptide complex of HCV genotype 1; and an E2 polypeptide of HCV genotype 3; iii) an E2 polypeptide of HCV genotype 1; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 3; iv) an E1/E2 heterodimeric polypeptide complex of HCV genotype 1; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 2; v) an E1/E2 heterodimeric polypeptide complex of HCV genotype 1; and an E2 polypeptide of HCV genotype 2; vi) an E2 polypeptide of HCV genotype 1; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 2; vii) an E1 polypeptide of HCV genotype 1; and an E2 polypeptide of HCV genotype 3; viii) an E1 polypeptide of HCV genotype 1; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 3; ix) an E2 polypeptide of HCV genotype 1; and an E1 polypeptide of HCV genotype 3; x) an E2 polypeptide of HCV genotype 1; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 3; xi) an E1 polypeptide of HCV genotype 1; and an E2 polypeptide of HCV genotype 2; xii) an E1 polypeptide of HCV genotype 1; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 2; xiii) an E2 polypeptide of HCV genotype 1; and an E1 polypeptide of HCV genotype 2; or xiv) an E2 polypeptide of HCV genotype 1; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 2. 5. The composition of claim 4, further comprising an HCV E1, E2, or E1/E2 polypeptide of a third HCV genotype. 6. The composition of claim 1, wherein HCV E2 polypeptide from the first HCV genotype is wild-type, and wherein the HCV E2 polypeptide from the second HCV genotype is wild-type. 7. The composition of claim 1, wherein HCV E2 polypeptide from the first HCV genotype is wild-type, and wherein the HCV E2 polypeptide from the second HCV genotype comprises an amino acid substitution of asparagine in an E2N1 site and/or an E2N6 site. 8. The composition of claim 1, wherein HCV E2 polypeptide from the first HCV genotype comprises an amino acid substitution of asparagine in an E2N1 site and/or an E2N6 site, and wherein the HCV E2 polypeptide from the second HCV genotype is wild-type. 9. The composition of claim 1, wherein the pharmaceutically acceptable excipient comprises an adjuvant. 10. The composition of claim 1, wherein the adjuvant is MF59, alum, poly(DL-lactide co-glycolide), or a CpG oligonucleotide. 11. An immunogenic composition comprising:
a) a hepatitis C virus (HCV) E1 polypeptide, E2 polypeptide, or E1/E2 polypeptide from a first HCV genotype; b) an HCV E1 polypeptide, E2 polypeptide, or E1/E2 polypeptide from a second HCV genotype; c) an HCV E1 polypeptide, E2 polypeptide, or E1/E2 polypeptide from a third HCV genotype; and d) a pharmaceutically acceptable excipient, with the proviso that the composition comprises at least one E1 polypeptide and at least one E2 polypeptide. 12. The immunogenic composition of claim 11, wherein the first HCV genotype is genotype 1, wherein the second HCV genotype is genotype 2, and wherein the third HCV genotype is genotype 3. 13. The immunogenic composition of claim 11, wherein the composition comprises:
i) an E1/E2 heterodimeric polypeptide complex of HCV genotype 1; an E1/E2 heterodimeric polypeptide complex of HCV genotype 2; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 3; ii) an E1/E2 heterodimeric polypeptide complex of HCV genotype 1; an E1/E2 heterodimeric polypeptide complex of HCV genotype 2; and an E2 polypeptide of HCV genotype 3; iii) an E1/E2 heterodimeric polypeptide complex of HCV genotype 1; an E2 polypeptide of HCV genotype 2; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 3; iv) an E2 polypeptide of HCV genotype 1; an E1/E2 heterodimeric polypeptide complex of HCV genotype 2; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 3; v) an E1/E2 heterodimeric polypeptide complex of HCV genotype 1; an E2 polypeptide of HCV genotype 2; and an E2 polypeptide of HCV genotype 3; vi) an E2 polypeptide of HCV genotype 1; an E1/E2 heterodimeric polypeptide complex of HCV genotype 2; and an E2 polypeptide of HCV genotype 3; vii) an E2 polypeptide of HCV genotype 1; an E2 polypeptide of HCV genotype 2; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 3; viii) an E1 polypeptide of HCV genotype 1; an E1/E2 heterodimeric polypeptide complex of HCV genotype 2; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 3; ix) an E1/E2 heterodimeric polypeptide complex of HCV genotype 1; an E1 polypeptide of HCV genotype 2; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 3; x) an E1/E2 heterodimeric polypeptide complex of HCV genotype 1; an E1/E2 heterodimeric polypeptide complex of HCV genotype 2; and an E1 polypeptide of HCV genotype 3; xi) an E1 polypeptide of HCV genotype 1; an E2 polypeptide of HCV genotype 2; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 3; xii) an E2 polypeptide of HCV genotype 1; an E1 polypeptide of HCV genotype 2; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 3; xiii) an E1/E2 heterodimeric polypeptide complex of HCV genotype 1; an E2 polypeptide of HCV genotype 2; and an E1 polypeptide of HCV genotype 3; xiv) an E1 polypeptide of HCV genotype 1; an E2 polypeptide of HCV genotype 2; and an E2 polypeptide of HCV genotype 3; xv) an E2 polypeptide of HCV genotype 1; an E1 polypeptide of HCV genotype 2; and an E2 polypeptide of HCV genotype 3; xvi) an E2 polypeptide of HCV genotype 1; an E2 polypeptide of HCV genotype 2; and an E1 polypeptide of HCV genotype 3; or xvii) an E1 polypeptide of HCV genotype 1; an E1/E2 heterodimeric polypeptide complex of HCV genotype 2; and an E2 polypeptide of HCV genotype 3. 14. The composition of claim 11, wherein HCV E2 polypeptide from the first HCV genotype is wild-type, wherein the HCV E2 polypeptide from the second HCV genotype is wild-type, and wherein the HCV E2 polypeptide from the third HCV genotype is wild-type. 15. The composition of claim 11, wherein HCV E2 polypeptide from the first HCV genotype is wild-type, wherein the HCV E2 polypeptide from the second HCV genotype is wild-type, and wherein the HCV E2 polypeptide from the third HCV genotype comprises an amino acid substitution of asparagine in an E2N1 site and/or an E2N6 site. 16. The composition of claim 11, wherein HCV E2 polypeptide from the first HCV genotype is wild-type, wherein the HCV E2 polypeptide from the second HCV genotype comprises an amino acid substitution of asparagine in an E2N1 site and/or an E2N6 site, and wherein the HCV E2 polypeptide from the third HCV genotype is wild-type. 17. The composition of claim 11, wherein HCV E2 polypeptide from the first HCV genotype comprises an amino acid substitution of asparagine in an E2N1 site and/or an E2N6 site, wherein the HCV E2 polypeptide from the second HCV genotype is wild-type, and wherein the HCV E2 polypeptide from the third HCV genotype is wild-type. 18. The composition of claim 11, wherein the pharmaceutically acceptable excipient comprises an adjuvant. 19. The composition of claim 11, wherein the adjuvant is MF59, alum, poly(DL-lactide co-glycolide), or a CpG oligonucleotide. 20. A method of inducing an immune response in an individual, the method comprising administering to the individual an effective amount of the composition of any of claims 1 to 19. 21. A composition comprising:
a) a hepatitis C virus (HCV) E2 polypeptide of HCV genotype 1a; b) an HCV E1/E2 heterodimeric polypeptide of HCV genotype 3a; and c) a pharmaceutically acceptable excipient. 22. The composition of claim 21, wherein all of the polypeptides are wild-type. 23. The composition of claim 21, wherein the E2 polypeptide is full-length. 24. The composition of claim 21, wherein the E2 polypeptide is a soluble E2 polypeptide. 25. A composition comprising:
a) a hepatitis C virus (HCV) E2 polypeptide or an HCV E1/E2 heterodimeric polypeptide of HCV genotype 3a; b) an HCV E2 polypeptide or an HCV E1/E2 heterodimeric polypeptide of HCV genotype 1a; and c) a pharmaceutically acceptable excipient. 26. The composition of claim 25, wherein all of the polypeptides are wild-type. 27. The composition of claim 25, wherein the E2 polypeptide is full-length. 28. The composition of claim 25, wherein the E2 polypeptide is a soluble E2 polypeptide. 29. A method of inducing an immune response in an individual, the method comprising administering to the individual an effective amount of the composition of any one of claims 21-28, wherein the composition is administered in an amount effective to induce neutralizing antibody to at least HCV genotypes 1a and 3a. 30. A method of inducing an immune response in an individual, the method comprising administering to the individual an effective amount of the composition of any one of claims 21-28, wherein the composition is administered in an amount effective to induce a cytotoxic T lymphocyte response to at least HCV genotypes 1a and 3a. 31. A method of inducing an immune response in an individual, the method comprising administering to the individual an effective amount of the composition of any one of claims 21-28, wherein the composition is administered in an amount effective to achieve 50% or greater neutralization of HCV genotypes 1a and 3a. 32. A composition comprising:
a) a hepatitis C virus (HCV) E2 polypeptide or an HCV E1/E2 heterodimeric polypeptide of HCV genotype 2a; b) an HCV E2 polypeptide or an HCV E1/E2 heterodimeric polypeptide of HCV genotype 1a; and c) a pharmaceutically acceptable excipient. 33. The composition of claim 32, wherein all of the polypeptides are wild-type. 34. The composition of claim 32, wherein the E2 polypeptide is full-length. 35. The composition of claim 32, wherein the E2 polypeptide is a soluble E2 polypeptide. 36. A method of inducing an immune response in an individual, the method comprising administering to the individual an effective amount of the composition of any one of claims 32-35, wherein the composition is administered in an amount effective to induce neutralizing antibody to at least HCV genotypes 1a and 2a. 37. A method of inducing an immune response in an individual, the method comprising administering to the individual an effective amount of the composition of any one of claims 32-35, wherein the composition is administered in an amount effective to induce a cytotoxic T lymphocyte response to at least HCV genotypes 1a and 2a. 38. A method of inducing an immune response in an individual, the method comprising administering to the individual an effective amount of the composition of any one of claims 32-35, wherein the composition is administered in an amount effective to achieve 50% or greater neutralization of HCV genotypes 1a and 2a. 39. A composition comprising:
a) a hepatitis C virus (HCV) E2 or an HCV E1/E2 heterodimeric polypeptide of HCV genotype 1a; b) an HCV E2 polypeptide or an HCV E1/E2 heterodimeric polypeptide of HCV genotype 2a; c) an E2 polypeptide or an HCV E1/E2 heterodimeric polypeptide of HCV genotype 3a; and d) a pharmaceutically acceptable excipient. 40. The composition of claim 39, wherein all of the polypeptides are wild-type. 41. The composition of claim 39, wherein the at least one of the E2 polypeptides are full-length. 42. The composition of claim 39, wherein at least one of the E2 polypeptides is a soluble E2 polypeptide. 43. The composition of any one of claims 39-42, comprising an E1/E2 polypeptide of HCV genotype 7a. 44. The composition of any one of claims 39-42, comprising an E2 polypeptide of HCV genotype 7a. 45. A method of inducing an immune response in an individual, the method comprising administering to the individual an effective amount of the composition of any one of claims 39-44, wherein the composition is administered in an amount effective to induce neutralizing antibody to HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 5a, 6a, and 7a. 46. A method of inducing an immune response in an individual, the method comprising administering to the individual an effective amount of the composition of any one of claims 39-44, wherein the composition is administered in an amount effective to induce a cytotoxic T lymphocyte response to HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 5a, 6a, and 7a. 47. A method of inducing an immune response in an individual, the method comprising administering to the individual an effective amount of the composition of any one of claims 39-44, wherein the composition is administered in an amount effective to achieve 50% or greater neutralization of HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 5a, 6a, and 7a. | The present disclosure provides immunogenic compositions comprising HCV E1, E2, or E1/E2 polypeptides from two or more different HCV genotypes. The present disclosure provides immunogenic compositions comprising HCV E2 or E1/E2 polypeptides from two or more different HCV genotypes. The immunogenic compositions are useful in carrying out methods of inducing an immune response to HCV. The present disclosure further provides methods of stimulating an immune response to HCV in an individual.1. An immunogenic composition comprising:
a) an hepatitis C virus (HCV) E1 polypeptide, E2 polypeptide or E1E2 polypeptide from a first HCV genotype; b) an HCV E1 polypeptide, E2 polypeptide, or E1E2 polypeptide from a second HCV genotype; and c) a pharmaceutically acceptable excipient, with the proviso that the composition comprises at least one E1 polypeptide and at least one E2 polypeptide. 2. The composition of claim 1, wherein the first HCV genotype is genotype 1; and
the second HCV genotype is genotype 2. 3. The composition of claim 1, wherein the first HCV genotype is genotype 1; and
the second HCV genotype is genotype 3. 4. The composition of claim 1, wherein composition comprises:
i) an E1/E2 heterodimeric polypeptide complex of HCV genotype 1; and E1/E2 polypeptide of HCV genotype 3; ii) an E1/E2 heterodimeric polypeptide complex of HCV genotype 1; and an E2 polypeptide of HCV genotype 3; iii) an E2 polypeptide of HCV genotype 1; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 3; iv) an E1/E2 heterodimeric polypeptide complex of HCV genotype 1; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 2; v) an E1/E2 heterodimeric polypeptide complex of HCV genotype 1; and an E2 polypeptide of HCV genotype 2; vi) an E2 polypeptide of HCV genotype 1; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 2; vii) an E1 polypeptide of HCV genotype 1; and an E2 polypeptide of HCV genotype 3; viii) an E1 polypeptide of HCV genotype 1; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 3; ix) an E2 polypeptide of HCV genotype 1; and an E1 polypeptide of HCV genotype 3; x) an E2 polypeptide of HCV genotype 1; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 3; xi) an E1 polypeptide of HCV genotype 1; and an E2 polypeptide of HCV genotype 2; xii) an E1 polypeptide of HCV genotype 1; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 2; xiii) an E2 polypeptide of HCV genotype 1; and an E1 polypeptide of HCV genotype 2; or xiv) an E2 polypeptide of HCV genotype 1; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 2. 5. The composition of claim 4, further comprising an HCV E1, E2, or E1/E2 polypeptide of a third HCV genotype. 6. The composition of claim 1, wherein HCV E2 polypeptide from the first HCV genotype is wild-type, and wherein the HCV E2 polypeptide from the second HCV genotype is wild-type. 7. The composition of claim 1, wherein HCV E2 polypeptide from the first HCV genotype is wild-type, and wherein the HCV E2 polypeptide from the second HCV genotype comprises an amino acid substitution of asparagine in an E2N1 site and/or an E2N6 site. 8. The composition of claim 1, wherein HCV E2 polypeptide from the first HCV genotype comprises an amino acid substitution of asparagine in an E2N1 site and/or an E2N6 site, and wherein the HCV E2 polypeptide from the second HCV genotype is wild-type. 9. The composition of claim 1, wherein the pharmaceutically acceptable excipient comprises an adjuvant. 10. The composition of claim 1, wherein the adjuvant is MF59, alum, poly(DL-lactide co-glycolide), or a CpG oligonucleotide. 11. An immunogenic composition comprising:
a) a hepatitis C virus (HCV) E1 polypeptide, E2 polypeptide, or E1/E2 polypeptide from a first HCV genotype; b) an HCV E1 polypeptide, E2 polypeptide, or E1/E2 polypeptide from a second HCV genotype; c) an HCV E1 polypeptide, E2 polypeptide, or E1/E2 polypeptide from a third HCV genotype; and d) a pharmaceutically acceptable excipient, with the proviso that the composition comprises at least one E1 polypeptide and at least one E2 polypeptide. 12. The immunogenic composition of claim 11, wherein the first HCV genotype is genotype 1, wherein the second HCV genotype is genotype 2, and wherein the third HCV genotype is genotype 3. 13. The immunogenic composition of claim 11, wherein the composition comprises:
i) an E1/E2 heterodimeric polypeptide complex of HCV genotype 1; an E1/E2 heterodimeric polypeptide complex of HCV genotype 2; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 3; ii) an E1/E2 heterodimeric polypeptide complex of HCV genotype 1; an E1/E2 heterodimeric polypeptide complex of HCV genotype 2; and an E2 polypeptide of HCV genotype 3; iii) an E1/E2 heterodimeric polypeptide complex of HCV genotype 1; an E2 polypeptide of HCV genotype 2; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 3; iv) an E2 polypeptide of HCV genotype 1; an E1/E2 heterodimeric polypeptide complex of HCV genotype 2; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 3; v) an E1/E2 heterodimeric polypeptide complex of HCV genotype 1; an E2 polypeptide of HCV genotype 2; and an E2 polypeptide of HCV genotype 3; vi) an E2 polypeptide of HCV genotype 1; an E1/E2 heterodimeric polypeptide complex of HCV genotype 2; and an E2 polypeptide of HCV genotype 3; vii) an E2 polypeptide of HCV genotype 1; an E2 polypeptide of HCV genotype 2; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 3; viii) an E1 polypeptide of HCV genotype 1; an E1/E2 heterodimeric polypeptide complex of HCV genotype 2; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 3; ix) an E1/E2 heterodimeric polypeptide complex of HCV genotype 1; an E1 polypeptide of HCV genotype 2; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 3; x) an E1/E2 heterodimeric polypeptide complex of HCV genotype 1; an E1/E2 heterodimeric polypeptide complex of HCV genotype 2; and an E1 polypeptide of HCV genotype 3; xi) an E1 polypeptide of HCV genotype 1; an E2 polypeptide of HCV genotype 2; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 3; xii) an E2 polypeptide of HCV genotype 1; an E1 polypeptide of HCV genotype 2; and an E1/E2 heterodimeric polypeptide complex of HCV genotype 3; xiii) an E1/E2 heterodimeric polypeptide complex of HCV genotype 1; an E2 polypeptide of HCV genotype 2; and an E1 polypeptide of HCV genotype 3; xiv) an E1 polypeptide of HCV genotype 1; an E2 polypeptide of HCV genotype 2; and an E2 polypeptide of HCV genotype 3; xv) an E2 polypeptide of HCV genotype 1; an E1 polypeptide of HCV genotype 2; and an E2 polypeptide of HCV genotype 3; xvi) an E2 polypeptide of HCV genotype 1; an E2 polypeptide of HCV genotype 2; and an E1 polypeptide of HCV genotype 3; or xvii) an E1 polypeptide of HCV genotype 1; an E1/E2 heterodimeric polypeptide complex of HCV genotype 2; and an E2 polypeptide of HCV genotype 3. 14. The composition of claim 11, wherein HCV E2 polypeptide from the first HCV genotype is wild-type, wherein the HCV E2 polypeptide from the second HCV genotype is wild-type, and wherein the HCV E2 polypeptide from the third HCV genotype is wild-type. 15. The composition of claim 11, wherein HCV E2 polypeptide from the first HCV genotype is wild-type, wherein the HCV E2 polypeptide from the second HCV genotype is wild-type, and wherein the HCV E2 polypeptide from the third HCV genotype comprises an amino acid substitution of asparagine in an E2N1 site and/or an E2N6 site. 16. The composition of claim 11, wherein HCV E2 polypeptide from the first HCV genotype is wild-type, wherein the HCV E2 polypeptide from the second HCV genotype comprises an amino acid substitution of asparagine in an E2N1 site and/or an E2N6 site, and wherein the HCV E2 polypeptide from the third HCV genotype is wild-type. 17. The composition of claim 11, wherein HCV E2 polypeptide from the first HCV genotype comprises an amino acid substitution of asparagine in an E2N1 site and/or an E2N6 site, wherein the HCV E2 polypeptide from the second HCV genotype is wild-type, and wherein the HCV E2 polypeptide from the third HCV genotype is wild-type. 18. The composition of claim 11, wherein the pharmaceutically acceptable excipient comprises an adjuvant. 19. The composition of claim 11, wherein the adjuvant is MF59, alum, poly(DL-lactide co-glycolide), or a CpG oligonucleotide. 20. A method of inducing an immune response in an individual, the method comprising administering to the individual an effective amount of the composition of any of claims 1 to 19. 21. A composition comprising:
a) a hepatitis C virus (HCV) E2 polypeptide of HCV genotype 1a; b) an HCV E1/E2 heterodimeric polypeptide of HCV genotype 3a; and c) a pharmaceutically acceptable excipient. 22. The composition of claim 21, wherein all of the polypeptides are wild-type. 23. The composition of claim 21, wherein the E2 polypeptide is full-length. 24. The composition of claim 21, wherein the E2 polypeptide is a soluble E2 polypeptide. 25. A composition comprising:
a) a hepatitis C virus (HCV) E2 polypeptide or an HCV E1/E2 heterodimeric polypeptide of HCV genotype 3a; b) an HCV E2 polypeptide or an HCV E1/E2 heterodimeric polypeptide of HCV genotype 1a; and c) a pharmaceutically acceptable excipient. 26. The composition of claim 25, wherein all of the polypeptides are wild-type. 27. The composition of claim 25, wherein the E2 polypeptide is full-length. 28. The composition of claim 25, wherein the E2 polypeptide is a soluble E2 polypeptide. 29. A method of inducing an immune response in an individual, the method comprising administering to the individual an effective amount of the composition of any one of claims 21-28, wherein the composition is administered in an amount effective to induce neutralizing antibody to at least HCV genotypes 1a and 3a. 30. A method of inducing an immune response in an individual, the method comprising administering to the individual an effective amount of the composition of any one of claims 21-28, wherein the composition is administered in an amount effective to induce a cytotoxic T lymphocyte response to at least HCV genotypes 1a and 3a. 31. A method of inducing an immune response in an individual, the method comprising administering to the individual an effective amount of the composition of any one of claims 21-28, wherein the composition is administered in an amount effective to achieve 50% or greater neutralization of HCV genotypes 1a and 3a. 32. A composition comprising:
a) a hepatitis C virus (HCV) E2 polypeptide or an HCV E1/E2 heterodimeric polypeptide of HCV genotype 2a; b) an HCV E2 polypeptide or an HCV E1/E2 heterodimeric polypeptide of HCV genotype 1a; and c) a pharmaceutically acceptable excipient. 33. The composition of claim 32, wherein all of the polypeptides are wild-type. 34. The composition of claim 32, wherein the E2 polypeptide is full-length. 35. The composition of claim 32, wherein the E2 polypeptide is a soluble E2 polypeptide. 36. A method of inducing an immune response in an individual, the method comprising administering to the individual an effective amount of the composition of any one of claims 32-35, wherein the composition is administered in an amount effective to induce neutralizing antibody to at least HCV genotypes 1a and 2a. 37. A method of inducing an immune response in an individual, the method comprising administering to the individual an effective amount of the composition of any one of claims 32-35, wherein the composition is administered in an amount effective to induce a cytotoxic T lymphocyte response to at least HCV genotypes 1a and 2a. 38. A method of inducing an immune response in an individual, the method comprising administering to the individual an effective amount of the composition of any one of claims 32-35, wherein the composition is administered in an amount effective to achieve 50% or greater neutralization of HCV genotypes 1a and 2a. 39. A composition comprising:
a) a hepatitis C virus (HCV) E2 or an HCV E1/E2 heterodimeric polypeptide of HCV genotype 1a; b) an HCV E2 polypeptide or an HCV E1/E2 heterodimeric polypeptide of HCV genotype 2a; c) an E2 polypeptide or an HCV E1/E2 heterodimeric polypeptide of HCV genotype 3a; and d) a pharmaceutically acceptable excipient. 40. The composition of claim 39, wherein all of the polypeptides are wild-type. 41. The composition of claim 39, wherein the at least one of the E2 polypeptides are full-length. 42. The composition of claim 39, wherein at least one of the E2 polypeptides is a soluble E2 polypeptide. 43. The composition of any one of claims 39-42, comprising an E1/E2 polypeptide of HCV genotype 7a. 44. The composition of any one of claims 39-42, comprising an E2 polypeptide of HCV genotype 7a. 45. A method of inducing an immune response in an individual, the method comprising administering to the individual an effective amount of the composition of any one of claims 39-44, wherein the composition is administered in an amount effective to induce neutralizing antibody to HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 5a, 6a, and 7a. 46. A method of inducing an immune response in an individual, the method comprising administering to the individual an effective amount of the composition of any one of claims 39-44, wherein the composition is administered in an amount effective to induce a cytotoxic T lymphocyte response to HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 5a, 6a, and 7a. 47. A method of inducing an immune response in an individual, the method comprising administering to the individual an effective amount of the composition of any one of claims 39-44, wherein the composition is administered in an amount effective to achieve 50% or greater neutralization of HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 5a, 6a, and 7a. | 1,600 |
1,160 | 14,409,522 | 1,623 | The invention relates to a process for the manufacture of an alkylfluoroacrylate starting from alkylfluoroacetate and an oxalic acid ester, wherein an alkane liquid under the reaction conditions is applied as the solvent in one of the reaction steps. | 1. Process for the manufacture of an alkylfluoroacrylate, comprising the following steps:
A. an alkylfluoroacetate with an ester of oxalic acid is reacted in the presence of a base and a suitable solvent in a crossed Claisen condensation reaction resulting in a Claisen salt, B. the Claisen salt obtained in step A is optionally filtered off and washed with a suitable solvent, C. the Claisen salt obtained in step A or B is reacted with paraformaldehyde and D. the alkylfluoroacrylate obtained in step C is isolated using a suitable solvent, wherein the solvent in at least step C and optionally in one of steps A, B or D comprises an alkane which is liquid under the reaction conditions of the steps in which the alkane is applied and wherein the alkane is pentane or hexane. 2. Process according to claim 1, wherein the alkane is pentane. 3. (canceled) 4. Process according to claim 1 or 2, wherein the solvent in steps C and D comprises the alkane. 5. (canceled) 6. Process according to claim 1 or claim 2, wherein the alkylfluoroacrylate is methylfluoroacrylate or ethylfluoroacrylate. 7. Process according to claim 1, wherein the ester of oxalic acid is dimethyloxalate. 8. Process according to claim 1, wherein the base in the Claisen condensation reaction is a metal alkoxide represented by the formula MOR, wherein M is sodium or potassium and R is a C1-C4 alkyl group. 9. Process according to claim 1, wherein the base in the Claisen condensation reaction is a metal alkoxide of the formula MOR in a C1-C4 alcohol. 10. Process according to claim 1, wherein the base is sodium methoxide in methanol. 11. Process according to claim 1, wherein the solvent in step A is methyl-tert-butylether or pentane. 12. Process according to claim 1, wherein alkylfluoroacrylate obtained after the reaction with paraformaldehyde is quenched with water before isolation. 13. Process according to claim 1, wherein the isolation comprises a filtration and a distillation. | The invention relates to a process for the manufacture of an alkylfluoroacrylate starting from alkylfluoroacetate and an oxalic acid ester, wherein an alkane liquid under the reaction conditions is applied as the solvent in one of the reaction steps.1. Process for the manufacture of an alkylfluoroacrylate, comprising the following steps:
A. an alkylfluoroacetate with an ester of oxalic acid is reacted in the presence of a base and a suitable solvent in a crossed Claisen condensation reaction resulting in a Claisen salt, B. the Claisen salt obtained in step A is optionally filtered off and washed with a suitable solvent, C. the Claisen salt obtained in step A or B is reacted with paraformaldehyde and D. the alkylfluoroacrylate obtained in step C is isolated using a suitable solvent, wherein the solvent in at least step C and optionally in one of steps A, B or D comprises an alkane which is liquid under the reaction conditions of the steps in which the alkane is applied and wherein the alkane is pentane or hexane. 2. Process according to claim 1, wherein the alkane is pentane. 3. (canceled) 4. Process according to claim 1 or 2, wherein the solvent in steps C and D comprises the alkane. 5. (canceled) 6. Process according to claim 1 or claim 2, wherein the alkylfluoroacrylate is methylfluoroacrylate or ethylfluoroacrylate. 7. Process according to claim 1, wherein the ester of oxalic acid is dimethyloxalate. 8. Process according to claim 1, wherein the base in the Claisen condensation reaction is a metal alkoxide represented by the formula MOR, wherein M is sodium or potassium and R is a C1-C4 alkyl group. 9. Process according to claim 1, wherein the base in the Claisen condensation reaction is a metal alkoxide of the formula MOR in a C1-C4 alcohol. 10. Process according to claim 1, wherein the base is sodium methoxide in methanol. 11. Process according to claim 1, wherein the solvent in step A is methyl-tert-butylether or pentane. 12. Process according to claim 1, wherein alkylfluoroacrylate obtained after the reaction with paraformaldehyde is quenched with water before isolation. 13. Process according to claim 1, wherein the isolation comprises a filtration and a distillation. | 1,600 |
1,161 | 12,522,214 | 1,633 | The present application describes an antibody-coding, non-modified or modified RNA and the use thereof for expression of this antibody, for the preparation of a pharmaceutical composition, in particular a passive vaccine, for treatment of tumours and cancer diseases, cardiovascular diseases, infectious diseases, auto-immune diseases, virus diseases and monogenetic diseases, e.g. also in gene therapy. The present invention furthermore describes an in vitro transcription method, in vitro methods for expression of this antibody using the RNA according to the invention and an in vivo method. | 1. RNA for intracellular expression of an antibody, wherein the RNA contains at least one coding region, wherein at least one coding region codes for at least one antibody. 2. RNA according to claim 1, wherein the RNA is single-stranded or double-stranded, linear or circular, in the form of rRNA, tRNA or mRNA. 3. RNA according to claim 1, wherein the RNA is an mRNA. 4. RNA according to claim 1, wherein the antibody coded is chosen from monoclonal and polyclonal antibodies, chimeric antibodies, human antibodies, humanized antibodies, bispecific antibodies, intrabodies and fragments of these antibodies. 5. RNA according to claim 1, wherein the coded antibody fragments are chosen from Fab, Fab′, F(abr)2, Fe, Facb, pFc′, Fd, and FIT or scFv fragments of these antibodies. 6. RNA according to claim 1, wherein the coded antibodies or antibody fragments specifically recognize and bind tumour-specific surface antigens chosen from (TSSA), 5T4, α5β1-integrin, 707-AP, AFP, ART-4, B7H4, BAGE, β-catenin/m, Bcr-abl, MN/C IX-antigen, CA125, CAMEL, CAP-1, CASP-8, β-catenin/m, CD4, CD19, CD20, CD22, CD25, CDC27/m, CD 30, CD33, CD52, CD56, CD80, CDK4/m, CEA, CT, Cyp-B, DAM, EGFR, ErbB3, ELF2M, EMMPRIN, EpCam, ETV6-AML1, G250, GAGE, GnT-V, Gp100, HAGE, HER-2/neu, HLAA*0201-R170I, HPV-E7, HSP70-2M, HAST-2, hTERT (or hTRT), iCE, IGF-1R, IL2R, IL-5, KIAA0205, LAGE, LDLR/FUT, MAGE, MART-1/Melan-A, MART-2/Ski, MC1R, myosin/m, MUC1, MUM-1, -2, -3, NA88-A, PAP, proteinase-3, p190 minor bcr-abl, Pml/RARα, PRAME, PSA, PSM, PSMA, RAGE, RU1 or RU2, SAGE, SART-1 or SART-3, survivin, TEL/AML1, TGFβ, TPI/m, TRP-1, TRP-2, TRP-2/INT2, VEGF and WT1, NY-Eso-1 and NY-Eso-B. 7. RNA according to one of claim 1, wherein the RNA is modified. 8. RNA according to claim 1, wherein the modification is chosen from modifications of the nucleotide sequence compared with a precursor RNA sequence by introduction of non-native nucleotides and/or by covalent coupling of the RNA with another group. 9. RNA according to claim 8, wherein the RNA has a G/C content in the coding region of the base-modified RNA which is greater than the G/C content of the coding region of the native RNA sequence, the coded amino acid sequence being unchanged with respect to the wild-type or, respectively, the precursor RNA. 10. RNA according to claim 8, wherein the coding region of the modified RNA is modified compared with the coding region of the native RNA such that at least one codon of the native RNA which codes for a tRNA which is relatively rare in the cell is exchanged for a codon which codes for a tRNA which is relatively frequent in the cell and which carries the same amino acid as the relatively rare tRNA. 11. RNA according to claim 8, wherein the RNA has a lipid modification. 12. RNA according to claim 8, wherein the RNA contains on at least one nucleotide of the RNA a modification of a nucleotide, wherein the nucleotides are chosen from 1-methyl-adenine, 2-methyl-adenine, 2-methylthio-N-6-isopentenyl-adenine, N6-methyl-adenine, N6-isopentenyl-adenine, 2-thio-cytosine, 3-methyl-cytosine, 4-acetyl-cytosine, 5-methyl-cytosine, 2,6-diaminopurine, 1-methyl-guanine, 2-methyl-guanine, 2,2-dimethyl-guanine, 7-methyl-guanine, inosine, 1-methyl-inosine, dihydro-uracil, 2-thio-uracil, 4-thio-uracil, 5-carboxymethylaminomethyl-2-thio-uracil, 5-(carboxyhydroxymethyl)-uracil, 5-fluoro-uracil, 5-bromo-uracil, 5-carboxymethylaminomethyl-uracil, 5-methyl-2-thio-uracil, 5-methyl-uracil, N-uracil-5-oxyacetic acid methyl ester, 5-methylaminomethyl-uracil, 5-methoxyaminomethyl-2-thio-uracil, 5-methoxycarbonylmethyl-uracil, 5-methoxy-uracil, uracil-5-oxyacetic acid methyl ester, uracil-5-oxyacetic acid (v), pseudouracil, 1-methyl-pseudouracil, queosine, β-D-mannosyl-queosine, wybutoxosine, and phosphoramidates, phosphorothioates, peptide nucleotides, methylphosphonates, 7-deazaguanosine, 5-methylcytosine and inosine. 13. RNA according to claim 8, wherein the RNA contains on at least one nucleotide of the RNA a modification of a nucleotide, wherein the nucleotides are base-modified nucleotides chosen from the group consisting of 2-amino-6-chloropurine riboside 5′-triphosphate, 2-aminoadenosine 5′-triphosphate, 2-thiocytidine 5′-triphosphate, 2-thiouridine 5′-triphosphate, 4-thiouridine 5′-triphosphate, 5-aminoallylcytidine 5′-triphosphate, 5-aminoallyluridine 51-triphosphate, 5-bromocytidine 51-triphosphate, 5-bromouridine 5r-triphosphate, 5-iodocytidine 5′-triphosphate, 5-iodouridine 5′-triphosphate, 5-methylcytidine 51-triphosphate, 5-methyluridine 5′-triphosphate, 6-azacytidine 5′-triphosphate, 6-azauridine 5′-triphosphate, 6-chloropurine riboside 5′-triphosphate, 7-deazaadenosine 5′-triphosphate, 7-deazaguanosine 5′-triphosphate, 8-azaadenosine 5′-triphosphate, 8-azidoadenosine 5′-triphosphate, benzimidazole riboside 5′-triphosphate, N1-methyladenosine 5′-triphosphate, N1-methylguanosine 5′-triphosphate, N6-methyladenosine 5′-triphosphate, O6-methylguanosine 5′-triphosphate, pseudouridine 5′-triphosphate, puromycin 5′-triphosphate or xanthosine 5′-triphosphate. 14. RNA according to claim 13, wherein the base-modified nucleotides are chosen from the group consisting of 5-methylcytidine 5′-triphosphate and pseudouridine 5′-triphosphate. 15. RNA according to claim 1, wherein the RNA additionally has a 5′ cap structure chosen from the group consisting of m7G(5′)ppp (5′(A,G(5′)ppp(5′)A and G(5′)ppp(5′)G. 16. RNA according to claim 1, wherein the RNA additionally has a poly-A tail of from about 10 to 200 adenosine nucleotides. 17. RNA according to claim 1, wherein the RNA additionally has a poly-C tail of from about 10 to 200 cytosine nucleotides. 18. RNA according to claim 1, wherein the RNA additionally codes a tag for purification chosen from the group consisting of a hexahistidine tag (HIS tag, polyhistidine tag), a streptavidin tag (Strep tag), an SBP tag (streptavidin-binding tag) or a GST (glutathione S-transferase) tag, or codes for a tag for purification via an antibody epitope chosen from the group consisting of antibody-binding tags, a Mye tag, a Swa11 epitope, a FLAG tag or an HA tag. 19. RNA according to claim 1, wherein the RNA additionally codes a signal peptide and/or a localization sequence, in particular a secretion sequence. 20. RNA according to claim 19, wherein the localization sequence is chosen from one of the sequences according to SEQ ID NO: 18 to 50. 21. RNA according to claim 1, wherein the RNA contains an antibody-coding sequence which codes for the heavy chains according to SEQ ID NO: 2 and the light chains according to SEQ ID NO: 4. 22. RNA according to claim 1, wherein the RNA contains an antibody-coding sequence according to SEQ ID NO: 5. 23. RNA according to claim 1, wherein the RNA contains an antibody-coding sequence which codes for the heavy chains according to SEQ ID NO: 7 and the light chains according to SEQ ID NO: 9. 24. RNA according to claim 1, wherein the RNA contains an antibody-coding sequence according to SEQ ID NO: 10. 25. RNA according to claim 1, wherein the modified RNA contains an antibody-coding sequence which codes for the heavy chains according to SEQ ID NO: 12 and the light chains according to SEQ ID NO: 14. 26. RNA according to claim 1, wherein the RNA contains an antibody-coding sequence according to SEQ ID NO: 15. 27. RNA according to claim 1, wherein the modified RNA contains an antibody-coding sequence which has a sequence identity of at least 70% to the sequence SEQ ID NO: 5, 10 or 15 over the total length of the nucleic acid sequence of SEQ ID NO: 5, 10 or 15. 28. Pharmaceutical composition comprising an RNA according to claim 1. 29. Use of an RNA sequence as defined in claim 1 for the preparation of a pharmaceutical composition for treatment of cancer diseases, cardiovascular diseases, infectious diseases or autoimmune diseases. 30. Use according to claim 29, wherein the pharmaceutical composition is in the form of a passive vaccine for treatment of tumour or infectious diseases. 31. Use according to claim 29, wherein the cancer diseases or tumour diseases are chosen from the group consisting of melanomas, malignant melanomas, colon carcinomas, lymphomas, sarcomas, blastomas, kidney carcinomas, gastrointestinal tumours, gliomas, prostate tumours, bladder cancer, rectal tumours, stomach cancer, oesophageal cancer, pancreatic cancer, liver cancer, mammary carcinomas (=breast cancer), uterine cancer, cervical cancer, acute myeloid leukaemia (AML), acute lymphoid leukaemia (ALL), chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL), hepatomas, diverse virus-induced tumours, such as e.g. papilloma virus-induced carcinomas (e.g. cervix carcinoma=cervical cancer), adenocarcinomas, herpes virus-induced tumours (e.g. Burkitt's lymphoma, EBV-induced B cell lymphoma), hepatitis B-induced tumours (hepatocell carcinomas), HTLV-1- and HTLV-2-induced lymphomas, acusticus neurinoma, lung carcinomas (=lung cancer=bronchial carcinoma), small cell lung carcinomas, throat cancer, anal carcinoma, glioblastoma, rectum carcinoma, astrocytoma, brain tumours, retinoblastoma, basalioma, brain metastases, medulloblastomas, vaginal cancer, testicular cancer, thyroid carcinoma, Hodgkin's syndrome, meningeomas, Schneeberger's disease, pituitary tumour, mycosis fungoides, carcinoids, neurinoma, spinalioma, Burkitt's lymphoma, laryngeal cancer, kidney cancer, thymoma, corpus carcinoma, bone cancer, non-Hodgkin's lymphomas, urethral cancer, CUP syndrome, head/neck tumours, oligodendroglioma, vulval cancer, intestinal cancer, colon carcinoma, oesophageal carcinoma (=oesophageal cancer), wart conditions, small intestine tumours, craniopharyngeomas, ovarian carcinoma, soft tissue tumours (sarcomas), ovarian cancer (=Ovarian carcinoma), pancreatic carcinoma (=pancreatic cancer), endometrium carcinoma, liver metastases, penis cancer, tongue cancer, gallbladder cancer, leukaemia, plasmocytoma, lid tumour and prostate cancer (=prostate tumours). 32. Use according to claim 29, wherein the infectious diseases are chosen from the group consisting of influenza, malaria, SARS, yellow fever, AIDS, Lyme borreliosis, leishmaniasis, anthrax, meningitis, viral infectious diseases, such as AIDS, condyloma acuminate, molluscum contagiosum, dengue fever, three-day fever, Ebola virus, colds, early summer meningoencephalitis (ESME), influenza, shingles, hepatitis, herpes simplex type I, herpes simplex type II, herpes zoster, influenza, Japanese encephalitis, Lassa fever, Marburg virus, measles, foot and mouth disease, mononucleosis, mumps, Norwalk virus infection, Pfeiffer's glandular fever, smallpox, polio (poliomyelitis), pseuodcroup, infectious erythema, rabies, warts, West Nile fever, chicken-pox, cytomegalovirus (CMV), bacterial infectious diseases, such as abortion (infectious, septic), prostatitis (prostate inflammation), anthrax, appendicitis (inflammation of the caecum), borreliosis, botulism, Campylobacter, Chlamydia trachomatis (inflammation of the urethra, conjunctiva), cholera, diphtheria, donavonosis, epiglottitis, louse-borne typhus, typhoid fever, gas gangrene, gonorrhoea, hare plague, Helicobacter pylori, whoopingcough, climatic bubo, osteomyelitis, legionnaires' disease, leprosy, listeriosis, pneumonia, meningitis, bacterial meningitis, anthrax, inflammation of the middle ear, Mycoplasma hominis, neonatal sepsis (chorioamnionitis), noma, paratyphoid fever, plague, Reiter's syndrome, Rocky Mountain spotted fever, Salmonella paratyphoid fever, Salmonella typhoid fever, scarlet fever, syphilis, tetanus, gonorrhoea, tsutsugamushi fever, tuberculosis, typhus, vaginitis (colpitis), soft chancre, and infectious diseases caused by parasites, protozoa or fungi, such as amoebic dysentery, bilharziosis, Chagas' disease, Echinococcus, fish tapeworm, ichthyotoxism (ciguatera), fox tapeworm, mycosis pedis, dog tapeworm, candiosis, ptyriasis, the itch (scabies), cutaneous leishmaniasis, lamblian dysentery (giadiasis), lice, malaria, onchocercosis (river blindness), fungal diseases, beef tapeworm, schistosomiasis, sleeping sickness, pork tapeworm, toxoplasmosis, trichomoniasis, trypanosomiasis (sleeping sickness), visceral leishmaniasis, nappy dermatitis, or infections caused by the dwarf tapeworm. 33. Use according to claim 29, wherein the cardiovascular diseases are chosen from the group consisting of coronary heart disease, arteriosclerosis, apoplexy and hypertension, and neuronal diseases chosen from Alzheimer's disease, amyotrophic lateral sclerosis, dystonia, epilepsy, multiple sclerosis and Parkinson's disease. 34. Use according to claim 29, wherein the autoimmune diseases are chosen from the group consisting of autoimmune type I diseases or autoimmune type H diseases or autoimmune type III diseases or autoimmune type IV diseases, such as, for example, multiple sclerosis (MS), rheumatoid arthritis, diabetes, diabetes type I (diabetes mellitus), systemic lupus erythematosus (SLE), chronic polyarthritis, Basedow's disease, autoimmune forms of chronic hepatitis, colitis ulcerosa, allergy type I diseases, allergy type II diseases, allergy type III diseases, allergy type IV diseases, fibromyalgia, hair loss, Bechterew's disease, Crohn's disease, myasthenia gravis, neurodermatitis, polymyalgia rheumatica, progressive systemic sclerosis (PSS), psoriasis, Reiter's syndrome, rheumatic arthritis, psoriasis or vasculitis. 35. In vitro transcription method for the preparation of an antibody-coding, optionally modified RNA, comprising the following steps:
a) provision of a nucleic acid which codes for an antibody, as defined in claim 4; b) addition of the nucleic acid to an in vitro transcription medium comprising an RNA polymerase, a suitable buffer, a nucleic acid mix comprising one or more modified nucleotides in exchange for one or more of the naturally occurring nucleotides A, G, C or U, and optionally one or more naturally occurring nucleotides A, G, C or U, if not all the naturally occurring nucleotides A, G, C or U are to be exchanged, or optionally only naturally occurring nucleotides and optionally an RNase inhibitor; c) incubation of the nucleic acid in the in vitro transcription medium and in vitro transcription of the nucleic acid to give an antibody-coding, optionally modified RNA according to claim 1; d) optionally purification of the antibody-coding, optionally modified RNA and removal of the non-incorporated nucleotides from the in vitro transcription medium. 36. In vitro transcription and translation method for expression of an antibody, comprising the following steps:
a) provision of a nucleic acid which codes for an antibody, as defined in claim 4; b) addition of the nucleic acid to an in vitro transcription medium comprising an RNA polymerase, a suitable buffer, a nucleic acid mix comprising one or more modified nucleotides in exchange for one or more of the naturally occurring nucleotides A, O, C or U, and optionally one or more naturally occurring nucleotides A, G, C or U, if not all the naturally occurring nucleotides A, G, C or U are to be exchanged, or optionally only naturally occurring nucleotides and optionally an RNase inhibitor; c) incubation of the nucleic acid in the in vitro transcription medium and in vitro transcription of the nucleic acid to give an antibody-coding, optionally modified RNA according to claim 1; d) optionally purification of the antibody-coding, optionally modified RNA and removal of the non-incorporated nucleotides from the in vitro transcription medium, e) addition of the optionally modified RNA obtained in step c) (and optionally in step d) to an in vitro translation medium; f) incubation of the optionally modified RNA in the in vitro translation medium and in vitro translation of the antibody coded by the optionally modified RNA; g) optionally purification of the antibody translated in step f). 37. In vitro transcription and translation method for expression of an antibody in a host cell, comprising the following steps:
a) provision of a nucleic acid which codes for an antibody, as defined in claim 4; b) addition of the nucleic acid to an in vitro transcription medium comprising an RNA polymerase, a suitable buffer, one or more modified nucleotides in exchange for one or more of the naturally occurring nucleotides A, G, C or U and optionally one or more naturally occurring nucleotides A, G, C or U, if not all the naturally occurring nucleotides A, G, C or U are to be exchanged, or only naturally occurring nucleotides and optionally an RNase inhibitor; c) incubation of the nucleic acid in the in vitro transcription medium and in vitro transcription of the nucleic acid to give an antibody-coding, optionally modified RNA according to claim 1; d) optionally purification of the antibody-coding, optionally modified RNA according to the invention and removal of the non-incorporated nucleotides from the in vitro transcription medium, e′) transfection of the optionally modified RNA obtained in step c) (and optionally d)) into a host cell; f′) incubation of the optionally modified nucleic acid in the host cell and translation of the antibody coded by the optionally modified RNA in the host cell; g′) optionally isolation and/or purification of the antibody translated in step f). | The present application describes an antibody-coding, non-modified or modified RNA and the use thereof for expression of this antibody, for the preparation of a pharmaceutical composition, in particular a passive vaccine, for treatment of tumours and cancer diseases, cardiovascular diseases, infectious diseases, auto-immune diseases, virus diseases and monogenetic diseases, e.g. also in gene therapy. The present invention furthermore describes an in vitro transcription method, in vitro methods for expression of this antibody using the RNA according to the invention and an in vivo method.1. RNA for intracellular expression of an antibody, wherein the RNA contains at least one coding region, wherein at least one coding region codes for at least one antibody. 2. RNA according to claim 1, wherein the RNA is single-stranded or double-stranded, linear or circular, in the form of rRNA, tRNA or mRNA. 3. RNA according to claim 1, wherein the RNA is an mRNA. 4. RNA according to claim 1, wherein the antibody coded is chosen from monoclonal and polyclonal antibodies, chimeric antibodies, human antibodies, humanized antibodies, bispecific antibodies, intrabodies and fragments of these antibodies. 5. RNA according to claim 1, wherein the coded antibody fragments are chosen from Fab, Fab′, F(abr)2, Fe, Facb, pFc′, Fd, and FIT or scFv fragments of these antibodies. 6. RNA according to claim 1, wherein the coded antibodies or antibody fragments specifically recognize and bind tumour-specific surface antigens chosen from (TSSA), 5T4, α5β1-integrin, 707-AP, AFP, ART-4, B7H4, BAGE, β-catenin/m, Bcr-abl, MN/C IX-antigen, CA125, CAMEL, CAP-1, CASP-8, β-catenin/m, CD4, CD19, CD20, CD22, CD25, CDC27/m, CD 30, CD33, CD52, CD56, CD80, CDK4/m, CEA, CT, Cyp-B, DAM, EGFR, ErbB3, ELF2M, EMMPRIN, EpCam, ETV6-AML1, G250, GAGE, GnT-V, Gp100, HAGE, HER-2/neu, HLAA*0201-R170I, HPV-E7, HSP70-2M, HAST-2, hTERT (or hTRT), iCE, IGF-1R, IL2R, IL-5, KIAA0205, LAGE, LDLR/FUT, MAGE, MART-1/Melan-A, MART-2/Ski, MC1R, myosin/m, MUC1, MUM-1, -2, -3, NA88-A, PAP, proteinase-3, p190 minor bcr-abl, Pml/RARα, PRAME, PSA, PSM, PSMA, RAGE, RU1 or RU2, SAGE, SART-1 or SART-3, survivin, TEL/AML1, TGFβ, TPI/m, TRP-1, TRP-2, TRP-2/INT2, VEGF and WT1, NY-Eso-1 and NY-Eso-B. 7. RNA according to one of claim 1, wherein the RNA is modified. 8. RNA according to claim 1, wherein the modification is chosen from modifications of the nucleotide sequence compared with a precursor RNA sequence by introduction of non-native nucleotides and/or by covalent coupling of the RNA with another group. 9. RNA according to claim 8, wherein the RNA has a G/C content in the coding region of the base-modified RNA which is greater than the G/C content of the coding region of the native RNA sequence, the coded amino acid sequence being unchanged with respect to the wild-type or, respectively, the precursor RNA. 10. RNA according to claim 8, wherein the coding region of the modified RNA is modified compared with the coding region of the native RNA such that at least one codon of the native RNA which codes for a tRNA which is relatively rare in the cell is exchanged for a codon which codes for a tRNA which is relatively frequent in the cell and which carries the same amino acid as the relatively rare tRNA. 11. RNA according to claim 8, wherein the RNA has a lipid modification. 12. RNA according to claim 8, wherein the RNA contains on at least one nucleotide of the RNA a modification of a nucleotide, wherein the nucleotides are chosen from 1-methyl-adenine, 2-methyl-adenine, 2-methylthio-N-6-isopentenyl-adenine, N6-methyl-adenine, N6-isopentenyl-adenine, 2-thio-cytosine, 3-methyl-cytosine, 4-acetyl-cytosine, 5-methyl-cytosine, 2,6-diaminopurine, 1-methyl-guanine, 2-methyl-guanine, 2,2-dimethyl-guanine, 7-methyl-guanine, inosine, 1-methyl-inosine, dihydro-uracil, 2-thio-uracil, 4-thio-uracil, 5-carboxymethylaminomethyl-2-thio-uracil, 5-(carboxyhydroxymethyl)-uracil, 5-fluoro-uracil, 5-bromo-uracil, 5-carboxymethylaminomethyl-uracil, 5-methyl-2-thio-uracil, 5-methyl-uracil, N-uracil-5-oxyacetic acid methyl ester, 5-methylaminomethyl-uracil, 5-methoxyaminomethyl-2-thio-uracil, 5-methoxycarbonylmethyl-uracil, 5-methoxy-uracil, uracil-5-oxyacetic acid methyl ester, uracil-5-oxyacetic acid (v), pseudouracil, 1-methyl-pseudouracil, queosine, β-D-mannosyl-queosine, wybutoxosine, and phosphoramidates, phosphorothioates, peptide nucleotides, methylphosphonates, 7-deazaguanosine, 5-methylcytosine and inosine. 13. RNA according to claim 8, wherein the RNA contains on at least one nucleotide of the RNA a modification of a nucleotide, wherein the nucleotides are base-modified nucleotides chosen from the group consisting of 2-amino-6-chloropurine riboside 5′-triphosphate, 2-aminoadenosine 5′-triphosphate, 2-thiocytidine 5′-triphosphate, 2-thiouridine 5′-triphosphate, 4-thiouridine 5′-triphosphate, 5-aminoallylcytidine 5′-triphosphate, 5-aminoallyluridine 51-triphosphate, 5-bromocytidine 51-triphosphate, 5-bromouridine 5r-triphosphate, 5-iodocytidine 5′-triphosphate, 5-iodouridine 5′-triphosphate, 5-methylcytidine 51-triphosphate, 5-methyluridine 5′-triphosphate, 6-azacytidine 5′-triphosphate, 6-azauridine 5′-triphosphate, 6-chloropurine riboside 5′-triphosphate, 7-deazaadenosine 5′-triphosphate, 7-deazaguanosine 5′-triphosphate, 8-azaadenosine 5′-triphosphate, 8-azidoadenosine 5′-triphosphate, benzimidazole riboside 5′-triphosphate, N1-methyladenosine 5′-triphosphate, N1-methylguanosine 5′-triphosphate, N6-methyladenosine 5′-triphosphate, O6-methylguanosine 5′-triphosphate, pseudouridine 5′-triphosphate, puromycin 5′-triphosphate or xanthosine 5′-triphosphate. 14. RNA according to claim 13, wherein the base-modified nucleotides are chosen from the group consisting of 5-methylcytidine 5′-triphosphate and pseudouridine 5′-triphosphate. 15. RNA according to claim 1, wherein the RNA additionally has a 5′ cap structure chosen from the group consisting of m7G(5′)ppp (5′(A,G(5′)ppp(5′)A and G(5′)ppp(5′)G. 16. RNA according to claim 1, wherein the RNA additionally has a poly-A tail of from about 10 to 200 adenosine nucleotides. 17. RNA according to claim 1, wherein the RNA additionally has a poly-C tail of from about 10 to 200 cytosine nucleotides. 18. RNA according to claim 1, wherein the RNA additionally codes a tag for purification chosen from the group consisting of a hexahistidine tag (HIS tag, polyhistidine tag), a streptavidin tag (Strep tag), an SBP tag (streptavidin-binding tag) or a GST (glutathione S-transferase) tag, or codes for a tag for purification via an antibody epitope chosen from the group consisting of antibody-binding tags, a Mye tag, a Swa11 epitope, a FLAG tag or an HA tag. 19. RNA according to claim 1, wherein the RNA additionally codes a signal peptide and/or a localization sequence, in particular a secretion sequence. 20. RNA according to claim 19, wherein the localization sequence is chosen from one of the sequences according to SEQ ID NO: 18 to 50. 21. RNA according to claim 1, wherein the RNA contains an antibody-coding sequence which codes for the heavy chains according to SEQ ID NO: 2 and the light chains according to SEQ ID NO: 4. 22. RNA according to claim 1, wherein the RNA contains an antibody-coding sequence according to SEQ ID NO: 5. 23. RNA according to claim 1, wherein the RNA contains an antibody-coding sequence which codes for the heavy chains according to SEQ ID NO: 7 and the light chains according to SEQ ID NO: 9. 24. RNA according to claim 1, wherein the RNA contains an antibody-coding sequence according to SEQ ID NO: 10. 25. RNA according to claim 1, wherein the modified RNA contains an antibody-coding sequence which codes for the heavy chains according to SEQ ID NO: 12 and the light chains according to SEQ ID NO: 14. 26. RNA according to claim 1, wherein the RNA contains an antibody-coding sequence according to SEQ ID NO: 15. 27. RNA according to claim 1, wherein the modified RNA contains an antibody-coding sequence which has a sequence identity of at least 70% to the sequence SEQ ID NO: 5, 10 or 15 over the total length of the nucleic acid sequence of SEQ ID NO: 5, 10 or 15. 28. Pharmaceutical composition comprising an RNA according to claim 1. 29. Use of an RNA sequence as defined in claim 1 for the preparation of a pharmaceutical composition for treatment of cancer diseases, cardiovascular diseases, infectious diseases or autoimmune diseases. 30. Use according to claim 29, wherein the pharmaceutical composition is in the form of a passive vaccine for treatment of tumour or infectious diseases. 31. Use according to claim 29, wherein the cancer diseases or tumour diseases are chosen from the group consisting of melanomas, malignant melanomas, colon carcinomas, lymphomas, sarcomas, blastomas, kidney carcinomas, gastrointestinal tumours, gliomas, prostate tumours, bladder cancer, rectal tumours, stomach cancer, oesophageal cancer, pancreatic cancer, liver cancer, mammary carcinomas (=breast cancer), uterine cancer, cervical cancer, acute myeloid leukaemia (AML), acute lymphoid leukaemia (ALL), chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL), hepatomas, diverse virus-induced tumours, such as e.g. papilloma virus-induced carcinomas (e.g. cervix carcinoma=cervical cancer), adenocarcinomas, herpes virus-induced tumours (e.g. Burkitt's lymphoma, EBV-induced B cell lymphoma), hepatitis B-induced tumours (hepatocell carcinomas), HTLV-1- and HTLV-2-induced lymphomas, acusticus neurinoma, lung carcinomas (=lung cancer=bronchial carcinoma), small cell lung carcinomas, throat cancer, anal carcinoma, glioblastoma, rectum carcinoma, astrocytoma, brain tumours, retinoblastoma, basalioma, brain metastases, medulloblastomas, vaginal cancer, testicular cancer, thyroid carcinoma, Hodgkin's syndrome, meningeomas, Schneeberger's disease, pituitary tumour, mycosis fungoides, carcinoids, neurinoma, spinalioma, Burkitt's lymphoma, laryngeal cancer, kidney cancer, thymoma, corpus carcinoma, bone cancer, non-Hodgkin's lymphomas, urethral cancer, CUP syndrome, head/neck tumours, oligodendroglioma, vulval cancer, intestinal cancer, colon carcinoma, oesophageal carcinoma (=oesophageal cancer), wart conditions, small intestine tumours, craniopharyngeomas, ovarian carcinoma, soft tissue tumours (sarcomas), ovarian cancer (=Ovarian carcinoma), pancreatic carcinoma (=pancreatic cancer), endometrium carcinoma, liver metastases, penis cancer, tongue cancer, gallbladder cancer, leukaemia, plasmocytoma, lid tumour and prostate cancer (=prostate tumours). 32. Use according to claim 29, wherein the infectious diseases are chosen from the group consisting of influenza, malaria, SARS, yellow fever, AIDS, Lyme borreliosis, leishmaniasis, anthrax, meningitis, viral infectious diseases, such as AIDS, condyloma acuminate, molluscum contagiosum, dengue fever, three-day fever, Ebola virus, colds, early summer meningoencephalitis (ESME), influenza, shingles, hepatitis, herpes simplex type I, herpes simplex type II, herpes zoster, influenza, Japanese encephalitis, Lassa fever, Marburg virus, measles, foot and mouth disease, mononucleosis, mumps, Norwalk virus infection, Pfeiffer's glandular fever, smallpox, polio (poliomyelitis), pseuodcroup, infectious erythema, rabies, warts, West Nile fever, chicken-pox, cytomegalovirus (CMV), bacterial infectious diseases, such as abortion (infectious, septic), prostatitis (prostate inflammation), anthrax, appendicitis (inflammation of the caecum), borreliosis, botulism, Campylobacter, Chlamydia trachomatis (inflammation of the urethra, conjunctiva), cholera, diphtheria, donavonosis, epiglottitis, louse-borne typhus, typhoid fever, gas gangrene, gonorrhoea, hare plague, Helicobacter pylori, whoopingcough, climatic bubo, osteomyelitis, legionnaires' disease, leprosy, listeriosis, pneumonia, meningitis, bacterial meningitis, anthrax, inflammation of the middle ear, Mycoplasma hominis, neonatal sepsis (chorioamnionitis), noma, paratyphoid fever, plague, Reiter's syndrome, Rocky Mountain spotted fever, Salmonella paratyphoid fever, Salmonella typhoid fever, scarlet fever, syphilis, tetanus, gonorrhoea, tsutsugamushi fever, tuberculosis, typhus, vaginitis (colpitis), soft chancre, and infectious diseases caused by parasites, protozoa or fungi, such as amoebic dysentery, bilharziosis, Chagas' disease, Echinococcus, fish tapeworm, ichthyotoxism (ciguatera), fox tapeworm, mycosis pedis, dog tapeworm, candiosis, ptyriasis, the itch (scabies), cutaneous leishmaniasis, lamblian dysentery (giadiasis), lice, malaria, onchocercosis (river blindness), fungal diseases, beef tapeworm, schistosomiasis, sleeping sickness, pork tapeworm, toxoplasmosis, trichomoniasis, trypanosomiasis (sleeping sickness), visceral leishmaniasis, nappy dermatitis, or infections caused by the dwarf tapeworm. 33. Use according to claim 29, wherein the cardiovascular diseases are chosen from the group consisting of coronary heart disease, arteriosclerosis, apoplexy and hypertension, and neuronal diseases chosen from Alzheimer's disease, amyotrophic lateral sclerosis, dystonia, epilepsy, multiple sclerosis and Parkinson's disease. 34. Use according to claim 29, wherein the autoimmune diseases are chosen from the group consisting of autoimmune type I diseases or autoimmune type H diseases or autoimmune type III diseases or autoimmune type IV diseases, such as, for example, multiple sclerosis (MS), rheumatoid arthritis, diabetes, diabetes type I (diabetes mellitus), systemic lupus erythematosus (SLE), chronic polyarthritis, Basedow's disease, autoimmune forms of chronic hepatitis, colitis ulcerosa, allergy type I diseases, allergy type II diseases, allergy type III diseases, allergy type IV diseases, fibromyalgia, hair loss, Bechterew's disease, Crohn's disease, myasthenia gravis, neurodermatitis, polymyalgia rheumatica, progressive systemic sclerosis (PSS), psoriasis, Reiter's syndrome, rheumatic arthritis, psoriasis or vasculitis. 35. In vitro transcription method for the preparation of an antibody-coding, optionally modified RNA, comprising the following steps:
a) provision of a nucleic acid which codes for an antibody, as defined in claim 4; b) addition of the nucleic acid to an in vitro transcription medium comprising an RNA polymerase, a suitable buffer, a nucleic acid mix comprising one or more modified nucleotides in exchange for one or more of the naturally occurring nucleotides A, G, C or U, and optionally one or more naturally occurring nucleotides A, G, C or U, if not all the naturally occurring nucleotides A, G, C or U are to be exchanged, or optionally only naturally occurring nucleotides and optionally an RNase inhibitor; c) incubation of the nucleic acid in the in vitro transcription medium and in vitro transcription of the nucleic acid to give an antibody-coding, optionally modified RNA according to claim 1; d) optionally purification of the antibody-coding, optionally modified RNA and removal of the non-incorporated nucleotides from the in vitro transcription medium. 36. In vitro transcription and translation method for expression of an antibody, comprising the following steps:
a) provision of a nucleic acid which codes for an antibody, as defined in claim 4; b) addition of the nucleic acid to an in vitro transcription medium comprising an RNA polymerase, a suitable buffer, a nucleic acid mix comprising one or more modified nucleotides in exchange for one or more of the naturally occurring nucleotides A, O, C or U, and optionally one or more naturally occurring nucleotides A, G, C or U, if not all the naturally occurring nucleotides A, G, C or U are to be exchanged, or optionally only naturally occurring nucleotides and optionally an RNase inhibitor; c) incubation of the nucleic acid in the in vitro transcription medium and in vitro transcription of the nucleic acid to give an antibody-coding, optionally modified RNA according to claim 1; d) optionally purification of the antibody-coding, optionally modified RNA and removal of the non-incorporated nucleotides from the in vitro transcription medium, e) addition of the optionally modified RNA obtained in step c) (and optionally in step d) to an in vitro translation medium; f) incubation of the optionally modified RNA in the in vitro translation medium and in vitro translation of the antibody coded by the optionally modified RNA; g) optionally purification of the antibody translated in step f). 37. In vitro transcription and translation method for expression of an antibody in a host cell, comprising the following steps:
a) provision of a nucleic acid which codes for an antibody, as defined in claim 4; b) addition of the nucleic acid to an in vitro transcription medium comprising an RNA polymerase, a suitable buffer, one or more modified nucleotides in exchange for one or more of the naturally occurring nucleotides A, G, C or U and optionally one or more naturally occurring nucleotides A, G, C or U, if not all the naturally occurring nucleotides A, G, C or U are to be exchanged, or only naturally occurring nucleotides and optionally an RNase inhibitor; c) incubation of the nucleic acid in the in vitro transcription medium and in vitro transcription of the nucleic acid to give an antibody-coding, optionally modified RNA according to claim 1; d) optionally purification of the antibody-coding, optionally modified RNA according to the invention and removal of the non-incorporated nucleotides from the in vitro transcription medium, e′) transfection of the optionally modified RNA obtained in step c) (and optionally d)) into a host cell; f′) incubation of the optionally modified nucleic acid in the host cell and translation of the antibody coded by the optionally modified RNA in the host cell; g′) optionally isolation and/or purification of the antibody translated in step f). | 1,600 |
1,162 | 14,303,492 | 1,649 | Methods of improving a condition in a subject are provided herein. Aspects of the methods include at least partially restoring normal function of a central nervous system endocrine gland in a manner sufficient to improve the condition in the subject. In some instances, the condition is an aging associated condition. Aspects of the invention further include compositions, systems and devices for practicing the methods. | 1. A method of improving a condition in a subject, the method comprising:
at least partially restoring normal function of a central nervous system endocrine gland in a manner sufficient to improve the condition in the subject. 2. The method according to claim 1, wherein the at least partially restoring normal function comprises restoring endocrine function so that the endocrine function is closer to that of a healthy human 25 year old. 3. The method according to claim 1, wherein the at least partially restoring endocrine function modulates autonomic function. 4. The method according to claim 3, wherein the autonomic function is modulated so that the sympathetic/parasympathetic bias of the subject is closer to the sympathetic/parasympathetic bias of a healthy human 25 year old. 5. The method according to claim 1, wherein the at least partially restoring normal function comprises restoring pituitary function so that the pituitary function is closer to that of a healthy human 25 year old. 6. The method according to claim 1, wherein the at least partially restoring normal function of the central nervous system endocrine gland comprises electrical stimulation. 7. The method according to claim 1, wherein the at least partially restoring normal function of the central nervous system endocrine gland comprises pharmacological agent administration. 8. The method according to claim 1, wherein the at least partially restoring normal function of the central nervous system endocrine gland comprises a cellular therapy. 9. The method according to claim 8, wherein the cellular therapy employs pluripotent cells. 10. The method according to claim 1, wherein the at least partially restoring normal function of the central nervous system endocrine gland comprises inhibiting apoptosis of cells of the endocrine gland. 11. The method according to claim 10, wherein the method further comprises inhibiting apoptosis of non-endocrine gland cells. 12. The method according to claim 1, wherein the at least partially restoring normal function of the central nervous system endocrine gland comprises decreasing degeneration of the endocrine gland. 13. The method according to claim 12, wherein the method further comprises decreasing degeneration of non-endocrine gland cells. 14-15. (canceled) 16. The method according to claim 1, wherein the condition is an autonomic nervous system associated condition. 17. The method according to claim 16, wherein the autonomic nervous system associated condition is a sympathetic bias associated condition. 18. The method according to claim 17, wherein the sympathetic bias associated condition is an aging associated condition. 19. The method according to claim 16, wherein the autonomic nervous system associated condition is a parasympathetic bias associated condition. 20. The method according to claim 19, wherein the parasympathetic bias associated condition is a vagal bias associated condition. 21. The method according to claim 1, wherein the condition is an aging associated condition. 22. A system comprising:
an algorithm recorded on a computer-readable medium for administering a stimulus to a subject according to a method of claim 6; and an electrical energy applying device. | Methods of improving a condition in a subject are provided herein. Aspects of the methods include at least partially restoring normal function of a central nervous system endocrine gland in a manner sufficient to improve the condition in the subject. In some instances, the condition is an aging associated condition. Aspects of the invention further include compositions, systems and devices for practicing the methods.1. A method of improving a condition in a subject, the method comprising:
at least partially restoring normal function of a central nervous system endocrine gland in a manner sufficient to improve the condition in the subject. 2. The method according to claim 1, wherein the at least partially restoring normal function comprises restoring endocrine function so that the endocrine function is closer to that of a healthy human 25 year old. 3. The method according to claim 1, wherein the at least partially restoring endocrine function modulates autonomic function. 4. The method according to claim 3, wherein the autonomic function is modulated so that the sympathetic/parasympathetic bias of the subject is closer to the sympathetic/parasympathetic bias of a healthy human 25 year old. 5. The method according to claim 1, wherein the at least partially restoring normal function comprises restoring pituitary function so that the pituitary function is closer to that of a healthy human 25 year old. 6. The method according to claim 1, wherein the at least partially restoring normal function of the central nervous system endocrine gland comprises electrical stimulation. 7. The method according to claim 1, wherein the at least partially restoring normal function of the central nervous system endocrine gland comprises pharmacological agent administration. 8. The method according to claim 1, wherein the at least partially restoring normal function of the central nervous system endocrine gland comprises a cellular therapy. 9. The method according to claim 8, wherein the cellular therapy employs pluripotent cells. 10. The method according to claim 1, wherein the at least partially restoring normal function of the central nervous system endocrine gland comprises inhibiting apoptosis of cells of the endocrine gland. 11. The method according to claim 10, wherein the method further comprises inhibiting apoptosis of non-endocrine gland cells. 12. The method according to claim 1, wherein the at least partially restoring normal function of the central nervous system endocrine gland comprises decreasing degeneration of the endocrine gland. 13. The method according to claim 12, wherein the method further comprises decreasing degeneration of non-endocrine gland cells. 14-15. (canceled) 16. The method according to claim 1, wherein the condition is an autonomic nervous system associated condition. 17. The method according to claim 16, wherein the autonomic nervous system associated condition is a sympathetic bias associated condition. 18. The method according to claim 17, wherein the sympathetic bias associated condition is an aging associated condition. 19. The method according to claim 16, wherein the autonomic nervous system associated condition is a parasympathetic bias associated condition. 20. The method according to claim 19, wherein the parasympathetic bias associated condition is a vagal bias associated condition. 21. The method according to claim 1, wherein the condition is an aging associated condition. 22. A system comprising:
an algorithm recorded on a computer-readable medium for administering a stimulus to a subject according to a method of claim 6; and an electrical energy applying device. | 1,600 |
1,163 | 15,015,657 | 1,633 | The present application describes an antibody-coding, non-modified or modified RNA and the use thereof for expression of this antibody, for the preparation of a pharmaceutical composition, in particular a passive vaccine, for treatment of tumours and cancer diseases, cardiovascular diseases, infectious diseases, autoimmune diseases, virus diseases and monogenetic diseases, e.g. also in gene therapy. The present invention furthermore describes an in vitro transcription method, in vitro methods for expression of this antibody using the RNA according to the invention and an in vivo method. | 1. A method of treating a subject comprising administering an effective amount of a pharmaceutical composition comprising mRNA encoding CD20-binding antibody. 2. The method of claim 1, wherein the subject has a cancer. 3. The method of claim 2, wherein the subject has a leukemia, lymphoma or myeloma. 4. The method of claim 1, wherein the pharmaceutical composition is administered by injection. 5. The method of claim 1, wherein the antibody comprises a Fab, Fab′, F(ab′)2, Fc, pFc′, Fd, FIT and scFv fragment of an antibody. 6. The method of claim 1, wherein the antibody comprises a human antibody or a humanized antibody. 7. The method of claim 1, wherein the mRNA comprises a sequence encoding an antibody operably linked to a heterologous secretory signal sequence. 8. The method of claim 1, wherein the composition comprises a mRNA that encodes an antibody light chain and a mRNA that encodes an antibody heavy chain. 9. The method of claim 1, wherein the composition comprises a mRNA that encodes an antibody light chain and an antibody heavy chain, wherein the antibody light chain and an antibody heavy chain coding sequences are linked by an internal ribosomal entry site (IRES). 10. The method of claim 1, wherein the mRNA comprises a 5′ cap structure. 11. The method of claim 1, wherein the mRNA additionally comprises a poly-A tail of 10 to 200 adenosine nucleotides and/or a poly-C tail of 10 to 200 cytosine nucleotides. 12. The method of claim 1, wherein the CD20-binding antibody comprises ibritumomab, tositumomab, ofatumamab or rituximab. 13. The method of claim 12, wherein the antibody comprises rituximab. 14. The method of claim 13, wherein the mRNA encodes: a sequence at least 80% identical to SEQ ID NOs: 1 or 2; and/or a sequence at least 80% identical to SEQ ID NOs: 4 or 5. 15. The method of claim 1, wherein the mRNA is modified by introduction of a non-native nucleotide compared with a native mRNA sequence and/or by covalent coupling of the mRNA with a further chemical moiety. 16. The method of claim 15, wherein the mRNA comprises:
(i) a G/C content in the antibody coding region which is greater than the G/C content of the coding region of the native mRNA sequence encoding the antibody; or (ii) an antibody coding sequence that is modified, compared with the native mRNA encoding the antibody, such that at least one codon of the native mRNA which codes for a tRNA which is relatively rare in the cell is exchanged for a codon which codes for a tRNA which is relatively frequent in the cell. 17. The method of claim 15, wherein the mRNA comprises a chemical modification relative to a naturally occurring mRNA. 18. The method of claim 15, wherein the mRNA comprises at least a nucleotide that is substituted with a nucleotide analog selected from the group consisting of: 1-methyl-adenine, 2-methyl-adenine, 2-methylthio-N-6-isopentenyl-adenine, N6-methyl-adenine, N6-isopentenyl-adenine, 2-thio-cytosine, 3-methylcytosine, 4-acetyl-cytosine, 5-methyl-cytosine, 2,6-diaminopurine, 1-methyl-guanine, 2-methyl-guanine, 2,2-dimethyl-guanine, 7-methyl-guanine, inosine, 1-methyl-inosine, dihydro-uracil, 2-thio-uracil, 4-thio-uracil, 5-carboxymethylaminomethyl-2-thio-uracil, 5-(carboxyhydroxymethyl)-uracil, 5-fluoro-uracil, 5-bromo-uracil, 5-carboxymethylaminomethyl-uracil, 5-methyl-2-thio-uracil, 5-methyl-uracil, N-uracil-5-oxyacetic acid methyl ester, 5-methylaminomethyl-uracil, 5-methoxyaminomethyl-2-thio-uracil, 5-methoxycarbonylmethyl-uracil, 5-methoxy-uracil, uracil-5-oxyacetic acid methyl ester, uracil-5-oxyacetic acid (v), pseudouracil, 1-methyl-pseudouracil, queosine, β-D-mannosyl-queosine, wybutoxosine, phosphoramidates, phosphorothioates, peptide nucleotides, methylphosphonates, 7-deazaguanosine, 5-methylcytosine and inosine. 19. The method of claim 15, wherein the mRNA modification comprises at least one base-modified nucleotide chosen from the group consisting of 2-amino-6-chloropurine riboside 5′-triphosphate, 2-aminoadenosine 5′-triphosphate, 2-thiocytidine 5′-triphosphate, 2-thiouridine 5′-triphosphate, 4-thiouridine 5′-triphosphate, 5-aminoallylcytidine 5′-triphosphate, 5-aminoallyluridine 5′-triphosphate, 5-bromocytidine 5′-triphosphate, 5-bromouridine 5′-triphosphate, 5-iodocytidine 5′-triphosphate, 5-iodouridine 5′-triphosphate, 5-methylcytidine 5′-triphosphate, 5-methyluridine 5′triphosphate, 6-azacytidine 5′-triphosphate, 6-azauridine 5′-triphosphate, 6-chloropurine riboside 5′-triphosphate, 7-deazaadenosine 5′-triphosphate, 7-deazaguanosine 5′-triphosphate, 8-azaadenosine 5′-triphosphate, 8-azidoadenosine 5′-triphosphate, benzimidazole riboside 5′-triphosphate, N1-methyladenosine 5′-triphosphate, N1-methylguanosine 5′-triphosphate, N6-methyladenosine 5′-triphosphate, 06-methylguanosine 5′-triphosphate, pseudouridine 5′-triphosphate, puromycin 5′-triphosphate and xanthosine 5′-triphosphate. 20. The method of claim 19, wherein the base-modified nucleotide is chosen from the group consisting of: 5-methylcytidine 5′-triphosphate, 1-methyl-pseudouracil and pseudouridine 5′-triphosphate. 21. A pharmaceutical composition comprising an isolated mRNA comprising a coding region encoding at least one antibody variable domain of a CD20-binding antibody, wherein said coding region is linked to a heterologous secretory signal sequence. | The present application describes an antibody-coding, non-modified or modified RNA and the use thereof for expression of this antibody, for the preparation of a pharmaceutical composition, in particular a passive vaccine, for treatment of tumours and cancer diseases, cardiovascular diseases, infectious diseases, autoimmune diseases, virus diseases and monogenetic diseases, e.g. also in gene therapy. The present invention furthermore describes an in vitro transcription method, in vitro methods for expression of this antibody using the RNA according to the invention and an in vivo method.1. A method of treating a subject comprising administering an effective amount of a pharmaceutical composition comprising mRNA encoding CD20-binding antibody. 2. The method of claim 1, wherein the subject has a cancer. 3. The method of claim 2, wherein the subject has a leukemia, lymphoma or myeloma. 4. The method of claim 1, wherein the pharmaceutical composition is administered by injection. 5. The method of claim 1, wherein the antibody comprises a Fab, Fab′, F(ab′)2, Fc, pFc′, Fd, FIT and scFv fragment of an antibody. 6. The method of claim 1, wherein the antibody comprises a human antibody or a humanized antibody. 7. The method of claim 1, wherein the mRNA comprises a sequence encoding an antibody operably linked to a heterologous secretory signal sequence. 8. The method of claim 1, wherein the composition comprises a mRNA that encodes an antibody light chain and a mRNA that encodes an antibody heavy chain. 9. The method of claim 1, wherein the composition comprises a mRNA that encodes an antibody light chain and an antibody heavy chain, wherein the antibody light chain and an antibody heavy chain coding sequences are linked by an internal ribosomal entry site (IRES). 10. The method of claim 1, wherein the mRNA comprises a 5′ cap structure. 11. The method of claim 1, wherein the mRNA additionally comprises a poly-A tail of 10 to 200 adenosine nucleotides and/or a poly-C tail of 10 to 200 cytosine nucleotides. 12. The method of claim 1, wherein the CD20-binding antibody comprises ibritumomab, tositumomab, ofatumamab or rituximab. 13. The method of claim 12, wherein the antibody comprises rituximab. 14. The method of claim 13, wherein the mRNA encodes: a sequence at least 80% identical to SEQ ID NOs: 1 or 2; and/or a sequence at least 80% identical to SEQ ID NOs: 4 or 5. 15. The method of claim 1, wherein the mRNA is modified by introduction of a non-native nucleotide compared with a native mRNA sequence and/or by covalent coupling of the mRNA with a further chemical moiety. 16. The method of claim 15, wherein the mRNA comprises:
(i) a G/C content in the antibody coding region which is greater than the G/C content of the coding region of the native mRNA sequence encoding the antibody; or (ii) an antibody coding sequence that is modified, compared with the native mRNA encoding the antibody, such that at least one codon of the native mRNA which codes for a tRNA which is relatively rare in the cell is exchanged for a codon which codes for a tRNA which is relatively frequent in the cell. 17. The method of claim 15, wherein the mRNA comprises a chemical modification relative to a naturally occurring mRNA. 18. The method of claim 15, wherein the mRNA comprises at least a nucleotide that is substituted with a nucleotide analog selected from the group consisting of: 1-methyl-adenine, 2-methyl-adenine, 2-methylthio-N-6-isopentenyl-adenine, N6-methyl-adenine, N6-isopentenyl-adenine, 2-thio-cytosine, 3-methylcytosine, 4-acetyl-cytosine, 5-methyl-cytosine, 2,6-diaminopurine, 1-methyl-guanine, 2-methyl-guanine, 2,2-dimethyl-guanine, 7-methyl-guanine, inosine, 1-methyl-inosine, dihydro-uracil, 2-thio-uracil, 4-thio-uracil, 5-carboxymethylaminomethyl-2-thio-uracil, 5-(carboxyhydroxymethyl)-uracil, 5-fluoro-uracil, 5-bromo-uracil, 5-carboxymethylaminomethyl-uracil, 5-methyl-2-thio-uracil, 5-methyl-uracil, N-uracil-5-oxyacetic acid methyl ester, 5-methylaminomethyl-uracil, 5-methoxyaminomethyl-2-thio-uracil, 5-methoxycarbonylmethyl-uracil, 5-methoxy-uracil, uracil-5-oxyacetic acid methyl ester, uracil-5-oxyacetic acid (v), pseudouracil, 1-methyl-pseudouracil, queosine, β-D-mannosyl-queosine, wybutoxosine, phosphoramidates, phosphorothioates, peptide nucleotides, methylphosphonates, 7-deazaguanosine, 5-methylcytosine and inosine. 19. The method of claim 15, wherein the mRNA modification comprises at least one base-modified nucleotide chosen from the group consisting of 2-amino-6-chloropurine riboside 5′-triphosphate, 2-aminoadenosine 5′-triphosphate, 2-thiocytidine 5′-triphosphate, 2-thiouridine 5′-triphosphate, 4-thiouridine 5′-triphosphate, 5-aminoallylcytidine 5′-triphosphate, 5-aminoallyluridine 5′-triphosphate, 5-bromocytidine 5′-triphosphate, 5-bromouridine 5′-triphosphate, 5-iodocytidine 5′-triphosphate, 5-iodouridine 5′-triphosphate, 5-methylcytidine 5′-triphosphate, 5-methyluridine 5′triphosphate, 6-azacytidine 5′-triphosphate, 6-azauridine 5′-triphosphate, 6-chloropurine riboside 5′-triphosphate, 7-deazaadenosine 5′-triphosphate, 7-deazaguanosine 5′-triphosphate, 8-azaadenosine 5′-triphosphate, 8-azidoadenosine 5′-triphosphate, benzimidazole riboside 5′-triphosphate, N1-methyladenosine 5′-triphosphate, N1-methylguanosine 5′-triphosphate, N6-methyladenosine 5′-triphosphate, 06-methylguanosine 5′-triphosphate, pseudouridine 5′-triphosphate, puromycin 5′-triphosphate and xanthosine 5′-triphosphate. 20. The method of claim 19, wherein the base-modified nucleotide is chosen from the group consisting of: 5-methylcytidine 5′-triphosphate, 1-methyl-pseudouracil and pseudouridine 5′-triphosphate. 21. A pharmaceutical composition comprising an isolated mRNA comprising a coding region encoding at least one antibody variable domain of a CD20-binding antibody, wherein said coding region is linked to a heterologous secretory signal sequence. | 1,600 |
1,164 | 14,871,327 | 1,639 | Disclosed are methods for cell transfection and regulating cellular behavior. More particularly, the present disclosure relates to methods of non-viral cell transfection and regulating cellular behavior using mineral coatings that allow for the enhanced transfection of cells with reduced cytotoxicity. The mineral coatings bind biomaterials and provide a source of calcium and phosphate ions to enhance transfection. The present disclosure also provides a high throughput platform for screening non-viral transfection of cells. The methods of the present disclosure also provide an advantageous biomaterial delivery platform because the mineral coatings may be deposited on various medical device materials after being specifically developed using the high throughput screening platform. | 1. A method of non-viral transfection comprising:
preparing a microparticle comprising a mineral coating, wherein the mineral coating is formed by incubating the substrate in a simulated body fluid, wherein the simulated body fluid comprises from about 5 mM to about 12.5 mM calcium ions, from about 2 mM to about 12.5 mM phosphate ions, from about 4 mM to about 100 mM carbonate ions, and a pH of from about 4 to about 7.5; contacting the microparticle comprising the mineral coating with a biomaterial, wherein the biomaterial binds the mineral coating; contacting a cell with the mineral coating; and culturing the cell. 2. The method of claim 1, wherein the mineral coating comprises a calcium to phosphate ratio of from about 2.5:1 to about 1:1. 3. The method of claim 1, wherein the mineral coating further comprises halogen ions. 4. The method of claim 3, wherein the mineral coating further comprises fluoride ions. 5. The method of claim 1, wherein the microparticle comprises a magnetic material. 6. The method of claim 1, wherein the microparticle comprises a material selected from the group consisting of ceramics, plastics, hydrogels, and combinations thereof. 7. The method of claim 1, further comprising culturing the cell in a biomaterial release medium, wherein the biomaterial release medium comprises an ion selected from the group consisting of calcium, phosphate, and combinations thereof, wherein the calcium ion concentration comprises from about 0 mM to about 2.5 mM, and the phosphate ion concentration comprises from about 0 mM to about 1 mM. 8. The method of claim 1, further comprising culturing the cell in a biomaterial release medium, wherein the biomaterial release medium comprises a pH of from about 6.2 to about 7.8. 9. The method of claim 1, wherein the cell is selected from the group consisting of a pluripotent stem cell, a mesenchymal stem cell, and an umbilical vein endothelial cell. 10. A high throughput non-viral transfection system comprising:
a microparticle that comprises:
a plurality of mineral coatings, wherein the plurality of mineral coatings comprise a calcium to phosphate ratio of from about 2.5:1 to about 1:1;
a biomaterial bound to the plurality of mineral coatings; and
a plurality of cells. 11. The system of claim 10, wherein the mineral coating further comprises halogen ions. 12. The system of claim 11, wherein the mineral coating further comprises fluoride ions. 13. The system of claim 10, wherein the microparticle comprises a magnetic material. 14. The system of claim 13, wherein the magnetic material comprises at least one of magnetite, magnetite-doped plastics, and neodymium. 15. The system of claim 10, wherein the microparticle comprises a material selected from the group consisting of ceramics, plastics, hydrogels, and combinations thereof. 16. A fluoride-doped mineral coated microparticle comprising at least one mineral coating layer surrounding the surface of the microparticle, the mineral coating layer comprising calcium, phosphate, and fluoride ions, wherein the calcium to phosphate ratio is from about 2.5:1 to about 1:1. 17. The microparticle of claim 16, wherein the mineral coating comprises from about 0.001 mM to 100 mM fluoride ions. 18. The microparticle of claim 16, wherein the mineral coating comprises about 1 mM fluoride ions. 19. The microparticle of claim 16, further comprising a magnetic material. 20. The microparticle of claim 19, wherein the magnetic material comprises at least one of magnetite, magnetite-doped plastics, and neodymium. | Disclosed are methods for cell transfection and regulating cellular behavior. More particularly, the present disclosure relates to methods of non-viral cell transfection and regulating cellular behavior using mineral coatings that allow for the enhanced transfection of cells with reduced cytotoxicity. The mineral coatings bind biomaterials and provide a source of calcium and phosphate ions to enhance transfection. The present disclosure also provides a high throughput platform for screening non-viral transfection of cells. The methods of the present disclosure also provide an advantageous biomaterial delivery platform because the mineral coatings may be deposited on various medical device materials after being specifically developed using the high throughput screening platform.1. A method of non-viral transfection comprising:
preparing a microparticle comprising a mineral coating, wherein the mineral coating is formed by incubating the substrate in a simulated body fluid, wherein the simulated body fluid comprises from about 5 mM to about 12.5 mM calcium ions, from about 2 mM to about 12.5 mM phosphate ions, from about 4 mM to about 100 mM carbonate ions, and a pH of from about 4 to about 7.5; contacting the microparticle comprising the mineral coating with a biomaterial, wherein the biomaterial binds the mineral coating; contacting a cell with the mineral coating; and culturing the cell. 2. The method of claim 1, wherein the mineral coating comprises a calcium to phosphate ratio of from about 2.5:1 to about 1:1. 3. The method of claim 1, wherein the mineral coating further comprises halogen ions. 4. The method of claim 3, wherein the mineral coating further comprises fluoride ions. 5. The method of claim 1, wherein the microparticle comprises a magnetic material. 6. The method of claim 1, wherein the microparticle comprises a material selected from the group consisting of ceramics, plastics, hydrogels, and combinations thereof. 7. The method of claim 1, further comprising culturing the cell in a biomaterial release medium, wherein the biomaterial release medium comprises an ion selected from the group consisting of calcium, phosphate, and combinations thereof, wherein the calcium ion concentration comprises from about 0 mM to about 2.5 mM, and the phosphate ion concentration comprises from about 0 mM to about 1 mM. 8. The method of claim 1, further comprising culturing the cell in a biomaterial release medium, wherein the biomaterial release medium comprises a pH of from about 6.2 to about 7.8. 9. The method of claim 1, wherein the cell is selected from the group consisting of a pluripotent stem cell, a mesenchymal stem cell, and an umbilical vein endothelial cell. 10. A high throughput non-viral transfection system comprising:
a microparticle that comprises:
a plurality of mineral coatings, wherein the plurality of mineral coatings comprise a calcium to phosphate ratio of from about 2.5:1 to about 1:1;
a biomaterial bound to the plurality of mineral coatings; and
a plurality of cells. 11. The system of claim 10, wherein the mineral coating further comprises halogen ions. 12. The system of claim 11, wherein the mineral coating further comprises fluoride ions. 13. The system of claim 10, wherein the microparticle comprises a magnetic material. 14. The system of claim 13, wherein the magnetic material comprises at least one of magnetite, magnetite-doped plastics, and neodymium. 15. The system of claim 10, wherein the microparticle comprises a material selected from the group consisting of ceramics, plastics, hydrogels, and combinations thereof. 16. A fluoride-doped mineral coated microparticle comprising at least one mineral coating layer surrounding the surface of the microparticle, the mineral coating layer comprising calcium, phosphate, and fluoride ions, wherein the calcium to phosphate ratio is from about 2.5:1 to about 1:1. 17. The microparticle of claim 16, wherein the mineral coating comprises from about 0.001 mM to 100 mM fluoride ions. 18. The microparticle of claim 16, wherein the mineral coating comprises about 1 mM fluoride ions. 19. The microparticle of claim 16, further comprising a magnetic material. 20. The microparticle of claim 19, wherein the magnetic material comprises at least one of magnetite, magnetite-doped plastics, and neodymium. | 1,600 |
1,165 | 14,128,681 | 1,647 | This invention provides, and in certain specific but non-limiting aspects relates to: assays that can be used to predict whether a given ISV will be subject to protein interference as described herein and/or give rise to an (aspecific) signal in such an assay (such as for example in an ADA immunoassay). Such predictive assays could for example be used to test whether a given ISV could have a tendency to give rise to such protein interference and/or such a signal; to select ISV's that are not or less prone to such protein interference or to giving such a signal; as an assay or test that can be used to test whether certain modification(s) to an ISV will (fully or partially) reduce its tendency to give rise to such interference or such a signal; and/or as an assay or test that can be used to guide modification or improvement of an ISV so as to reduce its tendency to give rise to such protein interference or signal; —methods for modifying and/or improving ISV's to as to remove or reduce their tendency to give rise to such protein interference or such a signal; —modifications that can be introduced into an ISV that remove or reduce its tendency to give rise to such protein interference or such a signal; ISV's that have been specifically selected (for example, using the assay(s) described herein) to have no or low(er)/reduced tendency to give rise to such protein interference or such a signal; modified and/or improved ISV's that have no or a low(er)/reduced tendency to give rise to such protein interference or such a signal. | 1. Protein or polypeptide for use in therapy that has a half-life (expressed as t½-beta) in a human subject of at least 3 days, which protein or polypeptide contains an immunoglobulin single variable domain (ISV) at its C-terminal end, wherein said ISV is either a Nanobody or an ISV that comprises a VH sequence (i.e. other than a Nanobody) or that is derived from a VH sequence, which ISV has a C-terminal end of the sequence VTVSS(X)n (SEQ ID NO: 34), in which:
n=1, 2 or 3 (and preferably 1 or 2) in which each X=Ala or Gly; or
n=1, 2 or 3 (and preferably 1 or 2) in which each X=Ala; or
n=1, 2 or 3 (and preferably 1 or 2) in which each X=Gly; or
n=2 or 3 in which at least one X=Ala or Gly (with the remaining amino acid residue X being independently chosen from any naturally occurring amino acid but preferably being independently chosen from Val, Leu and/or Ile); or
n=2 or 3 in which all but one X=Ala or Gly (with the remaining amino acid residue X being independently chosen from any naturally occurring amino acid but preferably being independently chosen from Val, Leu and/or Ile). 2. Protein or polypeptide according to claim 1, in which:
n=1, 2 or 3 (and preferably 1 or 2) in which each X=Ala or Gly; or n=1, 2 or 3 (and preferably 1 or 2) in which each X=Ala; or n=1, 2 or 3 (and preferably 1 or 2) in which each X=Gly. 3. Protein or polypeptide according to claim 1, in which X is not cysteine. 4. Protein or polypeptide for use in therapy that has a half-life (expressed as t½-beta) in a human subject of at least 3 days, which protein or polypeptide contains an ISV at its C-terminal end, wherein said ISV is either a Nanobody or an ISV that comprises a VH sequence or that is derived from a VH sequence, which ISV has a C-terminal end of the sequence VTVSS(X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1), and in which each X is an (preferably naturally occurring) amino acid residue that is independently chosen (and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I), with the proviso that X is not cysteine; or a protein or polypeptide which contains such an ISV (and preferably such a Nanobody) at its C-terminal end. 5. Protein or polypeptide according to claim 1, which in which said (C-terminal) ISV is a Nanobody. 6. Protein or polypeptide according to claim 1 which has an RU value for binding by monoclonal antibody 21-4 of less than 500, as determined using Biacore according to the protocol set out in Example 9, and after adjusting the measured RU value for the molecular weight of the ISV, protein or polypeptide according to the formula ([RU measured]/[MW of the protein]×106). 7. Method for predicting whether an ISV or protein or polypeptide comprising at least one ISV will give rise to protein interference in an immunoassay such as an ADA assay, said method comprising performing an immunoassay that at least comprises the steps of:
(i) contacting said ISV or protein/polypeptide with an antibody that has been obtained from a human subject and that has been selected/isolated based on its ability to recognize and/or bind to the C-terminal end of said ISV; and (ii) determining whether said ISV, protein or polypeptide is bound by said antibody in said immunoassay. 8. Method according to claim 7, in which the ISV is either a Nanobody or an(other) ISV (i.e. other than a Nanobody) that is a VH domain or that comprises a VH domain. 9. Method according to claim 7, in which the ISV is a Nanobody. 10. Method according to claim 7, in which the protein or polypeptide has said ISV at its C-terminal end. 11. Method according to claim 7, in which the fact that the ISV, protein or polypeptide binds to said antibod in step (ii) means that the ISV, protein or polypeptide can give rise to (or has a high or increased risk of giving rise to) such protein interference. 12. Method according to claim 7, in which the antibody is a polyclonal antibody. 13. Method according to claim 7, in which the antibody is a polyclonal antibody that has been obtained, starting from a biological sample that has been obtained from a human subject and that is suitable as a starting material for obtaining polyclonal antibodies, by a method that comprises at least one step of (immuno)affinity chromatography in which affinity matrix is used that carries the ISV or protein or polypeptide comprising at least one ISV and/or in which the ISV or protein or polypeptide comprising at least one ISV is used as the affinity moiety or antigen, and optionally one or more further steps for isolating and/or purifying a polyclonal antibody from said sample (performed either before and/or after said affinity step). 14. Method according to claim 13, in which the ISV or protein or polypeptide comprising at least one ISV that is carried on the affinity matrix and/or that is used as the affinity moiety or antigen is an ISV or protein or polypeptide comprising at least one ISV that ends at its C-terminal end with the amino acid sequence VTVSS (SEQ ID NO:33), or in which the ISV or protein or polypeptide comprising at least one ISV that is carried on the affinity matrix and/or that is used as the affinity moiety or antigen has at its C-terminal end an ISV or Nanobody that ends at its C-terminal end with the amino acid sequence VTVSS (SEQ ID NO:33). 15. Method according to claim 13, in which that the ISV or protein or polypeptide comprising at least one ISV that is carried on the affinity matrix and/or that is used as the affinity moiety or antigen is an ISV or protein or polypeptide comprising at least one ISV, that ends at its C-terminal end with the amino acid sequence VTVSS (SEQ ID NO:33) and that has a proline residue on position 14; or in which the ISV or protein or polypeptide comprising at least one ISV that is carried on the affinity matrix and/or that is used as the affinity moiety or antigen has at its C-terminal end is an ISV or protein or polypeptide comprising at least one ISV that ends at its C-terminal end with the amino acid sequence VTVSS (SEQ ID NO:33) and that has a proline residue on position 14. 16. Method according to claim 13, in which that the ISV or Nanobody that is carried on the affinity matrix and/or that is used as the affinity moiety or antigen is a sequence-optimized and/or humanized Nanobody (such as a sequence-optimized and/or humanized VHH or a camelized VH, such as a camelized human VH); or in which the ISV-based drug or Nanobody-based drug that is carried on the affinity matrix and/or that is used as the affinity moiety or antigen has at its C-terminal end an ISV or Nanobody that is a sequence-optimized and/or humanized Nanobody (such as a sequence-optimized and/or humanized VHH or a camelized VH, such as a camelized human VH). 17. Method according to claim 15, in which that the ISV or Nanobody that is carried on the affinity matrix and/or that is used as the affinity moiety or antigen is a sequence-optimized and/or humanized Nanobody that ends at its C-terminal end with the amino acid sequence VTVSS (SEQ ID NO:33) and that has a proline residue on position 14 which has been introduced as part of the humanization and/or sequence optimization of the corresponding naturally occurring VHH; or in which the ISV-based drug or Nanobody-based drug that is carried on the affinity matrix and/or that is used as the affinity moiety or antigen has at its C-terminal end a sequence-optimized and/or humanized Nanobody that ends at its C-terminal end with the amino acid sequence VTVSS (SEQ ID NO:33) and that has a proline residue on position 14 which has been introduced as part of the humanization and/or sequence optimization of the corresponding naturally occurring VHH. 18. Method according to claim 7, in which the antibody is a monoclonal antibody. 19. Method according to claim 7, in which the antibody is a polyclonal antibody that has been obtained, starting from a biological sample that has been obtained from a human subject and that is suitable as a starting material for obtaining monoclonal, by a method that comprises at least one screening or selection step in which an ISV, Nanobody, ISV-based drug or Nanobody-based drug is used for screening and selecting a monoclonal antibody that binds to said ISV, Nanobody, ISV-based drug or Nanobody-based drug (and in particular to the C-terminal end of the same), and optionally one or more further steps for isolating and/or purifying a monoclonal antibody from said sample (performed either before and/or after said screening and/or selection step(s)). 20. Method according to claim 19, in which the ISV or Nanobody that is used in the screening or selection step ends at its C-terminal end with the amino acid sequence VTVSS (SEQ ID NO:33), or in which the ISV-based drug or Nanobody-based drug that is used in the screening or selection step has at its C-terminal end an ISV or Nanobody that ends at its C-terminal end with the amino acid sequence VTVSS (SEQ ID NO:33). 21. Method according to claim 19, in which the ISV or Nanobody that is used in the screening or selection step ends at its C-terminal end with the amino acid sequence VTVSS (SEQ ID NO:33) and that has a proline residue at position 14, or in which the ISV-based drug or Nanobody-based drug that is used in the screening or selection step has at its C-terminal end an ISV or Nanobody that ends at its C-terminal end with the amino acid sequence VTVSS (SEQ ID NO:33) and that has a proline residue at position 14. 22. Method according to claim 19, in which the ISV or Nanobody that is used in the screening or selection step is a sequence-optimized and/or humanized Nanobody (such as a sequence-optimized and/or humanized VHH or a camelized VH, such as a camelized human VH); or in which the ISV-based drug or Nanobody-based drug that is used in the screening or selection step has at its C-terminal end an ISV or Nanobody that is a sequence-optimized and/or humanized Nanobody (such as a sequence-optimized and/or humanized VHH or a camelized VH, such as a camelized human VH). 23. Method according to claim 21, in which the ISV or Nanobody that is used in the screening or selection step is a sequence-optimized and/or humanized Nanobody that ends at its C-terminal end with the amino acid sequence VTVSS (SEQ ID NO:33) and that has a proline residue on position 14 which has been introduced as part of the humanization and/or sequence optimization of the corresponding naturally occurring VHH; or in which the ISV-based drug or Nanobody-based drug that is used in the screening or selection step has at its C-terminal end a sequence-optimized and/or humanized Nanobody that ends at its C-terminal end with the amino acid sequence VTVSS (SEQ ID NO:33) and that has a proline residue on position 14 which has been introduced as part of the humanization and/or sequence optimization of the corresponding naturally occurring VHH. 24. Method that can be used to predict whether an ISV or protein or polypeptide comprising at least one ISV will give rise to (or has high or increased tendency to give rise to) protein interference in an immunoassay (and/or to predict whether said ISV or protein or polypeptide comprising at least one ISV will be bound by interference factor(s) present in the blood or serum of a human being), said method comprising performing an immunoassay that at least comprises the steps of:
(i) contacting said ISV or Nanobody (or ISV-based or Nanobody-based drug) with the monoclonal antibody 21-4 (i.e. used as the “analytical antibody”); and (ii) determining whether said ISV or Nanobody (or ISV-based or Nanobody-based drug) is bound by the monoclonal antibody 21-4 in said immunoassay. 25. Method according to claim 24, in which the ISV is either a Nanobody or an(other) ISV (i.e. other than a Nanobody) that is a VH domain or that comprises a VH domain. 26. Method according to claim 24, in which the ISV is a Nanobody. 27. Method according to claim 24, in which the protein or polypeptide has said ISV at its C-terminal end. 28. Method according to claim 24, that is performed according to the protocol said out in Example 9. 29. Pharmaceutical composition that comprises an ISV, protein or polypeptide according to claim 1, and at least one suitable carrier, diluent or excipient. 30. Pharmaceutical composition according to claim 29, in which:
said composition, ISV, protein or polypeptide is intended for treatment of a chronic disease in a human being, and/or said ISV, protein, polypeptide is intended to be present in the circulation of the subject (i.e. at pharmacologically active levels) to which it is administered (i.e. at a therapeutically active dose) for at least a period of one week, preferably at least two weeks, such as at least a months; and/or said ISV, protein, polypeptide is such that it has a half-life (preferably expressed as t½-beta) in a human subject of at least 3 days, such as at least one week, and up to 10 days or more; and/or such said ISV, protein, polypeptide or pharmaceutical composition is intended to be administered to a human being as two or more doses that are administered over a period of at least 3 days, such as at least one week, for example at least two weeks or at least one month, or even longer (i.e. at least 3 months, at least 6 months or at least one year), or even chronically administered. 31. ISV, protein or polypeptide according to claim 1 for use in therapy of a disease in a human being. 32. ISV, protein or polypeptide according to claim 1, in which:
said ISV, protein or polypeptide is intended for treatment of a chronic disease in a human being, and/or said ISV, protein, polypeptide is intended to be present in the circulation of the subject (i.e. at pharmacologically active levels) to which it is administered (i.e. at a therapeutically active dose) for at least a period of one week, preferably at least two weeks, such as at least a months; and/or said ISV, protein, polypeptide is such that it has a half-life (preferably expressed as t½-beta) in a human subject of at least 3 days, such as at least one week, and up to 10 days or more; and/or such said ISV, protein or polypeptide is intended to be administered to a human being as two or more doses that are administered over a period of at least 3 days, such as at least one week, for example at least two weeks or at least one month, or even longer (i.e. at least 3 months, at least 6 months or at least one year), or even chronically administered. 33. A method for preparing a pharmaceutical composition that comprises an ISV, protein or polypeptide comprising combinind an ISV or a protein or polypeptide according to claim 1 and at least one suitable carrier, diluent or excipient. 34. The method according to claim 33, in which
said ISV, protein or polypeptide is intended for treatment of a chronic disease in a human being, and/or said ISV, protein, polypeptide is intended to be present in the circulation of the subject (i.e. at pharmacologically active levels) to which it is administered (i.e. at a therapeutically active dose) for at least a period of one week, preferably at least two weeks, such as at least a months; and/or said ISV, protein, polypeptide is such that it has a half-life (preferably expressed as t½-beta) in a human subject of at least 3 days, such as at least one week, and up to 10 days or more; and/or such said ISV, protein or polypeptide is intended to be administered to a human being as two or more doses that are administered over a period of at least 3 days, such as at least one week, for example at least two weeks or at least one month, or even longer (i.e. at least 3 months, at least 6 months or at least one year), or even chronically administered. 35. Method of treatment which comprises administering to a human subject (e.g to a patient in need of such treatment) an ISV or a protein or polypeptide according to claim 1. 36. Method of treatment according to claim 35, in which:
said pharmaceutical composition, ISV, protein or polypeptide is intended for treatment of a chronic disease in a human being, and/or said ISV, protein, polypeptide is intended to be present in the circulation of the subject (i.e. at pharmacologically active levels) to which it is administered (i.e. at a therapeutically active dose) for at least a period of one week, preferably at least two weeks, such as at least a months; and/or said ISV, protein, polypeptide is such that it has a half-life (preferably expressed as t½-beta) in a human subject of at least 3 days, such as at least one week, and up to 10 days or more; and/or such said pharmaceutical composition, ISV, protein or polypeptide is intended to be administered to a human being as two or more doses that are administered over a period of at least 3 days, such as at least one week, for example at least two weeks or at least one month, or even longer (i.e. at least 3 months, at least 6 months or at least one year), or even chronically administered. | This invention provides, and in certain specific but non-limiting aspects relates to: assays that can be used to predict whether a given ISV will be subject to protein interference as described herein and/or give rise to an (aspecific) signal in such an assay (such as for example in an ADA immunoassay). Such predictive assays could for example be used to test whether a given ISV could have a tendency to give rise to such protein interference and/or such a signal; to select ISV's that are not or less prone to such protein interference or to giving such a signal; as an assay or test that can be used to test whether certain modification(s) to an ISV will (fully or partially) reduce its tendency to give rise to such interference or such a signal; and/or as an assay or test that can be used to guide modification or improvement of an ISV so as to reduce its tendency to give rise to such protein interference or signal; —methods for modifying and/or improving ISV's to as to remove or reduce their tendency to give rise to such protein interference or such a signal; —modifications that can be introduced into an ISV that remove or reduce its tendency to give rise to such protein interference or such a signal; ISV's that have been specifically selected (for example, using the assay(s) described herein) to have no or low(er)/reduced tendency to give rise to such protein interference or such a signal; modified and/or improved ISV's that have no or a low(er)/reduced tendency to give rise to such protein interference or such a signal.1. Protein or polypeptide for use in therapy that has a half-life (expressed as t½-beta) in a human subject of at least 3 days, which protein or polypeptide contains an immunoglobulin single variable domain (ISV) at its C-terminal end, wherein said ISV is either a Nanobody or an ISV that comprises a VH sequence (i.e. other than a Nanobody) or that is derived from a VH sequence, which ISV has a C-terminal end of the sequence VTVSS(X)n (SEQ ID NO: 34), in which:
n=1, 2 or 3 (and preferably 1 or 2) in which each X=Ala or Gly; or
n=1, 2 or 3 (and preferably 1 or 2) in which each X=Ala; or
n=1, 2 or 3 (and preferably 1 or 2) in which each X=Gly; or
n=2 or 3 in which at least one X=Ala or Gly (with the remaining amino acid residue X being independently chosen from any naturally occurring amino acid but preferably being independently chosen from Val, Leu and/or Ile); or
n=2 or 3 in which all but one X=Ala or Gly (with the remaining amino acid residue X being independently chosen from any naturally occurring amino acid but preferably being independently chosen from Val, Leu and/or Ile). 2. Protein or polypeptide according to claim 1, in which:
n=1, 2 or 3 (and preferably 1 or 2) in which each X=Ala or Gly; or n=1, 2 or 3 (and preferably 1 or 2) in which each X=Ala; or n=1, 2 or 3 (and preferably 1 or 2) in which each X=Gly. 3. Protein or polypeptide according to claim 1, in which X is not cysteine. 4. Protein or polypeptide for use in therapy that has a half-life (expressed as t½-beta) in a human subject of at least 3 days, which protein or polypeptide contains an ISV at its C-terminal end, wherein said ISV is either a Nanobody or an ISV that comprises a VH sequence or that is derived from a VH sequence, which ISV has a C-terminal end of the sequence VTVSS(X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1), and in which each X is an (preferably naturally occurring) amino acid residue that is independently chosen (and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I), with the proviso that X is not cysteine; or a protein or polypeptide which contains such an ISV (and preferably such a Nanobody) at its C-terminal end. 5. Protein or polypeptide according to claim 1, which in which said (C-terminal) ISV is a Nanobody. 6. Protein or polypeptide according to claim 1 which has an RU value for binding by monoclonal antibody 21-4 of less than 500, as determined using Biacore according to the protocol set out in Example 9, and after adjusting the measured RU value for the molecular weight of the ISV, protein or polypeptide according to the formula ([RU measured]/[MW of the protein]×106). 7. Method for predicting whether an ISV or protein or polypeptide comprising at least one ISV will give rise to protein interference in an immunoassay such as an ADA assay, said method comprising performing an immunoassay that at least comprises the steps of:
(i) contacting said ISV or protein/polypeptide with an antibody that has been obtained from a human subject and that has been selected/isolated based on its ability to recognize and/or bind to the C-terminal end of said ISV; and (ii) determining whether said ISV, protein or polypeptide is bound by said antibody in said immunoassay. 8. Method according to claim 7, in which the ISV is either a Nanobody or an(other) ISV (i.e. other than a Nanobody) that is a VH domain or that comprises a VH domain. 9. Method according to claim 7, in which the ISV is a Nanobody. 10. Method according to claim 7, in which the protein or polypeptide has said ISV at its C-terminal end. 11. Method according to claim 7, in which the fact that the ISV, protein or polypeptide binds to said antibod in step (ii) means that the ISV, protein or polypeptide can give rise to (or has a high or increased risk of giving rise to) such protein interference. 12. Method according to claim 7, in which the antibody is a polyclonal antibody. 13. Method according to claim 7, in which the antibody is a polyclonal antibody that has been obtained, starting from a biological sample that has been obtained from a human subject and that is suitable as a starting material for obtaining polyclonal antibodies, by a method that comprises at least one step of (immuno)affinity chromatography in which affinity matrix is used that carries the ISV or protein or polypeptide comprising at least one ISV and/or in which the ISV or protein or polypeptide comprising at least one ISV is used as the affinity moiety or antigen, and optionally one or more further steps for isolating and/or purifying a polyclonal antibody from said sample (performed either before and/or after said affinity step). 14. Method according to claim 13, in which the ISV or protein or polypeptide comprising at least one ISV that is carried on the affinity matrix and/or that is used as the affinity moiety or antigen is an ISV or protein or polypeptide comprising at least one ISV that ends at its C-terminal end with the amino acid sequence VTVSS (SEQ ID NO:33), or in which the ISV or protein or polypeptide comprising at least one ISV that is carried on the affinity matrix and/or that is used as the affinity moiety or antigen has at its C-terminal end an ISV or Nanobody that ends at its C-terminal end with the amino acid sequence VTVSS (SEQ ID NO:33). 15. Method according to claim 13, in which that the ISV or protein or polypeptide comprising at least one ISV that is carried on the affinity matrix and/or that is used as the affinity moiety or antigen is an ISV or protein or polypeptide comprising at least one ISV, that ends at its C-terminal end with the amino acid sequence VTVSS (SEQ ID NO:33) and that has a proline residue on position 14; or in which the ISV or protein or polypeptide comprising at least one ISV that is carried on the affinity matrix and/or that is used as the affinity moiety or antigen has at its C-terminal end is an ISV or protein or polypeptide comprising at least one ISV that ends at its C-terminal end with the amino acid sequence VTVSS (SEQ ID NO:33) and that has a proline residue on position 14. 16. Method according to claim 13, in which that the ISV or Nanobody that is carried on the affinity matrix and/or that is used as the affinity moiety or antigen is a sequence-optimized and/or humanized Nanobody (such as a sequence-optimized and/or humanized VHH or a camelized VH, such as a camelized human VH); or in which the ISV-based drug or Nanobody-based drug that is carried on the affinity matrix and/or that is used as the affinity moiety or antigen has at its C-terminal end an ISV or Nanobody that is a sequence-optimized and/or humanized Nanobody (such as a sequence-optimized and/or humanized VHH or a camelized VH, such as a camelized human VH). 17. Method according to claim 15, in which that the ISV or Nanobody that is carried on the affinity matrix and/or that is used as the affinity moiety or antigen is a sequence-optimized and/or humanized Nanobody that ends at its C-terminal end with the amino acid sequence VTVSS (SEQ ID NO:33) and that has a proline residue on position 14 which has been introduced as part of the humanization and/or sequence optimization of the corresponding naturally occurring VHH; or in which the ISV-based drug or Nanobody-based drug that is carried on the affinity matrix and/or that is used as the affinity moiety or antigen has at its C-terminal end a sequence-optimized and/or humanized Nanobody that ends at its C-terminal end with the amino acid sequence VTVSS (SEQ ID NO:33) and that has a proline residue on position 14 which has been introduced as part of the humanization and/or sequence optimization of the corresponding naturally occurring VHH. 18. Method according to claim 7, in which the antibody is a monoclonal antibody. 19. Method according to claim 7, in which the antibody is a polyclonal antibody that has been obtained, starting from a biological sample that has been obtained from a human subject and that is suitable as a starting material for obtaining monoclonal, by a method that comprises at least one screening or selection step in which an ISV, Nanobody, ISV-based drug or Nanobody-based drug is used for screening and selecting a monoclonal antibody that binds to said ISV, Nanobody, ISV-based drug or Nanobody-based drug (and in particular to the C-terminal end of the same), and optionally one or more further steps for isolating and/or purifying a monoclonal antibody from said sample (performed either before and/or after said screening and/or selection step(s)). 20. Method according to claim 19, in which the ISV or Nanobody that is used in the screening or selection step ends at its C-terminal end with the amino acid sequence VTVSS (SEQ ID NO:33), or in which the ISV-based drug or Nanobody-based drug that is used in the screening or selection step has at its C-terminal end an ISV or Nanobody that ends at its C-terminal end with the amino acid sequence VTVSS (SEQ ID NO:33). 21. Method according to claim 19, in which the ISV or Nanobody that is used in the screening or selection step ends at its C-terminal end with the amino acid sequence VTVSS (SEQ ID NO:33) and that has a proline residue at position 14, or in which the ISV-based drug or Nanobody-based drug that is used in the screening or selection step has at its C-terminal end an ISV or Nanobody that ends at its C-terminal end with the amino acid sequence VTVSS (SEQ ID NO:33) and that has a proline residue at position 14. 22. Method according to claim 19, in which the ISV or Nanobody that is used in the screening or selection step is a sequence-optimized and/or humanized Nanobody (such as a sequence-optimized and/or humanized VHH or a camelized VH, such as a camelized human VH); or in which the ISV-based drug or Nanobody-based drug that is used in the screening or selection step has at its C-terminal end an ISV or Nanobody that is a sequence-optimized and/or humanized Nanobody (such as a sequence-optimized and/or humanized VHH or a camelized VH, such as a camelized human VH). 23. Method according to claim 21, in which the ISV or Nanobody that is used in the screening or selection step is a sequence-optimized and/or humanized Nanobody that ends at its C-terminal end with the amino acid sequence VTVSS (SEQ ID NO:33) and that has a proline residue on position 14 which has been introduced as part of the humanization and/or sequence optimization of the corresponding naturally occurring VHH; or in which the ISV-based drug or Nanobody-based drug that is used in the screening or selection step has at its C-terminal end a sequence-optimized and/or humanized Nanobody that ends at its C-terminal end with the amino acid sequence VTVSS (SEQ ID NO:33) and that has a proline residue on position 14 which has been introduced as part of the humanization and/or sequence optimization of the corresponding naturally occurring VHH. 24. Method that can be used to predict whether an ISV or protein or polypeptide comprising at least one ISV will give rise to (or has high or increased tendency to give rise to) protein interference in an immunoassay (and/or to predict whether said ISV or protein or polypeptide comprising at least one ISV will be bound by interference factor(s) present in the blood or serum of a human being), said method comprising performing an immunoassay that at least comprises the steps of:
(i) contacting said ISV or Nanobody (or ISV-based or Nanobody-based drug) with the monoclonal antibody 21-4 (i.e. used as the “analytical antibody”); and (ii) determining whether said ISV or Nanobody (or ISV-based or Nanobody-based drug) is bound by the monoclonal antibody 21-4 in said immunoassay. 25. Method according to claim 24, in which the ISV is either a Nanobody or an(other) ISV (i.e. other than a Nanobody) that is a VH domain or that comprises a VH domain. 26. Method according to claim 24, in which the ISV is a Nanobody. 27. Method according to claim 24, in which the protein or polypeptide has said ISV at its C-terminal end. 28. Method according to claim 24, that is performed according to the protocol said out in Example 9. 29. Pharmaceutical composition that comprises an ISV, protein or polypeptide according to claim 1, and at least one suitable carrier, diluent or excipient. 30. Pharmaceutical composition according to claim 29, in which:
said composition, ISV, protein or polypeptide is intended for treatment of a chronic disease in a human being, and/or said ISV, protein, polypeptide is intended to be present in the circulation of the subject (i.e. at pharmacologically active levels) to which it is administered (i.e. at a therapeutically active dose) for at least a period of one week, preferably at least two weeks, such as at least a months; and/or said ISV, protein, polypeptide is such that it has a half-life (preferably expressed as t½-beta) in a human subject of at least 3 days, such as at least one week, and up to 10 days or more; and/or such said ISV, protein, polypeptide or pharmaceutical composition is intended to be administered to a human being as two or more doses that are administered over a period of at least 3 days, such as at least one week, for example at least two weeks or at least one month, or even longer (i.e. at least 3 months, at least 6 months or at least one year), or even chronically administered. 31. ISV, protein or polypeptide according to claim 1 for use in therapy of a disease in a human being. 32. ISV, protein or polypeptide according to claim 1, in which:
said ISV, protein or polypeptide is intended for treatment of a chronic disease in a human being, and/or said ISV, protein, polypeptide is intended to be present in the circulation of the subject (i.e. at pharmacologically active levels) to which it is administered (i.e. at a therapeutically active dose) for at least a period of one week, preferably at least two weeks, such as at least a months; and/or said ISV, protein, polypeptide is such that it has a half-life (preferably expressed as t½-beta) in a human subject of at least 3 days, such as at least one week, and up to 10 days or more; and/or such said ISV, protein or polypeptide is intended to be administered to a human being as two or more doses that are administered over a period of at least 3 days, such as at least one week, for example at least two weeks or at least one month, or even longer (i.e. at least 3 months, at least 6 months or at least one year), or even chronically administered. 33. A method for preparing a pharmaceutical composition that comprises an ISV, protein or polypeptide comprising combinind an ISV or a protein or polypeptide according to claim 1 and at least one suitable carrier, diluent or excipient. 34. The method according to claim 33, in which
said ISV, protein or polypeptide is intended for treatment of a chronic disease in a human being, and/or said ISV, protein, polypeptide is intended to be present in the circulation of the subject (i.e. at pharmacologically active levels) to which it is administered (i.e. at a therapeutically active dose) for at least a period of one week, preferably at least two weeks, such as at least a months; and/or said ISV, protein, polypeptide is such that it has a half-life (preferably expressed as t½-beta) in a human subject of at least 3 days, such as at least one week, and up to 10 days or more; and/or such said ISV, protein or polypeptide is intended to be administered to a human being as two or more doses that are administered over a period of at least 3 days, such as at least one week, for example at least two weeks or at least one month, or even longer (i.e. at least 3 months, at least 6 months or at least one year), or even chronically administered. 35. Method of treatment which comprises administering to a human subject (e.g to a patient in need of such treatment) an ISV or a protein or polypeptide according to claim 1. 36. Method of treatment according to claim 35, in which:
said pharmaceutical composition, ISV, protein or polypeptide is intended for treatment of a chronic disease in a human being, and/or said ISV, protein, polypeptide is intended to be present in the circulation of the subject (i.e. at pharmacologically active levels) to which it is administered (i.e. at a therapeutically active dose) for at least a period of one week, preferably at least two weeks, such as at least a months; and/or said ISV, protein, polypeptide is such that it has a half-life (preferably expressed as t½-beta) in a human subject of at least 3 days, such as at least one week, and up to 10 days or more; and/or such said pharmaceutical composition, ISV, protein or polypeptide is intended to be administered to a human being as two or more doses that are administered over a period of at least 3 days, such as at least one week, for example at least two weeks or at least one month, or even longer (i.e. at least 3 months, at least 6 months or at least one year), or even chronically administered. | 1,600 |
1,166 | 15,870,745 | 1,619 | The present invention relates to novel anesthetic compositions containing a non-polymeric carrier material and an anesthetic, where the compositions are suitable for providing a sustained local anesthesia without an initial burst and having a duration for about 24 hours or longer. Certain compositions are also provided that include a first anesthetic and a second anesthetic. In such compositions, the second anesthetic is a solvent for the first anesthetic and provides an initial anesthetic effect upon administration to a subject. The non-polymeric carrier may optionally be a high viscosity liquid carrier material such as a suitable sugar ester. The compositions can further include one or more additional ingredients including active and inactive materials. Methods of using the compositions of the invention to produce a sustained anesthetic effect at a site in a subject are also provided. | 1. A composition comprising an anesthetic and a pharmaceutically acceptable non-polymeric carrier, wherein the non-polymeric carrier controls release of the anesthetic to provide an anesthetic effect characterized by sustained local anesthesia after administration to a subject without an initial burst and having a duration of at least about 24 hours after administration. 2. The composition of claim 1, wherein the non-polymeric carrier is sufficient to provide either a first order controlled-release profile of the anesthetic, or a pseudo-zero order release profile of said anesthetic. 3. The composition of claim 1, wherein the anesthetic provides sustained local anesthesia for at least about 36 to 48 hours after administration to a subject. 4. The composition of claim 3, wherein the anesthetic provides sustained local anesthesia for at least about 48 to 72 hours after administration to a subject. 5. The composition of claim 1, wherein the anesthetic is a local anesthetic. 6. The composition of claim 5, wherein the anesthetic is an amide- or ester-type local anesthetic. 7. The composition of claim 6, wherein the anesthetic is bupivacaine. 8. The composition of claim 1, wherein the anesthetic is present in free base form. 9. The composition of claim 1, wherein the non-polymeric carrier is substantially insoluble in water or aqueous biological systems. 10. The composition of claim 9 further comprising a solvent that is dispersible, soluble or miscible in water or in an aqueous system. 11. The composition of claim 10, wherein the solvent is an organic solvent. 12. The composition of claim 11, wherein the solvent is capable of dissipating, diffusing or leaching away from the composition upon placement within a biological system, whereby the non-polymeric carrier can coagulate or precipitate to form a solid implant in situ. 13. The composition of claim 9, wherein the non-polymeric carrier is a liquid. 14. The composition of claim 13, wherein the non-polymeric carrier is a high viscosity liquid carrier material (“HVLCM”) having a viscosity of at least about 5,000 cP at 37° C. that does not crystallize neat under ambient or physiological conditions. 15. The composition of claim 14 further comprising a solvent in which the non-polymeric carrier is soluble. 16. The composition of claim 15, wherein the solvent is selected from the group consisting of ethanol, dimethyl sulfoxide, triethyl citrate, ethyl lactate, ethyl acetate, benzyl benzoate, benzyl alcohol, triacetin, N-methylpyrrolidone, propylene carbonate, polyethylene glycol, glycerol, glycofurol, 2-pyrrolidone, tetrafluoroethane, esters of caprylic and/or capric acids with glycerol or alkylene glycols, and combinations thereof. 17. The composition of claim 15, wherein the solvent is sufficient to lower to viscosity of the HVLCM. 18. The composition of claim 15, wherein the solvent is a second anesthetic agent. 19.-166. (canceled) 167. A method for providing an anesthetic effect at a site in a subject, said method comprising administering a composition at, near, in, or adjacent to the site, wherein the composition comprises an anesthetic and a pharmaceutically acceptable non-polymeric carrier, and further wherein the non-polymeric carrier controls release of the anesthetic to provide an anesthetic effect characterized by sustained local anesthesia after administration to the subject without an initial burst and having a duration of at least about 24 hours after administration. 168. A method for providing an anesthetic effect at a site in a subject, said method comprising administering a composition at, near, in, or adjacent to the site, wherein the composition comprises an anesthetic and a pharmaceutically acceptable non-polymeric carrier, and further wherein the non-polymeric carrier controls release of the anesthetic to provide an anesthetic effect characterized by sustained local anesthesia after administration to the subject, and the composition is capable of providing a sustained mean steady state plasma concentration (Css) of the anesthetic of at least about 200 ng/mL for a period of at least about 24 hours when said composition is administered subcutaneously. 169.-181. (canceled) | The present invention relates to novel anesthetic compositions containing a non-polymeric carrier material and an anesthetic, where the compositions are suitable for providing a sustained local anesthesia without an initial burst and having a duration for about 24 hours or longer. Certain compositions are also provided that include a first anesthetic and a second anesthetic. In such compositions, the second anesthetic is a solvent for the first anesthetic and provides an initial anesthetic effect upon administration to a subject. The non-polymeric carrier may optionally be a high viscosity liquid carrier material such as a suitable sugar ester. The compositions can further include one or more additional ingredients including active and inactive materials. Methods of using the compositions of the invention to produce a sustained anesthetic effect at a site in a subject are also provided.1. A composition comprising an anesthetic and a pharmaceutically acceptable non-polymeric carrier, wherein the non-polymeric carrier controls release of the anesthetic to provide an anesthetic effect characterized by sustained local anesthesia after administration to a subject without an initial burst and having a duration of at least about 24 hours after administration. 2. The composition of claim 1, wherein the non-polymeric carrier is sufficient to provide either a first order controlled-release profile of the anesthetic, or a pseudo-zero order release profile of said anesthetic. 3. The composition of claim 1, wherein the anesthetic provides sustained local anesthesia for at least about 36 to 48 hours after administration to a subject. 4. The composition of claim 3, wherein the anesthetic provides sustained local anesthesia for at least about 48 to 72 hours after administration to a subject. 5. The composition of claim 1, wherein the anesthetic is a local anesthetic. 6. The composition of claim 5, wherein the anesthetic is an amide- or ester-type local anesthetic. 7. The composition of claim 6, wherein the anesthetic is bupivacaine. 8. The composition of claim 1, wherein the anesthetic is present in free base form. 9. The composition of claim 1, wherein the non-polymeric carrier is substantially insoluble in water or aqueous biological systems. 10. The composition of claim 9 further comprising a solvent that is dispersible, soluble or miscible in water or in an aqueous system. 11. The composition of claim 10, wherein the solvent is an organic solvent. 12. The composition of claim 11, wherein the solvent is capable of dissipating, diffusing or leaching away from the composition upon placement within a biological system, whereby the non-polymeric carrier can coagulate or precipitate to form a solid implant in situ. 13. The composition of claim 9, wherein the non-polymeric carrier is a liquid. 14. The composition of claim 13, wherein the non-polymeric carrier is a high viscosity liquid carrier material (“HVLCM”) having a viscosity of at least about 5,000 cP at 37° C. that does not crystallize neat under ambient or physiological conditions. 15. The composition of claim 14 further comprising a solvent in which the non-polymeric carrier is soluble. 16. The composition of claim 15, wherein the solvent is selected from the group consisting of ethanol, dimethyl sulfoxide, triethyl citrate, ethyl lactate, ethyl acetate, benzyl benzoate, benzyl alcohol, triacetin, N-methylpyrrolidone, propylene carbonate, polyethylene glycol, glycerol, glycofurol, 2-pyrrolidone, tetrafluoroethane, esters of caprylic and/or capric acids with glycerol or alkylene glycols, and combinations thereof. 17. The composition of claim 15, wherein the solvent is sufficient to lower to viscosity of the HVLCM. 18. The composition of claim 15, wherein the solvent is a second anesthetic agent. 19.-166. (canceled) 167. A method for providing an anesthetic effect at a site in a subject, said method comprising administering a composition at, near, in, or adjacent to the site, wherein the composition comprises an anesthetic and a pharmaceutically acceptable non-polymeric carrier, and further wherein the non-polymeric carrier controls release of the anesthetic to provide an anesthetic effect characterized by sustained local anesthesia after administration to the subject without an initial burst and having a duration of at least about 24 hours after administration. 168. A method for providing an anesthetic effect at a site in a subject, said method comprising administering a composition at, near, in, or adjacent to the site, wherein the composition comprises an anesthetic and a pharmaceutically acceptable non-polymeric carrier, and further wherein the non-polymeric carrier controls release of the anesthetic to provide an anesthetic effect characterized by sustained local anesthesia after administration to the subject, and the composition is capable of providing a sustained mean steady state plasma concentration (Css) of the anesthetic of at least about 200 ng/mL for a period of at least about 24 hours when said composition is administered subcutaneously. 169.-181. (canceled) | 1,600 |
1,167 | 16,281,026 | 1,619 | The present invention relates to novel anesthetic compositions containing a non-polymeric carrier material and an anesthetic, where the compositions are suitable for providing a sustained local anesthesia without an initial burst and having a duration for about 24 hours or longer. Certain compositions are also provided that include a first anesthetic and a second anesthetic. In such compositions, the second anesthetic is a solvent for the first anesthetic and provides an initial anesthetic effect upon administration to a subject. The non-polymeric carrier may optionally be a high viscosity liquid carrier material such as a suitable sugar ester. The compositions can further include one or more additional ingredients including active and inactive materials. Methods of using the compositions of the invention to produce a sustained anesthetic effect at a site in a subject are also provided. | 1.-181. (canceled) 182. A method for providing an anesthetic effect at a wound in a subject, comprising administering a controlled delivery composition into the wound, wherein the controlled delivery composition comprises bupivacaine, and further wherein the administering provides a sustained local anesthetic effect at the wound having a duration of at least 48 hours after the administration. 183. The method of claim 182, wherein the sustained local anesthetic effect is for at least 72 hours after the administration. 184. The method of claim 182, wherein the sustained local anesthetic effect is for up to 4 days after the administration. 185. The method of claim 182, wherein the bupivacaine is present in the controlled delivery composition in an amount ranging from 1 wt % to 10 wt %, based on weight of the controlled delivery composition. 186. The method of claim 182, wherein the bupivacaine is present in the controlled delivery composition in an amount ranging from 1 wt % to 5 wt %, based on weight of the controlled delivery composition. 187. The method of claim 182, wherein the bupivacaine is present in the controlled delivery composition in an amount ranging from 2 wt % to 5 wt %, based on weight of the controlled delivery composition. 188. The method of claim 182, wherein the bupivacaine is present in free base form. 189. The method of claim 182, wherein the controlled delivery composition comprises a polymer. 190. The method of claim 189, wherein the polymer comprises a polyorthoester. 191. The method of claim 182, wherein the controlled delivery composition comprises an organic solvent. 192. The method of claim 191, wherein the organic solvent comprises dimethyl sulfoxide and glyceryl triacetate. 193. The method of claim 191, wherein the organic solvent is present in the controlled delivery composition in an amount ranging from 10 wt % to 55 wt %, based on weight of the controlled delivery composition. 194. The method of claim 191, wherein the organic solvent is present in the controlled delivery composition in an amount ranging from 15 wt % to 50 wt %, based on weight of the controlled delivery composition. 195. The method of claim 191, wherein the organic solvent is present in the controlled delivery composition in an amount ranging from 25 wt % to 55 wt %, based on weight of the controlled delivery composition. 196. The method of claim 191, wherein the organic solvent is present in the controlled delivery composition in an amount ranging from 25 wt % to 50 wt %, based on weight of the controlled delivery composition. 197. The method of claim 182, wherein the wound is a surgical wound. 198. The method of claim 182, wherein
the bupivacaine is present in the controlled delivery composition in an amount ranging from 2 wt % to 5 wt %, based on weight of the controlled delivery composition; and the controlled delivery composition comprises an organic solvent present in the controlled delivery composition in an amount ranging from 25 wt % to 50 wt %, based on weight of the controlled delivery composition. 199. The method of claim 182, wherein
the bupivacaine is present in the controlled delivery composition in an amount ranging from 2 wt % to 5 wt %, based on weight of the controlled delivery composition; and the controlled delivery composition comprises a polymer comprising a polyorthoester. 200. The method of claim 182, wherein
the bupivacaine is present in the controlled delivery composition in an amount ranging from 2 wt % to 5 wt %, based on weight of the controlled delivery composition; the controlled delivery composition comprises a polymer comprising a polyorthoester; and the controlled delivery composition comprises an organic solvent present in the controlled delivery composition in an amount ranging from 25 wt % to 50 wt %, based on weight of the controlled delivery composition. 201. The method of claim 182, wherein
the bupivacaine is present in the controlled delivery composition in an amount ranging from 2 wt % to 5 wt %, based on weight of the controlled delivery composition; the controlled delivery composition comprises a polymer comprising a polyorthoester; the controlled delivery composition comprises an organic solvent present in the controlled delivery composition in an amount ranging from 25 wt % to 50 wt %, based on weight of the controlled delivery composition; and the wound is a surgical wound. 202. The method of claim 182, wherein
the bupivacaine is present in the controlled delivery composition in an amount ranging from 2 wt % to 5 wt %, based on weight of the controlled delivery composition; the bupivacaine is present in free base form; the controlled delivery composition comprises a polymer comprising a polyorthoester; the controlled delivery composition comprises an organic solvent present in the controlled delivery composition in an amount ranging from 25 wt % to 50 wt %, based on weight of the controlled delivery composition; and the wound is a surgical wound. 203. The method of claim 182, wherein
the bupivacaine is present in the controlled delivery composition in an amount ranging from 2 wt % to 5 wt %, based on weight of the controlled delivery composition; the controlled delivery composition comprises an organic solvent present in the controlled delivery composition in an amount ranging from 25 wt % to 50 wt %, based on weight of the controlled delivery composition; and the organic solvent comprises dimethyl sulfoxide and glyceryl triacetate. 204. The method of claim 182, wherein
the bupivacaine is present in the controlled delivery composition in an amount ranging from 2 wt % to 5 wt %, based on weight of the controlled delivery composition; the controlled delivery composition comprises a polymer comprising a polyorthoester; the controlled delivery composition comprises an organic solvent present in the controlled delivery composition in an amount ranging from 25 wt % to 50 wt %, based on weight of the controlled delivery composition; and the organic solvent comprises dimethyl sulfoxide and glyceryl triacetate. 205. The method of claim 182, wherein
the bupivacaine is present in the controlled delivery composition in an amount ranging from 2 wt % to 5 wt %, based on weight of the controlled delivery composition; the controlled delivery composition comprises a polymer comprising a polyorthoester; the controlled delivery composition comprises an organic solvent present in the controlled delivery composition in an amount ranging from 25 wt % to 50 wt %, based on weight of the controlled delivery composition; the organic solvent comprises dimethyl sulfoxide and glyceryl triacetate; and the wound is a surgical wound. 206. The method of claim 182, wherein
the bupivacaine is present in the controlled delivery composition in an amount ranging from 2 wt % to 5 wt %, based on weight of the controlled delivery composition; the bupivacaine is present in free base form; the controlled delivery composition comprises a polymer comprising a polyorthoester; the controlled delivery composition comprises an organic solvent present in the controlled delivery composition in an amount ranging from 25 wt % to 50 wt %, based on weight of the controlled delivery composition; the organic solvent comprises dimethyl sulfoxide and glyceryl triacetate; and the wound is a surgical wound. | The present invention relates to novel anesthetic compositions containing a non-polymeric carrier material and an anesthetic, where the compositions are suitable for providing a sustained local anesthesia without an initial burst and having a duration for about 24 hours or longer. Certain compositions are also provided that include a first anesthetic and a second anesthetic. In such compositions, the second anesthetic is a solvent for the first anesthetic and provides an initial anesthetic effect upon administration to a subject. The non-polymeric carrier may optionally be a high viscosity liquid carrier material such as a suitable sugar ester. The compositions can further include one or more additional ingredients including active and inactive materials. Methods of using the compositions of the invention to produce a sustained anesthetic effect at a site in a subject are also provided.1.-181. (canceled) 182. A method for providing an anesthetic effect at a wound in a subject, comprising administering a controlled delivery composition into the wound, wherein the controlled delivery composition comprises bupivacaine, and further wherein the administering provides a sustained local anesthetic effect at the wound having a duration of at least 48 hours after the administration. 183. The method of claim 182, wherein the sustained local anesthetic effect is for at least 72 hours after the administration. 184. The method of claim 182, wherein the sustained local anesthetic effect is for up to 4 days after the administration. 185. The method of claim 182, wherein the bupivacaine is present in the controlled delivery composition in an amount ranging from 1 wt % to 10 wt %, based on weight of the controlled delivery composition. 186. The method of claim 182, wherein the bupivacaine is present in the controlled delivery composition in an amount ranging from 1 wt % to 5 wt %, based on weight of the controlled delivery composition. 187. The method of claim 182, wherein the bupivacaine is present in the controlled delivery composition in an amount ranging from 2 wt % to 5 wt %, based on weight of the controlled delivery composition. 188. The method of claim 182, wherein the bupivacaine is present in free base form. 189. The method of claim 182, wherein the controlled delivery composition comprises a polymer. 190. The method of claim 189, wherein the polymer comprises a polyorthoester. 191. The method of claim 182, wherein the controlled delivery composition comprises an organic solvent. 192. The method of claim 191, wherein the organic solvent comprises dimethyl sulfoxide and glyceryl triacetate. 193. The method of claim 191, wherein the organic solvent is present in the controlled delivery composition in an amount ranging from 10 wt % to 55 wt %, based on weight of the controlled delivery composition. 194. The method of claim 191, wherein the organic solvent is present in the controlled delivery composition in an amount ranging from 15 wt % to 50 wt %, based on weight of the controlled delivery composition. 195. The method of claim 191, wherein the organic solvent is present in the controlled delivery composition in an amount ranging from 25 wt % to 55 wt %, based on weight of the controlled delivery composition. 196. The method of claim 191, wherein the organic solvent is present in the controlled delivery composition in an amount ranging from 25 wt % to 50 wt %, based on weight of the controlled delivery composition. 197. The method of claim 182, wherein the wound is a surgical wound. 198. The method of claim 182, wherein
the bupivacaine is present in the controlled delivery composition in an amount ranging from 2 wt % to 5 wt %, based on weight of the controlled delivery composition; and the controlled delivery composition comprises an organic solvent present in the controlled delivery composition in an amount ranging from 25 wt % to 50 wt %, based on weight of the controlled delivery composition. 199. The method of claim 182, wherein
the bupivacaine is present in the controlled delivery composition in an amount ranging from 2 wt % to 5 wt %, based on weight of the controlled delivery composition; and the controlled delivery composition comprises a polymer comprising a polyorthoester. 200. The method of claim 182, wherein
the bupivacaine is present in the controlled delivery composition in an amount ranging from 2 wt % to 5 wt %, based on weight of the controlled delivery composition; the controlled delivery composition comprises a polymer comprising a polyorthoester; and the controlled delivery composition comprises an organic solvent present in the controlled delivery composition in an amount ranging from 25 wt % to 50 wt %, based on weight of the controlled delivery composition. 201. The method of claim 182, wherein
the bupivacaine is present in the controlled delivery composition in an amount ranging from 2 wt % to 5 wt %, based on weight of the controlled delivery composition; the controlled delivery composition comprises a polymer comprising a polyorthoester; the controlled delivery composition comprises an organic solvent present in the controlled delivery composition in an amount ranging from 25 wt % to 50 wt %, based on weight of the controlled delivery composition; and the wound is a surgical wound. 202. The method of claim 182, wherein
the bupivacaine is present in the controlled delivery composition in an amount ranging from 2 wt % to 5 wt %, based on weight of the controlled delivery composition; the bupivacaine is present in free base form; the controlled delivery composition comprises a polymer comprising a polyorthoester; the controlled delivery composition comprises an organic solvent present in the controlled delivery composition in an amount ranging from 25 wt % to 50 wt %, based on weight of the controlled delivery composition; and the wound is a surgical wound. 203. The method of claim 182, wherein
the bupivacaine is present in the controlled delivery composition in an amount ranging from 2 wt % to 5 wt %, based on weight of the controlled delivery composition; the controlled delivery composition comprises an organic solvent present in the controlled delivery composition in an amount ranging from 25 wt % to 50 wt %, based on weight of the controlled delivery composition; and the organic solvent comprises dimethyl sulfoxide and glyceryl triacetate. 204. The method of claim 182, wherein
the bupivacaine is present in the controlled delivery composition in an amount ranging from 2 wt % to 5 wt %, based on weight of the controlled delivery composition; the controlled delivery composition comprises a polymer comprising a polyorthoester; the controlled delivery composition comprises an organic solvent present in the controlled delivery composition in an amount ranging from 25 wt % to 50 wt %, based on weight of the controlled delivery composition; and the organic solvent comprises dimethyl sulfoxide and glyceryl triacetate. 205. The method of claim 182, wherein
the bupivacaine is present in the controlled delivery composition in an amount ranging from 2 wt % to 5 wt %, based on weight of the controlled delivery composition; the controlled delivery composition comprises a polymer comprising a polyorthoester; the controlled delivery composition comprises an organic solvent present in the controlled delivery composition in an amount ranging from 25 wt % to 50 wt %, based on weight of the controlled delivery composition; the organic solvent comprises dimethyl sulfoxide and glyceryl triacetate; and the wound is a surgical wound. 206. The method of claim 182, wherein
the bupivacaine is present in the controlled delivery composition in an amount ranging from 2 wt % to 5 wt %, based on weight of the controlled delivery composition; the bupivacaine is present in free base form; the controlled delivery composition comprises a polymer comprising a polyorthoester; the controlled delivery composition comprises an organic solvent present in the controlled delivery composition in an amount ranging from 25 wt % to 50 wt %, based on weight of the controlled delivery composition; the organic solvent comprises dimethyl sulfoxide and glyceryl triacetate; and the wound is a surgical wound. | 1,600 |
1,168 | 15,323,772 | 1,662 | Compositions and methods are provided for agronomic trait modification of a target sequence in the genome of a plant or plant cell. The methods and compositions employ a guide RNA/Cas endonuclease system to provide an effective system for modifying or altering target sites within a genomic region of a plant, plant cell or seed to provide improvement in a desirable agronomic trait such as drought, yield, and stress tolerance. Breeding methods for selecting plants utilizing a two component RNA guide and Cas endonuclease system are also disclosed. Compositions and methods are also provided for editing a nucleotide sequence in the genome of a cell. | 1. A method of improving an agronomic trait of a plant, the method comprising providing a guide RNA that targets a polynucleotide involved in improving one or more agronomic characteristics of the plant in association with a Cas endonuclease that creates a double strand break at the polynucleotide and generating the plant, wherein the plant exhibits an improvement in the agronomic trait. 2. The method of claim 1, further comprising a donor polynucleotide that comprises one or more nucleotide changes as compared to a corresponding endogenous unmodified genomic DNA. 3. The method of claim 2, wherein the donor polynucleotide does not encode a full-length protein. 4. The method of claim 2, wherein the donor polynucleotide comprises a heterologous regulatory element. 5. The method of claim 4, wherein the regulatory element comprises a promoter. 6. The method of claim 4, wherein the regulatory element comprises an enhancer element. 7. The method of claim 6, wherein the enhancer element is plant derived. 8. The method of claim 1, wherein the polynucleotide is selected from the group consisting of a regulatory element, 5′-UTR, intron, exon, coding sequence, and a promoter. 9. The method of claim 4, wherein the heterologous regulatory element is from the same plant species as the polynucleotide involved in improving one or more agronomic characteristics of the plant. 10. The method of claim 1, wherein the guide RNA targets the polynucleotide selected from the group consisting of polynucleotide sequences involved in the expression of ZmArgos8, ZmACS6, ZmSRTF18, ZmXERICO1, trehalose 6 phosphate phosphatase (T6PP), and ZmSTPP3. 11. The method of claim 1, wherein the agronomic characteristics is selected from the group consisting of abiotic stress tolerance. 12. The method of claim 11, wherein the abiotic stress tolerance is drought or nutrient deficiency. 13. The method of claim 1, wherein the agronomic characteristic is an increase in yield or an increase in drought tolerance. 14. The method of claim 1, wherein Cas9 endonuclease creates the double strand break in a coding region of the polynucleotide. 15. The method of claim 1, where in the plant is selected from the group consisting of maize, soybean, rice, wheat, sorghum, brassica, sunflower, and camelina. 16. A method of improving grain yield of a maize plant, the method comprising providing a guide RNA that targets a polynucleotide involved in ethylene biosynthesis or ethylene signaling, the guide RNA acts in association with a Cas endonuclease that creates a double strand break at the polynucleotide and generating the plant, wherein the maize plant exhibits improved grain yield. 17. The method of claim 16, further comprising a donor polynucleotide that comprises one or more nucleotide changes as compared to a corresponding endogenous unmodified genomic DNA of the polynucleotide involved in ethylene biosynthesis or ethylene signaling. 18. The method of claim 16, wherein the polynucleotide is a maize ACC synthase. 19. The method of claim 16, wherein the polynucleotide is maize ARGOS. 20. The method of claim 18, wherein the expression of the maize ACC synthase is reduced as compared to a control maize plant. 21. The method of claim 19, wherein the expression of the maize ARGOS is increased as compared to a control maize plant. 22. The method of claim 21, wherein the expression of the maize ARGOS is increased by inserting a heterologous regulatory element. 23. The method of claim 22, wherein the heterologous regulatory element is a moderate constitutive promoter. 24. The method of claim 22, wherein the heterologous regulatory element is maize derived. 25. (canceled) 26. (canceled) 27. (canceled) 28. (canceled) 29. (canceled) 30. (canceled) 31. (canceled) 32. (canceled) 33. (canceled) 34. (canceled) 35. (canceled) 36. (canceled) 37. (canceled) 38. (canceled) 39. (canceled) 40. (canceled) 41. (canceled) 42. The method of claim 16, wherein the polynucleotide sequence in the genome of a cell is selected from the group consisting of a promoter sequence, a terminator sequence, a regulatory element sequence, a splice site, a coding sequence, a polyubiquitination site, an intron site and an intron enhancing motif. 43. A method for editing a regulatory sequence involved in the expression of a gene for abiotic stress tolerance, in the genome of a cell, the method comprising introducing a guide polynucleotide, a polynucleotide modification template and at least one Cas endonuclease into a cell, wherein said guide RNA and Cas endonuclease are capable of forming a complex that enables the Cas endonuclease to introduce a double strand break at a target site in the genome of said cell, wherein said polynucleotide modification template comprises at least one nucleotide modification of said nucleotide sequence. 44. A method for replacing a first regulatory sequence modulating the expression of a gene involved in agronomic trait in a cell, the method comprising introducing a guide RNA, a polynucleotide modification template, and a Cas endonuclease into said cell, wherein said guide RNA and Cas endonuclease are capable of forming a complex that enables the Cas endonuclease to introduce a double strand break at a target site in the genome of said cell, wherein said polynucleotide modification template comprises a second promoter or second promoter fragment that is different from said first promoter sequence. 45. The method of claim 44, wherein the replacement of the first regulatory sequence results in any one of the following, or any one combination of the following: an increased promoter activity, an increased promoter tissue specificity, a decreased promoter activity, a decreased promoter tissue specificity, a new promoter activity, an inducible promoter activity, an extended window of gene expression, or a modification of the timing or developmental progress of gene expression in the same cell layer or other cell layer. 46. The method of claim 45, wherein the first regulatory sequence is selected from the group consisting of Zea mays ARGOS 8 promoter, maize NPK1 promoter, wherein the second promoter sequence is selected from the group consisting of a Zea mays GOS2 PRO:GOS2-intron promoter, a soybean ubiquitin promoter, a stress inducible maize RAB17 promoter, a Zea mays-PEPC1 promoter, a Zea mays Ubiquitin promoter, a Zea mays-Rootmet2 promoter, a rice actin promoter, a sorghum RCC3 promoter, a Zea mays-GOS2 promoter, a Zea mays-ACO2 promoter, and a Zea mays oleosin promoter. 47. (canceled) 48. (canceled) 49. (canceled) 50. (canceled) 51. (canceled) | Compositions and methods are provided for agronomic trait modification of a target sequence in the genome of a plant or plant cell. The methods and compositions employ a guide RNA/Cas endonuclease system to provide an effective system for modifying or altering target sites within a genomic region of a plant, plant cell or seed to provide improvement in a desirable agronomic trait such as drought, yield, and stress tolerance. Breeding methods for selecting plants utilizing a two component RNA guide and Cas endonuclease system are also disclosed. Compositions and methods are also provided for editing a nucleotide sequence in the genome of a cell.1. A method of improving an agronomic trait of a plant, the method comprising providing a guide RNA that targets a polynucleotide involved in improving one or more agronomic characteristics of the plant in association with a Cas endonuclease that creates a double strand break at the polynucleotide and generating the plant, wherein the plant exhibits an improvement in the agronomic trait. 2. The method of claim 1, further comprising a donor polynucleotide that comprises one or more nucleotide changes as compared to a corresponding endogenous unmodified genomic DNA. 3. The method of claim 2, wherein the donor polynucleotide does not encode a full-length protein. 4. The method of claim 2, wherein the donor polynucleotide comprises a heterologous regulatory element. 5. The method of claim 4, wherein the regulatory element comprises a promoter. 6. The method of claim 4, wherein the regulatory element comprises an enhancer element. 7. The method of claim 6, wherein the enhancer element is plant derived. 8. The method of claim 1, wherein the polynucleotide is selected from the group consisting of a regulatory element, 5′-UTR, intron, exon, coding sequence, and a promoter. 9. The method of claim 4, wherein the heterologous regulatory element is from the same plant species as the polynucleotide involved in improving one or more agronomic characteristics of the plant. 10. The method of claim 1, wherein the guide RNA targets the polynucleotide selected from the group consisting of polynucleotide sequences involved in the expression of ZmArgos8, ZmACS6, ZmSRTF18, ZmXERICO1, trehalose 6 phosphate phosphatase (T6PP), and ZmSTPP3. 11. The method of claim 1, wherein the agronomic characteristics is selected from the group consisting of abiotic stress tolerance. 12. The method of claim 11, wherein the abiotic stress tolerance is drought or nutrient deficiency. 13. The method of claim 1, wherein the agronomic characteristic is an increase in yield or an increase in drought tolerance. 14. The method of claim 1, wherein Cas9 endonuclease creates the double strand break in a coding region of the polynucleotide. 15. The method of claim 1, where in the plant is selected from the group consisting of maize, soybean, rice, wheat, sorghum, brassica, sunflower, and camelina. 16. A method of improving grain yield of a maize plant, the method comprising providing a guide RNA that targets a polynucleotide involved in ethylene biosynthesis or ethylene signaling, the guide RNA acts in association with a Cas endonuclease that creates a double strand break at the polynucleotide and generating the plant, wherein the maize plant exhibits improved grain yield. 17. The method of claim 16, further comprising a donor polynucleotide that comprises one or more nucleotide changes as compared to a corresponding endogenous unmodified genomic DNA of the polynucleotide involved in ethylene biosynthesis or ethylene signaling. 18. The method of claim 16, wherein the polynucleotide is a maize ACC synthase. 19. The method of claim 16, wherein the polynucleotide is maize ARGOS. 20. The method of claim 18, wherein the expression of the maize ACC synthase is reduced as compared to a control maize plant. 21. The method of claim 19, wherein the expression of the maize ARGOS is increased as compared to a control maize plant. 22. The method of claim 21, wherein the expression of the maize ARGOS is increased by inserting a heterologous regulatory element. 23. The method of claim 22, wherein the heterologous regulatory element is a moderate constitutive promoter. 24. The method of claim 22, wherein the heterologous regulatory element is maize derived. 25. (canceled) 26. (canceled) 27. (canceled) 28. (canceled) 29. (canceled) 30. (canceled) 31. (canceled) 32. (canceled) 33. (canceled) 34. (canceled) 35. (canceled) 36. (canceled) 37. (canceled) 38. (canceled) 39. (canceled) 40. (canceled) 41. (canceled) 42. The method of claim 16, wherein the polynucleotide sequence in the genome of a cell is selected from the group consisting of a promoter sequence, a terminator sequence, a regulatory element sequence, a splice site, a coding sequence, a polyubiquitination site, an intron site and an intron enhancing motif. 43. A method for editing a regulatory sequence involved in the expression of a gene for abiotic stress tolerance, in the genome of a cell, the method comprising introducing a guide polynucleotide, a polynucleotide modification template and at least one Cas endonuclease into a cell, wherein said guide RNA and Cas endonuclease are capable of forming a complex that enables the Cas endonuclease to introduce a double strand break at a target site in the genome of said cell, wherein said polynucleotide modification template comprises at least one nucleotide modification of said nucleotide sequence. 44. A method for replacing a first regulatory sequence modulating the expression of a gene involved in agronomic trait in a cell, the method comprising introducing a guide RNA, a polynucleotide modification template, and a Cas endonuclease into said cell, wherein said guide RNA and Cas endonuclease are capable of forming a complex that enables the Cas endonuclease to introduce a double strand break at a target site in the genome of said cell, wherein said polynucleotide modification template comprises a second promoter or second promoter fragment that is different from said first promoter sequence. 45. The method of claim 44, wherein the replacement of the first regulatory sequence results in any one of the following, or any one combination of the following: an increased promoter activity, an increased promoter tissue specificity, a decreased promoter activity, a decreased promoter tissue specificity, a new promoter activity, an inducible promoter activity, an extended window of gene expression, or a modification of the timing or developmental progress of gene expression in the same cell layer or other cell layer. 46. The method of claim 45, wherein the first regulatory sequence is selected from the group consisting of Zea mays ARGOS 8 promoter, maize NPK1 promoter, wherein the second promoter sequence is selected from the group consisting of a Zea mays GOS2 PRO:GOS2-intron promoter, a soybean ubiquitin promoter, a stress inducible maize RAB17 promoter, a Zea mays-PEPC1 promoter, a Zea mays Ubiquitin promoter, a Zea mays-Rootmet2 promoter, a rice actin promoter, a sorghum RCC3 promoter, a Zea mays-GOS2 promoter, a Zea mays-ACO2 promoter, and a Zea mays oleosin promoter. 47. (canceled) 48. (canceled) 49. (canceled) 50. (canceled) 51. (canceled) | 1,600 |
1,169 | 16,073,105 | 1,631 | Systems and methods are presented that allow for selection of tumor neoepitopes that are filtered for various criteria. In particularly contemplated aspects, filtering includes a step in which the mutation leading to the neoepitope is ascertained as being located in a cancer driver gene. | 1-32. (canceled) 33. A method of treating a cancer in a patient using immune therapy, comprising:
obtaining from a patient omics data from a tumor tissue and a matched normal tissue, and using the omics data to determine a plurality of expressed missense based patient- and tumor-specific neoepitopes; deriving from the expressed missense based patient- and tumor-specific neoepitopes a cancer driver neoepitope; and administering to the patient an immune therapeutic agent that comprises at least one of a synthetic antibody having binding specificity to the cancer driver neoepitope, a synthetic cancer driver neoepitope, a nucleic acid encoding the cancer driver neoepitope, an immune competent cell carrying a chimeric antigen receptor having binding specificity to the cancer driver neoepitope, and a recombinant virus comprising a nucleic acid encoding the cancer driver neoepitope. 34-45. (canceled) 46. The method of claim 33 wherein the step of determining the plurality of expressed missense based patient- and tumor-specific neoepitopes comprises location-guided synchronous alignment of omics data from the tumor tissue and the matched normal tissue. 47. The method of claim 33 further comprising a step of filtering the expressed missense based patient- and tumor-specific neoepitopes by at least one of an a priori known molecular variation selected from the group consisting of a single nucleotide polymorphism, a short deletion and insertion polymorphism, a microsatellite marker, a short tandem repeat, a heterozygous sequence, a multinucleotide polymorphism, and a named variant. 48. The method of claim 33 wherein the tumor tissue is a solid tumor tissue and wherein the matched normal tissue is blood. 49. The method of claim 33 wherein the step of deriving the cancer driver neoepitope comprises a step of filtering the patient- and tumor-specific neoepitopes by HLA type of the patient. 50. The method of claim 49 wherein the step of filtering by HLA type uses a plurality of distinct individual neoepitope sequences in which a changed amino acid has a distinct position within the neoepitope sequence, and wherein the individual neoepitope sequences have a length of between 7 and 20 amino acids. 51. The method of claim 49 wherein the step of filtering by HLA type comprises determination of the HLA type from the patient omics data. 52. The method of claim 49 wherein the step of filtering by HLA type is performed to a depth of at least 4 digits. 53. The method of claim 49 wherein the step of filtering by HLA type comprises determination of affinity of the neoepitopes to at least one MHC Class I sub-type and to at least one MHC Class II sub-type of the patient. 54. The method of claim 33 wherein the cancer driver neoepitope is located in a gene selected from the group consisting of ALL, AML, BLCA, BRCA, CLL, CM, COREAD, ESCA, GBM, HC, HNSC, LUAD, LUSC, MB, NB, NSCLC, OV, PRAD, RCCC, SCLC, STAD, THCA, and UCEC. 55. The method of claim 33 wherein the cancer driver gene is listed in Table 1. 56. The method of claim 33 further comprising a step of administering a non-immune therapeutic drug that targets a protein comprising the cancer driver neoepitope. 57. An immune therapeutic composition, comprising:
a carrier coupled to (i) a synthetic antibody having binding specificity to a patient specific cancer driver neoepitope, (ii) a synthetic patient specific cancer driver neoepitope, (iii) a nucleic acid encoding the patient specific cancer driver neoepitope, or (iv) a chimeric antigen receptor having binding specificity to the patient specific cancer driver neoepitope. 58. The immune therapeutic composition of claim 57 wherein the carrier comprises a single protein or comprises a pharmaceutically acceptable polymer. 59. The immune therapeutic composition of claim 57 wherein the carrier is an immune competent cell. 60. The immune therapeutic composition of claim 59 wherein the immune competent cell is a CD8+ T cell or a NK cell. 61. The immune therapeutic composition of claim 57 wherein the carrier is a recombinant virus. 62. The immune therapeutic composition of claim 57 further comprising a pharmaceutically acceptable carrier suitable for injection or infusion. 63-66. (canceled) 67. A recombinant immune competent cell, comprising a nucleic acid encoding a chimeric antigen receptor having binding specificity to a patient specific cancer driver neoepitope, or encoding the patient specific cancer driver neoepitope. 68. The recombinant immune competent cell of claim 67 wherein the immune competent cell is a CD8+ T cell or a NK cell, or an NK92 derivative. | Systems and methods are presented that allow for selection of tumor neoepitopes that are filtered for various criteria. In particularly contemplated aspects, filtering includes a step in which the mutation leading to the neoepitope is ascertained as being located in a cancer driver gene.1-32. (canceled) 33. A method of treating a cancer in a patient using immune therapy, comprising:
obtaining from a patient omics data from a tumor tissue and a matched normal tissue, and using the omics data to determine a plurality of expressed missense based patient- and tumor-specific neoepitopes; deriving from the expressed missense based patient- and tumor-specific neoepitopes a cancer driver neoepitope; and administering to the patient an immune therapeutic agent that comprises at least one of a synthetic antibody having binding specificity to the cancer driver neoepitope, a synthetic cancer driver neoepitope, a nucleic acid encoding the cancer driver neoepitope, an immune competent cell carrying a chimeric antigen receptor having binding specificity to the cancer driver neoepitope, and a recombinant virus comprising a nucleic acid encoding the cancer driver neoepitope. 34-45. (canceled) 46. The method of claim 33 wherein the step of determining the plurality of expressed missense based patient- and tumor-specific neoepitopes comprises location-guided synchronous alignment of omics data from the tumor tissue and the matched normal tissue. 47. The method of claim 33 further comprising a step of filtering the expressed missense based patient- and tumor-specific neoepitopes by at least one of an a priori known molecular variation selected from the group consisting of a single nucleotide polymorphism, a short deletion and insertion polymorphism, a microsatellite marker, a short tandem repeat, a heterozygous sequence, a multinucleotide polymorphism, and a named variant. 48. The method of claim 33 wherein the tumor tissue is a solid tumor tissue and wherein the matched normal tissue is blood. 49. The method of claim 33 wherein the step of deriving the cancer driver neoepitope comprises a step of filtering the patient- and tumor-specific neoepitopes by HLA type of the patient. 50. The method of claim 49 wherein the step of filtering by HLA type uses a plurality of distinct individual neoepitope sequences in which a changed amino acid has a distinct position within the neoepitope sequence, and wherein the individual neoepitope sequences have a length of between 7 and 20 amino acids. 51. The method of claim 49 wherein the step of filtering by HLA type comprises determination of the HLA type from the patient omics data. 52. The method of claim 49 wherein the step of filtering by HLA type is performed to a depth of at least 4 digits. 53. The method of claim 49 wherein the step of filtering by HLA type comprises determination of affinity of the neoepitopes to at least one MHC Class I sub-type and to at least one MHC Class II sub-type of the patient. 54. The method of claim 33 wherein the cancer driver neoepitope is located in a gene selected from the group consisting of ALL, AML, BLCA, BRCA, CLL, CM, COREAD, ESCA, GBM, HC, HNSC, LUAD, LUSC, MB, NB, NSCLC, OV, PRAD, RCCC, SCLC, STAD, THCA, and UCEC. 55. The method of claim 33 wherein the cancer driver gene is listed in Table 1. 56. The method of claim 33 further comprising a step of administering a non-immune therapeutic drug that targets a protein comprising the cancer driver neoepitope. 57. An immune therapeutic composition, comprising:
a carrier coupled to (i) a synthetic antibody having binding specificity to a patient specific cancer driver neoepitope, (ii) a synthetic patient specific cancer driver neoepitope, (iii) a nucleic acid encoding the patient specific cancer driver neoepitope, or (iv) a chimeric antigen receptor having binding specificity to the patient specific cancer driver neoepitope. 58. The immune therapeutic composition of claim 57 wherein the carrier comprises a single protein or comprises a pharmaceutically acceptable polymer. 59. The immune therapeutic composition of claim 57 wherein the carrier is an immune competent cell. 60. The immune therapeutic composition of claim 59 wherein the immune competent cell is a CD8+ T cell or a NK cell. 61. The immune therapeutic composition of claim 57 wherein the carrier is a recombinant virus. 62. The immune therapeutic composition of claim 57 further comprising a pharmaceutically acceptable carrier suitable for injection or infusion. 63-66. (canceled) 67. A recombinant immune competent cell, comprising a nucleic acid encoding a chimeric antigen receptor having binding specificity to a patient specific cancer driver neoepitope, or encoding the patient specific cancer driver neoepitope. 68. The recombinant immune competent cell of claim 67 wherein the immune competent cell is a CD8+ T cell or a NK cell, or an NK92 derivative. | 1,600 |
1,170 | 15,997,481 | 1,644 | Isolated monoclonal antibodies that bind human tissue factor pathway inhibitor (TFPI) and the isolated nucleic acid molecules encoding them are provided. Pharmaceutical compositions comprising the anti-TFPI monoclonal antibodies and methods of treating deficiencies or defects in coagulation by administration of the antibodies are also provided. Methods of producing the antibodies are also provided. | 1. An isolated human monoclonal antibody that specifically binds to human tissue factor pathway inhibitor (TFPI), comprising:
(a) a heavy chain variable region, comprising:
a CDR1 region comprising F27, T28, F29, Y32, and M34;
a CDR2 region comprising 151, S54, T58, Y59, Y60, A61, D62, S63, V64, K65, and G66; and
a CDR3 region comprising D105;
wherein the amino acid number of the heavy chain variable region is relative to SEQ ID NO: 16; and
(b) a light chain variable region, comprising:
a CDR1 region comprising S26 and S28;
a CDR2 region comprising S57 and R59; and
a CDR3 region comprising Q94, Y96, and D97;
wherein the amino acid numbering of the light chain variable region is relative to SEQ ID NO: 158. 2. The isolated human monoclonal antibody of claim 1, wherein the antibody binds to TFPI with a binding affinity of 1140 nM or less as determined by a Biacore assay. 3. The isolated human monoclonal antibody of claim 1, wherein the antibody is capable of inhibiting TFPI activity. 4. The isolated human monoclonal antibody of claim 1, wherein the antibody is capable of inhibiting more than 50% of TFPI activity. 5. The isolated human monoclonal antibody of claim 1, wherein the antibody is capable of shortening bleeding time. 6. The isolated human monoclonal antibody of claim 1, wherein the antibody light chain variable region is at least 93% homologous to SEQ ID NO: 158. 7. The isolated human monoclonal antibody of claim 1, wherein the antibody heavy chain variable region is at least about 89% homologous to SEQ ID NO: 16. 8. A pharmaceutical composition comprising the isolated monoclonal antibody of claim 1 and a pharmaceutically acceptable carrier. 9. A method of treating Hemophilia A or Hemophilia B in an individual, comprising administering to the individual an effective amount of the pharmaceutical composition of claim 8. 10. The method of claim 9, wherein the pharmaceutical composition is administered subcutaneously. 11. The method of claim 9, wherein the pharmaceutical composition is administered at a dose of about 10 mg to about 100 mg. 12. The method of claim 9, wherein the pharmaceutical composition is administered weekly, biweekly, or monthly. 13. A method of shortening bleeding time in an individual, comprising administering to the individual an effective amount of the pharmaceutical composition of claim 8. 14. The method of claim 13, wherein the pharmaceutical composition is administered subcutaneously. 15. The method of claim 13, wherein the pharmaceutical composition is administered at a dose of about 10 mg to about 100 mg. 16. The method of claim 13, wherein the pharmaceutical composition is administered weekly, biweekly, or monthly. 17. A nucleic acid molecule encoding the human monoclonal antibody of claim 1. 18. A method of producing a human monoclonal antibody that specifically binds to human TFPI, comprising:
(a) transfecting the nucleic acid molecule of claim 17 into a host cell, and (b) culturing the host cell to express the monoclonal antibody. | Isolated monoclonal antibodies that bind human tissue factor pathway inhibitor (TFPI) and the isolated nucleic acid molecules encoding them are provided. Pharmaceutical compositions comprising the anti-TFPI monoclonal antibodies and methods of treating deficiencies or defects in coagulation by administration of the antibodies are also provided. Methods of producing the antibodies are also provided.1. An isolated human monoclonal antibody that specifically binds to human tissue factor pathway inhibitor (TFPI), comprising:
(a) a heavy chain variable region, comprising:
a CDR1 region comprising F27, T28, F29, Y32, and M34;
a CDR2 region comprising 151, S54, T58, Y59, Y60, A61, D62, S63, V64, K65, and G66; and
a CDR3 region comprising D105;
wherein the amino acid number of the heavy chain variable region is relative to SEQ ID NO: 16; and
(b) a light chain variable region, comprising:
a CDR1 region comprising S26 and S28;
a CDR2 region comprising S57 and R59; and
a CDR3 region comprising Q94, Y96, and D97;
wherein the amino acid numbering of the light chain variable region is relative to SEQ ID NO: 158. 2. The isolated human monoclonal antibody of claim 1, wherein the antibody binds to TFPI with a binding affinity of 1140 nM or less as determined by a Biacore assay. 3. The isolated human monoclonal antibody of claim 1, wherein the antibody is capable of inhibiting TFPI activity. 4. The isolated human monoclonal antibody of claim 1, wherein the antibody is capable of inhibiting more than 50% of TFPI activity. 5. The isolated human monoclonal antibody of claim 1, wherein the antibody is capable of shortening bleeding time. 6. The isolated human monoclonal antibody of claim 1, wherein the antibody light chain variable region is at least 93% homologous to SEQ ID NO: 158. 7. The isolated human monoclonal antibody of claim 1, wherein the antibody heavy chain variable region is at least about 89% homologous to SEQ ID NO: 16. 8. A pharmaceutical composition comprising the isolated monoclonal antibody of claim 1 and a pharmaceutically acceptable carrier. 9. A method of treating Hemophilia A or Hemophilia B in an individual, comprising administering to the individual an effective amount of the pharmaceutical composition of claim 8. 10. The method of claim 9, wherein the pharmaceutical composition is administered subcutaneously. 11. The method of claim 9, wherein the pharmaceutical composition is administered at a dose of about 10 mg to about 100 mg. 12. The method of claim 9, wherein the pharmaceutical composition is administered weekly, biweekly, or monthly. 13. A method of shortening bleeding time in an individual, comprising administering to the individual an effective amount of the pharmaceutical composition of claim 8. 14. The method of claim 13, wherein the pharmaceutical composition is administered subcutaneously. 15. The method of claim 13, wherein the pharmaceutical composition is administered at a dose of about 10 mg to about 100 mg. 16. The method of claim 13, wherein the pharmaceutical composition is administered weekly, biweekly, or monthly. 17. A nucleic acid molecule encoding the human monoclonal antibody of claim 1. 18. A method of producing a human monoclonal antibody that specifically binds to human TFPI, comprising:
(a) transfecting the nucleic acid molecule of claim 17 into a host cell, and (b) culturing the host cell to express the monoclonal antibody. | 1,600 |
1,171 | 13,634,093 | 1,617 | Improved aqueous herbicidal compositions comprising at least one water-soluble herbicide and a gel forming agent are provided. The compositions are generally characterized as pseudoplastic, elastic and having a relatively high stationary viscosity. The compositions provide enhanced foliar retention and resistance to drying thereby allowing for improved uptake of the herbicide into the plants and/or translocation within the plant in order to more effectively kill the plants at reduced application rates in kilograms of herbicide per hectare, even in the absence of a surfactant. Methods for confined application of the compositions of the invention to control the growth of unwanted plants are also provided. | 1. An aqueous agrochemical gel composition comprising:
(1) from 0.1 to 5 percent by weight on an acid equivalent basis of a water-soluble agrochemical component comprising at least one water-soluble agrochemical, (2) from 0.1 to 5 percent by weight of a polymeric gel forming agent component comprising at least one polymeric gel forming agent, and (3) from 85 to 98 percent by weight water wherein tan(delta) of the gel composition is less than 1 as measured by oscillation frequency sweep rheometric measurements between about 0.1 and about 600 rad/sec at 0.2 Pa and 1 Pa as measured using a cone and plate viscometer method with a 60 mm 2° acrylic cone and plate at 20° C. and wherein the yield point of the gel composition is at least about 50 dyne/cm2. 2. The gel composition of claim 1 wherein the yield point is at least about 75 dyne/cm2. 3-5. (canceled) 6. The gel composition of claim 1 wherein the polymeric gel forming component comprises at least one polymeric gel forming agent selected from the group consisting of polyacrylic acid, carboxymethyl cellulose and polysucrose. 7. The gel composition of claim 1 wherein tan(delta) of the gel composition is from 0.05 to 0.9. 8. The gel composition of claim 1 wherein the stationary viscosity of the gel composition is from about 500 to 150,000 mPa second as measured according to a cone and plate viscometer method using a 60 mm 2° acrylic cone and plate at 20° C. with an oscillating frequency of 100 rad/s. 9. The gel composition of claim 1 wherein the water content is from 90 to 98 percent by weight. 10. The gel composition of claim 1 wherein the water-soluble agrochemical content is from 0.5 to 5 percent by weight on an acid equivalent basis. 11. The gel composition of claim 1 wherein the polymeric gel forming agent content is from 1 to 5 percent by weight. 12. (canceled) 13. The gel composition of claim 1 further comprising a preservative. 14. The gel composition of claim 1 further comprising a surfactant component comprising at least one surfactant. 15. The gel composition of claim 14 wherein the surfactant component comprises at least one surfactant selected from the group consisting of alkoxylated tertiary etheramine, alkoxylated quaternary etheramine, alkoxylated tertiary amine oxide, alkoxylated tertiary amine, alkoxylated quaternary amine, alkoxylated etheramine oxide, polyamine, sulfate derivative, sulfonate derivative, phosphate ester of alkoxylated alcohol, alkyl polysaccharide, alkoxylated alcohol, amidoalkylamine, and combinations thereof. 16. (canceled) 17. The gel composition of claim 1 wherein the water-soluble agrochemical component comprises a water-soluble herbicide. 18. (canceled) 19. The gel composition of claim 17 wherein the water-soluble herbicide is selected from the group consisting of a salt of glyphosate, an ester of glyphosate, and mixtures thereof. 20. The gel composition of claim 17 wherein the water-soluble herbicide comprises a combination of two or more water-soluble co-herbicides selected from the group consisting of glyphosate, 2,4-D, dicamba, MCPA, MCPB, triclopyr, imazamethabenz-m, imazamox, imazapic, imazapyr, imazaquin, imazethapyr, paraquat, diquat, and salts and esters thereof. 21. (canceled) 22. The gel composition of claim 17 further comprising at least one water-insoluble agrochemical dispersed therein selected from dithiopyr, pyraflufen-ethyl, acifluorfen, aclonifen, bifenox, chlomethoxyfen, chlornitrofen, etnipromid, fluorodifen, fluoroglycofen, fluoronitrofen, fomesafen, furyloxyfen, halosafen, lactofen, nitrofen, nitrofluorfen, oxyfluorfen and atrazine. 23-24. (canceled) 25. The gel composition of claim 1 consisting essentially of at least one water-soluble agrochemical, at least one polymeric gel forming agent, a preservative and water. 26. The gel composition of claim 1 comprising from 0.5 to 1.5 percent by weight water-soluble agrochemical on an acid equivalent basis, from 2 to 4 percent by weight polymeric gel forming agent and from 94 to 97.5 percent by weight water. 27. A method for confined application of an agrochemical to plants, the method comprising applying the agrochemical gel composition of claim 1 to the plants. 28. The method of claim 27 wherein the agrochemical gel composition is applied to the foliage of the plants with a hand-held sprayer, a roller or a brush. 29-32. (canceled) 33. A method of confined application of a water-soluble herbicide to unwanted plants, the method comprising applying the agrochemical gel composition of claim 26 to the unwanted plants. 34-88. (canceled) | Improved aqueous herbicidal compositions comprising at least one water-soluble herbicide and a gel forming agent are provided. The compositions are generally characterized as pseudoplastic, elastic and having a relatively high stationary viscosity. The compositions provide enhanced foliar retention and resistance to drying thereby allowing for improved uptake of the herbicide into the plants and/or translocation within the plant in order to more effectively kill the plants at reduced application rates in kilograms of herbicide per hectare, even in the absence of a surfactant. Methods for confined application of the compositions of the invention to control the growth of unwanted plants are also provided.1. An aqueous agrochemical gel composition comprising:
(1) from 0.1 to 5 percent by weight on an acid equivalent basis of a water-soluble agrochemical component comprising at least one water-soluble agrochemical, (2) from 0.1 to 5 percent by weight of a polymeric gel forming agent component comprising at least one polymeric gel forming agent, and (3) from 85 to 98 percent by weight water wherein tan(delta) of the gel composition is less than 1 as measured by oscillation frequency sweep rheometric measurements between about 0.1 and about 600 rad/sec at 0.2 Pa and 1 Pa as measured using a cone and plate viscometer method with a 60 mm 2° acrylic cone and plate at 20° C. and wherein the yield point of the gel composition is at least about 50 dyne/cm2. 2. The gel composition of claim 1 wherein the yield point is at least about 75 dyne/cm2. 3-5. (canceled) 6. The gel composition of claim 1 wherein the polymeric gel forming component comprises at least one polymeric gel forming agent selected from the group consisting of polyacrylic acid, carboxymethyl cellulose and polysucrose. 7. The gel composition of claim 1 wherein tan(delta) of the gel composition is from 0.05 to 0.9. 8. The gel composition of claim 1 wherein the stationary viscosity of the gel composition is from about 500 to 150,000 mPa second as measured according to a cone and plate viscometer method using a 60 mm 2° acrylic cone and plate at 20° C. with an oscillating frequency of 100 rad/s. 9. The gel composition of claim 1 wherein the water content is from 90 to 98 percent by weight. 10. The gel composition of claim 1 wherein the water-soluble agrochemical content is from 0.5 to 5 percent by weight on an acid equivalent basis. 11. The gel composition of claim 1 wherein the polymeric gel forming agent content is from 1 to 5 percent by weight. 12. (canceled) 13. The gel composition of claim 1 further comprising a preservative. 14. The gel composition of claim 1 further comprising a surfactant component comprising at least one surfactant. 15. The gel composition of claim 14 wherein the surfactant component comprises at least one surfactant selected from the group consisting of alkoxylated tertiary etheramine, alkoxylated quaternary etheramine, alkoxylated tertiary amine oxide, alkoxylated tertiary amine, alkoxylated quaternary amine, alkoxylated etheramine oxide, polyamine, sulfate derivative, sulfonate derivative, phosphate ester of alkoxylated alcohol, alkyl polysaccharide, alkoxylated alcohol, amidoalkylamine, and combinations thereof. 16. (canceled) 17. The gel composition of claim 1 wherein the water-soluble agrochemical component comprises a water-soluble herbicide. 18. (canceled) 19. The gel composition of claim 17 wherein the water-soluble herbicide is selected from the group consisting of a salt of glyphosate, an ester of glyphosate, and mixtures thereof. 20. The gel composition of claim 17 wherein the water-soluble herbicide comprises a combination of two or more water-soluble co-herbicides selected from the group consisting of glyphosate, 2,4-D, dicamba, MCPA, MCPB, triclopyr, imazamethabenz-m, imazamox, imazapic, imazapyr, imazaquin, imazethapyr, paraquat, diquat, and salts and esters thereof. 21. (canceled) 22. The gel composition of claim 17 further comprising at least one water-insoluble agrochemical dispersed therein selected from dithiopyr, pyraflufen-ethyl, acifluorfen, aclonifen, bifenox, chlomethoxyfen, chlornitrofen, etnipromid, fluorodifen, fluoroglycofen, fluoronitrofen, fomesafen, furyloxyfen, halosafen, lactofen, nitrofen, nitrofluorfen, oxyfluorfen and atrazine. 23-24. (canceled) 25. The gel composition of claim 1 consisting essentially of at least one water-soluble agrochemical, at least one polymeric gel forming agent, a preservative and water. 26. The gel composition of claim 1 comprising from 0.5 to 1.5 percent by weight water-soluble agrochemical on an acid equivalent basis, from 2 to 4 percent by weight polymeric gel forming agent and from 94 to 97.5 percent by weight water. 27. A method for confined application of an agrochemical to plants, the method comprising applying the agrochemical gel composition of claim 1 to the plants. 28. The method of claim 27 wherein the agrochemical gel composition is applied to the foliage of the plants with a hand-held sprayer, a roller or a brush. 29-32. (canceled) 33. A method of confined application of a water-soluble herbicide to unwanted plants, the method comprising applying the agrochemical gel composition of claim 26 to the unwanted plants. 34-88. (canceled) | 1,600 |
1,172 | 15,751,542 | 1,627 | This disclosure provides a dosage regimen for co-administration of enzalutamide and a strong CYP3A4 inducer in the treatment of cancer. | 1. A method of treating cancer, comprising co-administration to a patient in need thereof a therapeutically effective dose of enzalutamide and a CYP3A4 inducer, wherein the therapeutically effective dose of enzalutamide is 200-300 mg per day. 2. The method of claim 1, wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, and ovarian cancer. 3. The method of claim 1, wherein the therapeutically effective dose of enzalutamide is 240 mg per day. 4. A method of treating metastatic castration-resistant prostate cancer, comprising co-administration to a patient in need thereof (i) 240 mg/day of enzalutamide and (ii) a CYP3A4 inducer. 5. The method of claim 1, wherein the CYP3A4 inducer is selected from the group consisting of carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and rifapentine. 6. The method of claim 4, wherein the CYP3A4 inducer is selected from the group consisting of carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and rifapentine. | This disclosure provides a dosage regimen for co-administration of enzalutamide and a strong CYP3A4 inducer in the treatment of cancer.1. A method of treating cancer, comprising co-administration to a patient in need thereof a therapeutically effective dose of enzalutamide and a CYP3A4 inducer, wherein the therapeutically effective dose of enzalutamide is 200-300 mg per day. 2. The method of claim 1, wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, and ovarian cancer. 3. The method of claim 1, wherein the therapeutically effective dose of enzalutamide is 240 mg per day. 4. A method of treating metastatic castration-resistant prostate cancer, comprising co-administration to a patient in need thereof (i) 240 mg/day of enzalutamide and (ii) a CYP3A4 inducer. 5. The method of claim 1, wherein the CYP3A4 inducer is selected from the group consisting of carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and rifapentine. 6. The method of claim 4, wherein the CYP3A4 inducer is selected from the group consisting of carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and rifapentine. | 1,600 |
1,173 | 15,337,302 | 1,623 | A method is provided for the post-treatment of nanoporous celluloses with an eye to scale up to plant operation wherein recycling and recovery of reagents is crucial in the efficient and cost effective operation of a full-scale plant. The instant method includes diminishing the alkali (e.g., sodium hydroxide) concentration of the treatment solution by converting it to a salt (e.g., a sodium salt). | 1. A method of treating and stabilizing a cellulosic material, comprising
a) contacting a cellulosic material with a treatment solution of an alkali in an alcohol/water co-solvent to yield a treated cellulosic material and dissolved phytochemicals in a post-treatment solution, b) treating the post-treatment solution with an acid to neutralize the alkali and precipitate the alkali as an alkali salt to yield a neutralized post-treatment solution, thereby reducing the pH of the post-treatment solution to a level such that the treated cellulosic material is not mercerized upon exposure to water, the neutralized post-treatment solution having the treated cellulosic material, the precipitated salt and dissolved phytochemicals. 2. The method of claim 1, further comprising
c) separating the treated cellulosic material and precipitated salt from the neutralized post-treatment solution, d) separating the alkali salt from the treated cellulosic material, and e) recovering the alkali by recausticizing the alkali salt to yield recovered alkali. 3. The method of claim 1, wherein the acid is carbonic acid formed by dissolving/reacting carbon dioxide (CO2) in/with post-treatment solution. 4. A method as claimed in claim 1, wherein the post-treatment solution has a pH in the range of 7-11 at the end of neutralization. 5. The method of claim 2, further comprising recycling the recovered alkali to form treatment solution. 6. The method of claim 2, further comprising distilling the neutralized post-treatment solution from step (b) of claim 1 to recover the alcohol, and recycling the recovered alcohol to form treatment solution. 7. The method of claim 1, furthering comprising recovering the phytochemicals from the neutralized post-treatment solution. 8. The method of claim 1, wherein the cellulosic material includes corn stover, wheat straw, corn stover, soybean stover, corn cobs, rice straw, rice hulls, corn fiber, wheat straw, barley straw, canola straw, oat straw, oat hulls, tree barks and foliage and combinations thereof. 9. The method of claim 1, wherein the alkali is an alkali metal hydroxide and the alkali salt is an alkali metal salt. 10. The method of claim 9, wherein the alkali metal hydroxide is sodium hydroxide and the alkali metal salt is sodium carbonate/sodium bicarbonate. 11. The method of claim 2, wherein the alkali salt is sodium carbonate/sodium bicarbonate and the sodium carbonate/bicarbonate is recausticized by treatment with quicklime, hydrated lime or slaked lime. 12. The method of claim 1, wherein the phytochemicals include hydroxy-cinnamic acids, phenolic lignin fragments and lignans. 13. A method for processing a cellulosic material comprising the steps of: (i) treating a cellulosic material with a treatment solution of sodium hydroxide in an ethanol/water co-solvent to produce a treated cellulosic material and dissolved phytochemicals in a post-treatment solution; (ii) adjusting the pH of the post-treatment solution by dissolving carbon dioxide in the post-treatment solution to produce a neutralized post-treatment solution having a pH between about 7 and about 11, the carbon dioxide reacting with the sodium hydroxide dissolved in the post-treatment solution to precipitate sodium carbonate/bicarbonate; (iii) separating the treated cellulosic material and the precipitated sodium carbonate/bicarbonate from the neutralized post-treatment solution; (iv) separating the treated cellulosic material from the precipitated sodium carbonate/bicarbonate salt; (v) recausticizing the sodium carbonate/bicarbonate to yield recovered sodium hydroxide; and (vii) recovering the ethanol from the neutralized post-treatment solution. 14. The method of claim 13, further comprising recycling the recovered sodium hydroxide to form the treatment solution. 15. The method of claim 13, further comprising recycling the recovered ethanol to form the treatment solution. 16. The method of claim 13, further comprising recovering of the phytochemicals from the neutralized post-treatment solution. 17. Phytochemicals produced by the method of claim 13. 18. A system for treating cellulosic material, comprising a treatment stage, a post-treatment stage and a recycling/recovery stage;
the treatment stage comprising reacting a cellulosic material with a treatment solution of sodium hydroxide in an ethanol/water co-solvent to produce a treated cellulosic material in a post-treatment solution; the post-treatment stage comprising treating the post-treatment solution with carbon dioxide to neutralize the alkali and precipitate an alkali salt: the recycling/recovery stage comprising (i) separating the treated cellulosic material and precipitated salt from the neutralized post-treatment solution, (ii) separating the alkali salt from the treated cellulosic material, (iii) recovering the alkali by recaustizing the alkali salt to yield recovered alkali, and (iv) recovering the ethanol from the neutralized post-treatment solution. 19. The system of claim 18, wherein the recycling/recovery stage further comprises recovering the phytochemicals from the neutralized post-treatment solution. 20. The method of claim 1, wherein the cellulosic material is a plant-based animal feed. 21. The method of claim 20, wherein the animal feed is the stover of a forage crop. 22. An animal feed prepared by the method of claim 20, wherein the treated cellulosic material is a treated feed. 23. The animal feed of claim 22, further comprising increased digestibility of the treated feed compared to an untreated feed. 24. A method of treating a plant-based animal feed to improve digestibility of the feed comprising treating an animal feed according to the method of claim 1. 25. The method of claim 1, wherein the method is a commercial scale method of production. | A method is provided for the post-treatment of nanoporous celluloses with an eye to scale up to plant operation wherein recycling and recovery of reagents is crucial in the efficient and cost effective operation of a full-scale plant. The instant method includes diminishing the alkali (e.g., sodium hydroxide) concentration of the treatment solution by converting it to a salt (e.g., a sodium salt).1. A method of treating and stabilizing a cellulosic material, comprising
a) contacting a cellulosic material with a treatment solution of an alkali in an alcohol/water co-solvent to yield a treated cellulosic material and dissolved phytochemicals in a post-treatment solution, b) treating the post-treatment solution with an acid to neutralize the alkali and precipitate the alkali as an alkali salt to yield a neutralized post-treatment solution, thereby reducing the pH of the post-treatment solution to a level such that the treated cellulosic material is not mercerized upon exposure to water, the neutralized post-treatment solution having the treated cellulosic material, the precipitated salt and dissolved phytochemicals. 2. The method of claim 1, further comprising
c) separating the treated cellulosic material and precipitated salt from the neutralized post-treatment solution, d) separating the alkali salt from the treated cellulosic material, and e) recovering the alkali by recausticizing the alkali salt to yield recovered alkali. 3. The method of claim 1, wherein the acid is carbonic acid formed by dissolving/reacting carbon dioxide (CO2) in/with post-treatment solution. 4. A method as claimed in claim 1, wherein the post-treatment solution has a pH in the range of 7-11 at the end of neutralization. 5. The method of claim 2, further comprising recycling the recovered alkali to form treatment solution. 6. The method of claim 2, further comprising distilling the neutralized post-treatment solution from step (b) of claim 1 to recover the alcohol, and recycling the recovered alcohol to form treatment solution. 7. The method of claim 1, furthering comprising recovering the phytochemicals from the neutralized post-treatment solution. 8. The method of claim 1, wherein the cellulosic material includes corn stover, wheat straw, corn stover, soybean stover, corn cobs, rice straw, rice hulls, corn fiber, wheat straw, barley straw, canola straw, oat straw, oat hulls, tree barks and foliage and combinations thereof. 9. The method of claim 1, wherein the alkali is an alkali metal hydroxide and the alkali salt is an alkali metal salt. 10. The method of claim 9, wherein the alkali metal hydroxide is sodium hydroxide and the alkali metal salt is sodium carbonate/sodium bicarbonate. 11. The method of claim 2, wherein the alkali salt is sodium carbonate/sodium bicarbonate and the sodium carbonate/bicarbonate is recausticized by treatment with quicklime, hydrated lime or slaked lime. 12. The method of claim 1, wherein the phytochemicals include hydroxy-cinnamic acids, phenolic lignin fragments and lignans. 13. A method for processing a cellulosic material comprising the steps of: (i) treating a cellulosic material with a treatment solution of sodium hydroxide in an ethanol/water co-solvent to produce a treated cellulosic material and dissolved phytochemicals in a post-treatment solution; (ii) adjusting the pH of the post-treatment solution by dissolving carbon dioxide in the post-treatment solution to produce a neutralized post-treatment solution having a pH between about 7 and about 11, the carbon dioxide reacting with the sodium hydroxide dissolved in the post-treatment solution to precipitate sodium carbonate/bicarbonate; (iii) separating the treated cellulosic material and the precipitated sodium carbonate/bicarbonate from the neutralized post-treatment solution; (iv) separating the treated cellulosic material from the precipitated sodium carbonate/bicarbonate salt; (v) recausticizing the sodium carbonate/bicarbonate to yield recovered sodium hydroxide; and (vii) recovering the ethanol from the neutralized post-treatment solution. 14. The method of claim 13, further comprising recycling the recovered sodium hydroxide to form the treatment solution. 15. The method of claim 13, further comprising recycling the recovered ethanol to form the treatment solution. 16. The method of claim 13, further comprising recovering of the phytochemicals from the neutralized post-treatment solution. 17. Phytochemicals produced by the method of claim 13. 18. A system for treating cellulosic material, comprising a treatment stage, a post-treatment stage and a recycling/recovery stage;
the treatment stage comprising reacting a cellulosic material with a treatment solution of sodium hydroxide in an ethanol/water co-solvent to produce a treated cellulosic material in a post-treatment solution; the post-treatment stage comprising treating the post-treatment solution with carbon dioxide to neutralize the alkali and precipitate an alkali salt: the recycling/recovery stage comprising (i) separating the treated cellulosic material and precipitated salt from the neutralized post-treatment solution, (ii) separating the alkali salt from the treated cellulosic material, (iii) recovering the alkali by recaustizing the alkali salt to yield recovered alkali, and (iv) recovering the ethanol from the neutralized post-treatment solution. 19. The system of claim 18, wherein the recycling/recovery stage further comprises recovering the phytochemicals from the neutralized post-treatment solution. 20. The method of claim 1, wherein the cellulosic material is a plant-based animal feed. 21. The method of claim 20, wherein the animal feed is the stover of a forage crop. 22. An animal feed prepared by the method of claim 20, wherein the treated cellulosic material is a treated feed. 23. The animal feed of claim 22, further comprising increased digestibility of the treated feed compared to an untreated feed. 24. A method of treating a plant-based animal feed to improve digestibility of the feed comprising treating an animal feed according to the method of claim 1. 25. The method of claim 1, wherein the method is a commercial scale method of production. | 1,600 |
1,174 | 13,483,190 | 1,619 | The present invention aims to provide a particulate formulation with an effectively controlled dissolution characteristic of a drug even if the average particle diameter is small. The present invention provides a particulate formulation containing drug particles and a first coating layer coating the drug particles and characterized in that the first coating layer contains a water-insoluble polymer, inorganic particles, and/or a lipid component and the lipid component contains a C 15 or higher fatty acid. | 1. A particulate formulation containing drug particles and a first coating layer coating said drug particles, characterized in that said first coating layer contains a water-insoluble polymer, inorganic particles, and/or a lipid component and said lipid component contains a C15 or higher fatty acid. 2. The particulate formulation according to claim 1, wherein the water-insoluble polymer contains an enteric polymer. 3. The particulate formulation according to claim 1, wherein the average particle diameter of the inorganic particles is 1 to 1000 nm. 4. The particulate formulation according to claim 1, wherein the inorganic particles are of silica and/or titanium dioxide. 5. The particulate formulation according to claim 1, wherein the inorganic particles are subjected to hydrophobization. 6. The particulate formulation according to claim 1, wherein the inorganic particles are contained in an amount of 0.5 to 2.4 parts by weight to 2.4 parts by weight of the water-insoluble polymer. 7. The particulate formulation according to claim 1, wherein the inorganic particles are contained in an amount of 0.5 to 2.4 parts by weight to 2.4 parts by weight of the drug particles. 8. The particulate formulation according to claim 1, wherein the lipid component contains a C15 to C21 fatty acid. 9. The particulate formulation according to claim 8, wherein the C15 to C21 fatty acid is stearic acid. 10. The particulate formulation according to claim 1, wherein the lipid component is contained in an amount of 0.1 to 0.8 parts by weight to 2.4 parts by weight of the water-insoluble polymer. 11. The particulate formulation according to claim 1, further containing a second coating layer coating the first coating layer. 12. The particulate formulation according to claim 11, wherein the first coating layer contains a cellulose enteric polymer and the second coating layer contains a water-insoluble polymer different from said cellulose enteric polymer. 13. The particulate formulation according to claim 12, wherein the cellulose enteric polymer contains hydroxypropylmethyl cellulose phthalate (HPMCP) and/or hydroxypropylmethyl cellulose acetate succinate (HPMCAS). 14. The particulate formulation according to claim 12, wherein the water-insoluble polymer different from the cellulose enteric polymer contains at least one kind selected from the group consisting of ethyl cellulose, a methacrylic acid-methyl acrylate copolymer, a methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer, polyvinyl acetal diethylaminoacetate, an ethyl acrylate-methyl methacrylate-chlorotrimethylammonium ethyl methacrylate copolymer, and an ethyl acrylate-methyl methacrylate copolymer. 15. The particulate formulation according to claim 1, having an average particle diameter of 0.1 to 200 μm. 16. A method for producing a particulate formulation, comprising the steps of:
forming a first coating layer on drug particles by dissolving and/or suspending said drug particles in a first coating solution containing a cellulose enteric polymer and carrying out a spray drying method; and forming a second coating layer by suspending said drug particles coated with said first coating layer in a second coating solution containing a water-insoluble polymer different from said cellulose enteric polymer and carrying out a spray drying method. 17. The method for producing a particulate formulation according to claim 16, wherein the first coating solution contains a first polar solvent. 18. The method for producing a particulate formulation according to claim 17, wherein the first polar solvent is acetone. 19. The method for producing a particulate formulation according to claim 16, wherein the second coating solution contains a second polar solvent different from the first polar solvent. 20. The method for producing a particulate formulation according to claim 19, wherein the second polar solvent is ethanol. | The present invention aims to provide a particulate formulation with an effectively controlled dissolution characteristic of a drug even if the average particle diameter is small. The present invention provides a particulate formulation containing drug particles and a first coating layer coating the drug particles and characterized in that the first coating layer contains a water-insoluble polymer, inorganic particles, and/or a lipid component and the lipid component contains a C 15 or higher fatty acid.1. A particulate formulation containing drug particles and a first coating layer coating said drug particles, characterized in that said first coating layer contains a water-insoluble polymer, inorganic particles, and/or a lipid component and said lipid component contains a C15 or higher fatty acid. 2. The particulate formulation according to claim 1, wherein the water-insoluble polymer contains an enteric polymer. 3. The particulate formulation according to claim 1, wherein the average particle diameter of the inorganic particles is 1 to 1000 nm. 4. The particulate formulation according to claim 1, wherein the inorganic particles are of silica and/or titanium dioxide. 5. The particulate formulation according to claim 1, wherein the inorganic particles are subjected to hydrophobization. 6. The particulate formulation according to claim 1, wherein the inorganic particles are contained in an amount of 0.5 to 2.4 parts by weight to 2.4 parts by weight of the water-insoluble polymer. 7. The particulate formulation according to claim 1, wherein the inorganic particles are contained in an amount of 0.5 to 2.4 parts by weight to 2.4 parts by weight of the drug particles. 8. The particulate formulation according to claim 1, wherein the lipid component contains a C15 to C21 fatty acid. 9. The particulate formulation according to claim 8, wherein the C15 to C21 fatty acid is stearic acid. 10. The particulate formulation according to claim 1, wherein the lipid component is contained in an amount of 0.1 to 0.8 parts by weight to 2.4 parts by weight of the water-insoluble polymer. 11. The particulate formulation according to claim 1, further containing a second coating layer coating the first coating layer. 12. The particulate formulation according to claim 11, wherein the first coating layer contains a cellulose enteric polymer and the second coating layer contains a water-insoluble polymer different from said cellulose enteric polymer. 13. The particulate formulation according to claim 12, wherein the cellulose enteric polymer contains hydroxypropylmethyl cellulose phthalate (HPMCP) and/or hydroxypropylmethyl cellulose acetate succinate (HPMCAS). 14. The particulate formulation according to claim 12, wherein the water-insoluble polymer different from the cellulose enteric polymer contains at least one kind selected from the group consisting of ethyl cellulose, a methacrylic acid-methyl acrylate copolymer, a methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer, polyvinyl acetal diethylaminoacetate, an ethyl acrylate-methyl methacrylate-chlorotrimethylammonium ethyl methacrylate copolymer, and an ethyl acrylate-methyl methacrylate copolymer. 15. The particulate formulation according to claim 1, having an average particle diameter of 0.1 to 200 μm. 16. A method for producing a particulate formulation, comprising the steps of:
forming a first coating layer on drug particles by dissolving and/or suspending said drug particles in a first coating solution containing a cellulose enteric polymer and carrying out a spray drying method; and forming a second coating layer by suspending said drug particles coated with said first coating layer in a second coating solution containing a water-insoluble polymer different from said cellulose enteric polymer and carrying out a spray drying method. 17. The method for producing a particulate formulation according to claim 16, wherein the first coating solution contains a first polar solvent. 18. The method for producing a particulate formulation according to claim 17, wherein the first polar solvent is acetone. 19. The method for producing a particulate formulation according to claim 16, wherein the second coating solution contains a second polar solvent different from the first polar solvent. 20. The method for producing a particulate formulation according to claim 19, wherein the second polar solvent is ethanol. | 1,600 |
1,175 | 15,660,924 | 1,612 | Compositions, devices, and methods for transdermal administration of active agents provided in their salt form instead of neutral form are provided. | 1. A composition for transdermal delivery, comprising:
a drug reservoir comprising an amine salt form of an active agent and an amphoteric inorganic base compound, wherein the pKa of the amphoteric inorganic base compound is lower than that of the amine salt form of the active agent. 2. The composition of claim 1, wherein the amphoteric inorganic base compound is sodium bicarbonate. 3. The composition of claim 1, wherein the active agent is selected from the group consisting of donepezil, memantine, fentanyl, oxybutynin, rotigotine, ropinirole, rivastigmine, tamsulosin, methylphenidate, fingolimod, and buprenorphine. 4. The composition of claim 1, wherein the drug reservoir comprises between about 5-35% w/w of the active agent. 5. The composition of claim 1, wherein the drug reservoir comprises between about 0.5-35% w/w of the sodium bicarbonate. 6. The composition of claim 1, further comprising a salt form solubilizer selected from the group consisting of water, alcohols, glycerol, propylene glycol, ethylene glycol, dimethyl sulfoxide, and N-methylpyrrolidone. 7. The composition of claim 6, wherein the drug reservoir comprises up to 15% w/w of the salt form solubilizer. 8. The composition of claim 1, further comprising a neutral form solubilizer selected from the group consisting of a fatty acid ester, a dicarboxylic acid ester, a glycerol ester, a lactate, a fatty alcohol, sorbitan monolaurate, sorbitan monooleate, lauryl lactate, propylene glycol monolaurate, dimethyl succinate, lauryl alcohol, and oleyl alcohol. 9. The composition of claim 8, wherein the drug reservoir comprises up to 20% w/w of the neutral form solubilizer. 10. The composition of claim 1, further comprising a plasticizer selected from the group consisting of a dicarboxylic acid ester, an adipate, a sebacate, a maleate, a tricarboxylic ester, triethyl citrate, tributyl citrate, a glycerol ester, and triacetin. 11. The composition of claim 10, wherein the drug reservoir comprises up to 20% w/w of the plasticizer. 12. The composition of claim 1, further comprising an additive selected from the group consisting of crospovidone and colloidal silicone dioxide. 13. The composition of claim 12, wherein the composition comprises up to 25% w/w of the additive. 14. The composition of claim 1, wherein the drug reservoir further comprises an adhesive agent selected from the group consisting of an acrylate, polyisobutylene, silicone adhesive, and styrene block copolymer based adhesive. 15. The composition of claim 14, wherein the adhesive agent comprises up to 65% w/w of the composition. 16. A transdermal patch comprising the composition of claim 1 as a first drug reservoir and a backing layer. 17. The transdermal patch of claim 16, wherein the backing layer is an occlusive polymer film. 18. The transdermal patch of claim 16, further comprising a contact adhesive layer comprised of an adhesive selected from the group consisting of an acrylate, polyisobutylene, silicone adhesive, and styrene block copolymer based adhesive. 19. The transdermal patch of claim 16, further comprising a nonwoven tie layer between the drug reservoir and the contact adhesive layer. 20. The transdermal patch of claim 16, further comprising a rate-controlling membrane between the drug reservoir and the contact adhesive layer. 21. The transdermal patch of claim 16, wherein the patch comprises a second drug reservoir comprising an adhesive matrix comprising an amine salt form of an active agent and an amphoteric inorganic base compound, wherein the pKa of the amphoteric inorganic base compound is lower than that of the amine salt form of the active agent. 22. The transdermal patch of claim 21, wherein the first drug reservoir and second drug reservoir are separated by a nonwoven tie layer. 23. The transdermal patch of claim 22, wherein the first drug reservoir and second drug reservoir are separated by a rate-controlling membrane. 24. A method of transdermally administering an active agent to a patient in need thereof, comprising: providing a composition according to claim 1 to a patient in need thereof. 25. A method for treating Alzheimer's disease, Parkinson's disease, restless leg syndrome, attention deficit hyperactivity disorder, narcolepsy, depression, anxiety disorder, obsessive compulsive disorder, benign prostatic hyperplasia, acute urinary retention, opioid dependence, moderate acute pain in non-opioid-tolerant individuals, or moderate chronic pain, comprising: providing a composition according to claim 1 to a patient in need thereof. 26. The method of claim 25, further comprising administering or instructing to administer to the skin of the patient the composition. 27. The method of claim 26, wherein said administering achieves a therapeutically effective blood concentration of the active agent. 28. A method of transdermally administering an active agent to a patient in need thereof, comprising: providing a transdermal patch according to claim 16 to a patient in need thereof. 29. A method for treating Alzheimer's disease, Parkinson's disease, restless leg syndrome, attention deficit hyperactivity disorder, narcolepsy, depression, anxiety disorder, obsessive compulsive disorder, benign prostatic hyperplasia, acute urinary retention, opioid dependence, moderate acute pain in non-opioid-tolerant individuals, or moderate chronic pain, comprising: providing a transdermal patch according to claim 16 to a patient in need thereof. 30. The method of claim 28, further comprising administering or instructing to administer to the skin of the patient the transdermal patch. 31. The method of claim 28, wherein said administering achieves a therapeutically effective blood concentration of the active agent. | Compositions, devices, and methods for transdermal administration of active agents provided in their salt form instead of neutral form are provided.1. A composition for transdermal delivery, comprising:
a drug reservoir comprising an amine salt form of an active agent and an amphoteric inorganic base compound, wherein the pKa of the amphoteric inorganic base compound is lower than that of the amine salt form of the active agent. 2. The composition of claim 1, wherein the amphoteric inorganic base compound is sodium bicarbonate. 3. The composition of claim 1, wherein the active agent is selected from the group consisting of donepezil, memantine, fentanyl, oxybutynin, rotigotine, ropinirole, rivastigmine, tamsulosin, methylphenidate, fingolimod, and buprenorphine. 4. The composition of claim 1, wherein the drug reservoir comprises between about 5-35% w/w of the active agent. 5. The composition of claim 1, wherein the drug reservoir comprises between about 0.5-35% w/w of the sodium bicarbonate. 6. The composition of claim 1, further comprising a salt form solubilizer selected from the group consisting of water, alcohols, glycerol, propylene glycol, ethylene glycol, dimethyl sulfoxide, and N-methylpyrrolidone. 7. The composition of claim 6, wherein the drug reservoir comprises up to 15% w/w of the salt form solubilizer. 8. The composition of claim 1, further comprising a neutral form solubilizer selected from the group consisting of a fatty acid ester, a dicarboxylic acid ester, a glycerol ester, a lactate, a fatty alcohol, sorbitan monolaurate, sorbitan monooleate, lauryl lactate, propylene glycol monolaurate, dimethyl succinate, lauryl alcohol, and oleyl alcohol. 9. The composition of claim 8, wherein the drug reservoir comprises up to 20% w/w of the neutral form solubilizer. 10. The composition of claim 1, further comprising a plasticizer selected from the group consisting of a dicarboxylic acid ester, an adipate, a sebacate, a maleate, a tricarboxylic ester, triethyl citrate, tributyl citrate, a glycerol ester, and triacetin. 11. The composition of claim 10, wherein the drug reservoir comprises up to 20% w/w of the plasticizer. 12. The composition of claim 1, further comprising an additive selected from the group consisting of crospovidone and colloidal silicone dioxide. 13. The composition of claim 12, wherein the composition comprises up to 25% w/w of the additive. 14. The composition of claim 1, wherein the drug reservoir further comprises an adhesive agent selected from the group consisting of an acrylate, polyisobutylene, silicone adhesive, and styrene block copolymer based adhesive. 15. The composition of claim 14, wherein the adhesive agent comprises up to 65% w/w of the composition. 16. A transdermal patch comprising the composition of claim 1 as a first drug reservoir and a backing layer. 17. The transdermal patch of claim 16, wherein the backing layer is an occlusive polymer film. 18. The transdermal patch of claim 16, further comprising a contact adhesive layer comprised of an adhesive selected from the group consisting of an acrylate, polyisobutylene, silicone adhesive, and styrene block copolymer based adhesive. 19. The transdermal patch of claim 16, further comprising a nonwoven tie layer between the drug reservoir and the contact adhesive layer. 20. The transdermal patch of claim 16, further comprising a rate-controlling membrane between the drug reservoir and the contact adhesive layer. 21. The transdermal patch of claim 16, wherein the patch comprises a second drug reservoir comprising an adhesive matrix comprising an amine salt form of an active agent and an amphoteric inorganic base compound, wherein the pKa of the amphoteric inorganic base compound is lower than that of the amine salt form of the active agent. 22. The transdermal patch of claim 21, wherein the first drug reservoir and second drug reservoir are separated by a nonwoven tie layer. 23. The transdermal patch of claim 22, wherein the first drug reservoir and second drug reservoir are separated by a rate-controlling membrane. 24. A method of transdermally administering an active agent to a patient in need thereof, comprising: providing a composition according to claim 1 to a patient in need thereof. 25. A method for treating Alzheimer's disease, Parkinson's disease, restless leg syndrome, attention deficit hyperactivity disorder, narcolepsy, depression, anxiety disorder, obsessive compulsive disorder, benign prostatic hyperplasia, acute urinary retention, opioid dependence, moderate acute pain in non-opioid-tolerant individuals, or moderate chronic pain, comprising: providing a composition according to claim 1 to a patient in need thereof. 26. The method of claim 25, further comprising administering or instructing to administer to the skin of the patient the composition. 27. The method of claim 26, wherein said administering achieves a therapeutically effective blood concentration of the active agent. 28. A method of transdermally administering an active agent to a patient in need thereof, comprising: providing a transdermal patch according to claim 16 to a patient in need thereof. 29. A method for treating Alzheimer's disease, Parkinson's disease, restless leg syndrome, attention deficit hyperactivity disorder, narcolepsy, depression, anxiety disorder, obsessive compulsive disorder, benign prostatic hyperplasia, acute urinary retention, opioid dependence, moderate acute pain in non-opioid-tolerant individuals, or moderate chronic pain, comprising: providing a transdermal patch according to claim 16 to a patient in need thereof. 30. The method of claim 28, further comprising administering or instructing to administer to the skin of the patient the transdermal patch. 31. The method of claim 28, wherein said administering achieves a therapeutically effective blood concentration of the active agent. | 1,600 |
1,176 | 15,763,892 | 1,645 | The present invention provides compositions or vaccines that contain a recombinant or an attenuated Leptospira interrogans that elicit an immune response in animals against Leptospira infection, including compositions comprising said recombinant or attenuated L. interrogans, methods of vaccination against Leptospira, and kits for use with such methods and compositions. | 1. A composition or vaccine comprising a recombinant or an attenuated Leptospira interrogans, wherein the Leptospira interrogans comprises a mutated non-functional fliM gene. 2. The composition or vaccine of claim 1, wherein the mutated fliM gene encodes a mutated fliM protein, and wherein the C-terminal region of the fliM protein is deleted. 3. The composition or vaccine of claim 1 or 2, wherein the fliM gene is deleted. 4. The composition or vaccine of any one of claims 1-3, wherein the fliM gene encodes an fliM protein having at least 90% sequence identity to SEQ ID NO:17, 18, 19 or 20. 5. The composition or vaccine of any one of claims 1-4, wherein the fliM gene has at least 90% sequence identity to SEQ ID NO: 13, 14, 15, or 16. 6. The composition or vaccine of any one of claims 1-5, wherein the attenuated Leptospira interrogans is deposited under the CNCM deposit Nos. CNCM I-5132 and CNCM I-5133, or is a progeny or descendant of CNCM I-5132 and CNCM I-5133, wherein the progeny or descendant comprises a mutated fliM gene encoding an fliM protein having at least 90% sequence identity to SEQ ID NO: 17, 18, 19 or 20. 7. The composition or vaccine of any one of claims 1-6, wherein the attenuated Leptospira interrogans is deposited under the CNCM deposit Nos. CNCM I-5132 and CNCM I-5133, or is a progeny or descendant of CNCM I-5132 and CNCM I-5133, wherein the progeny or descendant comprises a mutated fliM gene having at least 90% sequence identity to SEQ ID NO: 13, 14, 15, or 16. 8. The composition or vaccine of any one of claims 1-7, wherein the composition or vaccine further comprises one or more pharmaceutically or veterinarily acceptable carrier, vehicle, or excipient. 9. An isolated attenuated Leptospira interrogans, wherein the Leptospira interrogans comprises a mutated non-functional fliM gene. 10. The attenuated Leptospira interrogans of claim 9, wherein the mutated fliM gene encodes a mutated fliM protein, and wherein the C-terminal region of the fliM protein is deleted. 11. The attenuated Leptospira interrogans of claim 9 or 10, wherein the fliM gene is deleted. 12. The attenuated Leptospira interrogans of any one of claims 9-11, wherein the fliM gene encodes an fliM protein having at least 90% sequence identity to SEQ ID NO:17, 18, 19 or 20. 13. The attenuated Leptospira interrogans of any one of claims 9-12, wherein the fliM gene has at least 90% sequence identity to SEQ ID NO: 13, 14, 15, or 16. 14. The attenuated Leptospira interrogans of any one of claims 9-13, wherein the attenuated Leptospira interrogans is deposited under the CNCM deposit Nos. CNCM I-5132 and CNCM I-5133, or is a progeny or descendant of CNCM I-5132 and CNCM I-5133, wherein the progeny or descendant comprises a mutated fliM gene encoding an fliM protein having at least 90% sequence identity to SEQ ID NO: 17, 18, 19 or 20. 15. The attenuated Leptospira interrogans of any one of claims 9-14, wherein the attenuated Leptospira interrogans is deposited under the CNCM deposit Nos. CNCM I-5132 and CNCM I-5133, or is a progeny or descendant of CNCM I-5132 and CNCM I-5133, wherein the progeny or descendant comprises a mutated fliM gene having at least 90% sequence identity to SEQ ID NO: 13, 14, 15, or 16. 16. A method of vaccinating an animal, or for inducing an immunogenic or protective response against Leptospira infection, comprising at least one administration of the composition or vaccine of any one of claims 1-8 or the attenuated Leptospira interrogans of claims 9-15. 17. The method of claim 16, wherein the animal is a canine or feline. 18. An isolated polynucleotide encoding an fliM protein having at least 98% sequence identity to SEQ ID NO:2, 4, or 6, or encoding an NA protein having at least 98% sequence identity to SEQ ID NO:8, 10, or 12. | The present invention provides compositions or vaccines that contain a recombinant or an attenuated Leptospira interrogans that elicit an immune response in animals against Leptospira infection, including compositions comprising said recombinant or attenuated L. interrogans, methods of vaccination against Leptospira, and kits for use with such methods and compositions.1. A composition or vaccine comprising a recombinant or an attenuated Leptospira interrogans, wherein the Leptospira interrogans comprises a mutated non-functional fliM gene. 2. The composition or vaccine of claim 1, wherein the mutated fliM gene encodes a mutated fliM protein, and wherein the C-terminal region of the fliM protein is deleted. 3. The composition or vaccine of claim 1 or 2, wherein the fliM gene is deleted. 4. The composition or vaccine of any one of claims 1-3, wherein the fliM gene encodes an fliM protein having at least 90% sequence identity to SEQ ID NO:17, 18, 19 or 20. 5. The composition or vaccine of any one of claims 1-4, wherein the fliM gene has at least 90% sequence identity to SEQ ID NO: 13, 14, 15, or 16. 6. The composition or vaccine of any one of claims 1-5, wherein the attenuated Leptospira interrogans is deposited under the CNCM deposit Nos. CNCM I-5132 and CNCM I-5133, or is a progeny or descendant of CNCM I-5132 and CNCM I-5133, wherein the progeny or descendant comprises a mutated fliM gene encoding an fliM protein having at least 90% sequence identity to SEQ ID NO: 17, 18, 19 or 20. 7. The composition or vaccine of any one of claims 1-6, wherein the attenuated Leptospira interrogans is deposited under the CNCM deposit Nos. CNCM I-5132 and CNCM I-5133, or is a progeny or descendant of CNCM I-5132 and CNCM I-5133, wherein the progeny or descendant comprises a mutated fliM gene having at least 90% sequence identity to SEQ ID NO: 13, 14, 15, or 16. 8. The composition or vaccine of any one of claims 1-7, wherein the composition or vaccine further comprises one or more pharmaceutically or veterinarily acceptable carrier, vehicle, or excipient. 9. An isolated attenuated Leptospira interrogans, wherein the Leptospira interrogans comprises a mutated non-functional fliM gene. 10. The attenuated Leptospira interrogans of claim 9, wherein the mutated fliM gene encodes a mutated fliM protein, and wherein the C-terminal region of the fliM protein is deleted. 11. The attenuated Leptospira interrogans of claim 9 or 10, wherein the fliM gene is deleted. 12. The attenuated Leptospira interrogans of any one of claims 9-11, wherein the fliM gene encodes an fliM protein having at least 90% sequence identity to SEQ ID NO:17, 18, 19 or 20. 13. The attenuated Leptospira interrogans of any one of claims 9-12, wherein the fliM gene has at least 90% sequence identity to SEQ ID NO: 13, 14, 15, or 16. 14. The attenuated Leptospira interrogans of any one of claims 9-13, wherein the attenuated Leptospira interrogans is deposited under the CNCM deposit Nos. CNCM I-5132 and CNCM I-5133, or is a progeny or descendant of CNCM I-5132 and CNCM I-5133, wherein the progeny or descendant comprises a mutated fliM gene encoding an fliM protein having at least 90% sequence identity to SEQ ID NO: 17, 18, 19 or 20. 15. The attenuated Leptospira interrogans of any one of claims 9-14, wherein the attenuated Leptospira interrogans is deposited under the CNCM deposit Nos. CNCM I-5132 and CNCM I-5133, or is a progeny or descendant of CNCM I-5132 and CNCM I-5133, wherein the progeny or descendant comprises a mutated fliM gene having at least 90% sequence identity to SEQ ID NO: 13, 14, 15, or 16. 16. A method of vaccinating an animal, or for inducing an immunogenic or protective response against Leptospira infection, comprising at least one administration of the composition or vaccine of any one of claims 1-8 or the attenuated Leptospira interrogans of claims 9-15. 17. The method of claim 16, wherein the animal is a canine or feline. 18. An isolated polynucleotide encoding an fliM protein having at least 98% sequence identity to SEQ ID NO:2, 4, or 6, or encoding an NA protein having at least 98% sequence identity to SEQ ID NO:8, 10, or 12. | 1,600 |
1,177 | 15,521,490 | 1,616 | An oil-in-water emulsified sunblock cosmetic has excellent feeling when used and maintains a high ultraviolet-ray protective effect even upon contact with water or sweat. The oil-in-water emulsified sunblock cosmetic contains an (A) ultraviolet-ray protective agent and a (B) fatty acid forming a solid at room temperature, the cosmetic is characterized in that 51% or less of the fatty acid is neutralized, and the formulation ratio ((A)/(B) of the (A) ultraviolet-ray protective agent to the (B) fatty acid is in the range of at least 0.1 and less than 10.0. The cosmetic exhibits the unprecedented and surprising property of contact with water causing an improvement to the ultraviolet-ray protective ability. It is preferable for the cosmetic to contain an (C) oily component having IOB of 0.5 or higher. | 1. An oil-in-water emulsion sunscreen cosmetic, comprising:
(A) a UV protective agent; (B) a fatty acid that is solid at room temperature; wherein a neutralization rate of the fatty acid is 51% or less; and wherein a blending ratio ((A)/(B)) between the (A) UV protective agent and the (B) fatty acid that is solid at room temperature is within a range of at least 0.1 and less than 10.0. 2. The cosmetic according to claim 1, further comprising:
(C) an oil having at least an 0.5 IOB. 3. The cosmetic according to claim 2, wherein:
the (C) oil is of one or more types selected from among alkylene oxide derivatives. 4. The cosmetic according to claim 3, wherein:
the alkylene oxide derivative is at least one selected from the group consisting of: polyoxyethylene/polyoxypropylene dimethyl ethers and polyalkylene glycols. 5. The cosmetic according to claim 4, wherein:
the alkylene oxide derivatives include at least one of the group consisting of: polyoxyethylene (14) polyoxypropylene (7) dimethyl ether, polyethylene glycol, polypropylene glycol, and polyoxybutylene polyoxypropylene glycol. 6. The cosmetic according to claim 1, wherein:
the (B) fatty acid is one or more linear fatty acids selected from the group consisting of: stearic acid, palmitic acid, myristic acid, and behenic acid. | An oil-in-water emulsified sunblock cosmetic has excellent feeling when used and maintains a high ultraviolet-ray protective effect even upon contact with water or sweat. The oil-in-water emulsified sunblock cosmetic contains an (A) ultraviolet-ray protective agent and a (B) fatty acid forming a solid at room temperature, the cosmetic is characterized in that 51% or less of the fatty acid is neutralized, and the formulation ratio ((A)/(B) of the (A) ultraviolet-ray protective agent to the (B) fatty acid is in the range of at least 0.1 and less than 10.0. The cosmetic exhibits the unprecedented and surprising property of contact with water causing an improvement to the ultraviolet-ray protective ability. It is preferable for the cosmetic to contain an (C) oily component having IOB of 0.5 or higher.1. An oil-in-water emulsion sunscreen cosmetic, comprising:
(A) a UV protective agent; (B) a fatty acid that is solid at room temperature; wherein a neutralization rate of the fatty acid is 51% or less; and wherein a blending ratio ((A)/(B)) between the (A) UV protective agent and the (B) fatty acid that is solid at room temperature is within a range of at least 0.1 and less than 10.0. 2. The cosmetic according to claim 1, further comprising:
(C) an oil having at least an 0.5 IOB. 3. The cosmetic according to claim 2, wherein:
the (C) oil is of one or more types selected from among alkylene oxide derivatives. 4. The cosmetic according to claim 3, wherein:
the alkylene oxide derivative is at least one selected from the group consisting of: polyoxyethylene/polyoxypropylene dimethyl ethers and polyalkylene glycols. 5. The cosmetic according to claim 4, wherein:
the alkylene oxide derivatives include at least one of the group consisting of: polyoxyethylene (14) polyoxypropylene (7) dimethyl ether, polyethylene glycol, polypropylene glycol, and polyoxybutylene polyoxypropylene glycol. 6. The cosmetic according to claim 1, wherein:
the (B) fatty acid is one or more linear fatty acids selected from the group consisting of: stearic acid, palmitic acid, myristic acid, and behenic acid. | 1,600 |
1,178 | 14,441,352 | 1,619 | The present invention relates to a cosmetic composition comprising
one or more dicarbonyl compound corresponding to formula (I) below thereof and/or hydrates thereof and/or salts thereof:
in which formula (I) R═H, COOH, linear or branched C 1 -C 6 alkyl optionally substituted with an OH or COOH or Br radical; phenyl or benzyl optionally substituted with an OH or COOH radical; or alternatively an indolyl radical or
with * representing the part linked to the rest of the molecule, the dicarbonyl compounds corresponding to formula (I) and/or hydrates thereof and/or salts thereof being present in an amount ranging from 3 to 15% by weight relative to the total weight of the composition,
one or more cationic surfactants, one or more non liquid preferably solid fatty substances, the non liquid preferably solid fatty substances being present in an amount ranging from 1% to 30% by weight relative to the total weight of the composition,
the composition having a pH of less than or equal to 4.
The invention also relates to a process for straightening keratin fibres, especially the hair, which comprises the application to the hair of the composition of the invention, followed by a straightening step using a straightening iron at a temperature of at least 150° C., preferably ranging from 150 to 250° C. | 1. Cosmetic composition comprising
one or more dicarbonyl compounds corresponding to formula (I) below and/or hydrates thereof and/or salts thereof:
in which formula (I):
R represents an atom or group chosen from i) hydrogen, ii) carboxyl —C(O)OH, iii) linear or branched C1-C6 alkyl which is optionally substituted, preferably with at least one hydroxyl —OH radical, carboxyl —C(O)—OH radical or halogen radical such as Br; iv) optionally substituted phenyl, v) optionally substituted benzyl, iv) and v) preferably being optionally substituted with at least one —OH or —C(O)OH radical; vi) an indolyl radical and vii) an imidazolylmethyl radical and tautomers thereof such as
with * representing the part linked to the rest of the molecule, the dicarbonyl compounds corresponding to formula (I) and/or hydrates thereof and/or salts thereof being present in an amount ranging from 3 to 15% by weight relative to the total weight of the composition,
one or more cationic surfactants,
one or more non liquid and preferably solid fatty substances, the non liquid and preferably solid fatty substances being present in an amount ranging from 1% to 30% by weight relative to the total weight of the composition,
the composition having a pH of less than or equal to 4. 2. Composition according to claim 1, in which R represents i) a hydrogen atom or ii) a linear or branched C1-C6 alkyl group optionally substituted with a carboxyl group. 3. Composition according to either of the preceding claims, in which the dicarbonyl compound(s) corresponding to formula (I) and/or hydrates thereof and/or salts thereof are chosen from glyoxylic acid and pyruvic acid, salts thereof and hydrates thereof, preferably from glyoxylic acid and the hydrate forms of this compound. 4. Composition according to claim 3, in which the glyoxylic acid is in its hydrate form. 5. Composition according to any one of claims 1 to 4, comprising from 5% to 15% by weight of one or more dicarbonyl compounds corresponding to formula (I) and/or hydrates thereof and/or salts thereof, preferably from 5% to 10% by weight relative to the total weight of the composition. 6. Composition according to any one of the preceding claims, in which the cationic surfactant(s) are chosen from:
those corresponding to the general formula (II) below:
with R8 to R11, which may be identical or different, representing a linear or branched aliphatic group comprising from 1 to 30 carbon atoms, or an aromatic group such as aryl or alkylaryl, at least one of the groups R8 to R11 denoting a group comprising from 8 to 30 carbon atoms, preferably from 12 to 24 carbon atoms;
X− is an anion chosen from the group of halides, phosphates, acetates, lactates, (C1-C4)alkyl sulfates, (C1-C4) alkyl- or (C1-C4)alkylarylsulfonates;
quaternary ammonium salts of imidazoline, more particularly those of formula (III) below:
in which R12 represents an alkyl or alkenyl group comprising from 8 to 30 carbon atoms, R13 represents a hydrogen atom, a C1-C4 alkyl group or an alkyl or alkenyl group comprising from 8 to 30 carbon atoms, R14 represents a C1-C4 alkyl group, R15 represents a hydrogen atom or a C1-C4 alkyl group, X− is an anion chosen from the group of halides, phosphates, acetates, lactates, alkyl sulfates and alkyl- or alkylarylsulfonates, the alkyl and aryl groups of which preferably comprise from 1 to 20 carbon atoms and from 6 to 30 carbon atoms respectively;
quaternary di- or triammonium salts, in particular of formula (IV):
in which R16 denotes an alkyl radical comprising approximately 16 to 30 carbon atoms, optionally hydroxylated and/or interrupted with one or more oxygen atoms, R17 is chosen from hydrogen, an alkyl radical comprising from 1 to 4 carbon atoms or a group [(R16a)(R17a)(R18a)N—(CH2)3,
R16a, R17a, R18a, R18, R19, R20 and R21, which may be identical or different, are chosen from hydrogen or an alkyl radical comprising from 1 to 4 carbon atoms;
X− is an anion chosen from the group of halides, acetates, phosphates, nitrates and methyl sulfates;
quaternary ammonium salts containing at least one ester function, such as those of formula (V) below:
in which:
R22 is chosen from C1-C6 alkyl and C1-C6 hydroxyalkyl or dihydroxyalkyl groups;
R23 is chosen from:
the group
groups R27, which are linear or branched, saturated or unsaturated C1-C22 hydrocarbon-based groups,
a hydrogen atom,
R25 is chosen from:
the group
groups R29, which are linear or branched, saturated or unsaturated C1-C6 hydrocarbon-based groups,
a hydrogen atom,
R24, R26 and R28, which may be identical or different, are chosen from linear or branched, saturated or unsaturated C7-C21 hydrocarbon-based groups;
r, s and t, which may be identical or different, are integers ranging from 2 to 6;
y is an integer ranging from 1 to 10;
x and z, which may be identical or different, are integers ranging from 0 to 10;
X− is a simple or complex, organic or mineral anion;
with the proviso that the sum x+y+z is from 1 to 15, that when x is 0, then R23 denotes R22 and that when z is 0, then R25 denotes R. 7. Composition according to any one of the preceding claims, in which the cationic surfactant(s) are chosen from cetyltrimethylammonium, behenyltrimethylammonium and dipalmitoylethylhydroxyethylmethylammonium salts, and mixtures thereof, and more particularly behenyltrimethylammonium chloride, cetyltrimethylammonium chloride, and dipalmitoylethylhydroxyethylammonium methosulfate, and mixtures thereof. 8. Composition according to one of the preceding claims, characterized in that the cationic surfactant(s) are present in an active material content ranging from 0.1% to 15% by weight and preferably from 0.2% to 8% by weight, preferably ranging from 0.4% to 3% by weight relative to the total weight of the composition. 9. Composition according to any one of the preceding claims, in which the weight ratio of dicarbonyl compounds corresponding to formula (I) and/or hydrate form thereof and/or salts thereof/cationic surfactants ranges from 0.1 to 20 and better still from 1 to 10. 10. Composition according to any one of the preceding claims, in which the fatty substance(s) are chosen from non-silicone fatty substances. 11. Composition according to any one of the preceding claims, in which the fatty substance(s) are chosen from fatty alcohols, esters of a fatty acid and/or of a fatty alcohol, or mixtures thereof, and more preferably from fatty alcohols. 12. Composition according to any one of the preceding claims, in which the fatty substance(s) are present in an amount ranging from 1 to 20% by weight, preferably from 5 to 20% by weight relative to the total weight of the composition. 13. Composition according to any one of the preceding claims, characterized in that it is aqueous and comprises water in a concentration preferably ranging from 5% to 98%, better still from 5% to 90% and even better still from 10% to 90% by weight relative to the total weight of the composition. 14. Composition according to any one of the preceding claims, characterized in that it has a pH of less than or equal to 4, the pH preferentially ranging from 1 to 4, preferentially from 1 to 3, better still from 1.5 to 3 and even better still from 1.7 to 3. 15. Composition according to any one of the preceding claims, characterized in that it results from the mixing of several compositions. 16. Process for straightening keratin fibres, especially the hair, which comprises the application to the hair of the composition according to any one of the preceding claims, and then a straightening step using a straightening iron at a temperature of at least 150° C., preferably ranging from 150 to 250° C. 17. Process according to claim 16, wherein the time of contact of the composition with the hair ranging from 10 to 60 minutes. 18. Use of the composition according to any one of claims 1 to 15, for straightening/relaxing keratin fibres, especially the hair. | The present invention relates to a cosmetic composition comprising
one or more dicarbonyl compound corresponding to formula (I) below thereof and/or hydrates thereof and/or salts thereof:
in which formula (I) R═H, COOH, linear or branched C 1 -C 6 alkyl optionally substituted with an OH or COOH or Br radical; phenyl or benzyl optionally substituted with an OH or COOH radical; or alternatively an indolyl radical or
with * representing the part linked to the rest of the molecule, the dicarbonyl compounds corresponding to formula (I) and/or hydrates thereof and/or salts thereof being present in an amount ranging from 3 to 15% by weight relative to the total weight of the composition,
one or more cationic surfactants, one or more non liquid preferably solid fatty substances, the non liquid preferably solid fatty substances being present in an amount ranging from 1% to 30% by weight relative to the total weight of the composition,
the composition having a pH of less than or equal to 4.
The invention also relates to a process for straightening keratin fibres, especially the hair, which comprises the application to the hair of the composition of the invention, followed by a straightening step using a straightening iron at a temperature of at least 150° C., preferably ranging from 150 to 250° C.1. Cosmetic composition comprising
one or more dicarbonyl compounds corresponding to formula (I) below and/or hydrates thereof and/or salts thereof:
in which formula (I):
R represents an atom or group chosen from i) hydrogen, ii) carboxyl —C(O)OH, iii) linear or branched C1-C6 alkyl which is optionally substituted, preferably with at least one hydroxyl —OH radical, carboxyl —C(O)—OH radical or halogen radical such as Br; iv) optionally substituted phenyl, v) optionally substituted benzyl, iv) and v) preferably being optionally substituted with at least one —OH or —C(O)OH radical; vi) an indolyl radical and vii) an imidazolylmethyl radical and tautomers thereof such as
with * representing the part linked to the rest of the molecule, the dicarbonyl compounds corresponding to formula (I) and/or hydrates thereof and/or salts thereof being present in an amount ranging from 3 to 15% by weight relative to the total weight of the composition,
one or more cationic surfactants,
one or more non liquid and preferably solid fatty substances, the non liquid and preferably solid fatty substances being present in an amount ranging from 1% to 30% by weight relative to the total weight of the composition,
the composition having a pH of less than or equal to 4. 2. Composition according to claim 1, in which R represents i) a hydrogen atom or ii) a linear or branched C1-C6 alkyl group optionally substituted with a carboxyl group. 3. Composition according to either of the preceding claims, in which the dicarbonyl compound(s) corresponding to formula (I) and/or hydrates thereof and/or salts thereof are chosen from glyoxylic acid and pyruvic acid, salts thereof and hydrates thereof, preferably from glyoxylic acid and the hydrate forms of this compound. 4. Composition according to claim 3, in which the glyoxylic acid is in its hydrate form. 5. Composition according to any one of claims 1 to 4, comprising from 5% to 15% by weight of one or more dicarbonyl compounds corresponding to formula (I) and/or hydrates thereof and/or salts thereof, preferably from 5% to 10% by weight relative to the total weight of the composition. 6. Composition according to any one of the preceding claims, in which the cationic surfactant(s) are chosen from:
those corresponding to the general formula (II) below:
with R8 to R11, which may be identical or different, representing a linear or branched aliphatic group comprising from 1 to 30 carbon atoms, or an aromatic group such as aryl or alkylaryl, at least one of the groups R8 to R11 denoting a group comprising from 8 to 30 carbon atoms, preferably from 12 to 24 carbon atoms;
X− is an anion chosen from the group of halides, phosphates, acetates, lactates, (C1-C4)alkyl sulfates, (C1-C4) alkyl- or (C1-C4)alkylarylsulfonates;
quaternary ammonium salts of imidazoline, more particularly those of formula (III) below:
in which R12 represents an alkyl or alkenyl group comprising from 8 to 30 carbon atoms, R13 represents a hydrogen atom, a C1-C4 alkyl group or an alkyl or alkenyl group comprising from 8 to 30 carbon atoms, R14 represents a C1-C4 alkyl group, R15 represents a hydrogen atom or a C1-C4 alkyl group, X− is an anion chosen from the group of halides, phosphates, acetates, lactates, alkyl sulfates and alkyl- or alkylarylsulfonates, the alkyl and aryl groups of which preferably comprise from 1 to 20 carbon atoms and from 6 to 30 carbon atoms respectively;
quaternary di- or triammonium salts, in particular of formula (IV):
in which R16 denotes an alkyl radical comprising approximately 16 to 30 carbon atoms, optionally hydroxylated and/or interrupted with one or more oxygen atoms, R17 is chosen from hydrogen, an alkyl radical comprising from 1 to 4 carbon atoms or a group [(R16a)(R17a)(R18a)N—(CH2)3,
R16a, R17a, R18a, R18, R19, R20 and R21, which may be identical or different, are chosen from hydrogen or an alkyl radical comprising from 1 to 4 carbon atoms;
X− is an anion chosen from the group of halides, acetates, phosphates, nitrates and methyl sulfates;
quaternary ammonium salts containing at least one ester function, such as those of formula (V) below:
in which:
R22 is chosen from C1-C6 alkyl and C1-C6 hydroxyalkyl or dihydroxyalkyl groups;
R23 is chosen from:
the group
groups R27, which are linear or branched, saturated or unsaturated C1-C22 hydrocarbon-based groups,
a hydrogen atom,
R25 is chosen from:
the group
groups R29, which are linear or branched, saturated or unsaturated C1-C6 hydrocarbon-based groups,
a hydrogen atom,
R24, R26 and R28, which may be identical or different, are chosen from linear or branched, saturated or unsaturated C7-C21 hydrocarbon-based groups;
r, s and t, which may be identical or different, are integers ranging from 2 to 6;
y is an integer ranging from 1 to 10;
x and z, which may be identical or different, are integers ranging from 0 to 10;
X− is a simple or complex, organic or mineral anion;
with the proviso that the sum x+y+z is from 1 to 15, that when x is 0, then R23 denotes R22 and that when z is 0, then R25 denotes R. 7. Composition according to any one of the preceding claims, in which the cationic surfactant(s) are chosen from cetyltrimethylammonium, behenyltrimethylammonium and dipalmitoylethylhydroxyethylmethylammonium salts, and mixtures thereof, and more particularly behenyltrimethylammonium chloride, cetyltrimethylammonium chloride, and dipalmitoylethylhydroxyethylammonium methosulfate, and mixtures thereof. 8. Composition according to one of the preceding claims, characterized in that the cationic surfactant(s) are present in an active material content ranging from 0.1% to 15% by weight and preferably from 0.2% to 8% by weight, preferably ranging from 0.4% to 3% by weight relative to the total weight of the composition. 9. Composition according to any one of the preceding claims, in which the weight ratio of dicarbonyl compounds corresponding to formula (I) and/or hydrate form thereof and/or salts thereof/cationic surfactants ranges from 0.1 to 20 and better still from 1 to 10. 10. Composition according to any one of the preceding claims, in which the fatty substance(s) are chosen from non-silicone fatty substances. 11. Composition according to any one of the preceding claims, in which the fatty substance(s) are chosen from fatty alcohols, esters of a fatty acid and/or of a fatty alcohol, or mixtures thereof, and more preferably from fatty alcohols. 12. Composition according to any one of the preceding claims, in which the fatty substance(s) are present in an amount ranging from 1 to 20% by weight, preferably from 5 to 20% by weight relative to the total weight of the composition. 13. Composition according to any one of the preceding claims, characterized in that it is aqueous and comprises water in a concentration preferably ranging from 5% to 98%, better still from 5% to 90% and even better still from 10% to 90% by weight relative to the total weight of the composition. 14. Composition according to any one of the preceding claims, characterized in that it has a pH of less than or equal to 4, the pH preferentially ranging from 1 to 4, preferentially from 1 to 3, better still from 1.5 to 3 and even better still from 1.7 to 3. 15. Composition according to any one of the preceding claims, characterized in that it results from the mixing of several compositions. 16. Process for straightening keratin fibres, especially the hair, which comprises the application to the hair of the composition according to any one of the preceding claims, and then a straightening step using a straightening iron at a temperature of at least 150° C., preferably ranging from 150 to 250° C. 17. Process according to claim 16, wherein the time of contact of the composition with the hair ranging from 10 to 60 minutes. 18. Use of the composition according to any one of claims 1 to 15, for straightening/relaxing keratin fibres, especially the hair. | 1,600 |
1,179 | 16,261,459 | 1,627 | Disclosed herein are methods of administering pharmaceutical formulations of a neurokinin-1 (NK-1) receptor antagonist to a subject in need of treatment of emesis. | 1. A method for treating a subject in need thereof, comprising intravenously administering to the subject a single dose of a stable emulsion at an average rate of about 6.5 to 70 mg/minute of an NK-1 receptor antagonist comprised in the stable emulsion, wherein the stable emulsion comprises:
the NK-1 receptor antagonist; 11 wt/wt % to 15 wt/wt % of an emulsifier; an oil; a co-surfactant which comprises an alcohol; a tonicity agent; a pH modifier; and water; wherein the ratio of the emulsifier to the NK-1 receptor antagonist ranges from about 18:1 to 22:1 (wt/wt %), wherein the pH of the emulsion ranges from about 7.5 to 9.0. 2. A method for treating a subject in need thereof, comprising intravenously administering to the subject a single dose of a stable emulsion over about 30 seconds to 15 minutes, wherein the stable emulsion comprises:
an NK-1 receptor antagonist; 11 wt/wt % to 15 wt/wt % of an emulsifier; an oil; a co-surfactant which comprises an alcohol; a tonicity agent; a pH modifier; and water; wherein the ratio of the emulsifier to the NK-1 receptor antagonist ranges from about 18:1 to 22:1 (wt/wt %), wherein the pH of the emulsion ranges from about 7.5 to 9.0. 3. The method according to claim 1, wherein the average rate is about 8 to 65 mg/minute of the NK-1 receptor antagonist comprised in the stable emulsion. 4. The method according to claim 1, wherein the average rate is about 8, 20, 26, 50, or 65 mg/minute of the NK-1 receptor antagonist comprised in the stable emulsion. 5. The method according to claim 2, comprising intravenously administering the single dose of the stable emulsion to the subject over about 2, 5, or 15 minutes. 6. The method according to claim 1, wherein the ratio of the oil to the NK-1 receptor antagonist ranges from about 5:1 to 15:1 (wt/wt %). 7. The method according to claim 6, wherein the ratio of the oil to the NK-1 receptor antagonist ranges from about 10:1 to 15:1 (wt/wt %). 8. The method according to claim 1, wherein the ratio of emulsifier to oil ranges from about 1:1 to 3:1 (wt/wt %). 9. The method according to claim 1, wherein the emulsifier is a phospholipid. 10. The method according to claim 1, wherein the emulsifier is an egg lecithin. 11. The method according to claim 1, further comprising dexamethasone sodium phosphate, wherein the dexamethasone sodium phosphate is present in the aqueous phase. 12. The method according to claim 1, wherein the NK-1 receptor antagonist is selected from the group consisting of aprepitant, rolapitant, netupitant, ezlopitant, vestipitant, serlopitant, maropitant, casopitant, befetupitant, and orvepitant, or a pharmaceutically acceptable salt thereof. 13. The method according to claim 12, wherein the NK-1 receptor antagonist is not aprepitant. 14. The method according to claim 1, wherein the pH modifier is sodium oleate or a salt thereof. 15. The method according to claim 1, wherein the pH modifier is a buffer. 16. The method according to claim 15, wherein the buffer is Tris buffer. 17. The method according to claim 1, wherein the oil is soybean oil. 18. The method according to claim 1, wherein the alcohol is ethanol. 19. The method according to 18, wherein the ethanol is present in the emulsion at less than 10 wt/wt %. 20. The method according to claim 1, wherein the NK-1 receptor antagonist is aprepitant. 21. The method according to claim 1, wherein the single dose of the emulsion has a volume of about 18 mL and comprises about 130 mg NK-1 receptor antagonist or the single dose of the emulsion has a volume of about 14 mL and comprises about 100 mg NK-1 receptor antagonist. 22. The method of claim 21, wherein the ratio of the emulsifier to the NK-1 receptor antagonist is about 20:1 (wt/wt %). 23. The method of claim 21, wherein the single dose of the emulsion has a volume of about 18 mL and comprises the NK-1 receptor antagonist (about 130 mg), the emulsifier (about 2.6 g), the co-surfactant (about 0.5 g), the pH modifier (about 0.1 g), the oil (about 1.7 g), the tonicity agent (about 1 g), and water (about 12 g). 24. The method of claim 21, wherein the single dose of the emulsion has a volume of about 14 mL and comprises the NK-1 receptor antagonist (about 100 mg), the emulsifier (about 2 g), the co-surfactant (about 0.4 g), the pH modifier (about 0.08 g), the oil (about 1.3 g), the tonicity agent (about 0.8 g), and water (about 9 g). 25. The method of claim 21, wherein the NK-1 receptor antagonist is aprepitant. 26. The method of claim 23, wherein the NK-1 receptor antagonist is aprepitant, the emulsifier is egg lecithin, the co-surfactant is ethanol, the pH modifier is sodium oleate, the oil is soybean oil and the tonicity agent is sucrose. 27. The method according to claim 1, wherein the subject is at risk of or is suffering from nausea and/or vomiting and is need of treatment for nausea and/or vomiting. 28. The method according to claim 27, wherein the nausea and/or vomiting is induced by chemotherapy, surgery, or radiotherapy. 29. The method of claim 28, wherein the nausea and/or vomiting is associated with highly emetogenic cancer chemotherapy. 30. The method of claim 28, wherein the nausea and/or vomiting is associated with moderately emetogenic cancer chemotherapy. | Disclosed herein are methods of administering pharmaceutical formulations of a neurokinin-1 (NK-1) receptor antagonist to a subject in need of treatment of emesis.1. A method for treating a subject in need thereof, comprising intravenously administering to the subject a single dose of a stable emulsion at an average rate of about 6.5 to 70 mg/minute of an NK-1 receptor antagonist comprised in the stable emulsion, wherein the stable emulsion comprises:
the NK-1 receptor antagonist; 11 wt/wt % to 15 wt/wt % of an emulsifier; an oil; a co-surfactant which comprises an alcohol; a tonicity agent; a pH modifier; and water; wherein the ratio of the emulsifier to the NK-1 receptor antagonist ranges from about 18:1 to 22:1 (wt/wt %), wherein the pH of the emulsion ranges from about 7.5 to 9.0. 2. A method for treating a subject in need thereof, comprising intravenously administering to the subject a single dose of a stable emulsion over about 30 seconds to 15 minutes, wherein the stable emulsion comprises:
an NK-1 receptor antagonist; 11 wt/wt % to 15 wt/wt % of an emulsifier; an oil; a co-surfactant which comprises an alcohol; a tonicity agent; a pH modifier; and water; wherein the ratio of the emulsifier to the NK-1 receptor antagonist ranges from about 18:1 to 22:1 (wt/wt %), wherein the pH of the emulsion ranges from about 7.5 to 9.0. 3. The method according to claim 1, wherein the average rate is about 8 to 65 mg/minute of the NK-1 receptor antagonist comprised in the stable emulsion. 4. The method according to claim 1, wherein the average rate is about 8, 20, 26, 50, or 65 mg/minute of the NK-1 receptor antagonist comprised in the stable emulsion. 5. The method according to claim 2, comprising intravenously administering the single dose of the stable emulsion to the subject over about 2, 5, or 15 minutes. 6. The method according to claim 1, wherein the ratio of the oil to the NK-1 receptor antagonist ranges from about 5:1 to 15:1 (wt/wt %). 7. The method according to claim 6, wherein the ratio of the oil to the NK-1 receptor antagonist ranges from about 10:1 to 15:1 (wt/wt %). 8. The method according to claim 1, wherein the ratio of emulsifier to oil ranges from about 1:1 to 3:1 (wt/wt %). 9. The method according to claim 1, wherein the emulsifier is a phospholipid. 10. The method according to claim 1, wherein the emulsifier is an egg lecithin. 11. The method according to claim 1, further comprising dexamethasone sodium phosphate, wherein the dexamethasone sodium phosphate is present in the aqueous phase. 12. The method according to claim 1, wherein the NK-1 receptor antagonist is selected from the group consisting of aprepitant, rolapitant, netupitant, ezlopitant, vestipitant, serlopitant, maropitant, casopitant, befetupitant, and orvepitant, or a pharmaceutically acceptable salt thereof. 13. The method according to claim 12, wherein the NK-1 receptor antagonist is not aprepitant. 14. The method according to claim 1, wherein the pH modifier is sodium oleate or a salt thereof. 15. The method according to claim 1, wherein the pH modifier is a buffer. 16. The method according to claim 15, wherein the buffer is Tris buffer. 17. The method according to claim 1, wherein the oil is soybean oil. 18. The method according to claim 1, wherein the alcohol is ethanol. 19. The method according to 18, wherein the ethanol is present in the emulsion at less than 10 wt/wt %. 20. The method according to claim 1, wherein the NK-1 receptor antagonist is aprepitant. 21. The method according to claim 1, wherein the single dose of the emulsion has a volume of about 18 mL and comprises about 130 mg NK-1 receptor antagonist or the single dose of the emulsion has a volume of about 14 mL and comprises about 100 mg NK-1 receptor antagonist. 22. The method of claim 21, wherein the ratio of the emulsifier to the NK-1 receptor antagonist is about 20:1 (wt/wt %). 23. The method of claim 21, wherein the single dose of the emulsion has a volume of about 18 mL and comprises the NK-1 receptor antagonist (about 130 mg), the emulsifier (about 2.6 g), the co-surfactant (about 0.5 g), the pH modifier (about 0.1 g), the oil (about 1.7 g), the tonicity agent (about 1 g), and water (about 12 g). 24. The method of claim 21, wherein the single dose of the emulsion has a volume of about 14 mL and comprises the NK-1 receptor antagonist (about 100 mg), the emulsifier (about 2 g), the co-surfactant (about 0.4 g), the pH modifier (about 0.08 g), the oil (about 1.3 g), the tonicity agent (about 0.8 g), and water (about 9 g). 25. The method of claim 21, wherein the NK-1 receptor antagonist is aprepitant. 26. The method of claim 23, wherein the NK-1 receptor antagonist is aprepitant, the emulsifier is egg lecithin, the co-surfactant is ethanol, the pH modifier is sodium oleate, the oil is soybean oil and the tonicity agent is sucrose. 27. The method according to claim 1, wherein the subject is at risk of or is suffering from nausea and/or vomiting and is need of treatment for nausea and/or vomiting. 28. The method according to claim 27, wherein the nausea and/or vomiting is induced by chemotherapy, surgery, or radiotherapy. 29. The method of claim 28, wherein the nausea and/or vomiting is associated with highly emetogenic cancer chemotherapy. 30. The method of claim 28, wherein the nausea and/or vomiting is associated with moderately emetogenic cancer chemotherapy. | 1,600 |
1,180 | 11,503,418 | 1,618 | In one embodiment, a composition comprises a microparticle including a radioactive isotope and an imageable element. In another embodiment, a method includes forming a microparticle including a target isotope and an enriched paramagnetic isotope, and transforming the target isotope into a radioactive isotope. In yet another embodiment, an apparatus includes an imaging system to image a subject; and a radioactive microparticle suitable for infusion into the subject for imaging by the imaging system and including an enriched paramagnetic isotope that is enriched to reduce generation of radioactive impurities while maintaining or improving imaging sensitivity. | 1. A composition comprising
a microparticle including a radioactive isotope and an imageable element. 2. The composition of claim 1, wherein the imageable element comprises a paramagnetic material. 3. The composition of claim 1, wherein the imageable element comprises an enriched paramagnetic isotope. 4. The composition of claim 3, wherein the enriched paramagnetic isotope is enriched to a concentration after enrichment of at least about 90%. 5. The composition of claim 1, wherein the imageable element comprises a radiopaque material. 6. The composition of claim 5, wherein the radiopaque material comprises enriched Pb-206. 7. The composition of claim 1, wherein the microparticle comprises a microsphere. 8. The composition of claim 7, wherein the radioactive isotope comprises Y-90. 9. The composition of claim 8, wherein the enriched paramagnetic isotope comprises Fe-57. 10. A composition comprising:
a material including a radioactive isotope; and a dopant included in the material, the dopant including an enriched paramagnetic isotope. 11. The composition of claim 10, wherein the material comprises a solid. 12. The composition of claim 11, wherein the enriched paramagnetic isotope comprises Gd-155. 13. The composition of claim 10, wherein the material comprises a liquid. 14. The composition of claim 10, wherein the material comprises a gas. 15. The composition of claim 14, wherein the enriched paramagnetic isotope comprises O-17. 16. A method comprising:
forming a microparticle including a target isotope and an enriched paramagnetic isotope; and transforming the target isotope into a radioactive isotope. 17. The method of claim 16, wherein forming the microparticle including the target isotope and the enriched paramagnetic isotope comprises:
forming the enriched paramagnetic isotope on a surface of the microparticle. 18. The method of claim 16, wherein forming the microparticle including the target isotope and the enriched paramagnetic isotope comprises:
enriching the enriched paramagnetic isotope to a concentration of at least about 90%. 19. The method of claim 16, wherein transforming the target isotope into the radioactive isotope comprises:
transforming the target isotope into the radioactive isotope without forming a substantial number of undesired isotopes. 20. The method of claim 16, further comprising:
infusing the microparticle into living tissue to form a distribution of microparticles in the living tissue; and imaging the hydrogen near the microparticles. 21. A method comprising:
forming a microparticle including Y-89; doping the microparticle with an enriched paramagnetic isotope; and transforming the Y-89 into Y-90. 22. The method of claim 21, further comprising:
infusing the microparticle into living tissue to form a distribution of microparticles in the living tissue; and imaging the distribution of microparticles to provide information for analyzing the distribution of the microparticles. 23. The method of claim 22, wherein imaging the distribution of microparticles to provide information for analyzing the distribution of the microparticles comprises:
using magnetic resonance imaging (MRI) to image the distribution of microparticles. 24. A method, comprising:
selecting a paramagnetic material that requires more than one neutron capture to create a radioactive impurity; selecting a material that activates as a result of nuclear particle absorption before the paramagnetic material acquires two neutrons; and forming a composition including the material and the paramagnetic material. 25. The method of claim 24, further comprising:
introducing the composition into a subject. 26. The method of claim 25, further comprising:
forming an image of the composition and the subject by magnetic resonance imaging (MRI). 27. The method of claim 25, further comprising:
forming and analyzing an image of the composition to determine whether a disease is present in the subject. 28. The method of claim 24, further comprising:
treating a disease with the composition; and forming an image of the composition using an imaging system. 29. The method of claim 24, wherein forming the composition including the material and the paramagnetic material comprises:
activating the composition through nuclear particle absorption. 30. An apparatus comprising:
an imaging system to image a subject; and a radioactive microparticle suitable for infusion into the subject for imaging by the imaging system and including an enriched paramagnetic isotope that is enriched to reduce generation of radioactive impurities while maintaining or improving imaging sensitivity. 31. The apparatus of claim 30, wherein the imaging system comprises a magnetic resonance imaging (MRI) system. 32. The apparatus of claim 30, wherein the enriched paramagnetic isotope comprises:
a material capable of neutron activation having a first neutron absorption cross-section; and a paramagnetic isotope having a second neutron absorption cross-section within a factor of about 1000 of the first neutron absorption cross-section and which requires more than one neutron capture to create a radioactive impurity. 33. A method comprising:
forming a radioactive material including a detectable element; infusing the radioactive material including the detectable element into a subject; and treating a disease in the subject with radiation emitted from the radioactive material and substantially simultaneously imaging the detectable element. 34. The method of claim 33, wherein forming the radioactive material including the detectable element comprises:
forming the radioactive material through activation by nuclear particle absorption. 35. The method of claim 34, wherein forming the radioactive material through activation by nuclear particle absorption comprises:
forming the radioactive material by absorption of neutrons, protons, particles heavier than protons, deuterium+, tritium+, or helium++. 36. The method of claim 34, wherein imaging the detectable element comprises:
imaging the detectable element using computer-aided tomography (CT). 37. The method of claim 34, wherein imaging the detectable element comprises:
imaging the detectable element using fluoroscopy. 38. The method of claim 34, wherein imaging the detectable element comprises:
imaging the detectable element using positron emission tomography (PET). 39. The method of claim 33, wherein infusing the radioactive material including the paramagnetic isotope into the subject having the disease comprises:
infusing the radioactive material including the paramagnetic isotope into a living animal. 40. A method comprising:
forming a radioactive material including a detectable element; infusing the radioactive material including the detectable element into a subject; and analyzing a disease state in the subject through the substantially simultaneous use of a plurality of imaging systems. 41. The method of claim 40, wherein forming the radioactive material including the detectable element comprises:
forming the radioactive material through activation by nuclear particle absorption of a target material including the detectable element. 42. A method comprising:
forming a radioactive material including an enriched paramagnetic isotope; infusing the radioactive material including the enriched paramagnetic isotope into a subject; and analyzing a disease state in the subject through the substantially simultaneous use of a plurality of imaging systems. 43. The method of claim 42, wherein forming the radioactive material including the paramagnetic isotope comprises:
forming the radioactive material through activation by nuclear particle absorption. 44. The method of claim 42, wherein infusing the radioactive material including the paramagnetic isotope into the subject comprises:
delivering the radioactive material including the paramagnetic isotope in the form of one or more microspheres to the subject where the subject includes a mammal. 45. The method of claim 42, wherein analyzing the disease state in the subject through the substantially simultaneous imaging using a plurality of imaging systems comprises:
analyzing the disease state using a magnetic resonance imaging and single photon emission computed tomography (SPECT). 46. An apparatus comprising:
an imaging system to image a subject; and a microparticle suitable for infusion into the subject for imaging by the imaging system and including an enriched paramagnetic isotope that is enriched to reduce generation of radioactive impurities while maintaining or improving imaging sensitivity. 47. The apparatus of claim 46, wherein the imaging system comprises a magnetic resonance imaging (MRI) system. 48. The apparatus of claim 46, wherein the microparticle comprises:
a material capable of neutron activation having a first neutron absorption cross-section; and a paramagnetic isotope having a second neutron absorption cross-section within a factor of about 1000 of the first neutron absorption cross-section and which requires more than one neutron capture to create a radioactive impurity. 49. A composition comprising:
a microparticle including Y-90 and an enriched paramagnetic material Fe-57. 50. The composition of claim 49, wherein the microparticle comprises a microsphere. | In one embodiment, a composition comprises a microparticle including a radioactive isotope and an imageable element. In another embodiment, a method includes forming a microparticle including a target isotope and an enriched paramagnetic isotope, and transforming the target isotope into a radioactive isotope. In yet another embodiment, an apparatus includes an imaging system to image a subject; and a radioactive microparticle suitable for infusion into the subject for imaging by the imaging system and including an enriched paramagnetic isotope that is enriched to reduce generation of radioactive impurities while maintaining or improving imaging sensitivity.1. A composition comprising
a microparticle including a radioactive isotope and an imageable element. 2. The composition of claim 1, wherein the imageable element comprises a paramagnetic material. 3. The composition of claim 1, wherein the imageable element comprises an enriched paramagnetic isotope. 4. The composition of claim 3, wherein the enriched paramagnetic isotope is enriched to a concentration after enrichment of at least about 90%. 5. The composition of claim 1, wherein the imageable element comprises a radiopaque material. 6. The composition of claim 5, wherein the radiopaque material comprises enriched Pb-206. 7. The composition of claim 1, wherein the microparticle comprises a microsphere. 8. The composition of claim 7, wherein the radioactive isotope comprises Y-90. 9. The composition of claim 8, wherein the enriched paramagnetic isotope comprises Fe-57. 10. A composition comprising:
a material including a radioactive isotope; and a dopant included in the material, the dopant including an enriched paramagnetic isotope. 11. The composition of claim 10, wherein the material comprises a solid. 12. The composition of claim 11, wherein the enriched paramagnetic isotope comprises Gd-155. 13. The composition of claim 10, wherein the material comprises a liquid. 14. The composition of claim 10, wherein the material comprises a gas. 15. The composition of claim 14, wherein the enriched paramagnetic isotope comprises O-17. 16. A method comprising:
forming a microparticle including a target isotope and an enriched paramagnetic isotope; and transforming the target isotope into a radioactive isotope. 17. The method of claim 16, wherein forming the microparticle including the target isotope and the enriched paramagnetic isotope comprises:
forming the enriched paramagnetic isotope on a surface of the microparticle. 18. The method of claim 16, wherein forming the microparticle including the target isotope and the enriched paramagnetic isotope comprises:
enriching the enriched paramagnetic isotope to a concentration of at least about 90%. 19. The method of claim 16, wherein transforming the target isotope into the radioactive isotope comprises:
transforming the target isotope into the radioactive isotope without forming a substantial number of undesired isotopes. 20. The method of claim 16, further comprising:
infusing the microparticle into living tissue to form a distribution of microparticles in the living tissue; and imaging the hydrogen near the microparticles. 21. A method comprising:
forming a microparticle including Y-89; doping the microparticle with an enriched paramagnetic isotope; and transforming the Y-89 into Y-90. 22. The method of claim 21, further comprising:
infusing the microparticle into living tissue to form a distribution of microparticles in the living tissue; and imaging the distribution of microparticles to provide information for analyzing the distribution of the microparticles. 23. The method of claim 22, wherein imaging the distribution of microparticles to provide information for analyzing the distribution of the microparticles comprises:
using magnetic resonance imaging (MRI) to image the distribution of microparticles. 24. A method, comprising:
selecting a paramagnetic material that requires more than one neutron capture to create a radioactive impurity; selecting a material that activates as a result of nuclear particle absorption before the paramagnetic material acquires two neutrons; and forming a composition including the material and the paramagnetic material. 25. The method of claim 24, further comprising:
introducing the composition into a subject. 26. The method of claim 25, further comprising:
forming an image of the composition and the subject by magnetic resonance imaging (MRI). 27. The method of claim 25, further comprising:
forming and analyzing an image of the composition to determine whether a disease is present in the subject. 28. The method of claim 24, further comprising:
treating a disease with the composition; and forming an image of the composition using an imaging system. 29. The method of claim 24, wherein forming the composition including the material and the paramagnetic material comprises:
activating the composition through nuclear particle absorption. 30. An apparatus comprising:
an imaging system to image a subject; and a radioactive microparticle suitable for infusion into the subject for imaging by the imaging system and including an enriched paramagnetic isotope that is enriched to reduce generation of radioactive impurities while maintaining or improving imaging sensitivity. 31. The apparatus of claim 30, wherein the imaging system comprises a magnetic resonance imaging (MRI) system. 32. The apparatus of claim 30, wherein the enriched paramagnetic isotope comprises:
a material capable of neutron activation having a first neutron absorption cross-section; and a paramagnetic isotope having a second neutron absorption cross-section within a factor of about 1000 of the first neutron absorption cross-section and which requires more than one neutron capture to create a radioactive impurity. 33. A method comprising:
forming a radioactive material including a detectable element; infusing the radioactive material including the detectable element into a subject; and treating a disease in the subject with radiation emitted from the radioactive material and substantially simultaneously imaging the detectable element. 34. The method of claim 33, wherein forming the radioactive material including the detectable element comprises:
forming the radioactive material through activation by nuclear particle absorption. 35. The method of claim 34, wherein forming the radioactive material through activation by nuclear particle absorption comprises:
forming the radioactive material by absorption of neutrons, protons, particles heavier than protons, deuterium+, tritium+, or helium++. 36. The method of claim 34, wherein imaging the detectable element comprises:
imaging the detectable element using computer-aided tomography (CT). 37. The method of claim 34, wherein imaging the detectable element comprises:
imaging the detectable element using fluoroscopy. 38. The method of claim 34, wherein imaging the detectable element comprises:
imaging the detectable element using positron emission tomography (PET). 39. The method of claim 33, wherein infusing the radioactive material including the paramagnetic isotope into the subject having the disease comprises:
infusing the radioactive material including the paramagnetic isotope into a living animal. 40. A method comprising:
forming a radioactive material including a detectable element; infusing the radioactive material including the detectable element into a subject; and analyzing a disease state in the subject through the substantially simultaneous use of a plurality of imaging systems. 41. The method of claim 40, wherein forming the radioactive material including the detectable element comprises:
forming the radioactive material through activation by nuclear particle absorption of a target material including the detectable element. 42. A method comprising:
forming a radioactive material including an enriched paramagnetic isotope; infusing the radioactive material including the enriched paramagnetic isotope into a subject; and analyzing a disease state in the subject through the substantially simultaneous use of a plurality of imaging systems. 43. The method of claim 42, wherein forming the radioactive material including the paramagnetic isotope comprises:
forming the radioactive material through activation by nuclear particle absorption. 44. The method of claim 42, wherein infusing the radioactive material including the paramagnetic isotope into the subject comprises:
delivering the radioactive material including the paramagnetic isotope in the form of one or more microspheres to the subject where the subject includes a mammal. 45. The method of claim 42, wherein analyzing the disease state in the subject through the substantially simultaneous imaging using a plurality of imaging systems comprises:
analyzing the disease state using a magnetic resonance imaging and single photon emission computed tomography (SPECT). 46. An apparatus comprising:
an imaging system to image a subject; and a microparticle suitable for infusion into the subject for imaging by the imaging system and including an enriched paramagnetic isotope that is enriched to reduce generation of radioactive impurities while maintaining or improving imaging sensitivity. 47. The apparatus of claim 46, wherein the imaging system comprises a magnetic resonance imaging (MRI) system. 48. The apparatus of claim 46, wherein the microparticle comprises:
a material capable of neutron activation having a first neutron absorption cross-section; and a paramagnetic isotope having a second neutron absorption cross-section within a factor of about 1000 of the first neutron absorption cross-section and which requires more than one neutron capture to create a radioactive impurity. 49. A composition comprising:
a microparticle including Y-90 and an enriched paramagnetic material Fe-57. 50. The composition of claim 49, wherein the microparticle comprises a microsphere. | 1,600 |
1,181 | 14,636,729 | 1,619 | The invention relates to cleaning and food processing aide applications whereby unique compositions of GRAS or food additives were developed to assess the effectiveness of cleaning procedures at various stages of the processes and to assess the delivery and adherence of food processing aides. Employing such solutions to clean and/or sanitize processing equipment provides a method to evaluate and enhance the effectiveness of procedures used to remove the respective fluorescent detergents, sanitizers or organic residues from equipment or niches and reduce contamination. Similar compositions were developed for assessing processing aide food surface coverage, contact time and adherence. In addition, unique compositions were invented that increase processing aide coverage and adherence. Quantification of the presence or absence of the fluorescent GRAS or food additive compositions produces results for validation, monitoring and/or verification of food safety intervention procedures/processes. | 1-3. (canceled) 4. A method of processing a food, an animal hide or a hard surface comprising the steps of:
applying a composition to a surface of the food, the animal hide or the hard surface; and visually inspecting the surface of the food, the animal hide or the hard surface under ultraviolet light to detect fluorescence where the composition was applied on the surface, the composition comprising a food-grade anionic surfactant or a food-grade fatty acid mono- or di-glyceride; a food-grade fluorescent tracer; a food-grade organic acid or salt thereof; and a carrier; wherein the composition is a solution having a pH ranging from 1 to 7, and the ratio of the anionic surfactant to the fluorescent tracer ranges from 1:1 to 200:1, or the ratio of the fatty acid mono- or di-glyceride to the fluorescent tracer ranges from 1:2 to 200:1. 5. The method of claim 4 further comprising the step of applying the composition to a portion of the exterior surface of the food or the animal hide if fluorescence was not detected on that portion of the exterior surface. 6. The method of claim 4 wherein the method is used in processing food and the food comprises meat, poultry, fruit, or a vegetable. 7. The method of claim 4 wherein the composition is applied to the exterior surface of the food by spray, waterfall drench, flume drench, or moat drench. 8. The method of claim 4 comprising the fatty acid monoglyceride, the fatty acid monoglyceride comprising glycerol monolaurate (monolaurin). 9. The method of claim 4 comprising the food-grade anionic surfactant, the food-grade anionic surfactant comprising sodium lauryl sulfate. 10. The method of claim 4 comprising the food-grade fatty acid mono- or di-glyceride, wherein the food-grade fluorescent tracer comprises riboflavin. 11. The method of claim 4 comprising the food-grade fatty acid mono- or di-glyceride, wherein the food-grade organic acid comprises citric acid, tartaric acid, fumaric acid, ascorbic acid, lactic acid, peroxyacetic acid, or a salt or mixture thereof. 12. The method of claim 4 wherein the carrier comprises water, propylene glycol, or a mixture thereof. 13. The method of claim 4 comprising the food-grade fatty acid mono- or di-glyceride, wherein the pH ranges from 1 to 4. 14. The method of claim 4 further comprising a cationic surfactant. 15. The method of claim 14 wherein the cationic surfactant comprises lauric arginate. 16. The method of claim 10 further comprising folic acid in a ratio of the anionic surfactant to folic acid ranging from 2:1 to 400:1 or in a ratio of the fatty acid mono- or di-glyceride to folic acid ranging from 1:1 to 400:1. 17. The method of claim 10 further comprising quinine in a ratio of the anionic surfactant to quinine ranging from 2:1 to 250:1 or in a ratio of the fatty acid mono- or di-glyceride to quinine ranging from 1:1 to 250:1. 18. The method of claim 4 further comprising a cleaning agent. 19. The method of claim 18 wherein the cleaning agent is a liquid soap, a detergent, a quaternary ammonium sanitizer, or a chlorinated alkaline compound. 20. The method of claim 4 wherein the composition, when applied to a surface in an amount containing 100 ppm of the fluorescent tracer, has greater adherence to the surface and covers a greater area of the surface than the same amount of the same composition which does not contain the food-grade fatty acid mono- or di-glyceride. 21. The method of claim 4 wherein the composition, when applied to a surface in an amount containing 50 ppm of the fluorescent tracer, has greater adherence to the surface and covers a greater area of the surface than the same amount of the same composition which does not contain the food-grade fatty acid mono- or di-glyceride. 22. The method of claim 4 wherein the composition, when applied to a surface in an amount containing 1 ppm of the fluorescent tracer, has greater adherence to the surface and covers a greater area of the surface than the same amount of the same composition which does not contain the food-grade fatty acid mono- or di-glyceride. 23. The method of claim 4 wherein the composition is applied to the hard surface to form a treated surface which is visually inspected under ultraviolet light to detect fluorescence on a portion of the treated surface where contamination remains, and the method further comprises the steps of:
rinsing the treated surface;
cleaning the portion of the treated surface where contamination was detected;
reapplying the composition to the portion of the treated surface if contamination was detected; and
repeating the visually inspecting, rinsing, cleaning, and reapplying steps until no fluorescence is detected on the surface. | The invention relates to cleaning and food processing aide applications whereby unique compositions of GRAS or food additives were developed to assess the effectiveness of cleaning procedures at various stages of the processes and to assess the delivery and adherence of food processing aides. Employing such solutions to clean and/or sanitize processing equipment provides a method to evaluate and enhance the effectiveness of procedures used to remove the respective fluorescent detergents, sanitizers or organic residues from equipment or niches and reduce contamination. Similar compositions were developed for assessing processing aide food surface coverage, contact time and adherence. In addition, unique compositions were invented that increase processing aide coverage and adherence. Quantification of the presence or absence of the fluorescent GRAS or food additive compositions produces results for validation, monitoring and/or verification of food safety intervention procedures/processes.1-3. (canceled) 4. A method of processing a food, an animal hide or a hard surface comprising the steps of:
applying a composition to a surface of the food, the animal hide or the hard surface; and visually inspecting the surface of the food, the animal hide or the hard surface under ultraviolet light to detect fluorescence where the composition was applied on the surface, the composition comprising a food-grade anionic surfactant or a food-grade fatty acid mono- or di-glyceride; a food-grade fluorescent tracer; a food-grade organic acid or salt thereof; and a carrier; wherein the composition is a solution having a pH ranging from 1 to 7, and the ratio of the anionic surfactant to the fluorescent tracer ranges from 1:1 to 200:1, or the ratio of the fatty acid mono- or di-glyceride to the fluorescent tracer ranges from 1:2 to 200:1. 5. The method of claim 4 further comprising the step of applying the composition to a portion of the exterior surface of the food or the animal hide if fluorescence was not detected on that portion of the exterior surface. 6. The method of claim 4 wherein the method is used in processing food and the food comprises meat, poultry, fruit, or a vegetable. 7. The method of claim 4 wherein the composition is applied to the exterior surface of the food by spray, waterfall drench, flume drench, or moat drench. 8. The method of claim 4 comprising the fatty acid monoglyceride, the fatty acid monoglyceride comprising glycerol monolaurate (monolaurin). 9. The method of claim 4 comprising the food-grade anionic surfactant, the food-grade anionic surfactant comprising sodium lauryl sulfate. 10. The method of claim 4 comprising the food-grade fatty acid mono- or di-glyceride, wherein the food-grade fluorescent tracer comprises riboflavin. 11. The method of claim 4 comprising the food-grade fatty acid mono- or di-glyceride, wherein the food-grade organic acid comprises citric acid, tartaric acid, fumaric acid, ascorbic acid, lactic acid, peroxyacetic acid, or a salt or mixture thereof. 12. The method of claim 4 wherein the carrier comprises water, propylene glycol, or a mixture thereof. 13. The method of claim 4 comprising the food-grade fatty acid mono- or di-glyceride, wherein the pH ranges from 1 to 4. 14. The method of claim 4 further comprising a cationic surfactant. 15. The method of claim 14 wherein the cationic surfactant comprises lauric arginate. 16. The method of claim 10 further comprising folic acid in a ratio of the anionic surfactant to folic acid ranging from 2:1 to 400:1 or in a ratio of the fatty acid mono- or di-glyceride to folic acid ranging from 1:1 to 400:1. 17. The method of claim 10 further comprising quinine in a ratio of the anionic surfactant to quinine ranging from 2:1 to 250:1 or in a ratio of the fatty acid mono- or di-glyceride to quinine ranging from 1:1 to 250:1. 18. The method of claim 4 further comprising a cleaning agent. 19. The method of claim 18 wherein the cleaning agent is a liquid soap, a detergent, a quaternary ammonium sanitizer, or a chlorinated alkaline compound. 20. The method of claim 4 wherein the composition, when applied to a surface in an amount containing 100 ppm of the fluorescent tracer, has greater adherence to the surface and covers a greater area of the surface than the same amount of the same composition which does not contain the food-grade fatty acid mono- or di-glyceride. 21. The method of claim 4 wherein the composition, when applied to a surface in an amount containing 50 ppm of the fluorescent tracer, has greater adherence to the surface and covers a greater area of the surface than the same amount of the same composition which does not contain the food-grade fatty acid mono- or di-glyceride. 22. The method of claim 4 wherein the composition, when applied to a surface in an amount containing 1 ppm of the fluorescent tracer, has greater adherence to the surface and covers a greater area of the surface than the same amount of the same composition which does not contain the food-grade fatty acid mono- or di-glyceride. 23. The method of claim 4 wherein the composition is applied to the hard surface to form a treated surface which is visually inspected under ultraviolet light to detect fluorescence on a portion of the treated surface where contamination remains, and the method further comprises the steps of:
rinsing the treated surface;
cleaning the portion of the treated surface where contamination was detected;
reapplying the composition to the portion of the treated surface if contamination was detected; and
repeating the visually inspecting, rinsing, cleaning, and reapplying steps until no fluorescence is detected on the surface. | 1,600 |
1,182 | 12,253,943 | 1,653 | A unique, innovative, and efficient system in order to convert ferulic acid into vanillin which involves the immobilization of actinomycetes in an effective solid support structure which is comprised of one or more pieces of a material, that is configured so as to allow effective aeration.
For the immobilization of actinomycetes a surface culture is employed in which these microorganisms develop a mycelial growth pattern and adhere to the solid support structure. The use of surface culture also allows us to benefit from enhanced physiological responses such as increased growth rates and production yields of the actinomycetes when they are cultivated in this surface culture.
Since the microorganisms are held captive in the supports, the step of biocatalysis can be repeated up to 15 times before the biocatalytic capacity is lost. An evaluation of the whole transformation process results in a higher vanillin yield. | 1. A biotransformation process to produce vanillin from cinnamic acid derivatives which is comprised of the following steps:
(a) immobilizing a microorganism from the actinomycetales group in an effective solid support structure, said solid support structure comprising one or more pieces of a material which is effectively inert, porous, absorbent and compressible, said material configured so as to allow effective aeration (b) eliminating any excess liquid resulting from step (a) (c) adding a solution comprised of one or more cinnamic acid derivatives or optionally their salts (d) incubating for a period of time to allow a biotransformative reaction to produce a biotransformation solution (e) collecting said biotransformation solution by using a force to compress some or all of said plurality of pieces of material containing immobilized microorganisms; and thereby producing vanillin 2. The biotransformation process in accordance with claim 1, wherein step (a) is comprised of the following actions:
(f) Adding an inoculum of said microorganisms to a liquid culture broth; (g) Add the resulting inoculated culture broth to said solid support structure (h) Growing said microorganism in said solid support structure 3. The process of biotransformation of claim 1 wherein said microorganism is Streptomyces 3a. The process of biotransformation of claim 2 wherein said microorganism is Streptomyces 4. The process of biotransformation of claim 3 wherein said microorganism is the particular strain Streptomyces setonii strain defined as ATCC 39116 4a. The process of biotransformation of claim 3a wherein said microorganism is the particular strain Streptomyces setonii strain defined as ATCC 39116 5. The process of biotransformation of claim 2 action (f) uses an amount of inoculum such that inoculum comprises 3% to 6% of the total volume 6. The process of biotransformation of claim 2 wherein said liquid culture broth is comprised of the following in accordance with claim 2, is characterized by the fact that the liquid culture broth is comprised of the following:
one or more sugars in a concentration ranging between 8 to 40 gl−1;
complex nitrogen sources in a concentration ranging between 1 to 15 gl−1. 7. The process of biotransformation of claim 1 wherein said solid support structure is comprised of polyurethane foam of an effective density 7a. The process of biotransformation of claim 2 wherein said solid support structure is comprised of polyurethane foam of an effective density 8. The process of biotransformation of claim 2 wherein the volume of said inoculated culture broth that is added is 5 to 50 ml per gram of solid support structure 9. The process of biotransformation in accordance with claim 1, is characterized by the fact that steps (b) of eliminating the residual culture broth is carried out by applying a force to some or all of said plurality of pieces of material containing immobilized microorganisms. The force types are:
(a) compressing (b) squeezing (c) squishing (d) wringing (e) centrifugation (f) vacuuming 9a. The process of biotransformation in accordance with claim 1, is characterized by the fact that step (e) of eliminating the residual culture broth is carried out by applying a force to some or all of said plurality of pieces of material containing immobilized microorganisms. The force types are:
(a) compressing (b) squeezing (c) squishing (d) wringing (e) centrifugation (f) vacuuming 10. The process of biotransformation in accordance with claim 1, action (c), is characterized by the fact that the cinnamic acid derivatives are ferulic acid or of some of the ferulic salts in solution, having a concentration ranging from 5 to 30 gl−1 11. The process of biotransformation in accordance with claim 1, is characterized by the fact that the solution of ferulic acid or of some of the ferulic salts from step (b) have a pH between 7 and 9 12. The process of biotransformation in accordance with claim 1, is characterized by the fact that the incubation period for the reaction of the biotransformation from action (d) is from 7 to 48 hours 13. The process of biotransformation in accordance with claim 1, is characterized by the fact that the actions (c), (d) and (e) can repeated up to 15 times 14. A biotransformation process to produce vanillin from cynammic acid derivatives which is comprised of the following steps:
(a) adding a solution comprised of one or more cinnamic acid derivatives or optionally their salts to a solid support structure having a microorganism from the actinomycetales group locked into it, said solid support structure comprising one or more pieces of a material which is effectively inert, porous, absorbent and compressible, said material configured so as to allow effective aeration (b) incubating for a period of time to allow a biotransformative reaction to produce a biotransformation solution (c) collecting said biotransformation solution by using a force to compress some or all of said plurality of pieces of material containing immobilized microorganisms; and thereby producing vanillin 15. The process of biotransformation in accordance with claim 14, is characterized by the fact that can repeated up to 15 times | A unique, innovative, and efficient system in order to convert ferulic acid into vanillin which involves the immobilization of actinomycetes in an effective solid support structure which is comprised of one or more pieces of a material, that is configured so as to allow effective aeration.
For the immobilization of actinomycetes a surface culture is employed in which these microorganisms develop a mycelial growth pattern and adhere to the solid support structure. The use of surface culture also allows us to benefit from enhanced physiological responses such as increased growth rates and production yields of the actinomycetes when they are cultivated in this surface culture.
Since the microorganisms are held captive in the supports, the step of biocatalysis can be repeated up to 15 times before the biocatalytic capacity is lost. An evaluation of the whole transformation process results in a higher vanillin yield.1. A biotransformation process to produce vanillin from cinnamic acid derivatives which is comprised of the following steps:
(a) immobilizing a microorganism from the actinomycetales group in an effective solid support structure, said solid support structure comprising one or more pieces of a material which is effectively inert, porous, absorbent and compressible, said material configured so as to allow effective aeration (b) eliminating any excess liquid resulting from step (a) (c) adding a solution comprised of one or more cinnamic acid derivatives or optionally their salts (d) incubating for a period of time to allow a biotransformative reaction to produce a biotransformation solution (e) collecting said biotransformation solution by using a force to compress some or all of said plurality of pieces of material containing immobilized microorganisms; and thereby producing vanillin 2. The biotransformation process in accordance with claim 1, wherein step (a) is comprised of the following actions:
(f) Adding an inoculum of said microorganisms to a liquid culture broth; (g) Add the resulting inoculated culture broth to said solid support structure (h) Growing said microorganism in said solid support structure 3. The process of biotransformation of claim 1 wherein said microorganism is Streptomyces 3a. The process of biotransformation of claim 2 wherein said microorganism is Streptomyces 4. The process of biotransformation of claim 3 wherein said microorganism is the particular strain Streptomyces setonii strain defined as ATCC 39116 4a. The process of biotransformation of claim 3a wherein said microorganism is the particular strain Streptomyces setonii strain defined as ATCC 39116 5. The process of biotransformation of claim 2 action (f) uses an amount of inoculum such that inoculum comprises 3% to 6% of the total volume 6. The process of biotransformation of claim 2 wherein said liquid culture broth is comprised of the following in accordance with claim 2, is characterized by the fact that the liquid culture broth is comprised of the following:
one or more sugars in a concentration ranging between 8 to 40 gl−1;
complex nitrogen sources in a concentration ranging between 1 to 15 gl−1. 7. The process of biotransformation of claim 1 wherein said solid support structure is comprised of polyurethane foam of an effective density 7a. The process of biotransformation of claim 2 wherein said solid support structure is comprised of polyurethane foam of an effective density 8. The process of biotransformation of claim 2 wherein the volume of said inoculated culture broth that is added is 5 to 50 ml per gram of solid support structure 9. The process of biotransformation in accordance with claim 1, is characterized by the fact that steps (b) of eliminating the residual culture broth is carried out by applying a force to some or all of said plurality of pieces of material containing immobilized microorganisms. The force types are:
(a) compressing (b) squeezing (c) squishing (d) wringing (e) centrifugation (f) vacuuming 9a. The process of biotransformation in accordance with claim 1, is characterized by the fact that step (e) of eliminating the residual culture broth is carried out by applying a force to some or all of said plurality of pieces of material containing immobilized microorganisms. The force types are:
(a) compressing (b) squeezing (c) squishing (d) wringing (e) centrifugation (f) vacuuming 10. The process of biotransformation in accordance with claim 1, action (c), is characterized by the fact that the cinnamic acid derivatives are ferulic acid or of some of the ferulic salts in solution, having a concentration ranging from 5 to 30 gl−1 11. The process of biotransformation in accordance with claim 1, is characterized by the fact that the solution of ferulic acid or of some of the ferulic salts from step (b) have a pH between 7 and 9 12. The process of biotransformation in accordance with claim 1, is characterized by the fact that the incubation period for the reaction of the biotransformation from action (d) is from 7 to 48 hours 13. The process of biotransformation in accordance with claim 1, is characterized by the fact that the actions (c), (d) and (e) can repeated up to 15 times 14. A biotransformation process to produce vanillin from cynammic acid derivatives which is comprised of the following steps:
(a) adding a solution comprised of one or more cinnamic acid derivatives or optionally their salts to a solid support structure having a microorganism from the actinomycetales group locked into it, said solid support structure comprising one or more pieces of a material which is effectively inert, porous, absorbent and compressible, said material configured so as to allow effective aeration (b) incubating for a period of time to allow a biotransformative reaction to produce a biotransformation solution (c) collecting said biotransformation solution by using a force to compress some or all of said plurality of pieces of material containing immobilized microorganisms; and thereby producing vanillin 15. The process of biotransformation in accordance with claim 14, is characterized by the fact that can repeated up to 15 times | 1,600 |
1,183 | 16,291,297 | 1,613 | The present invention provides a composition comprising a high load of metal oxides that is phase stable and sprayable. It comprises a branched hydrophobically modified ethoxylated urethane copolymer and a hydrophobically modified alkali swellable emulsion copolymer comprising of one or more acrylate monomers and an ethoxylated associative comonomer. | 1.-10. (canceled) 11. A composition comprising at least about 10 weight percent of a metal oxide having a viscosity less than 50,000 cP within a shear rate rage of 0.01 to 0.1 s−1, and a loss tangent greater than 2.5 in an angular frequency range of 0.1 to 1 rad/s. 12. The composition of claim 11, wherein the metal oxide is selected from the group consisting of zinc oxide, titanium dioxide and mixtures thereof. 13. The composition of claim 11, wherein the metal oxide comprises zinc oxide. 14. The composition of claim 13, wherein the zinc oxide comprises coated particles. 15. The composition of claim 11 comprising a branched hydrophobically modified ethoxylated urethane copolymer. 16. The composition of claim 11 comprising a hydrophobically modified alkali swellable emulsion copolymer. 17. The composition of claim 11 substantially free of organic UV filters. 18. The composition of claim 11 comprising an organic UV filter. 19.-20. (canceled) | The present invention provides a composition comprising a high load of metal oxides that is phase stable and sprayable. It comprises a branched hydrophobically modified ethoxylated urethane copolymer and a hydrophobically modified alkali swellable emulsion copolymer comprising of one or more acrylate monomers and an ethoxylated associative comonomer.1.-10. (canceled) 11. A composition comprising at least about 10 weight percent of a metal oxide having a viscosity less than 50,000 cP within a shear rate rage of 0.01 to 0.1 s−1, and a loss tangent greater than 2.5 in an angular frequency range of 0.1 to 1 rad/s. 12. The composition of claim 11, wherein the metal oxide is selected from the group consisting of zinc oxide, titanium dioxide and mixtures thereof. 13. The composition of claim 11, wherein the metal oxide comprises zinc oxide. 14. The composition of claim 13, wherein the zinc oxide comprises coated particles. 15. The composition of claim 11 comprising a branched hydrophobically modified ethoxylated urethane copolymer. 16. The composition of claim 11 comprising a hydrophobically modified alkali swellable emulsion copolymer. 17. The composition of claim 11 substantially free of organic UV filters. 18. The composition of claim 11 comprising an organic UV filter. 19.-20. (canceled) | 1,600 |
1,184 | 14,932,986 | 1,653 | A selective isolation medium that is not influenced by existence of ESBL-producing bacteria and can clearly detect Campylobacter bacteria.
Cefoperazone and Cefoxitin are incorporated into the culture medium for detecting Campylobacter bacteria. | 1. A method for detecting Campylobacter bacteria, comprising:
a step of inoculating a specimen to a culture medium comprising Cefoperazone and Cefoxitin; a step of culturing Campylobacter bacteria contained in the specimen; and a step of detecting colony of Campylobacter bacteria. 2. The method according to claim 1, wherein the culture medium further comprises a color former. 3. The method according to claim 1, wherein the culture medium further comprises bile acid, salt of bile acid, or combination thereof. 4. A method for producing a culture medium for detecting Campylobacter bacteria, comprising:
a step of mixing water with Cefoperazone, Cefoxitin, granular activated-carbon, a nutritional ingredient and a gelling agent to obtain a mixed liquid; a step of removing the granular activated-carbon from the mixed liquid; and a step of solidifying the mixed liquid. | A selective isolation medium that is not influenced by existence of ESBL-producing bacteria and can clearly detect Campylobacter bacteria.
Cefoperazone and Cefoxitin are incorporated into the culture medium for detecting Campylobacter bacteria.1. A method for detecting Campylobacter bacteria, comprising:
a step of inoculating a specimen to a culture medium comprising Cefoperazone and Cefoxitin; a step of culturing Campylobacter bacteria contained in the specimen; and a step of detecting colony of Campylobacter bacteria. 2. The method according to claim 1, wherein the culture medium further comprises a color former. 3. The method according to claim 1, wherein the culture medium further comprises bile acid, salt of bile acid, or combination thereof. 4. A method for producing a culture medium for detecting Campylobacter bacteria, comprising:
a step of mixing water with Cefoperazone, Cefoxitin, granular activated-carbon, a nutritional ingredient and a gelling agent to obtain a mixed liquid; a step of removing the granular activated-carbon from the mixed liquid; and a step of solidifying the mixed liquid. | 1,600 |
1,185 | 15,378,165 | 1,645 | The present invention relates to compositions or vaccines for combating Mycoplasma hyopneumoniae (M hyo), Porcine Circovirus type 2 (PCV2), and Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) infections in animals and for increasing the ability of pigs to gain weight and/or improve death loss, methods of vaccination against the infections, and kits for use with such methods and compositions. | 1. A composition or vaccine comprising: i) an M hyo antigen, and ii) a porcine circovirus type 2 (PCV2) antigen, a Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) antigen, or a combination thereof. 2. The composition or vaccine of claim 1, wherein the composition of vaccine comprises an M hyo antigen and a PCV2 antigen. 3. The composition or vaccine of claim 1, wherein the composition of vaccine comprises an M hyo antigen and a PRRSV antigen. 4. The composition or vaccine of claim 1, wherein the composition of vaccine comprises an M hyo antigen, a PCV2 antigen and a PRRSV antigen. 5. The composition or vaccine of claim 1, wherein the M hyo antigen is an inactivated M hyo. 6. The composition or vaccine of claim 1, wherein the PRRSV antigen is a modified-live and/or an inactivated PRRSV. 7. The composition or vaccine of claim 1, wherein the PCV2 antigen is an inactivated PCV2. 8. The composition or vaccine of claim 1, wherein the PRRSV antigen comprises an inactivated PRRSV comprising a polynucleotide encoding an ORF5 protein having at least 91% sequence identity to the sequence as set forth in SEQ ID NO:2, 3, 4, 5, 6, 7, 8, or 9. 9. A composition or vaccine comprising one or more PRRSV antigens, wherein the PRRSV is a modified-live and/or an inactivated PRRSV. 10. The composition or vaccine of claim 9, wherein the PRRSV antigen comprises an inactivated PRRSV comprising a polynucleotide encoding an ORF5 protein having at least 91% sequence identity to the sequence as set forth in SEQ ID NO:2, 3, 4, 5, 6, 7, 8, or 9. 11. The composition or vaccine of claim 9, wherein the composition or vaccine comprises a modified-live PRRSV antigen and an inactivated PRRSV antigen. 12. The composition or vaccine of claim 1 or 9, wherein the composition or vaccine increases the ability of pigs to gain weight or improve death loss. 13. The composition or vaccine of claim 1 or 9, wherein the composition further comprises one or more pharmaceutically or veterinarily acceptable carrier, adjuvant, vehicle, or excipient. 14. A method of vaccinating an animal or inducing an immunogenic or protective response in the animal against one or more pig pathogens, or increasing the ability of pigs to gain weight or improve death loss, comprising at least one administration of the composition or vaccine of claim 1 or 9. 15. The method of claim 14, wherein the method comprises a prime-boost administration regimen. 16. The method of claim 15, wherein the method comprises a primary administration of a composition or vaccine comprising an M hyo antigen, a PCV2 antigen, and a PRRSV antigen and a boost administration of a composition or vaccine comprising a PRRSV antigen. 17. The method of claim 16, wherein the PRRSV antigen of the primary administration is a modified-live PRRSV, and wherein the PRRSV antigen of the boost administration is an inactivated PRRSV. 18. A method of vaccinating an animal or inducing an immunogenic or protective response in the animal against one or more pig pathogens, or improve death loss, comprising at least one administration of the composition or vaccine of a modified-live PRRSV and an inactivated PRRSV. 19. The method of claim 14 or 18, wherein the animal is swine. 20. A vaccination kit or set comprising one or more vaccine vials containing the composition or vaccine of claim 1 or 9. | The present invention relates to compositions or vaccines for combating Mycoplasma hyopneumoniae (M hyo), Porcine Circovirus type 2 (PCV2), and Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) infections in animals and for increasing the ability of pigs to gain weight and/or improve death loss, methods of vaccination against the infections, and kits for use with such methods and compositions.1. A composition or vaccine comprising: i) an M hyo antigen, and ii) a porcine circovirus type 2 (PCV2) antigen, a Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) antigen, or a combination thereof. 2. The composition or vaccine of claim 1, wherein the composition of vaccine comprises an M hyo antigen and a PCV2 antigen. 3. The composition or vaccine of claim 1, wherein the composition of vaccine comprises an M hyo antigen and a PRRSV antigen. 4. The composition or vaccine of claim 1, wherein the composition of vaccine comprises an M hyo antigen, a PCV2 antigen and a PRRSV antigen. 5. The composition or vaccine of claim 1, wherein the M hyo antigen is an inactivated M hyo. 6. The composition or vaccine of claim 1, wherein the PRRSV antigen is a modified-live and/or an inactivated PRRSV. 7. The composition or vaccine of claim 1, wherein the PCV2 antigen is an inactivated PCV2. 8. The composition or vaccine of claim 1, wherein the PRRSV antigen comprises an inactivated PRRSV comprising a polynucleotide encoding an ORF5 protein having at least 91% sequence identity to the sequence as set forth in SEQ ID NO:2, 3, 4, 5, 6, 7, 8, or 9. 9. A composition or vaccine comprising one or more PRRSV antigens, wherein the PRRSV is a modified-live and/or an inactivated PRRSV. 10. The composition or vaccine of claim 9, wherein the PRRSV antigen comprises an inactivated PRRSV comprising a polynucleotide encoding an ORF5 protein having at least 91% sequence identity to the sequence as set forth in SEQ ID NO:2, 3, 4, 5, 6, 7, 8, or 9. 11. The composition or vaccine of claim 9, wherein the composition or vaccine comprises a modified-live PRRSV antigen and an inactivated PRRSV antigen. 12. The composition or vaccine of claim 1 or 9, wherein the composition or vaccine increases the ability of pigs to gain weight or improve death loss. 13. The composition or vaccine of claim 1 or 9, wherein the composition further comprises one or more pharmaceutically or veterinarily acceptable carrier, adjuvant, vehicle, or excipient. 14. A method of vaccinating an animal or inducing an immunogenic or protective response in the animal against one or more pig pathogens, or increasing the ability of pigs to gain weight or improve death loss, comprising at least one administration of the composition or vaccine of claim 1 or 9. 15. The method of claim 14, wherein the method comprises a prime-boost administration regimen. 16. The method of claim 15, wherein the method comprises a primary administration of a composition or vaccine comprising an M hyo antigen, a PCV2 antigen, and a PRRSV antigen and a boost administration of a composition or vaccine comprising a PRRSV antigen. 17. The method of claim 16, wherein the PRRSV antigen of the primary administration is a modified-live PRRSV, and wherein the PRRSV antigen of the boost administration is an inactivated PRRSV. 18. A method of vaccinating an animal or inducing an immunogenic or protective response in the animal against one or more pig pathogens, or improve death loss, comprising at least one administration of the composition or vaccine of a modified-live PRRSV and an inactivated PRRSV. 19. The method of claim 14 or 18, wherein the animal is swine. 20. A vaccination kit or set comprising one or more vaccine vials containing the composition or vaccine of claim 1 or 9. | 1,600 |
1,186 | 16,050,059 | 1,612 | Described herein are oral care compositions comprising a zinc ion source, a fluoride ion source, and a basic amino acid; along with methods of making and using the same. | 1-12. (canceled) 13. A method of treating or reducing dental enamel erosion comprising administering a composition to the oral cavity of a subject in need thereof, wherein the composition comprises, based on the weight of the composition:
from 0.5 to 2.5% by weight of a zinc ion source comprising zinc citrate; about 1450 ppm fluoride, wherein the fluoride source is sodium fluoride; from 0.1 to 10%, by weight of arginine; and one or more alkali phosphate salts. 14. (canceled) 15. The method of claim 13, wherein the composition delivers nearly 20% higher level of fluoride to the enamel of teeth than the amount of fluoride delivered to teeth by a comparative composition containing zinc without arginine, when applied to polished and acid etched enamel substrates, as shown by the ratio of atomic percent fluoride to atomic percent calcium, measured by x-ray photoelectron spectroscopy. 16. The method of claim 13, wherein the composition produces enhanced resistance to acid, as shown by lower percent reduction in microhardness hardness in polished and acid etched enamel substrates, when compared to a composition containing zinc without arginine. 17. The method of claim 13, wherein the composition contains 2 to 8% of the one or more alkali phosphate salts, selected from sodium phosphate dibasic, potassium phosphate dibasic, dicalcium phosphate dihydrate, tetrasodium pyrophosphate, tetrapotassium pyrophosphate, calcium pyrophosphate, sodium tripolyphosphate, and a combination of two or more thereof, based on the weight of the composition. 18. The method of claim 17, wherein the composition contains about 5% by weight of the one or more alkali phosphate salts, based on the weight of the composition. 19. The method of claim 13, wherein the composition contains 1% to 2% of zinc citrate 20. The method of claim 13, wherein the composition is in the form of a dentifrice comprising an abrasive. 21. The method of claim 13, wherein the composition further comprises one or more abrasives, one or more humectants, and one or more surfactants. 22. The method of claim 13, wherein the composition further comprises or more antibacterial agents. 23. The method of claim 13, wherein the composition further comprises a whitening agent. 24. The method of claim 13, wherein the pH of the composition is basic. 25. The method of claim 13, wherein the zinc ion source in the composition further comprises zinc oxide. | Described herein are oral care compositions comprising a zinc ion source, a fluoride ion source, and a basic amino acid; along with methods of making and using the same.1-12. (canceled) 13. A method of treating or reducing dental enamel erosion comprising administering a composition to the oral cavity of a subject in need thereof, wherein the composition comprises, based on the weight of the composition:
from 0.5 to 2.5% by weight of a zinc ion source comprising zinc citrate; about 1450 ppm fluoride, wherein the fluoride source is sodium fluoride; from 0.1 to 10%, by weight of arginine; and one or more alkali phosphate salts. 14. (canceled) 15. The method of claim 13, wherein the composition delivers nearly 20% higher level of fluoride to the enamel of teeth than the amount of fluoride delivered to teeth by a comparative composition containing zinc without arginine, when applied to polished and acid etched enamel substrates, as shown by the ratio of atomic percent fluoride to atomic percent calcium, measured by x-ray photoelectron spectroscopy. 16. The method of claim 13, wherein the composition produces enhanced resistance to acid, as shown by lower percent reduction in microhardness hardness in polished and acid etched enamel substrates, when compared to a composition containing zinc without arginine. 17. The method of claim 13, wherein the composition contains 2 to 8% of the one or more alkali phosphate salts, selected from sodium phosphate dibasic, potassium phosphate dibasic, dicalcium phosphate dihydrate, tetrasodium pyrophosphate, tetrapotassium pyrophosphate, calcium pyrophosphate, sodium tripolyphosphate, and a combination of two or more thereof, based on the weight of the composition. 18. The method of claim 17, wherein the composition contains about 5% by weight of the one or more alkali phosphate salts, based on the weight of the composition. 19. The method of claim 13, wherein the composition contains 1% to 2% of zinc citrate 20. The method of claim 13, wherein the composition is in the form of a dentifrice comprising an abrasive. 21. The method of claim 13, wherein the composition further comprises one or more abrasives, one or more humectants, and one or more surfactants. 22. The method of claim 13, wherein the composition further comprises or more antibacterial agents. 23. The method of claim 13, wherein the composition further comprises a whitening agent. 24. The method of claim 13, wherein the pH of the composition is basic. 25. The method of claim 13, wherein the zinc ion source in the composition further comprises zinc oxide. | 1,600 |
1,187 | 15,305,410 | 1,699 | A NOx concentration measurement system has a NOx sensor, a detection section, a NH 3 concentration estimation section and a calculation section. The NOx sensor measures a sum concentration c 4 of a concentration of NOx (a concentration c 1 of combustion derived NOx) in exhaust gas g, and a concentration of NO (concentration c 3 of derived NO which has been derived from NH 3 ) oxidized from NH 3 . The calculation section calculates the concentration c 3 of derived NO by using a concentration c 2 of NH 3 contained in outside exhaust gas which is present around the NOx sensor, not inside of the NOx sensor, and at least one of an air fuel ratio A/F, a concentration of O 2 and a concentration of H 2 O. The concentration c 1 of the is calculated based on the sum concentration c 4 and the concentration c 3 of derived NO. | 1. A NOx concentration measurement system capable of measuring a concentration of NOx contained in exhaust gas which contains NOx and NH3, comprising a NOx sensor, a detection section, a NH3 concentration estimation section, and a calculation section, wherein
the NOx sensor comprises: a gas chamber into which exhaust gas is introduced; a sensor cell having a solid electrolyte body of oxygen ion conductivity having a plate shape, on the surfaces of which electrodes are formed; and a gas introduction section through which the exhaust gas is introduced into the gas chamber, the NOx sensor measures a sum concentration of a concentration of combustion derived NOx as NOx, which has being contained in the exhaust gas, and a concentration of derived NO which has been derived from NH3 as a concentration of NO generated by oxidization of the NH3, and the detection section detects at least one of an air fuel ratio of the exhaust gas, a concentration of O2 contained in the exhaust gas and a concentration of H2O contained in the exhaust gas, the NH3 concentration estimation section estimates a concentration of NH3 contained in outside exhaust gas which is present around the NOx sensor, not inside of the NOx sensor before the outside exhaust gas is introduced into the gas introduction section of the NOx sensor, the calculation section calculates the concentration of the derived NO which has been derived from NH3 on the basis of the concentration of the NH3 contained in the outside exhaust gas and at least one of the air fuel ratio, the concentration of O2 and the concentration of H2O, and the calculation section calculates the concentration of the combustion derived NOx on the basis of the sum concentration and the concentration of the derived NO which has been derived from NH3. 2. The NOx concentration measurement system according to claim 1, wherein the calculation section subtracts the concentration of the derived NO which has been derived from NH3 from the sum concentration, and calculates the concentration of the combustion derived NOx by using the subtraction result. 3. The NOx concentration measurement system according to claim 1, wherein the detection section detects the air fuel ratio of the exhaust gas, and calculates at least one of the concentration of O2 and the concentration of H2O on the basis of the detected air fuel ratio. 4. The NOx concentration measurement system according to claim 3, wherein the NOx sensor is equipped with a pump cell of adjusting the concentration of O2 contained in the exhaust gas, and
the detection section is configured to measure a pump cell current which flows in the pump cell to obtain the air fuel ratio of the exhaust gas. 5. The NOx concentration measurement system according to claim 1, wherein the gas introduction section is configured to have a temperature within a range of 600 to 850° C. during the use of the NOx sensor. 6. The NOx concentration measurement system according to claim 1, wherein the gas introduction section of the NOx sensor is composed of at least one of a trap layer and a diffusion layer, where the trap layer has a porosity within a range of 10 to 90% and traps poison material contained in the exhaust gas, and the diffusion layer has a porosity within a range of 10 to 90% and limits a flow speed of the exhaust gas to be introduced into the gas chamber. 7. The NOx concentration measurement system according to claim 6, wherein the trap layer has a thickness of not more than 1200 μm, and the diffusion layer has a thickness of not more than 5 mm. 8. The NOx concentration measurement system according to claim 1, wherein the calculation section is configured to calculate the concentration of the derived NO which has been derived from NH3 by using the concentration of O2 and the concentration of the NH3 contained in the exhaust gas outside of the NOx sensor. 9. The NOx concentration measurement system according to claim 1, wherein the calculation section is configured to calculate the concentration of the derived NO which has been derived from NH3 by using the concentration of H2O and the concentration of the NH3 contained in the exhaust gas outside of the NOx sensor. 10. The NOx concentration measurement system according to claim 1, wherein the calculation section is configured to select one of the concentration of O2 and the concentration of H2O so that the calculated concentration of the derived NO which has been derived from NH3 has a higher accuracy. | A NOx concentration measurement system has a NOx sensor, a detection section, a NH 3 concentration estimation section and a calculation section. The NOx sensor measures a sum concentration c 4 of a concentration of NOx (a concentration c 1 of combustion derived NOx) in exhaust gas g, and a concentration of NO (concentration c 3 of derived NO which has been derived from NH 3 ) oxidized from NH 3 . The calculation section calculates the concentration c 3 of derived NO by using a concentration c 2 of NH 3 contained in outside exhaust gas which is present around the NOx sensor, not inside of the NOx sensor, and at least one of an air fuel ratio A/F, a concentration of O 2 and a concentration of H 2 O. The concentration c 1 of the is calculated based on the sum concentration c 4 and the concentration c 3 of derived NO.1. A NOx concentration measurement system capable of measuring a concentration of NOx contained in exhaust gas which contains NOx and NH3, comprising a NOx sensor, a detection section, a NH3 concentration estimation section, and a calculation section, wherein
the NOx sensor comprises: a gas chamber into which exhaust gas is introduced; a sensor cell having a solid electrolyte body of oxygen ion conductivity having a plate shape, on the surfaces of which electrodes are formed; and a gas introduction section through which the exhaust gas is introduced into the gas chamber, the NOx sensor measures a sum concentration of a concentration of combustion derived NOx as NOx, which has being contained in the exhaust gas, and a concentration of derived NO which has been derived from NH3 as a concentration of NO generated by oxidization of the NH3, and the detection section detects at least one of an air fuel ratio of the exhaust gas, a concentration of O2 contained in the exhaust gas and a concentration of H2O contained in the exhaust gas, the NH3 concentration estimation section estimates a concentration of NH3 contained in outside exhaust gas which is present around the NOx sensor, not inside of the NOx sensor before the outside exhaust gas is introduced into the gas introduction section of the NOx sensor, the calculation section calculates the concentration of the derived NO which has been derived from NH3 on the basis of the concentration of the NH3 contained in the outside exhaust gas and at least one of the air fuel ratio, the concentration of O2 and the concentration of H2O, and the calculation section calculates the concentration of the combustion derived NOx on the basis of the sum concentration and the concentration of the derived NO which has been derived from NH3. 2. The NOx concentration measurement system according to claim 1, wherein the calculation section subtracts the concentration of the derived NO which has been derived from NH3 from the sum concentration, and calculates the concentration of the combustion derived NOx by using the subtraction result. 3. The NOx concentration measurement system according to claim 1, wherein the detection section detects the air fuel ratio of the exhaust gas, and calculates at least one of the concentration of O2 and the concentration of H2O on the basis of the detected air fuel ratio. 4. The NOx concentration measurement system according to claim 3, wherein the NOx sensor is equipped with a pump cell of adjusting the concentration of O2 contained in the exhaust gas, and
the detection section is configured to measure a pump cell current which flows in the pump cell to obtain the air fuel ratio of the exhaust gas. 5. The NOx concentration measurement system according to claim 1, wherein the gas introduction section is configured to have a temperature within a range of 600 to 850° C. during the use of the NOx sensor. 6. The NOx concentration measurement system according to claim 1, wherein the gas introduction section of the NOx sensor is composed of at least one of a trap layer and a diffusion layer, where the trap layer has a porosity within a range of 10 to 90% and traps poison material contained in the exhaust gas, and the diffusion layer has a porosity within a range of 10 to 90% and limits a flow speed of the exhaust gas to be introduced into the gas chamber. 7. The NOx concentration measurement system according to claim 6, wherein the trap layer has a thickness of not more than 1200 μm, and the diffusion layer has a thickness of not more than 5 mm. 8. The NOx concentration measurement system according to claim 1, wherein the calculation section is configured to calculate the concentration of the derived NO which has been derived from NH3 by using the concentration of O2 and the concentration of the NH3 contained in the exhaust gas outside of the NOx sensor. 9. The NOx concentration measurement system according to claim 1, wherein the calculation section is configured to calculate the concentration of the derived NO which has been derived from NH3 by using the concentration of H2O and the concentration of the NH3 contained in the exhaust gas outside of the NOx sensor. 10. The NOx concentration measurement system according to claim 1, wherein the calculation section is configured to select one of the concentration of O2 and the concentration of H2O so that the calculated concentration of the derived NO which has been derived from NH3 has a higher accuracy. | 1,600 |
1,188 | 13,518,971 | 1,612 | The present invention relates to oral care compositions with improved flavor release characteristics and improved taste, and methods of using the same. | 1. An oral care composition comprising:
a whitening agent, wherein the whitening agent is bound; an anionic surfactant present in an amount from 1.75% to 2.0% w/w; and an orally acceptable carrier having a total concentration of water of 0% to 4% w/w and wherein the water content of the oral care composition is less than 4% w/w. 2. The composition of claim 1, wherein the anionic surfactant is selected from the group consisting of sodium lauryl sulfate and sodium lauryl sulfoacetate. 3. The composition of claim 1, wherein the whitening agent is a bound peroxide. 4. The composition of claim 3, wherein the bound peroxide compound is selected from the group consisting of hydrogen peroxide, peroxides of alkali and alkaline earth metals, organic peroxy compounds, peroxy acids, pharmaceutically acceptable salts thereof and mixtures thereof. 5. The composition of claim 4, wherein the bound peroxide is hydrogen peroxide and is present in an amount from 0.1% to 2% w/w. 6. The composition of claim 5, wherein the bound peroxide is hydrogen peroxide and is present in an amount from 1% to 2% w/w. 7. The composition of claim 3, wherein the bound peroxide includes a peroxide compound and a cross-linked polymer. 8. The composition of claim 7, wherein the cross-linked polymer is selected from the group consisting of polyvinyl pyrrolidone, polyacrylate, a polymethacrylate and polyitaconates. 9. The composition of claim 1, wherein the whitening agent is present in an amount from 0.1% to 30% w/w. 10. The composition of claim 1, wherein the anionic surfactant is present in an amount from 1.8% to 2% w/w. 11. The composition of claim 1, wherein the anionic surfactant is present in the amount of 2% w/w. 12. The composition of claim 1, wherein the water content of the orally acceptable carrier is from 0% to 2% w/w. 13. The composition of claim 1, wherein the water content of the orally acceptable carrier is from 0% to 1% w/w. 14. The composition of claim 1, wherein the water content of the orally acceptable carrier is less than 0.1% w/w. 15. The composition of claim 1, wherein the orally acceptable carrier is selected from the group consisting of polymers and copolymers of polyethylene glycol, ethylene oxide and propylene oxide. 16. The composition of claim 1, wherein the carrier further comprises fumed silica, an abrasive, a poloxamer and a flavoring agent. 17. The composition of claim 1, further comprising a fluoride salt. 18. The composition of claim 1, further comprising an active agent selected from the group consisting of an antimicrobial agent, an anti-inflammatory agent, a zinc salt and triclosan. 19. The composition of claim 1, wherein the composition comprises a single phase. 20. A method of improving patient compliance with an oral care composition, comprising applying to an oral surface an effective amount of the oral care composition of claim 1. 21. A method of whitening a tooth surface, the method comprising contacting the tooth surface with a composition of claim 1. 22. An oral care composition according to claim 1 for use in a method of improving patient compliance with an oral care composition, said method comprising applying to an oral surface an effective amount of the oral care composition. 23. An oral care composition according to claim 1 for use in a method of whitening a tooth surface, said method comprising contacting the tooth surface with the oral care composition. | The present invention relates to oral care compositions with improved flavor release characteristics and improved taste, and methods of using the same.1. An oral care composition comprising:
a whitening agent, wherein the whitening agent is bound; an anionic surfactant present in an amount from 1.75% to 2.0% w/w; and an orally acceptable carrier having a total concentration of water of 0% to 4% w/w and wherein the water content of the oral care composition is less than 4% w/w. 2. The composition of claim 1, wherein the anionic surfactant is selected from the group consisting of sodium lauryl sulfate and sodium lauryl sulfoacetate. 3. The composition of claim 1, wherein the whitening agent is a bound peroxide. 4. The composition of claim 3, wherein the bound peroxide compound is selected from the group consisting of hydrogen peroxide, peroxides of alkali and alkaline earth metals, organic peroxy compounds, peroxy acids, pharmaceutically acceptable salts thereof and mixtures thereof. 5. The composition of claim 4, wherein the bound peroxide is hydrogen peroxide and is present in an amount from 0.1% to 2% w/w. 6. The composition of claim 5, wherein the bound peroxide is hydrogen peroxide and is present in an amount from 1% to 2% w/w. 7. The composition of claim 3, wherein the bound peroxide includes a peroxide compound and a cross-linked polymer. 8. The composition of claim 7, wherein the cross-linked polymer is selected from the group consisting of polyvinyl pyrrolidone, polyacrylate, a polymethacrylate and polyitaconates. 9. The composition of claim 1, wherein the whitening agent is present in an amount from 0.1% to 30% w/w. 10. The composition of claim 1, wherein the anionic surfactant is present in an amount from 1.8% to 2% w/w. 11. The composition of claim 1, wherein the anionic surfactant is present in the amount of 2% w/w. 12. The composition of claim 1, wherein the water content of the orally acceptable carrier is from 0% to 2% w/w. 13. The composition of claim 1, wherein the water content of the orally acceptable carrier is from 0% to 1% w/w. 14. The composition of claim 1, wherein the water content of the orally acceptable carrier is less than 0.1% w/w. 15. The composition of claim 1, wherein the orally acceptable carrier is selected from the group consisting of polymers and copolymers of polyethylene glycol, ethylene oxide and propylene oxide. 16. The composition of claim 1, wherein the carrier further comprises fumed silica, an abrasive, a poloxamer and a flavoring agent. 17. The composition of claim 1, further comprising a fluoride salt. 18. The composition of claim 1, further comprising an active agent selected from the group consisting of an antimicrobial agent, an anti-inflammatory agent, a zinc salt and triclosan. 19. The composition of claim 1, wherein the composition comprises a single phase. 20. A method of improving patient compliance with an oral care composition, comprising applying to an oral surface an effective amount of the oral care composition of claim 1. 21. A method of whitening a tooth surface, the method comprising contacting the tooth surface with a composition of claim 1. 22. An oral care composition according to claim 1 for use in a method of improving patient compliance with an oral care composition, said method comprising applying to an oral surface an effective amount of the oral care composition. 23. An oral care composition according to claim 1 for use in a method of whitening a tooth surface, said method comprising contacting the tooth surface with the oral care composition. | 1,600 |
1,189 | 15,577,969 | 1,634 | The present invention relates to methods for diagnosing, monitoring or prognosticating prostate cancer or the progression state of prostate cancer wherein said method determines the state of the prostate cancer, based on the expression level of phosphodiesterase 4D (PDE4D) variants. The invention further relates to a method of identifying an individual for eligibility for prostate cancer therapy. The invention also relates to products for the analysis of phosphodiesterase 4D (PDE4D) variants as well as pharmaceutical compositions modulating the activity and/or expression of PDE4D variants. | 1. A method comprising the step of:
a) determining a prostate cancer progression state based on a gene expression profile including the expression level of at least two phosphodiesterase 4D (PDE4D) variants selected from the group consisting of PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D5, PDE4D6, PDE4D7, PDE4D8 and PDE4D9, and wherein none of the PDE4D variants serves as a reference gene. 2. A method comprising the step of:
a) determining the presence or absence of TMPRSS2-ERG gene fusion or the expression level of transcription factor ERG, based on a gene expression profile including the expression level of at least two phosphodiesterase 4D (PDE4D) variants selected from the group consisting of PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D5, PDE4D6, PDE4D7, PDE4D8 and PDE4D9, and wherein none of the PDE4D variants serves as a reference gene. 3. The method of claim 1, wherein the gene expression profile is converted into at least one prostate cancer PDE index (PDE-Index) indicative for the prostate cancer progression state. 4. The method of claim 1, wherein the PDE4D variants are selected from the group consisting of PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D5, PDE4D6, PDE4D8 and PDE4D9. 5. The method of claim 1, wherein the gene expression profile is a normalized gene expression profile which is obtained by normalizing the expression level of the PDE4D variants to the expression of at least one reference gene, the method optionally comprising, before the normalization, the step of determining the expression level of at least one reference gene in a sample. 6. The method of claim 5,
which is a method for monitoring or prognosticating prostate cancer or the progression state of prostate cancer; or which is a method for identifying an individual for eligibility for a prostate cancer therapy, further comprising identifying an individual as eligible to receive a prostate cancer therapy where the PDE-Index of the individual indicates the presence of prostate cancer or wherein the PDE-Index of the individual indicates a non-progressive or progressive prostate cancer progression state; or which is a method for treating an individual, further comprising i) identifying an individual as eligible to receive a prostate cancer therapy where the PDE-Index of the individual indicates the presence of prostate cancer or wherein the PDE-Index of the individual indicates a non-progressive or progressive prostate cancer progression state and ii) treating the individual eligible to receive the prostate cancer therapy. 7. The method of claim 1, comprising, before step a), the step of determining the expression level of at least two phosphodiesterase 4D (PDE4D) variants selected from the group consisting of PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D5, PDE4D6, PDE4D7, PDE4D8 and PDE4D9 in a sample to obtain a gene expression profile. 8. The method of claim 3, wherein the at least one PDE-Index is selected from the following:
i) PDE-Index_1: PDE4D7_exp—PDE4D5 exp ii) PDE-Index_2: MEAN(PDE4D7 exp & PDE4D5 exp) iii) PDE-Index_3: (MEAN(PDE4D5_exp & PDE4D7_exp & PDE4D9_exp))/(PDE4D4_exp) iv) PDE-Index_4: (MEAN(PDE4D5_exp & PDE4D7_exp & PDE4D9_exp))/(PDE4D1&PDE4D2_exp) v) PDE-Index_5: (MEAN(PDE4D5_exp & PDE4D7_exp & PDE4D9_exp)). 9. A product comprising:
primers and/or probes for determining the expression level of at least two phosphodiesterase 4D (PDE4D) variants selected from the group consisting of PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D5, PDE4D6, PDE4D7, PDE4D8 and PDE4D9; further comprising primers and/or probes for determining the gene expression level of a reference gene, preferably a housekeeping gene, more preferably TBP, HPRT1, ACTB, RPLP0, PUM1, POLR2A, B2M, K-ALPHA-1 or ALAS-1. 10. The product is a product for performing the method of claim 7, or wherein the product is a product for monitoring or prognosticating prostate cancer or the progression state of prostate cancer or for identifying an individual for eligibility for prostate cancer therapy. 11. A computer program product, comprising computer readable code stored on a computer readable medium or downloadable from a communications network, which, when run on a computer, implement one or more steps of claim 1. 12. A system comprising the product of and the computer program product of claim 11. 13. A stimulatory pharmaceutical composition for use in the treatment or prevention of prostate cancer comprising at least one element selected from the group of:
a) a compound directly stimulating or modulating the activity of a PDE4D variant selected from the group consisting of PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D5, PDE4D6, PDE4D8, PDE4D9, preferably an allosteric agonist of the enzymatic activity; b) a compound indirectly stimulating or modulating the activity of the PDE4D variant of (a); c) the protein of the PDE4D variant of (a) or a biologically active equivalent thereof; d) a nucleic acid encoding and expressing the PDE4D variant of (a); e) a miRNA inhibitor specific for miRNAs of the PDE4D variant of (a); f) a demethylation agent; and g) a phosphodiesterase displacement factor, preferably a peptide, a peptidomimetic, a small molecule, an antibody or an aptamer,
wherein the PDE4D variant is preferably selected from the group consisting of PDE4D5, PDE4D8, PDE4D9. 14. An inhibitory pharmaceutical composition for use in the treatment or prevention of prostate cancer comprising at least one element selected from the group of:
a) a compound directly inhibiting the activity of a PDE4D variant selected from the group consisting of PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D5, PDE4D6, PDE4D8, PDE4D9; b) a compound indirectly inhibiting the activity of the PDE4D variant of (a); c) a dominant negative form of the protein of the PDE4D variant of (a) or a biologically active equivalent thereof; d) a nucleic acid encoding and expressing a dominant negative form of the PDE4D variant of (a); e) a miRNA specific for the PDE4D variant of (a); f) an antisense molecule for the PDE4D variant of (a); g) a siRNA specific for the PDE4D variant of (a); h) an aptamer specific for the expression product of the PDE4D variant of (a) or for the protein of the PDE4D variant of (a); i) a small molecule or peptidomimetic capable of specifically binding to the protein of the PDE4D variant of (a); and j) an antibody specific for the protein of the PDE4D variant of (a) and/or an antibody variant specific for the protein of the PDE4D variant of (a),
wherein the PDE4D variant is preferably selected from the group consisting of PDE4D5, PDE4D8, PDE4D9. | The present invention relates to methods for diagnosing, monitoring or prognosticating prostate cancer or the progression state of prostate cancer wherein said method determines the state of the prostate cancer, based on the expression level of phosphodiesterase 4D (PDE4D) variants. The invention further relates to a method of identifying an individual for eligibility for prostate cancer therapy. The invention also relates to products for the analysis of phosphodiesterase 4D (PDE4D) variants as well as pharmaceutical compositions modulating the activity and/or expression of PDE4D variants.1. A method comprising the step of:
a) determining a prostate cancer progression state based on a gene expression profile including the expression level of at least two phosphodiesterase 4D (PDE4D) variants selected from the group consisting of PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D5, PDE4D6, PDE4D7, PDE4D8 and PDE4D9, and wherein none of the PDE4D variants serves as a reference gene. 2. A method comprising the step of:
a) determining the presence or absence of TMPRSS2-ERG gene fusion or the expression level of transcription factor ERG, based on a gene expression profile including the expression level of at least two phosphodiesterase 4D (PDE4D) variants selected from the group consisting of PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D5, PDE4D6, PDE4D7, PDE4D8 and PDE4D9, and wherein none of the PDE4D variants serves as a reference gene. 3. The method of claim 1, wherein the gene expression profile is converted into at least one prostate cancer PDE index (PDE-Index) indicative for the prostate cancer progression state. 4. The method of claim 1, wherein the PDE4D variants are selected from the group consisting of PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D5, PDE4D6, PDE4D8 and PDE4D9. 5. The method of claim 1, wherein the gene expression profile is a normalized gene expression profile which is obtained by normalizing the expression level of the PDE4D variants to the expression of at least one reference gene, the method optionally comprising, before the normalization, the step of determining the expression level of at least one reference gene in a sample. 6. The method of claim 5,
which is a method for monitoring or prognosticating prostate cancer or the progression state of prostate cancer; or which is a method for identifying an individual for eligibility for a prostate cancer therapy, further comprising identifying an individual as eligible to receive a prostate cancer therapy where the PDE-Index of the individual indicates the presence of prostate cancer or wherein the PDE-Index of the individual indicates a non-progressive or progressive prostate cancer progression state; or which is a method for treating an individual, further comprising i) identifying an individual as eligible to receive a prostate cancer therapy where the PDE-Index of the individual indicates the presence of prostate cancer or wherein the PDE-Index of the individual indicates a non-progressive or progressive prostate cancer progression state and ii) treating the individual eligible to receive the prostate cancer therapy. 7. The method of claim 1, comprising, before step a), the step of determining the expression level of at least two phosphodiesterase 4D (PDE4D) variants selected from the group consisting of PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D5, PDE4D6, PDE4D7, PDE4D8 and PDE4D9 in a sample to obtain a gene expression profile. 8. The method of claim 3, wherein the at least one PDE-Index is selected from the following:
i) PDE-Index_1: PDE4D7_exp—PDE4D5 exp ii) PDE-Index_2: MEAN(PDE4D7 exp & PDE4D5 exp) iii) PDE-Index_3: (MEAN(PDE4D5_exp & PDE4D7_exp & PDE4D9_exp))/(PDE4D4_exp) iv) PDE-Index_4: (MEAN(PDE4D5_exp & PDE4D7_exp & PDE4D9_exp))/(PDE4D1&PDE4D2_exp) v) PDE-Index_5: (MEAN(PDE4D5_exp & PDE4D7_exp & PDE4D9_exp)). 9. A product comprising:
primers and/or probes for determining the expression level of at least two phosphodiesterase 4D (PDE4D) variants selected from the group consisting of PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D5, PDE4D6, PDE4D7, PDE4D8 and PDE4D9; further comprising primers and/or probes for determining the gene expression level of a reference gene, preferably a housekeeping gene, more preferably TBP, HPRT1, ACTB, RPLP0, PUM1, POLR2A, B2M, K-ALPHA-1 or ALAS-1. 10. The product is a product for performing the method of claim 7, or wherein the product is a product for monitoring or prognosticating prostate cancer or the progression state of prostate cancer or for identifying an individual for eligibility for prostate cancer therapy. 11. A computer program product, comprising computer readable code stored on a computer readable medium or downloadable from a communications network, which, when run on a computer, implement one or more steps of claim 1. 12. A system comprising the product of and the computer program product of claim 11. 13. A stimulatory pharmaceutical composition for use in the treatment or prevention of prostate cancer comprising at least one element selected from the group of:
a) a compound directly stimulating or modulating the activity of a PDE4D variant selected from the group consisting of PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D5, PDE4D6, PDE4D8, PDE4D9, preferably an allosteric agonist of the enzymatic activity; b) a compound indirectly stimulating or modulating the activity of the PDE4D variant of (a); c) the protein of the PDE4D variant of (a) or a biologically active equivalent thereof; d) a nucleic acid encoding and expressing the PDE4D variant of (a); e) a miRNA inhibitor specific for miRNAs of the PDE4D variant of (a); f) a demethylation agent; and g) a phosphodiesterase displacement factor, preferably a peptide, a peptidomimetic, a small molecule, an antibody or an aptamer,
wherein the PDE4D variant is preferably selected from the group consisting of PDE4D5, PDE4D8, PDE4D9. 14. An inhibitory pharmaceutical composition for use in the treatment or prevention of prostate cancer comprising at least one element selected from the group of:
a) a compound directly inhibiting the activity of a PDE4D variant selected from the group consisting of PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D5, PDE4D6, PDE4D8, PDE4D9; b) a compound indirectly inhibiting the activity of the PDE4D variant of (a); c) a dominant negative form of the protein of the PDE4D variant of (a) or a biologically active equivalent thereof; d) a nucleic acid encoding and expressing a dominant negative form of the PDE4D variant of (a); e) a miRNA specific for the PDE4D variant of (a); f) an antisense molecule for the PDE4D variant of (a); g) a siRNA specific for the PDE4D variant of (a); h) an aptamer specific for the expression product of the PDE4D variant of (a) or for the protein of the PDE4D variant of (a); i) a small molecule or peptidomimetic capable of specifically binding to the protein of the PDE4D variant of (a); and j) an antibody specific for the protein of the PDE4D variant of (a) and/or an antibody variant specific for the protein of the PDE4D variant of (a),
wherein the PDE4D variant is preferably selected from the group consisting of PDE4D5, PDE4D8, PDE4D9. | 1,600 |
1,190 | 15,027,429 | 1,653 | It has been found in accordance with the invention that a biomass comprising an oxidation-sensitive material of value may be particularly readily converted into a particulate, flowable composition if a silica, especially a hydrophilic or hydrophobic silica, is added as additive. | 1-15. (canceled) 16. A method for preparing a particulate free-flowing biomass comprising an oxidation-sensitive material of value, wherein said method comprises:
a) obtaining a fermentation broth comprising biomass; b) optionally concentrating said fermentation broth to produce a concentrated broth; c) drying either said fermentation broth or said concentrated broth; d) adjusting the amount of silica in said fermentation broth or said concentrated broth either before or after the drying of step c) so that the concentration of silica in said particulate free-flowing biomass is 0.1-8% by weight. 17. The method of claim 16, wherein the silica is a hydrophilic silica. 18. The method of claim 17, wherein the hydrophilic silica has a specific surface area of 150 to 600 m2/g and a dioctyl adipate absorption value of 2-3.5 ml/g. 19. The method of claim 16, wherein the silica is a hydrophobic silica. 20. The method of claim 19, wherein the hydrophobic silica has a methanol wettability of at least 40%. 21. The method of claim 16, wherein the oxidation-sensitive material of value is an unsaturated fatty acid. 22. The method of claim 16, wherein the silica is adjusted so that the concentration of silica in the particulate biomass is 0.2 to 6% by weight. 23. The method of claim 16, wherein the biomass comprises cells from the taxon Labyrinthulomycetes. 24. The method of claim 16, wherein the fermentation broth has a solids content of 10 to 50% by weight, and is converted to the particulate biomass by drying. 25. The method of claim 16, wherein biomass is dried by a thermal process and silica is added during the drying process. 26. The method of claim 16, wherein:
a) the oxidation-sensitive material of value is an omega-3 fatty acid or an omega-6 fatty acid; b) the silica is adjusted so that the concentration of silica in the particulate biomass is 0.2 to 6% by weight; and c) the biomass comprises cells from the family of Thraustochytriaceae. 27. The method of claim 16, wherein:
a) the oxidation-sensitive material of value is DHA; b) the silica is adjusted so that the concentration of silica in the particulate biomass is 0.5 to 2.5% by weight; and c) the biomass comprises cells from the genera Thraustochytrium, Schizochytrium or Aurantiochytrium. 28. A particulate free-flowing biomass comprising an oxidation-sensitive material of value and silica in an amount of 0.1 to 8% by weight. 29. The particulate biomass of claim 28, wherein the silica is a hydrophilic silica with a specific surface area of 130 to 600 m2/g and a dioctyl adipate absorption value of 1.5-4.0 ml/g. 30. The particulate biomass of claim 28, wherein the silica is a hydrophobic silica with a methanol wettability of at least 40%. 31. The particulate biomass of claim 28, wherein at least 80% of particles by weight have a particle size of 100 to 3500 micrometres. 32. The particulate biomass of claim 28, wherein the biomass comprises cells from the taxon Labyrinthulomycetes. 33. The particulate biomass of claim 28, wherein:
a) the particulate biomass comprises silica in an amount of 0.2 to 6% by weight; b) the silica is either:
i) a hydrophilic silica with a specific surface area of 130 to 600 m2/g, and a dioctyl adipate absorption value of 1.5-4.0 ml/g; or
ii) a hydrophobic silica with a methanol wettability of at least 40%;
c) at least 80% by weight of the particles have a particle size of 100 to 3500 micrometres; d) the biomass comprises cells from the family Thraustochytriaceae. 34. The particulate biomass of claim 28, wherein:
a) the particulate biomass comprises silica in an amount of 0.5 to 2.5% by weight; b) the silica is either:
i) a hydrophilic silica with a specific surface area of 160 to 550 m2/g, and a dioctyl adipate absorption value of 2.0 to 3.2 ml/g; or
ii) a hydrophobic silica, with a methanol wettability of at least at least 50%;
c) at least 95% by weight, of the particles have a particle size of 100 to 2500 micrometres; d) the biomass comprises cells from the genera Thraustochytrium, Schizochytrium or Ulkenia. 35. A feedstuff or foodstuff containing the particulate biomass of claim 28 and also other feedstuff ingredients. | It has been found in accordance with the invention that a biomass comprising an oxidation-sensitive material of value may be particularly readily converted into a particulate, flowable composition if a silica, especially a hydrophilic or hydrophobic silica, is added as additive.1-15. (canceled) 16. A method for preparing a particulate free-flowing biomass comprising an oxidation-sensitive material of value, wherein said method comprises:
a) obtaining a fermentation broth comprising biomass; b) optionally concentrating said fermentation broth to produce a concentrated broth; c) drying either said fermentation broth or said concentrated broth; d) adjusting the amount of silica in said fermentation broth or said concentrated broth either before or after the drying of step c) so that the concentration of silica in said particulate free-flowing biomass is 0.1-8% by weight. 17. The method of claim 16, wherein the silica is a hydrophilic silica. 18. The method of claim 17, wherein the hydrophilic silica has a specific surface area of 150 to 600 m2/g and a dioctyl adipate absorption value of 2-3.5 ml/g. 19. The method of claim 16, wherein the silica is a hydrophobic silica. 20. The method of claim 19, wherein the hydrophobic silica has a methanol wettability of at least 40%. 21. The method of claim 16, wherein the oxidation-sensitive material of value is an unsaturated fatty acid. 22. The method of claim 16, wherein the silica is adjusted so that the concentration of silica in the particulate biomass is 0.2 to 6% by weight. 23. The method of claim 16, wherein the biomass comprises cells from the taxon Labyrinthulomycetes. 24. The method of claim 16, wherein the fermentation broth has a solids content of 10 to 50% by weight, and is converted to the particulate biomass by drying. 25. The method of claim 16, wherein biomass is dried by a thermal process and silica is added during the drying process. 26. The method of claim 16, wherein:
a) the oxidation-sensitive material of value is an omega-3 fatty acid or an omega-6 fatty acid; b) the silica is adjusted so that the concentration of silica in the particulate biomass is 0.2 to 6% by weight; and c) the biomass comprises cells from the family of Thraustochytriaceae. 27. The method of claim 16, wherein:
a) the oxidation-sensitive material of value is DHA; b) the silica is adjusted so that the concentration of silica in the particulate biomass is 0.5 to 2.5% by weight; and c) the biomass comprises cells from the genera Thraustochytrium, Schizochytrium or Aurantiochytrium. 28. A particulate free-flowing biomass comprising an oxidation-sensitive material of value and silica in an amount of 0.1 to 8% by weight. 29. The particulate biomass of claim 28, wherein the silica is a hydrophilic silica with a specific surface area of 130 to 600 m2/g and a dioctyl adipate absorption value of 1.5-4.0 ml/g. 30. The particulate biomass of claim 28, wherein the silica is a hydrophobic silica with a methanol wettability of at least 40%. 31. The particulate biomass of claim 28, wherein at least 80% of particles by weight have a particle size of 100 to 3500 micrometres. 32. The particulate biomass of claim 28, wherein the biomass comprises cells from the taxon Labyrinthulomycetes. 33. The particulate biomass of claim 28, wherein:
a) the particulate biomass comprises silica in an amount of 0.2 to 6% by weight; b) the silica is either:
i) a hydrophilic silica with a specific surface area of 130 to 600 m2/g, and a dioctyl adipate absorption value of 1.5-4.0 ml/g; or
ii) a hydrophobic silica with a methanol wettability of at least 40%;
c) at least 80% by weight of the particles have a particle size of 100 to 3500 micrometres; d) the biomass comprises cells from the family Thraustochytriaceae. 34. The particulate biomass of claim 28, wherein:
a) the particulate biomass comprises silica in an amount of 0.5 to 2.5% by weight; b) the silica is either:
i) a hydrophilic silica with a specific surface area of 160 to 550 m2/g, and a dioctyl adipate absorption value of 2.0 to 3.2 ml/g; or
ii) a hydrophobic silica, with a methanol wettability of at least at least 50%;
c) at least 95% by weight, of the particles have a particle size of 100 to 2500 micrometres; d) the biomass comprises cells from the genera Thraustochytrium, Schizochytrium or Ulkenia. 35. A feedstuff or foodstuff containing the particulate biomass of claim 28 and also other feedstuff ingredients. | 1,600 |
1,191 | 13,412,887 | 1,631 | Methods and articles of manufacture for modeling molecular properties using data regarding the partial orderings of compound properties, or by considering measurements of compound properties in terms of partial orderings are disclosed. One embodiment provides for constructing such partial orderings from data that is not already in an ordered form by processing training data to produce a partial ordering of the compounds with respect to a property of interest. Another embodiment of the invention may process the modified training data to construct a model that predicts the property of interest for arbitrary compounds. | 1-10. (canceled) 11. A method for training a molecular properties model, comprising:
obtaining a pseudo-partial ordering of molecules, wherein the pseudo partial ordering includes at least a representation of a first and second molecule, ordered relative to one another and a property of interest; and generating a representation of the molecules included in the pseudo partial ordering of molecules that is appropriate for a selected machine learning algorithm, wherein the pseudo partial ordering of molecules is provided to the selected machine learning algorithm, and wherein executing the selected machine learning algorithm, using the pseudo partial ordering, trains a molecular properties model configured to generate a prediction regarding additional molecules supplied to the model. 12. The method of claim 11, wherein the molecular properties model generates predictions related to a property of interest selected from at least one of a pharmacokinetic property, pharmacodynamic property, physiological or pharmacological activity, toxicity or selectivity; a chemical property including reactivity, binding affinity, pKa, or a property of a specific atom or bond in a molecule; or a physical property including melting point, solubility, a membrane permeability, and a force-field parameter. 13. The method of claim 11, wherein the selected machine learning algorithm comprises a classification learning algorithm. 14. The method of claim 11, wherein the selected machine learning algorithm comprises a kernel based learning algorithm. 15. The method of claim 11, wherein the selected machine learning algorithm comprises a variant of a Boosting algorithm, RankBoost algorithm, Alternating Decision Trees algorithm, Support Vector Machines algorithm, a Perceptron algorithm, Winnow, a Hedge Algorithm, decision trees, neural networks, genetic algorithms, genetic programming or any modifications thereof modified to process the pseudo partial ordering of ranked pairs. 16. The method of claim 11, wherein the selected machine learning algorithm is configured to minimize, either directly or indirectly, an area above, or below, a receiver operator characteristic curve. 17. The method of claim 11, wherein the selected machine learning algorithm is configured to minimize, either directly or indirectly, a function of the rank ordering of molecules in the pseudo partial ordering. 18. The method of claim 11, further comprising, determining an accuracy of the prediction for the additional molecule by carrying out laboratory experimentation using physically existing samples of the additional molecule, or by performing a research study using physical samples of the additional molecule. 19. The method of claim 11, wherein generating the representation of the molecules included in the pseudo partial ordering of molecules comprises: generating a vector representation of the molecules, wherein the vector representation is configured to encode the structure of the molecules included the pseudo-partial ordering; or comprises generating an n-point pharmacophore representation of the molecules included in the pseudo-partial ordering. 20. The method of claim 11, wherein a threshold value or cutoff molecule is selected for the molecular proprieties model and used to create a classification model. 21. The method of claim 11, wherein the at least one additional molecule comprises two or more additional molecules, and wherein the prediction comprises a ranked ordering of the two or more additional molecules, relative to one another and to the property of interest. 22. The method of claim 11, wherein at least two of the molecules in the training set are alternative representations of the same physical molecule and the property of interest is a property of the alternative representations. 23. The method of claim 11, wherein at least two of the molecules in the training set are encoded to represent different atoms, bonds or substituent groups of the same molecule and the property of interest is a property of the atoms, bonds or substituent groups. 24-34. (canceled) 35. A computer-storage medium containing a program which, when executed by a processor, performs a method for training a molecular properties model, comprising:
receiving a pseudo-partial ordering of molecules, wherein the pseudo partial ordering includes at least a representation of a first and second molecule, ordered relative to one another and a property of interest; and generating a representation of the molecules included in the pseudo partial ordering of molecules that is appropriate for a selected machine learning algorithm, wherein the pseudo partial ordering of molecules is provided to the selected machine learning algorithm, and wherein executing the selected machine learning algorithm, using the pseudo partial ordering, trains a molecular properties model configured to generate a prediction regarding additional molecules supplied to the model. 36-40. (canceled) | Methods and articles of manufacture for modeling molecular properties using data regarding the partial orderings of compound properties, or by considering measurements of compound properties in terms of partial orderings are disclosed. One embodiment provides for constructing such partial orderings from data that is not already in an ordered form by processing training data to produce a partial ordering of the compounds with respect to a property of interest. Another embodiment of the invention may process the modified training data to construct a model that predicts the property of interest for arbitrary compounds.1-10. (canceled) 11. A method for training a molecular properties model, comprising:
obtaining a pseudo-partial ordering of molecules, wherein the pseudo partial ordering includes at least a representation of a first and second molecule, ordered relative to one another and a property of interest; and generating a representation of the molecules included in the pseudo partial ordering of molecules that is appropriate for a selected machine learning algorithm, wherein the pseudo partial ordering of molecules is provided to the selected machine learning algorithm, and wherein executing the selected machine learning algorithm, using the pseudo partial ordering, trains a molecular properties model configured to generate a prediction regarding additional molecules supplied to the model. 12. The method of claim 11, wherein the molecular properties model generates predictions related to a property of interest selected from at least one of a pharmacokinetic property, pharmacodynamic property, physiological or pharmacological activity, toxicity or selectivity; a chemical property including reactivity, binding affinity, pKa, or a property of a specific atom or bond in a molecule; or a physical property including melting point, solubility, a membrane permeability, and a force-field parameter. 13. The method of claim 11, wherein the selected machine learning algorithm comprises a classification learning algorithm. 14. The method of claim 11, wherein the selected machine learning algorithm comprises a kernel based learning algorithm. 15. The method of claim 11, wherein the selected machine learning algorithm comprises a variant of a Boosting algorithm, RankBoost algorithm, Alternating Decision Trees algorithm, Support Vector Machines algorithm, a Perceptron algorithm, Winnow, a Hedge Algorithm, decision trees, neural networks, genetic algorithms, genetic programming or any modifications thereof modified to process the pseudo partial ordering of ranked pairs. 16. The method of claim 11, wherein the selected machine learning algorithm is configured to minimize, either directly or indirectly, an area above, or below, a receiver operator characteristic curve. 17. The method of claim 11, wherein the selected machine learning algorithm is configured to minimize, either directly or indirectly, a function of the rank ordering of molecules in the pseudo partial ordering. 18. The method of claim 11, further comprising, determining an accuracy of the prediction for the additional molecule by carrying out laboratory experimentation using physically existing samples of the additional molecule, or by performing a research study using physical samples of the additional molecule. 19. The method of claim 11, wherein generating the representation of the molecules included in the pseudo partial ordering of molecules comprises: generating a vector representation of the molecules, wherein the vector representation is configured to encode the structure of the molecules included the pseudo-partial ordering; or comprises generating an n-point pharmacophore representation of the molecules included in the pseudo-partial ordering. 20. The method of claim 11, wherein a threshold value or cutoff molecule is selected for the molecular proprieties model and used to create a classification model. 21. The method of claim 11, wherein the at least one additional molecule comprises two or more additional molecules, and wherein the prediction comprises a ranked ordering of the two or more additional molecules, relative to one another and to the property of interest. 22. The method of claim 11, wherein at least two of the molecules in the training set are alternative representations of the same physical molecule and the property of interest is a property of the alternative representations. 23. The method of claim 11, wherein at least two of the molecules in the training set are encoded to represent different atoms, bonds or substituent groups of the same molecule and the property of interest is a property of the atoms, bonds or substituent groups. 24-34. (canceled) 35. A computer-storage medium containing a program which, when executed by a processor, performs a method for training a molecular properties model, comprising:
receiving a pseudo-partial ordering of molecules, wherein the pseudo partial ordering includes at least a representation of a first and second molecule, ordered relative to one another and a property of interest; and generating a representation of the molecules included in the pseudo partial ordering of molecules that is appropriate for a selected machine learning algorithm, wherein the pseudo partial ordering of molecules is provided to the selected machine learning algorithm, and wherein executing the selected machine learning algorithm, using the pseudo partial ordering, trains a molecular properties model configured to generate a prediction regarding additional molecules supplied to the model. 36-40. (canceled) | 1,600 |
1,192 | 16,285,457 | 1,649 | Methods and compositions are disclosed for enhancing neurogenesis, resolving neuropathy and improving neurological health and functioning using fungal extracts and their active ingredients, including species of mushrooms and mycelia containing psilocybin and psilocin, combined with erinacines and hericenones or fungal extracts containing those active ingredients, with the addition of nicotinic acid. The compositions may optionally be combined with nervine plants. | 1. A composition comprising:
0.1 mg to 10 mg of psilocybin, psilocin, baeocystin, norbaeocystin, salts thereof, or combinations thereof, or about 0.1 gram to 1 gram of psilocybin mushrooms, or combinations thereof; 0.1 mg to 200 mg of erinacines, hericenones or combinations thereof; and 1 mg to 200 mg of niacin. 2. The composition method of claim 1, wherein the composition further comprises: extracts of Bacopa species (Bacopa monnien), Gotu kola (Centella asiatica), Gingko (Gingko biloba), Ginger (Zingiber officinale), Holy Basil (Ocimum sanctum), Hu Zhang (Polygonum cuspid atum), Oregano (Origanum vulgare, Origanum onites), Rosemary (Rosmarinus officinalis, Rosmarinus eriocalyx, Rosmarinus species), Turmeric (Curcuma longa), Green Tea (Camellia sinensis), lavender (Lavandula spica and Lavandula species), skullcap (Scutellaria lateriflora), oat straw (Avena sativa and Avena byzantine), Diviner's Sage (Salvia divinorum), ayahuasca (Banisteriopsis caapi and Psychotria species), Tabemanthe iboga, Voacanga africana, Tabemaemontana undulate, peyote (Lophophora williamsil), morning glory (Ipomoea tricolor, Argyreia nervosa), Cannabis sativa, Cannabis indica or Cannabis ruderalis, or combinations thereof. 3. The composition of claim 1, wherein the composition further comprises: mycelium of Antrodia, Beauveria, Copelandia, Cordyceps, Ganoderma, Grifola, Hericium, Inonotus, Isaria, Panaeolus or Phellinus fungi, or combinations thereof; a mycelium extract of Antrodia, Beauveria, Copelandia, Cordyceps, Ganoderma, Grifola, Hericium, Inonotus, Isaria, Panaeolus or Phellinus, or combinations; or a fruitbody extract of Antrodia, Beauveria, Copelandia, Cordyceps, Ganoderma, Grifola, Hericium, Inonotus, Isaria, Panaeolus or Phellinus, or combinations thereof. 4. A method for improving neurological health of an animal comprising: administering the composition of claim 1. 5. The method of claim 4, wherein the animal is a human. 6. The method of claim 5, wherein the administration results in one or more of improved memory and cognition, improved motor skills and coordination, improved sensory function, improved learning, or promotion of neurogenesis. 7. A composition comprising:
about 0.1 mg to 10 mg of psilocybin, psilocin, baeocystin, norbaeocystin, or salts thereof, or about 0.1 gram to 1 gram of psilocybin mushrooms, or combinations thereof; about 0.1 mg to 200 mg of erinacines, hericenones, or combinations thereof; about 100 mg of Cannabis extracts comprising cannabidiol; and about 1 mg to 200 mg of niacin. 8. The composition method of claim 7, wherein the composition comprises:
about 0.6 mg to 10 mg of one or more of psilocybin, psilocin, baeocystin, norbaeocystin, salts thereof, or combinations thereof; about 20 mg to 200 mg of one or more of erinacines, hericenones, or combinations thereof; about 100 mg of Cannabis extracts comprising cannabidiol; and about 50 mg to 200 mg of niacin. 9. The composition method of claim 7, wherein the composition comprises:
about 0.9 mg to 10 mg of one or more of psilocybin, psilocin, baeocystin, norbaeocystin, salts thereof, or combinations thereof; about 50 mg to 200 mg of one or more of erinacines, hericenones, or combinations thereof; about 100 mg of Cannabis extracts comprising cannabidiol; and about 50 mg to 200 mg of niacin. 10. The composition method of claim 7, wherein the composition further comprises one or more extracts of Bacopa species (Bacopa monnien), Gotu kola (Centella asiatica), Gingko (Gingko biloba), Ginger (Zingiber officinale), Holy Basil (Ocimum sanctum), Hu Zhang (Polygonum cuspid atum), Oregano (Origanum vulgare, Origanum onites), Rosemary (Rosmarinus officinalis, Rosmarinus eriocalyx, Rosmarinus species), Turmeric (Curcuma longa), Green Tea (Camellia sinensis), lavender (Lavandula spica and Lavandula species), skullcap (Scutellaria lateriflora), oat straw (Avena sativa and Avena byzantine), Diviner's Sage (Salvia divinorum), ayahuasca (Banisteriopsis caapi and Psychotria species), Tabemanthe iboga, Voacanga africana, Tabemaemontana undulate, peyote (Lophophora williamsil), morning glory (Ipomoea tricolor, Argyreia nervosa), Cannabis sativa, Cannabis indica or Cannabis ruderalis, or combinations thereof. 11. A method for improving neurological health comprising: administering the composition of claim 7 to a human. 12. The method of claim 11, wherein the administration results in one or more of improved memory and cognition, improved motor skills and coordination, improved sensory function, improved learning, or promotion of neurogenesis. 13. A composition comprising erinacines, hericenones, or combinations thereof; and niacin. 14. A composition comprising extract of Hericium mycelium or mushrooms; and niacin. 15. A composition comprising Cannabis extracts comprising cannabidiol, tetrahydrocannabinol, or combinations thereof; and niacin. 16. A composition comprising:
mycelia, fruitbodies, or extracts thereof of Cordyceps, Ganoderma, Grifola, Hericium, or combinations thereof; and Cannabis extracts comprising cannabidiol, tetrahydrocannabinol, or combinations thereof. 17. The composition of claim 16, further comprising niacin. 18. A method for treating or improving neurological or mental health conditions comprising administration of an effective amount of the composition of claim 16 to a subject in need thereof. 19. The method of claim 16, where the neurological or mental health conditions comprise depression, memory loss, dementia, cognitive dysfunction, hearing loss, vision loss, neurologic pain, or combinations thereof. | Methods and compositions are disclosed for enhancing neurogenesis, resolving neuropathy and improving neurological health and functioning using fungal extracts and their active ingredients, including species of mushrooms and mycelia containing psilocybin and psilocin, combined with erinacines and hericenones or fungal extracts containing those active ingredients, with the addition of nicotinic acid. The compositions may optionally be combined with nervine plants.1. A composition comprising:
0.1 mg to 10 mg of psilocybin, psilocin, baeocystin, norbaeocystin, salts thereof, or combinations thereof, or about 0.1 gram to 1 gram of psilocybin mushrooms, or combinations thereof; 0.1 mg to 200 mg of erinacines, hericenones or combinations thereof; and 1 mg to 200 mg of niacin. 2. The composition method of claim 1, wherein the composition further comprises: extracts of Bacopa species (Bacopa monnien), Gotu kola (Centella asiatica), Gingko (Gingko biloba), Ginger (Zingiber officinale), Holy Basil (Ocimum sanctum), Hu Zhang (Polygonum cuspid atum), Oregano (Origanum vulgare, Origanum onites), Rosemary (Rosmarinus officinalis, Rosmarinus eriocalyx, Rosmarinus species), Turmeric (Curcuma longa), Green Tea (Camellia sinensis), lavender (Lavandula spica and Lavandula species), skullcap (Scutellaria lateriflora), oat straw (Avena sativa and Avena byzantine), Diviner's Sage (Salvia divinorum), ayahuasca (Banisteriopsis caapi and Psychotria species), Tabemanthe iboga, Voacanga africana, Tabemaemontana undulate, peyote (Lophophora williamsil), morning glory (Ipomoea tricolor, Argyreia nervosa), Cannabis sativa, Cannabis indica or Cannabis ruderalis, or combinations thereof. 3. The composition of claim 1, wherein the composition further comprises: mycelium of Antrodia, Beauveria, Copelandia, Cordyceps, Ganoderma, Grifola, Hericium, Inonotus, Isaria, Panaeolus or Phellinus fungi, or combinations thereof; a mycelium extract of Antrodia, Beauveria, Copelandia, Cordyceps, Ganoderma, Grifola, Hericium, Inonotus, Isaria, Panaeolus or Phellinus, or combinations; or a fruitbody extract of Antrodia, Beauveria, Copelandia, Cordyceps, Ganoderma, Grifola, Hericium, Inonotus, Isaria, Panaeolus or Phellinus, or combinations thereof. 4. A method for improving neurological health of an animal comprising: administering the composition of claim 1. 5. The method of claim 4, wherein the animal is a human. 6. The method of claim 5, wherein the administration results in one or more of improved memory and cognition, improved motor skills and coordination, improved sensory function, improved learning, or promotion of neurogenesis. 7. A composition comprising:
about 0.1 mg to 10 mg of psilocybin, psilocin, baeocystin, norbaeocystin, or salts thereof, or about 0.1 gram to 1 gram of psilocybin mushrooms, or combinations thereof; about 0.1 mg to 200 mg of erinacines, hericenones, or combinations thereof; about 100 mg of Cannabis extracts comprising cannabidiol; and about 1 mg to 200 mg of niacin. 8. The composition method of claim 7, wherein the composition comprises:
about 0.6 mg to 10 mg of one or more of psilocybin, psilocin, baeocystin, norbaeocystin, salts thereof, or combinations thereof; about 20 mg to 200 mg of one or more of erinacines, hericenones, or combinations thereof; about 100 mg of Cannabis extracts comprising cannabidiol; and about 50 mg to 200 mg of niacin. 9. The composition method of claim 7, wherein the composition comprises:
about 0.9 mg to 10 mg of one or more of psilocybin, psilocin, baeocystin, norbaeocystin, salts thereof, or combinations thereof; about 50 mg to 200 mg of one or more of erinacines, hericenones, or combinations thereof; about 100 mg of Cannabis extracts comprising cannabidiol; and about 50 mg to 200 mg of niacin. 10. The composition method of claim 7, wherein the composition further comprises one or more extracts of Bacopa species (Bacopa monnien), Gotu kola (Centella asiatica), Gingko (Gingko biloba), Ginger (Zingiber officinale), Holy Basil (Ocimum sanctum), Hu Zhang (Polygonum cuspid atum), Oregano (Origanum vulgare, Origanum onites), Rosemary (Rosmarinus officinalis, Rosmarinus eriocalyx, Rosmarinus species), Turmeric (Curcuma longa), Green Tea (Camellia sinensis), lavender (Lavandula spica and Lavandula species), skullcap (Scutellaria lateriflora), oat straw (Avena sativa and Avena byzantine), Diviner's Sage (Salvia divinorum), ayahuasca (Banisteriopsis caapi and Psychotria species), Tabemanthe iboga, Voacanga africana, Tabemaemontana undulate, peyote (Lophophora williamsil), morning glory (Ipomoea tricolor, Argyreia nervosa), Cannabis sativa, Cannabis indica or Cannabis ruderalis, or combinations thereof. 11. A method for improving neurological health comprising: administering the composition of claim 7 to a human. 12. The method of claim 11, wherein the administration results in one or more of improved memory and cognition, improved motor skills and coordination, improved sensory function, improved learning, or promotion of neurogenesis. 13. A composition comprising erinacines, hericenones, or combinations thereof; and niacin. 14. A composition comprising extract of Hericium mycelium or mushrooms; and niacin. 15. A composition comprising Cannabis extracts comprising cannabidiol, tetrahydrocannabinol, or combinations thereof; and niacin. 16. A composition comprising:
mycelia, fruitbodies, or extracts thereof of Cordyceps, Ganoderma, Grifola, Hericium, or combinations thereof; and Cannabis extracts comprising cannabidiol, tetrahydrocannabinol, or combinations thereof. 17. The composition of claim 16, further comprising niacin. 18. A method for treating or improving neurological or mental health conditions comprising administration of an effective amount of the composition of claim 16 to a subject in need thereof. 19. The method of claim 16, where the neurological or mental health conditions comprise depression, memory loss, dementia, cognitive dysfunction, hearing loss, vision loss, neurologic pain, or combinations thereof. | 1,600 |
1,193 | 15,312,409 | 1,663 | The disclosure relates to improving plant breeding methods by controlling for microbial diversity present in the plant breeding process. | 1. A method for controlling the microbial variability associated with selective plant breeding, comprising:
a) subjecting one or more plants to a growth medium in the presence of a first set of one or more microorganisms; b) selecting one or more plants and/or growth medium following step a); c) acquiring a second set of one or more microorganisms from said one or more plants and/or growth medium selected in step b); d) repeating steps a) to c) one or more times, wherein the second set of one or more microorganisms acquired in step c) is used as the first set of microorganisms in step a) of any successive repeat; e) selecting one or more microorganisms that is associated with imparting a beneficial property to a plant; and f) providing the selected one or more microorganisms to a plant undergoing a selective plant breeding program or a growth medium used to grow said plant during the selective plant breeding program. 2. The method of claim 1, wherein the selected one or more microorganisms is provided as a seed coating to said plant undergoing a selective plant breeding program. 3. The method of claim 1, wherein the selected one or more microorganisms is provided in the form of a granule, plug, liquid drench, topical formulation, or foliar application. 4. The method of claim 1, wherein the one or more microorganisms is provided to the growth medium used to grow said plant undergoing a selective plant breeding program and wherein said provided one or more microorganisms account for approximately at least 1%, or at least 10%, or at least 25%, or at least 50%, or at least 75%, or at least 90% of the total microbial diversity present in said growth medium. 5. The method of claim 1, wherein the one or more microorganisms is provided to the growth medium used to grow said plant undergoing a selective plant breeding program and wherein said provided one or more microorganisms account for approximately at least 1%, or at least 10%, or at least 25%, or at least 50%, or at least 75%, or at least 90% of the total microbial diversity present in said growth medium and wherein said microbial diversity present in the growth medium is maintained from an F1 generation through each successive selective generation. 6. The method of claim 1, wherein the one or more microorganisms is provided to the growth medium used to grow said plant undergoing a selective plant breeding program and wherein said provided one or more microorganisms account for approximately at least 1%, or at least 10%, or at least 25%, or at least 50%, or at least 75%, or at least 90% of the total microbial diversity present in said growth medium and wherein said microbial diversity present in the growth medium is maintained from an F1 generation through each successive selective generation, such that upon reaching at least an F4 generation the microbial diversity in said plant growth medium is at least 90% similar to the microbial diversity found in the growth medium of the F1 generation. 7. The method of claim 1, further comprising:
g) selecting a plant based upon a desired phenotypic or genotypic trait during the course of the selective plant breeding program and simultaneously collecting the microorganisms associated with said plant or plant growth medium. 8. The method of claim 1, further comprising:
g) selecting a plant based upon a desired phenotypic or genotypic trait during the course of the selective plant breeding program and simultaneously collecting the microorganisms associated with said plant or plant growth medium; and h) providing the microorganisms collected from step g) to a plant or plant growth medium utilized in the next subsequent generation of the selective plant breeding program. 9. The method of claim 1, wherein a selective pressure is applied in step a). 10. The method of claim 1, wherein a selective pressure is applied in step a) and wherein the selective pressure is biotic and includes exposing the one or more plants to an organism selected from the group consisting of: fungi, bacteria, viruses, insects, mites, nematodes, and combinations thereof. 11. The method of claim 1, wherein a selective pressure is applied in step a) and wherein the selective pressure is abiotic and includes exposing the one or more plants to an abiotic pressure selected from the group consisting of: salt concentration, temperature, pH, water, minerals, organic nutrients, inorganic nutrients, organic toxins, inorganic toxins, metals, and combinations thereof. 12. The method of claim 1, wherein the selective plant breeding program is conducted in a soil-free or hydroponic system. 13. A method for conducting holobiome plant breeding, comprising:
a) subjecting one or more plants to a growth medium in the presence of a first set of one or more microorganisms; b) selecting one or more plants and/or growth medium following step a); c) acquiring a second set of one or more microorganisms from said one or more plants and/or growth medium selected in step b); d) repeating steps a) to c) one or more times, wherein the second set of one or more microorganisms acquired in step c) is used as the first set of microorganisms in step a) of any successive repeat; e) selecting one or more microorganisms that is associated with imparting a beneficial property to a plant; f) providing the selected one or more microorganisms to a plant undergoing a selective plant breeding program or a growth medium used to grow said plant during the selective plant breeding program; g) selecting a plant based upon a desired phenotypic or genotypic trait during the course of the selective plant breeding program and simultaneously collecting the microorganisms associated with said plant or plant growth medium; and h) providing the microorganisms collected from step g) to a plant or plant growth medium utilized in the next subsequent generation of the selective plant breeding program. 14. A method for conducting holobiome plant breeding, comprising:
a) crossing two plant cultivars to produce F1 hybrid plants; b) selfing the F1 hybrid plants to produce F2 seed; c) planting the F2 seed in soil collected from a region exhibiting a desired environmental property,
wherein said desired environmental property represents an environmental property for which the successive cohort plants of the selective plant breeding process are selected to tolerate;
d) growing the F2 seed under environmental conditions that approximate the desired environmental property; e) selecting F2 plants that exhibit the best phenotypic response to said environmental property and allowing said selected F2 plants to reach maturity and set F3 seed; f) harvesting F3 seed from the selected F2 plants and simultaneously harvesting a microbial community associated with the F2 plants and/or the soil utilized to grow said F2 plants; g) planting the F3 seed in soil from step c) that has been inoculated with the microbial community collected in step f); and h) repeating steps d) to g) one or more times. 15. The method of claim 14, wherein the soil utilized in step g), and any successive repeats of the plant selection process, is autoclaved before being inoculated with the microbial community collected in the preceding step. 16. The method of claim 15, wherein the desired environmental property is selected from the group consisting of: cold temperature, high temperature, high humidity, drought, salinity, low nitrogen, low phosphorous, low photosynthetically active radiation, high elemental metal concentrations, high soil acidity, and combinations thereof. 17. The method of claim 15, wherein the soil from step c) is inoculated by applying to said soil a granule, plug, or liquid drench, comprising the harvested microbial community. 18. The method of claim 15, wherein the plant selection process is repeated through the production of F5 seed. 19. The method of claim 15, further comprising: maintaining parental lines as controls through each successive plant selection cycle and said parental lines are grown in the soil from step c), but said soil is not inoculated with a harvested microbial community during successive plant selection cycles. 20. The method of claim 15, further comprising:
maintaining parental lines as controls through each successive plant selection cycle and said parental lines are grown in the soil from step c), but said soil is not inoculated with a harvested microbial community during successive plant selection cycles; and wherein the plant selection process is repeated through the production of F5 seed; and wherein the selected F4 plants that produced the F5 seed demonstrate an increased desired phenotypic response to said environmental property, as compared to the parental line plants. 21. The method of claim 15, further comprising:
h) repeating steps d) to g) through the production of F5 seed; i) planting the harvested F5 seed, and the microbial community harvested in association with the F4 plants and/or the soil utilized to grow said F4 plants that produced the F5 seed, in a replicated field trial; and j) selecting the best performing F5 plants. | The disclosure relates to improving plant breeding methods by controlling for microbial diversity present in the plant breeding process.1. A method for controlling the microbial variability associated with selective plant breeding, comprising:
a) subjecting one or more plants to a growth medium in the presence of a first set of one or more microorganisms; b) selecting one or more plants and/or growth medium following step a); c) acquiring a second set of one or more microorganisms from said one or more plants and/or growth medium selected in step b); d) repeating steps a) to c) one or more times, wherein the second set of one or more microorganisms acquired in step c) is used as the first set of microorganisms in step a) of any successive repeat; e) selecting one or more microorganisms that is associated with imparting a beneficial property to a plant; and f) providing the selected one or more microorganisms to a plant undergoing a selective plant breeding program or a growth medium used to grow said plant during the selective plant breeding program. 2. The method of claim 1, wherein the selected one or more microorganisms is provided as a seed coating to said plant undergoing a selective plant breeding program. 3. The method of claim 1, wherein the selected one or more microorganisms is provided in the form of a granule, plug, liquid drench, topical formulation, or foliar application. 4. The method of claim 1, wherein the one or more microorganisms is provided to the growth medium used to grow said plant undergoing a selective plant breeding program and wherein said provided one or more microorganisms account for approximately at least 1%, or at least 10%, or at least 25%, or at least 50%, or at least 75%, or at least 90% of the total microbial diversity present in said growth medium. 5. The method of claim 1, wherein the one or more microorganisms is provided to the growth medium used to grow said plant undergoing a selective plant breeding program and wherein said provided one or more microorganisms account for approximately at least 1%, or at least 10%, or at least 25%, or at least 50%, or at least 75%, or at least 90% of the total microbial diversity present in said growth medium and wherein said microbial diversity present in the growth medium is maintained from an F1 generation through each successive selective generation. 6. The method of claim 1, wherein the one or more microorganisms is provided to the growth medium used to grow said plant undergoing a selective plant breeding program and wherein said provided one or more microorganisms account for approximately at least 1%, or at least 10%, or at least 25%, or at least 50%, or at least 75%, or at least 90% of the total microbial diversity present in said growth medium and wherein said microbial diversity present in the growth medium is maintained from an F1 generation through each successive selective generation, such that upon reaching at least an F4 generation the microbial diversity in said plant growth medium is at least 90% similar to the microbial diversity found in the growth medium of the F1 generation. 7. The method of claim 1, further comprising:
g) selecting a plant based upon a desired phenotypic or genotypic trait during the course of the selective plant breeding program and simultaneously collecting the microorganisms associated with said plant or plant growth medium. 8. The method of claim 1, further comprising:
g) selecting a plant based upon a desired phenotypic or genotypic trait during the course of the selective plant breeding program and simultaneously collecting the microorganisms associated with said plant or plant growth medium; and h) providing the microorganisms collected from step g) to a plant or plant growth medium utilized in the next subsequent generation of the selective plant breeding program. 9. The method of claim 1, wherein a selective pressure is applied in step a). 10. The method of claim 1, wherein a selective pressure is applied in step a) and wherein the selective pressure is biotic and includes exposing the one or more plants to an organism selected from the group consisting of: fungi, bacteria, viruses, insects, mites, nematodes, and combinations thereof. 11. The method of claim 1, wherein a selective pressure is applied in step a) and wherein the selective pressure is abiotic and includes exposing the one or more plants to an abiotic pressure selected from the group consisting of: salt concentration, temperature, pH, water, minerals, organic nutrients, inorganic nutrients, organic toxins, inorganic toxins, metals, and combinations thereof. 12. The method of claim 1, wherein the selective plant breeding program is conducted in a soil-free or hydroponic system. 13. A method for conducting holobiome plant breeding, comprising:
a) subjecting one or more plants to a growth medium in the presence of a first set of one or more microorganisms; b) selecting one or more plants and/or growth medium following step a); c) acquiring a second set of one or more microorganisms from said one or more plants and/or growth medium selected in step b); d) repeating steps a) to c) one or more times, wherein the second set of one or more microorganisms acquired in step c) is used as the first set of microorganisms in step a) of any successive repeat; e) selecting one or more microorganisms that is associated with imparting a beneficial property to a plant; f) providing the selected one or more microorganisms to a plant undergoing a selective plant breeding program or a growth medium used to grow said plant during the selective plant breeding program; g) selecting a plant based upon a desired phenotypic or genotypic trait during the course of the selective plant breeding program and simultaneously collecting the microorganisms associated with said plant or plant growth medium; and h) providing the microorganisms collected from step g) to a plant or plant growth medium utilized in the next subsequent generation of the selective plant breeding program. 14. A method for conducting holobiome plant breeding, comprising:
a) crossing two plant cultivars to produce F1 hybrid plants; b) selfing the F1 hybrid plants to produce F2 seed; c) planting the F2 seed in soil collected from a region exhibiting a desired environmental property,
wherein said desired environmental property represents an environmental property for which the successive cohort plants of the selective plant breeding process are selected to tolerate;
d) growing the F2 seed under environmental conditions that approximate the desired environmental property; e) selecting F2 plants that exhibit the best phenotypic response to said environmental property and allowing said selected F2 plants to reach maturity and set F3 seed; f) harvesting F3 seed from the selected F2 plants and simultaneously harvesting a microbial community associated with the F2 plants and/or the soil utilized to grow said F2 plants; g) planting the F3 seed in soil from step c) that has been inoculated with the microbial community collected in step f); and h) repeating steps d) to g) one or more times. 15. The method of claim 14, wherein the soil utilized in step g), and any successive repeats of the plant selection process, is autoclaved before being inoculated with the microbial community collected in the preceding step. 16. The method of claim 15, wherein the desired environmental property is selected from the group consisting of: cold temperature, high temperature, high humidity, drought, salinity, low nitrogen, low phosphorous, low photosynthetically active radiation, high elemental metal concentrations, high soil acidity, and combinations thereof. 17. The method of claim 15, wherein the soil from step c) is inoculated by applying to said soil a granule, plug, or liquid drench, comprising the harvested microbial community. 18. The method of claim 15, wherein the plant selection process is repeated through the production of F5 seed. 19. The method of claim 15, further comprising: maintaining parental lines as controls through each successive plant selection cycle and said parental lines are grown in the soil from step c), but said soil is not inoculated with a harvested microbial community during successive plant selection cycles. 20. The method of claim 15, further comprising:
maintaining parental lines as controls through each successive plant selection cycle and said parental lines are grown in the soil from step c), but said soil is not inoculated with a harvested microbial community during successive plant selection cycles; and wherein the plant selection process is repeated through the production of F5 seed; and wherein the selected F4 plants that produced the F5 seed demonstrate an increased desired phenotypic response to said environmental property, as compared to the parental line plants. 21. The method of claim 15, further comprising:
h) repeating steps d) to g) through the production of F5 seed; i) planting the harvested F5 seed, and the microbial community harvested in association with the F4 plants and/or the soil utilized to grow said F4 plants that produced the F5 seed, in a replicated field trial; and j) selecting the best performing F5 plants. | 1,600 |
1,194 | 15,751,889 | 1,619 | Use of a water-soluble polymer having a solubility in water of greater than 5% (m/m) in the pH range of 1 to 13 and which is obtained by free-radically initiated polymerization of a monomer mixture of i) 70 to 90% by weight N-vinylpyrrolidone and ii) 10 to 30% by weight acrylic acid, wherein the sum total of i) and ii) corresponds to 100% by weight, for the formulation of basic active ingredients sparingly soluble in water, wherein the active ingredients in uncharged form or as hydrochloride have a solubility of less than 0.1% (m/m) in water, artificial intestinal juice or gastric juice. | 1. A method of formulating a basic active ingredient sparingly soluble in water comprising adding a water-soluble polymer having a solubility in water of greater than 5% (m/m) in a pH range of 1 to 13 and which is obtained by a free-radically initiated polymerization of a monomer mixture of i) 70 to 90% by weight N-vinylpyrrolidone and ii) 10 to 30% by weight acrylic acid, wherein the sum total of i) and ii) corresponds to 100% by weight, to the basic active ingredient to provide a water-soluble salt, wherein the active ingredient in uncharged form or as hydrochloride has a solubility of less than 0.1% (m/m) in water, artificial intestinal juice, or gastric juice. 2. The method according to claim 1 for solubilizing the basic active ingredient. 3. The method according to claim 1, wherein the active ingredient has at least one and at most two groups capable of salt formation. 4. The method according to claim 1, wherein the water-soluble salt has a higher water solubility than the basic active ingredient and the corresponding hydrochloride of the basic active ingredient. 5. The method according to claim 1, wherein the water-soluble polymer has a solubility in water of greater than 10% (m/m) in the pH range of 1 to 13. 6. The method according to claim 1, wherein the water-soluble polymer in 5% by weight aqueous solution has a Fikentscher K-value of less than 30. 7. The method according to claim 1, wherein the water-soluble polymer in 5% by weight aqueous solution has a Fikentscher K-value of less than 20. 8. The method according to claim 1, comprising a water-soluble polymer which is obtained by free-radically initiated polymerization of a monomer mixture of i) 79 to 81% by weight N-vinylpyrrolidone and ii) 18 to 22% by weight acrylic acid, wherein the sum total of i) and ii) corresponds to 100% by weight. 9. The method according to claim 1, comprising a water-soluble polymer which is obtained by free-radically initiated polymerization of a monomer mixture of i) 80% by weight N-vinylpyrrolidone and ii) 20% by weight acrylic acid, wherein the sum total of i) and ii) corresponds to 100% by weight. 10. The method according to claim 1, wherein the formulation is in the form of a solid solution. 11. The method according to claim 1, wherein the water-soluble polymer acts as binder. 12. A dosage form comprising a water-soluble formulation of an active ingredient sparingly soluble in water and a polymer according to claim 1, wherein the formulation consists of a basic active ingredient, which in uncharged form or as the hydrochloride has a solubility of less than 0.1% (m/m) in water, artificial intestinal juice, or gastric juice, and a water-soluble polymer having a solubility in water of greater than 10% (m/m) in a pH range of 1 to 13 and which is obtained by a free-radically initiated polymerization of a monomer mixture of i) 78 to 82% by weight N-vinylpyrrolidone and ii) 18 to 22% by weight acrylic acid, wherein the sum total of i) and ii) corresponds to 100% by weight. 13. The dosage form according to claim 13, additionally comprising pharmaceutical auxiliaries. 14. The dosage form according to claim 13, prepared by compression. | Use of a water-soluble polymer having a solubility in water of greater than 5% (m/m) in the pH range of 1 to 13 and which is obtained by free-radically initiated polymerization of a monomer mixture of i) 70 to 90% by weight N-vinylpyrrolidone and ii) 10 to 30% by weight acrylic acid, wherein the sum total of i) and ii) corresponds to 100% by weight, for the formulation of basic active ingredients sparingly soluble in water, wherein the active ingredients in uncharged form or as hydrochloride have a solubility of less than 0.1% (m/m) in water, artificial intestinal juice or gastric juice.1. A method of formulating a basic active ingredient sparingly soluble in water comprising adding a water-soluble polymer having a solubility in water of greater than 5% (m/m) in a pH range of 1 to 13 and which is obtained by a free-radically initiated polymerization of a monomer mixture of i) 70 to 90% by weight N-vinylpyrrolidone and ii) 10 to 30% by weight acrylic acid, wherein the sum total of i) and ii) corresponds to 100% by weight, to the basic active ingredient to provide a water-soluble salt, wherein the active ingredient in uncharged form or as hydrochloride has a solubility of less than 0.1% (m/m) in water, artificial intestinal juice, or gastric juice. 2. The method according to claim 1 for solubilizing the basic active ingredient. 3. The method according to claim 1, wherein the active ingredient has at least one and at most two groups capable of salt formation. 4. The method according to claim 1, wherein the water-soluble salt has a higher water solubility than the basic active ingredient and the corresponding hydrochloride of the basic active ingredient. 5. The method according to claim 1, wherein the water-soluble polymer has a solubility in water of greater than 10% (m/m) in the pH range of 1 to 13. 6. The method according to claim 1, wherein the water-soluble polymer in 5% by weight aqueous solution has a Fikentscher K-value of less than 30. 7. The method according to claim 1, wherein the water-soluble polymer in 5% by weight aqueous solution has a Fikentscher K-value of less than 20. 8. The method according to claim 1, comprising a water-soluble polymer which is obtained by free-radically initiated polymerization of a monomer mixture of i) 79 to 81% by weight N-vinylpyrrolidone and ii) 18 to 22% by weight acrylic acid, wherein the sum total of i) and ii) corresponds to 100% by weight. 9. The method according to claim 1, comprising a water-soluble polymer which is obtained by free-radically initiated polymerization of a monomer mixture of i) 80% by weight N-vinylpyrrolidone and ii) 20% by weight acrylic acid, wherein the sum total of i) and ii) corresponds to 100% by weight. 10. The method according to claim 1, wherein the formulation is in the form of a solid solution. 11. The method according to claim 1, wherein the water-soluble polymer acts as binder. 12. A dosage form comprising a water-soluble formulation of an active ingredient sparingly soluble in water and a polymer according to claim 1, wherein the formulation consists of a basic active ingredient, which in uncharged form or as the hydrochloride has a solubility of less than 0.1% (m/m) in water, artificial intestinal juice, or gastric juice, and a water-soluble polymer having a solubility in water of greater than 10% (m/m) in a pH range of 1 to 13 and which is obtained by a free-radically initiated polymerization of a monomer mixture of i) 78 to 82% by weight N-vinylpyrrolidone and ii) 18 to 22% by weight acrylic acid, wherein the sum total of i) and ii) corresponds to 100% by weight. 13. The dosage form according to claim 13, additionally comprising pharmaceutical auxiliaries. 14. The dosage form according to claim 13, prepared by compression. | 1,600 |
1,195 | 16,157,263 | 1,613 | A wipe includes a cleansing composition disposed on a cloth. The cleansing composition can include an antiseptic, a humectant, an emollient, a surfactant, and a monohydric alcohol. A wipe can be made by preparing a cleansing composition and disposing the cleansing composition on a cloth. Two or more wipes may be included in a sealed package to maintain the sterile state of the wipes. A method of disinfecting skin can include applying a wipe to skin. | 1. A wipe comprising:
a nonwoven cloth comprising plural fibers having a denier in the range from 2.6 to 3.7, and a cleansing composition disposed on the cloth, the cleansing composition comprising chlorhexidine gluconate in an amount sufficient to reduce the number of active pathogens present on skin upon contact between the cleansing composition and the skin, a monohydric alcohol in an amount effective to provide a defoaming effect, a wetting agent, and water. 2. A wipe according to claim 1, the cleansing composition comprising chlorhexidine gluconate, isopropyl alcohol, and benzalkonium chloride. 3. A wipe according to claim 1, further comprising dimethicone. 4. A wipe according to claim 1, further comprising a humectant. 5. A wipe according to claim 1, further comprising an additional surfactant. 6. A wipe according to claim 5, the additional surfactant comprising at least one of octoxynol-9 and polysorbate 20. 7. A wipe according to claim 1, the cleansing composition consisting essentially of chlorhexidine gluconate, glycerin, propylene glycol, isopropyl alcohol, dimethicone, and benzalkonium chloride. 8. A wipe according to claim 7, the cleansing composition consisting essentially of chlorhexidine gluconate in an amount ranging from 1 to 3%, glycerin in an amount ranging from 2 to 8%, propylene glycol in an amount ranging from 0.5 to 3%, isopropyl alcohol in an amount ranging from 0.2 to 0.8%, dimethicone in an amount ranging from 0.1% to 0.4%, benzalkonium chloride in an amount ranging from 0.02 to 0.08%, and water. 9. A method of disinfecting skin comprising applying the wipe according to claim 1 to skin. 10. A method according to claim 9, the method comprising applying the wipe according to claim 1 within eight hours prior to a surgical procedure. 11. A package comprising a container having contained therewithin at least two wipes according to claim 1. 12. A method of making a wipe, the method comprising:
preparing a cleansing composition consisting essentially of chlorhexidine gluconate in an amount ranging from 1 to 3%, glycerin in an amount ranging from 2 to 8%, propylene glycol in an amount ranging from 0.5 to 3%, isopropyl alcohol in an amount ranging from 0.2 to 0.8%, dimethicone in an amount ranging from 0.1% to 0.4%, benzalkonium chloride in an amount ranging from 0.02 to 0.08%, and water; and introducing the cleansing composition onto a nonwoven cloth having a denier ranging from 2.6 to 3.7. | A wipe includes a cleansing composition disposed on a cloth. The cleansing composition can include an antiseptic, a humectant, an emollient, a surfactant, and a monohydric alcohol. A wipe can be made by preparing a cleansing composition and disposing the cleansing composition on a cloth. Two or more wipes may be included in a sealed package to maintain the sterile state of the wipes. A method of disinfecting skin can include applying a wipe to skin.1. A wipe comprising:
a nonwoven cloth comprising plural fibers having a denier in the range from 2.6 to 3.7, and a cleansing composition disposed on the cloth, the cleansing composition comprising chlorhexidine gluconate in an amount sufficient to reduce the number of active pathogens present on skin upon contact between the cleansing composition and the skin, a monohydric alcohol in an amount effective to provide a defoaming effect, a wetting agent, and water. 2. A wipe according to claim 1, the cleansing composition comprising chlorhexidine gluconate, isopropyl alcohol, and benzalkonium chloride. 3. A wipe according to claim 1, further comprising dimethicone. 4. A wipe according to claim 1, further comprising a humectant. 5. A wipe according to claim 1, further comprising an additional surfactant. 6. A wipe according to claim 5, the additional surfactant comprising at least one of octoxynol-9 and polysorbate 20. 7. A wipe according to claim 1, the cleansing composition consisting essentially of chlorhexidine gluconate, glycerin, propylene glycol, isopropyl alcohol, dimethicone, and benzalkonium chloride. 8. A wipe according to claim 7, the cleansing composition consisting essentially of chlorhexidine gluconate in an amount ranging from 1 to 3%, glycerin in an amount ranging from 2 to 8%, propylene glycol in an amount ranging from 0.5 to 3%, isopropyl alcohol in an amount ranging from 0.2 to 0.8%, dimethicone in an amount ranging from 0.1% to 0.4%, benzalkonium chloride in an amount ranging from 0.02 to 0.08%, and water. 9. A method of disinfecting skin comprising applying the wipe according to claim 1 to skin. 10. A method according to claim 9, the method comprising applying the wipe according to claim 1 within eight hours prior to a surgical procedure. 11. A package comprising a container having contained therewithin at least two wipes according to claim 1. 12. A method of making a wipe, the method comprising:
preparing a cleansing composition consisting essentially of chlorhexidine gluconate in an amount ranging from 1 to 3%, glycerin in an amount ranging from 2 to 8%, propylene glycol in an amount ranging from 0.5 to 3%, isopropyl alcohol in an amount ranging from 0.2 to 0.8%, dimethicone in an amount ranging from 0.1% to 0.4%, benzalkonium chloride in an amount ranging from 0.02 to 0.08%, and water; and introducing the cleansing composition onto a nonwoven cloth having a denier ranging from 2.6 to 3.7. | 1,600 |
1,196 | 16,115,973 | 1,612 | A process for treating tumors by administering a mixture of cancer fighting drugs incorporated into a stabilized liposomal formulation. Each cancer drug is selected to target a different phase of the cell-cycle of the cancer cell thus expanding the number of cancer cells that can be killed at one time without compromising the safety of the patient. The stabilized multi-drug liposomes are designed to extravasate thru “leaky” blood capillaries supplying the tumor and enter the tumor tissue where they will accumulate over time and ultimately release the mixture of cancer drugs to kill surrounding tumor cells. The multi-drug liposomes are likewise unable to extravasate thru normal blood capillaries and will thus be less toxic to normal tissues. | 1-13. (canceled) 14. A method for forming a pharmaceutical composition for targeting tumor cells based upon their proliferative capacity, the method comprising the steps of:
selecting a first cytotoxic drug based upon that first cytotoxic drug selectively targeting a first phase in the cell-cycle of tumor cells; selecting a second cytotoxic drug based upon that second cytotoxic drug selectively targeting a second phase in the cell-cycle of tumor cells, the second phase in the cell-cycle of tumor cells being different from the first phase in the cell-cycle of tumor cells; and enclosing the first and second cytotoxic drugs within a liposome; wherein the first cytotoxic drug is water soluble and enclosed within an aqueous interior of the liposome; and wherein the second cytotoxic drug is lipid soluble and incorporated into a lipid bilayer of the liposome. 15. The method of claim 14, wherein the liposome further comprises a tumor targeting agent attached to the exterior surface of the liposome. 16. The method of claim 15, wherein the tumor targeting agent is selected from the group consisting of an antibody, a binding peptide, an aptamer, a hormone, a cytokine, a growth factor, and a compound capable of binding to the surface of the tumor cell. 17. The method of claim 14, wherein the first cytotoxic drug and the second cytotoxic drug are small molecule drugs that affect cell-division and/or DNA synthesis and function. 18. The method of claim 17 wherein at least one of the first cytotoxic drug and the second cytotoxic drug are selected from the group consisting of alkylating agents, antimetabolites, anthracyclines, plant alkaloids and topoisomerase inhibitors. 19. The method of claim 14 wherein the liposome is comprised of a mixture of one or more compounds selected from the group consisting of: egg phosphatidylcholine (EPC), hydrogenated egg phosphatidylcholine (HEPC); soy phosphatidylcholine (SPC), hydrogenated soy phosphatidylcholine (HSPC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylinositol (PI), monosialoganglioside and sphingomyelin (SPM); distearoyl-phosphatidylcholine (DSPC), dimyristoyl-phosphatidylcholine (DMPC), dimyristoyl-phosphatidylglycerol (DMPG), and dipalmitoylphosphatidylcholine (DPPC), poly(ethyleneglycol)-derivatized distearoylphosphatidylethanolamine (PEG-DSPE), poly(ethyleneglycol)-derivatized ceramides (PEG-CER), and cholesterol. 20. The method of claim 19 wherein the liposome is stabilized by attaching on or more PEGn-DSPE polymer chains to the exterior surface of the liposome, wherein “n” is the molecular weight of the polymer chains and exceeds 2,000 daltons. 21. The method of claim 16 wherein the targeting agent is an anti-epidermal growth factor 1 receptor antibody, or an aptamer or binding peptide that targets epidermal growth factor 1 receptor. 22. The method of claim 16 wherein the selected targeting agent is an anti-human epidermal growth factor 2 receptor antibody, or an aptamer or binding peptide that targets human epidermal growth factor 2 receptor. 23. The method of claim 16 wherein the selected targeting agent is an anti-nuclear antibody, an aptamer, or a binding peptide, and targets one or more nuclear materials released from dead cells within a tumor selected from the group consisting of: dsDNA, ssDNA, ENA/RNP, Sm and DNP. | A process for treating tumors by administering a mixture of cancer fighting drugs incorporated into a stabilized liposomal formulation. Each cancer drug is selected to target a different phase of the cell-cycle of the cancer cell thus expanding the number of cancer cells that can be killed at one time without compromising the safety of the patient. The stabilized multi-drug liposomes are designed to extravasate thru “leaky” blood capillaries supplying the tumor and enter the tumor tissue where they will accumulate over time and ultimately release the mixture of cancer drugs to kill surrounding tumor cells. The multi-drug liposomes are likewise unable to extravasate thru normal blood capillaries and will thus be less toxic to normal tissues.1-13. (canceled) 14. A method for forming a pharmaceutical composition for targeting tumor cells based upon their proliferative capacity, the method comprising the steps of:
selecting a first cytotoxic drug based upon that first cytotoxic drug selectively targeting a first phase in the cell-cycle of tumor cells; selecting a second cytotoxic drug based upon that second cytotoxic drug selectively targeting a second phase in the cell-cycle of tumor cells, the second phase in the cell-cycle of tumor cells being different from the first phase in the cell-cycle of tumor cells; and enclosing the first and second cytotoxic drugs within a liposome; wherein the first cytotoxic drug is water soluble and enclosed within an aqueous interior of the liposome; and wherein the second cytotoxic drug is lipid soluble and incorporated into a lipid bilayer of the liposome. 15. The method of claim 14, wherein the liposome further comprises a tumor targeting agent attached to the exterior surface of the liposome. 16. The method of claim 15, wherein the tumor targeting agent is selected from the group consisting of an antibody, a binding peptide, an aptamer, a hormone, a cytokine, a growth factor, and a compound capable of binding to the surface of the tumor cell. 17. The method of claim 14, wherein the first cytotoxic drug and the second cytotoxic drug are small molecule drugs that affect cell-division and/or DNA synthesis and function. 18. The method of claim 17 wherein at least one of the first cytotoxic drug and the second cytotoxic drug are selected from the group consisting of alkylating agents, antimetabolites, anthracyclines, plant alkaloids and topoisomerase inhibitors. 19. The method of claim 14 wherein the liposome is comprised of a mixture of one or more compounds selected from the group consisting of: egg phosphatidylcholine (EPC), hydrogenated egg phosphatidylcholine (HEPC); soy phosphatidylcholine (SPC), hydrogenated soy phosphatidylcholine (HSPC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylinositol (PI), monosialoganglioside and sphingomyelin (SPM); distearoyl-phosphatidylcholine (DSPC), dimyristoyl-phosphatidylcholine (DMPC), dimyristoyl-phosphatidylglycerol (DMPG), and dipalmitoylphosphatidylcholine (DPPC), poly(ethyleneglycol)-derivatized distearoylphosphatidylethanolamine (PEG-DSPE), poly(ethyleneglycol)-derivatized ceramides (PEG-CER), and cholesterol. 20. The method of claim 19 wherein the liposome is stabilized by attaching on or more PEGn-DSPE polymer chains to the exterior surface of the liposome, wherein “n” is the molecular weight of the polymer chains and exceeds 2,000 daltons. 21. The method of claim 16 wherein the targeting agent is an anti-epidermal growth factor 1 receptor antibody, or an aptamer or binding peptide that targets epidermal growth factor 1 receptor. 22. The method of claim 16 wherein the selected targeting agent is an anti-human epidermal growth factor 2 receptor antibody, or an aptamer or binding peptide that targets human epidermal growth factor 2 receptor. 23. The method of claim 16 wherein the selected targeting agent is an anti-nuclear antibody, an aptamer, or a binding peptide, and targets one or more nuclear materials released from dead cells within a tumor selected from the group consisting of: dsDNA, ssDNA, ENA/RNP, Sm and DNP. | 1,600 |
1,197 | 15,304,626 | 1,616 | Vitamin E-based amphiphilic copolymers are disclosed. Compositions containing vitamin E-based amphiphilic copolymers and/or nanocarriers are also disclosed. Methods of making vitamin E-based amphiphilic copolymers and/or nanocarriers and methods of using vitamin E-based amphiphilic copolymers and/or nanocarriers are also disclosed. | 1. An amphiphilic copolymer comprising:
polyethylene glycol, and three or more vitamin E units bonded to the polyethylene glycol. 2. A crosslinked amphiphilic copolymer comprising:
polyethylene glycol, and two or more vitamin E units bonded to the polyethylene glycol. 3. The amphiphilic copolymer of claim 2, wherein said amphiphilic copolymer comprises three or more vitamin E units bonded to the polyethylene glycol. 4. The amphiphilic copolymer of any one of claims 1 to 3, wherein said amphiphilic copolymer comprises from four to eight vitamin E units bonded to the polyethylene glycol. 5. The amphiphilic copolymer of any one of claims 1 to 4, wherein said amphiphilic copolymer comprises four vitamin E units bonded to the polyethylene glycol. 6. The amphiphilic copolymer of any one of claims 1 to 5, wherein said polyethylene glycol has a molecular weight of from about 1000 to 500,000. 7. The amphiphilic copolymer of any one of claims 1 to 6, wherein said polyethylene glycol has a molecular weight of from about 5000 to 20,000. 8. The amphiphilic copolymer of any one of claims 1 to 7, wherein each vitamin E unit is bonded to said polyethylene glycol via one or more divalent linkages. 9. The amphiphilic copolymer of any one of claims 1 to 8, said amphiphilic copolymer having a structure:
wherein PEG represents said polyethylene glycol, V represents a given vitamin E unit, K represents a first divalent linkage, and independently each n=0 to 5. 10. The amphiphilic copolymer of any one of claims 1 to 9, said amphiphilic copolymer having a structure: 11. The amphiphilic copolymer of any one of claims 1 to 8, said amphiphilic copolymer having a structure:
wherein PEG represents said polyethylene glycol, V represents a given vitamin E unit, K represents a first divalent linkage, R represents a crosslinking or cationic moiety, independently each m=0 to 5, and independently each n=0 to 20. 12. The amphiphilic copolymer of any one of claims 1 to 8 and 11, said amphiphilic copolymer having a structure: 13. The amphiphilic copolymer of any one of claims 1 to 8, said amphiphilic copolymer having a structure:
wherein PEG represents said polyethylene glycol, V represents a given vitamin E unit, K represents a first divalent linkage, A represents a second divalent linkage, R represents a crosslinking or cationic moiety, independently each m=0 to 5, and independently each n=0 to 20. 14. The amphiphilic copolymer of any one of claims 1 to 8 and 13, said amphiphilic copolymer having a structure: 15. The amphiphilic copolymer of any one of claims 1 to 8, said amphiphilic copolymer having a structure:
wherein PEG represents said polyethylene glycol, V represents a given vitamin E unit, K represents a first divalent linkage, independently each m=0 to 5, and independently each n=0 to 20. 16. The amphiphilic copolymer of any one of claims 1 to 8 and 15, said amphiphilic copolymer having a structure: 17. The amphiphilic copolymer of any one of claims 1 to 8, said amphiphilic copolymer having a structure:
wherein PEG represents said polyethylene glycol, V represents a given vitamin E unit, K represents a first divalent linkage, A represents a second divalent linkage, PEI represents a polyetitylenimine unit, and independently each m=0 to 5. 18. The amphiphilic copolymer of any one of claims 1 to 8 and 17, said amphiphilic copolymer having a structure: 19. The amphiphilic copolymer of any one of claims 8 to 18, wherein each of said one or more divalent linkages independently comprises lysine, Nα-Fmoc-Nε-Boc-L-lysine, or aspartic acid. 20. The amphiphilic copolymer of any one of claims 8 to 19, wherein each K comprises lysine or Nα-Fmoc-Nε-Boc-L-lysine. 21. The amphiphilic copolymer of any one of claims 8 to 20, wherein each K comprises Nα-Fmoc-Nε-Boc-L-lysine. 22. The amphiphilic copolymer of any one of claims 13 to 14 and 17 to 21, wherein each A comprises aspartic acid or β-benzyl-L-aspartate N-carboxy anhydride. 23. The amphiphilic copolymer of any one of claims 13 to 14 and 17 to 22, wherein each A comprises β-benzyl-L-aspartate N-carboxy anhydride. 24. The amphiphilic copolymer of any one of claims 1 to 8, 13 and 19 to 23, said amphiphilic copolymer having a structure:
wherein x equals a number from 0 to 10. 25. The amphiphilic copolymer of any one of claims 9 to 24, wherein each V comprises α-tocopheryloxyacetic acid. 26. The amphiphilic copolymer of any one of claims 1 to 25, wherein each vitamin E unit comprises α-tocopheryloxyacetic acid. 27. The amphiphilic copolymer of any one of claims 11 to 14 and 19 to 26, wherein each R independently comprises thioctic acid, cysteine, diethylenetriamine, triethylenetetramine, tris(2-aminoethyl)amine or N,N-diisopropylethylenediamine. 28. The amphiphilic copolymer of any one of claims 11 to 14 and 19 to 27, wherein each R independently comprises diethylenetriamine, triethylenetetramine, tris(2-aminoethyl)amine or N,N-diisopropylethylenediamine. 29. The amphiphilic copolymer of any one of claims 17 to 20, 22 and 25 to 27, wherein each PEI independently comprises a polyethylenimine unit having a molecular weight ranging from about 200 to about 2500. 30. The amphiphilic copolymer of any one of claims 9 to 29, wherein each PEG is represented by:
H3CO—(CH2CH2O)z—CH2CH2NH—
wherein z ranges from about 25 to 12,500. 31. The amphiphilic copolymer of claim 30, wherein z ranges from about 100 to about 125. 32. The amphiphilic copolymer of any one of claims 2 to 31, wherein said crosslinking amphiphilic copolymer comprises one or more crosslinking moieties bonded to said polyethylene glycol, wherein each crosslinking moiety independently comprises thioctic acid and cysteine. 33. The amphiphilic copolymer of any one of claims 2 to 32, wherein said crosslinked amphiphilic copolymer comprises one or more crosslinking moieties bonded to said polyethylene glycol, wherein each crosslinking moiety comprises thioctic acid. 34. A nanocarrier comprising one or more amphiphilic copolymers, wherein each amphiphilic copolymer independently comprises the amphiphilic copolymer of any one of claims 1 to 33. 35. The nanocarrier of claim 34, wherein said nanocarrier has an average particle size ranging from about 10 nm to about 1000 nm. 36. A composition comprising (i)(a) one or more amphiphilic copolymers, wherein each amphiphilic copolymer of said composition independently comprises the amphiphilic copolymer of any one of claims 1 to 33 or (i)(b) the nanocarrier of claim 34 or 35, and (ii) at least one biologically active substance combined with the one or more amphiphilic copolymers or the nanocarrier. 37. The composition of claim 36, wherein the at least one biologically active substance comprises a drug, an anti-carcinogenic compound, a nucleic acid, another small molecule, or any combination thereof. 38. The composition of claim 36 or 37, wherein the at least one biologically active substance comprises an anti-carcinogenic compound. 39. The composition of any one of claims 36 to 38, wherein the at least one biologically active substance comprises paclitaxel, docetaxel, carbazitaxel, ixabepilone, eribulin, topotecan, irinotecan, SN-38, doxorubicin, daunorubicin, idarubicin, epirubicin, etoposide, omacetaxine, or any combination thereof. 40. The composition of any one of claims 36 to 39, wherein the at least one biologically active substance comprises paclitaxel. 41. The composition of any one of claims 36 to 40, wherein the at least one biologically active substance comprises let-7 mimic. 42. The composition of any one of claims 36 to 41, wherein the at least one biologically active substance comprises a combination of paclitaxel and let-7 mimic. 43. The composition of claim 42, wherein the combination of paclitaxel and let-7 mimic is present with the amphiphilic copolymer of claim 24 with the paclitaxel being associated with hydrophobic portions of the vitamin E units, and the let-7 mimic being associated with cationic portions of the diethylenetriamine groups. 44. The composition of any one of claims 36 to 43, wherein said composition comprises (1) a first amphiphilic copolymer of any one of claims 1 to 10, 15 to 16, 19 to 21, 25 to 26 and 30 to 31, and (2) a second amphiphilic copolymer of any one of claims 11 to 14 and 17 to 33, the at least one biologically active substance being incorporated within or along at least the second amphiphilic copolymer. 45. The composition of claim 44, wherein the first amphiphilic copolymer comprises the amphiphilic copolymer of claim 10; the second amphiphilic copolymer comprises the amphiphilic copolymer of claim 24; and the at least one biologically active substance comprises paclitaxel and let-7 mimic with the paclitaxel being associated with hydrophobic portions of the vitamin E units, and let-7 mimic being associated with cationic portions of the diethylenetriamine groups. 46. The composition of claim 44 or 45, wherein the first amphiphilic copolymer and the second amphiphilic copolymer are present at a weight ratio of from about 1:1 to about 16:1. 47. The composition of any one of claims 44 to 46, wherein the first amphiphilic copolymer and the second amphiphilic copolymer are present at a weight ratio of about 8:1. 48. The composition of any one of claims 44 to 47, further comprising a third amphiphilic copolymer comprising the amphiphilic copolymer of any one of claims 11 to 12, 19 to 23, 25 to 27 and 30 to 33, wherein R represents a crosslinking moiety. 49. The composition of claim 48, wherein each R represents thioctic acid. 50. The composition of claim 48 or 49, wherein the third amphiphilic copolymer comprises the amphiphilic copolymer of claim 12. 51. The composition of any one of claims 48 to 50, wherein a weight ratio of (i) a combined weight of the first amphiphilic copolymer and the third amphiphilic copolymer to (ii) the second amphiphilic copolymer is from about 1:1 to about 16:1. 52. The composition of any one of claims 48 to 51, wherein a weight ratio of (i) a combined weight of the first amphiphilic copolymer and the third amphiphilic copolymer to (ii) the second amphiphilic copolymer is from about 8:1. 53. The composition of any one of claims 36 to 43, wherein said composition comprises (1) a first amphiphilic copolymer of any one of claims 11 to 12, 19 to 23, 25 to 27 and 30 to 33, wherein R represents a crosslinking moiety, and (2) a second amphiphilic copolymer of any one of claims 11 to 14 and 17 to 33, wherein R represents a cationic moiety, the at least one biologically active substance being incorporated within or along at least the second amphiphilic copolymer. 54. The composition of claim 53, wherein each crosslinking moiety comprises thioctic acid. 55. The composition of claim 53 or 54, wherein each cationic moiety comprises diethylenetriamine. 56. The composition of any one of claims 53 to 55, wherein the first amphiphilic copolymer comprises the amphiphilic copolymer of claim 12; the second amphiphilic copolymer comprises the amphiphilic copolymer of claim 24; and the at least one biologically active substance comprises paclitaxel and let-7 mimic with the paclitaxel being associated with hydrophobic portions of the vitamin E units, and let-7 mimic being associated with cationic portions of the diethylenetriamine groups. 57. The composition of any one of claims 53 to 56, wherein the first amphiphilic copolymer and the second amphiphilic copolymer are present at a weight ratio of from about 1:1 to about 16:1. 58. The composition of any one of claims 53 to 57, wherein the first amphiphilic copolymer and the second amphiphilic copolymer are present at a weight ratio of about 8:1. 59. The composition of any one of claims 36 to 58, further comprising water. 60. The composition of any one of claims 36 to 59, further comprising one or more additional components selected from the group consisting of sodium phosphate, sodium chloride, glucose, HEPES, mannitol, and combinations thereof. 61. The composition of any one of claims 36 to 60, wherein said composition does not contain any organic solvents or surfactants. 62. The composition of any one of claims 36 to 61, wherein each amphiphilic copolymer is present in any amount of up to about 20 mg/mL. 63. The composition of any one of claims 36 to 62, wherein each biologically active substance is present in any amount of up to about 6.0 mM. 64. A method of making the amphiphilic copolymer of any one of claims 1 to 33, the nanocarrier of claim 34 or 35, or the composition of any one of embodiments 36 to 63, said method comprising:
covalently bonding three or more vitamin E units to the polyethylene glycol. 65. The method of claim 64, wherein the covalently bonding step comprises:
reacting a functionalized polyethylene glycol having a terminal amine end group and a terminal carboxyl end group with one or more divalent linkages; and reacting functional groups on the one or more divalent linkages with the three or more vitamin E units. 66. The method of claim 65, wherein the covalently bonding step further comprises:
reacting one or more crosslinking moieties with either the polyethylene glycol, the one or more divalent linkages, or both. 67. The method of any one of claims 64 to 66, further comprising:
combining the at least one biologically active substance with the amphiphilic copolymer or the nanocarrier. 68. The method of claim 67, wherein the at least one biologically active substance comprises paclitaxel, docetaxel, carbazitaxel, ixabepilone, eribulin, topotecan, irinotecan, SN-38, doxorubicin, daunorubicin, idarubicin, epirubicin, etoposide, omacetaxine, or any combination thereof. 69. The method of claim 67 or 68, wherein the at least one biologically active substance comprises paclitaxel. 70. The method of any one of claims 67 to 69, wherein the at least one biologically active substance comprises let-7 mimic. 71. The method of any one of claims 67 to 70, wherein the at least one biologically active substance comprises a combination of paclitaxel and let-7 mimic. 72. The method of claim 71, wherein the combination of paclitaxel and let-7 mimic is combined with the amphiphilic copolymer of claim 24 so that the paclitaxel is associated with hydrophobic portions of the vitamin E units, and the let-7 mimic is associated with cationic portions of the diethylenetriamine groups. 73. The method of any one of claims 64 to 72, said method comprising:
forming a composition comprising (1) a first amphiphilic copolymer of any one of claims 1 to 10, 15 to 16, 19 to 21, 25 to 26 and 30 to 31, and (2) a second amphiphilic copolymer of any one of claims 11 to 14 and 17 to 33, the at least one biologically active substance being incorporated within or along at least the second amphiphilic copolymer. 74. The method of claim 73, wherein the first amphiphilic copolymer comprises the amphiphilic copolymer of claim 10; the second amphiphilic copolymer comprises the amphiphilic copolymer of claim 24; and the at least one biologically active substance comprises paclitaxel and let-7 mimic with the paclitaxel being associated with hydrophobic portions of the vitamin E units, and let-7 mimic being associated with cationic portions of the diethylenetriamine groups. 75. The method of claim 73 or 74, wherein the first amphiphilic copolymer and the second amphiphilic copolymer are present at a weight ratio of from about 1:1 to about 16:1. 76. The method of any one of claims 73 to 75, wherein the first amphiphilic copolymer and the second amphiphilic copolymer are present at a weight ratio of about 8:1. 77. The method of any one of claims 73 to 76, further comprising:
forming the composition with a third amphiphilic copolymer comprising the amphiphilic copolymer of any one of claims 11 to 12, 19 to 23, 25 to 27 and 30 to 33, wherein R represents a crosslinking moiety. 78. The method of claim 77, wherein each R represents thioctic acid. 79. The method of claim 77 or 78, wherein the third amphiphilic copolymer comprises the amphiphilic copolymer of claim 12. 80. The method of any one of claims 77 to 79, wherein a weight ratio of (i) a combined weight of the first amphiphilic copolymer and the third amphiphilic copolymer to (ii) the second amphiphilic copolymer is from about 1:1 to about 16:1. 81. The method of any one of claims 77 to 80, wherein a weight ratio of (i) a combined weight of the first amphiphilic copolymer and the third amphiphilic copolymer to (ii) the second amphiphilic copolymer is from about 8:1. 82. The method of any one of claims 64 to 72, said method comprising:
forming a composition comprising (1) a first amphiphilic copolymer of any one of claims 11 to 12, 19 to 23, 25 to 27 and 30 to 33, wherein R represents a crosslinking moiety, and (2) a second amphiphilic copolymer of any one of claims 11 to 14 and 17 to 33, wherein R represents a cationic moiety, the at least one biologically active substance being incorporated within or along at least the second amphiphilic copolymer. 83. The method of claim 82, wherein each crosslinking moiety comprises thioctic acid. 84. The method of claim 82 or 83, wherein each cationic moiety comprises diethylenetriamine. 85. The method of any one of claims 82 to 84, wherein the first amphiphilic copolymer comprises the amphiphilic copolymer of claim 12; the second amphiphilic copolymer comprises the amphiphilic copolymer of claim 24; and the at least one biologically active substance comprises paclitaxel and let-7 mimic with the paclitaxel being associated with hydrophobic portions of the vitamin E units, and let-7 mimic being associated with cationic portions of the diethylenetriamine groups. 86. The method of any one of claims 82 to 85, wherein the first amphiphilic copolymer and the second amphiphilic copolymer are present at a weight ratio of from about 1:1 to about 16:1. 87. The method of any one of claims 82 to 86, wherein the first amphiphilic copolymer and the second amphiphilic copolymer are present at a weight ratio of about 8:1. 88. The method of any one of claims 64 to 87, further comprising:
incorporating the at least one biologically active substance and each amphiphilic copolymer or nanocarrier into an aqueous solution. 89. A method of delivering one or more drugs to a patient, said method comprising:
administering an effective amount of the amphiphilic copolymer of any one of claims 1 to 33, the nanocarrier of claim 34 or 35, or the composition of any one of claims 36 to 63 to the patient. | Vitamin E-based amphiphilic copolymers are disclosed. Compositions containing vitamin E-based amphiphilic copolymers and/or nanocarriers are also disclosed. Methods of making vitamin E-based amphiphilic copolymers and/or nanocarriers and methods of using vitamin E-based amphiphilic copolymers and/or nanocarriers are also disclosed.1. An amphiphilic copolymer comprising:
polyethylene glycol, and three or more vitamin E units bonded to the polyethylene glycol. 2. A crosslinked amphiphilic copolymer comprising:
polyethylene glycol, and two or more vitamin E units bonded to the polyethylene glycol. 3. The amphiphilic copolymer of claim 2, wherein said amphiphilic copolymer comprises three or more vitamin E units bonded to the polyethylene glycol. 4. The amphiphilic copolymer of any one of claims 1 to 3, wherein said amphiphilic copolymer comprises from four to eight vitamin E units bonded to the polyethylene glycol. 5. The amphiphilic copolymer of any one of claims 1 to 4, wherein said amphiphilic copolymer comprises four vitamin E units bonded to the polyethylene glycol. 6. The amphiphilic copolymer of any one of claims 1 to 5, wherein said polyethylene glycol has a molecular weight of from about 1000 to 500,000. 7. The amphiphilic copolymer of any one of claims 1 to 6, wherein said polyethylene glycol has a molecular weight of from about 5000 to 20,000. 8. The amphiphilic copolymer of any one of claims 1 to 7, wherein each vitamin E unit is bonded to said polyethylene glycol via one or more divalent linkages. 9. The amphiphilic copolymer of any one of claims 1 to 8, said amphiphilic copolymer having a structure:
wherein PEG represents said polyethylene glycol, V represents a given vitamin E unit, K represents a first divalent linkage, and independently each n=0 to 5. 10. The amphiphilic copolymer of any one of claims 1 to 9, said amphiphilic copolymer having a structure: 11. The amphiphilic copolymer of any one of claims 1 to 8, said amphiphilic copolymer having a structure:
wherein PEG represents said polyethylene glycol, V represents a given vitamin E unit, K represents a first divalent linkage, R represents a crosslinking or cationic moiety, independently each m=0 to 5, and independently each n=0 to 20. 12. The amphiphilic copolymer of any one of claims 1 to 8 and 11, said amphiphilic copolymer having a structure: 13. The amphiphilic copolymer of any one of claims 1 to 8, said amphiphilic copolymer having a structure:
wherein PEG represents said polyethylene glycol, V represents a given vitamin E unit, K represents a first divalent linkage, A represents a second divalent linkage, R represents a crosslinking or cationic moiety, independently each m=0 to 5, and independently each n=0 to 20. 14. The amphiphilic copolymer of any one of claims 1 to 8 and 13, said amphiphilic copolymer having a structure: 15. The amphiphilic copolymer of any one of claims 1 to 8, said amphiphilic copolymer having a structure:
wherein PEG represents said polyethylene glycol, V represents a given vitamin E unit, K represents a first divalent linkage, independently each m=0 to 5, and independently each n=0 to 20. 16. The amphiphilic copolymer of any one of claims 1 to 8 and 15, said amphiphilic copolymer having a structure: 17. The amphiphilic copolymer of any one of claims 1 to 8, said amphiphilic copolymer having a structure:
wherein PEG represents said polyethylene glycol, V represents a given vitamin E unit, K represents a first divalent linkage, A represents a second divalent linkage, PEI represents a polyetitylenimine unit, and independently each m=0 to 5. 18. The amphiphilic copolymer of any one of claims 1 to 8 and 17, said amphiphilic copolymer having a structure: 19. The amphiphilic copolymer of any one of claims 8 to 18, wherein each of said one or more divalent linkages independently comprises lysine, Nα-Fmoc-Nε-Boc-L-lysine, or aspartic acid. 20. The amphiphilic copolymer of any one of claims 8 to 19, wherein each K comprises lysine or Nα-Fmoc-Nε-Boc-L-lysine. 21. The amphiphilic copolymer of any one of claims 8 to 20, wherein each K comprises Nα-Fmoc-Nε-Boc-L-lysine. 22. The amphiphilic copolymer of any one of claims 13 to 14 and 17 to 21, wherein each A comprises aspartic acid or β-benzyl-L-aspartate N-carboxy anhydride. 23. The amphiphilic copolymer of any one of claims 13 to 14 and 17 to 22, wherein each A comprises β-benzyl-L-aspartate N-carboxy anhydride. 24. The amphiphilic copolymer of any one of claims 1 to 8, 13 and 19 to 23, said amphiphilic copolymer having a structure:
wherein x equals a number from 0 to 10. 25. The amphiphilic copolymer of any one of claims 9 to 24, wherein each V comprises α-tocopheryloxyacetic acid. 26. The amphiphilic copolymer of any one of claims 1 to 25, wherein each vitamin E unit comprises α-tocopheryloxyacetic acid. 27. The amphiphilic copolymer of any one of claims 11 to 14 and 19 to 26, wherein each R independently comprises thioctic acid, cysteine, diethylenetriamine, triethylenetetramine, tris(2-aminoethyl)amine or N,N-diisopropylethylenediamine. 28. The amphiphilic copolymer of any one of claims 11 to 14 and 19 to 27, wherein each R independently comprises diethylenetriamine, triethylenetetramine, tris(2-aminoethyl)amine or N,N-diisopropylethylenediamine. 29. The amphiphilic copolymer of any one of claims 17 to 20, 22 and 25 to 27, wherein each PEI independently comprises a polyethylenimine unit having a molecular weight ranging from about 200 to about 2500. 30. The amphiphilic copolymer of any one of claims 9 to 29, wherein each PEG is represented by:
H3CO—(CH2CH2O)z—CH2CH2NH—
wherein z ranges from about 25 to 12,500. 31. The amphiphilic copolymer of claim 30, wherein z ranges from about 100 to about 125. 32. The amphiphilic copolymer of any one of claims 2 to 31, wherein said crosslinking amphiphilic copolymer comprises one or more crosslinking moieties bonded to said polyethylene glycol, wherein each crosslinking moiety independently comprises thioctic acid and cysteine. 33. The amphiphilic copolymer of any one of claims 2 to 32, wherein said crosslinked amphiphilic copolymer comprises one or more crosslinking moieties bonded to said polyethylene glycol, wherein each crosslinking moiety comprises thioctic acid. 34. A nanocarrier comprising one or more amphiphilic copolymers, wherein each amphiphilic copolymer independently comprises the amphiphilic copolymer of any one of claims 1 to 33. 35. The nanocarrier of claim 34, wherein said nanocarrier has an average particle size ranging from about 10 nm to about 1000 nm. 36. A composition comprising (i)(a) one or more amphiphilic copolymers, wherein each amphiphilic copolymer of said composition independently comprises the amphiphilic copolymer of any one of claims 1 to 33 or (i)(b) the nanocarrier of claim 34 or 35, and (ii) at least one biologically active substance combined with the one or more amphiphilic copolymers or the nanocarrier. 37. The composition of claim 36, wherein the at least one biologically active substance comprises a drug, an anti-carcinogenic compound, a nucleic acid, another small molecule, or any combination thereof. 38. The composition of claim 36 or 37, wherein the at least one biologically active substance comprises an anti-carcinogenic compound. 39. The composition of any one of claims 36 to 38, wherein the at least one biologically active substance comprises paclitaxel, docetaxel, carbazitaxel, ixabepilone, eribulin, topotecan, irinotecan, SN-38, doxorubicin, daunorubicin, idarubicin, epirubicin, etoposide, omacetaxine, or any combination thereof. 40. The composition of any one of claims 36 to 39, wherein the at least one biologically active substance comprises paclitaxel. 41. The composition of any one of claims 36 to 40, wherein the at least one biologically active substance comprises let-7 mimic. 42. The composition of any one of claims 36 to 41, wherein the at least one biologically active substance comprises a combination of paclitaxel and let-7 mimic. 43. The composition of claim 42, wherein the combination of paclitaxel and let-7 mimic is present with the amphiphilic copolymer of claim 24 with the paclitaxel being associated with hydrophobic portions of the vitamin E units, and the let-7 mimic being associated with cationic portions of the diethylenetriamine groups. 44. The composition of any one of claims 36 to 43, wherein said composition comprises (1) a first amphiphilic copolymer of any one of claims 1 to 10, 15 to 16, 19 to 21, 25 to 26 and 30 to 31, and (2) a second amphiphilic copolymer of any one of claims 11 to 14 and 17 to 33, the at least one biologically active substance being incorporated within or along at least the second amphiphilic copolymer. 45. The composition of claim 44, wherein the first amphiphilic copolymer comprises the amphiphilic copolymer of claim 10; the second amphiphilic copolymer comprises the amphiphilic copolymer of claim 24; and the at least one biologically active substance comprises paclitaxel and let-7 mimic with the paclitaxel being associated with hydrophobic portions of the vitamin E units, and let-7 mimic being associated with cationic portions of the diethylenetriamine groups. 46. The composition of claim 44 or 45, wherein the first amphiphilic copolymer and the second amphiphilic copolymer are present at a weight ratio of from about 1:1 to about 16:1. 47. The composition of any one of claims 44 to 46, wherein the first amphiphilic copolymer and the second amphiphilic copolymer are present at a weight ratio of about 8:1. 48. The composition of any one of claims 44 to 47, further comprising a third amphiphilic copolymer comprising the amphiphilic copolymer of any one of claims 11 to 12, 19 to 23, 25 to 27 and 30 to 33, wherein R represents a crosslinking moiety. 49. The composition of claim 48, wherein each R represents thioctic acid. 50. The composition of claim 48 or 49, wherein the third amphiphilic copolymer comprises the amphiphilic copolymer of claim 12. 51. The composition of any one of claims 48 to 50, wherein a weight ratio of (i) a combined weight of the first amphiphilic copolymer and the third amphiphilic copolymer to (ii) the second amphiphilic copolymer is from about 1:1 to about 16:1. 52. The composition of any one of claims 48 to 51, wherein a weight ratio of (i) a combined weight of the first amphiphilic copolymer and the third amphiphilic copolymer to (ii) the second amphiphilic copolymer is from about 8:1. 53. The composition of any one of claims 36 to 43, wherein said composition comprises (1) a first amphiphilic copolymer of any one of claims 11 to 12, 19 to 23, 25 to 27 and 30 to 33, wherein R represents a crosslinking moiety, and (2) a second amphiphilic copolymer of any one of claims 11 to 14 and 17 to 33, wherein R represents a cationic moiety, the at least one biologically active substance being incorporated within or along at least the second amphiphilic copolymer. 54. The composition of claim 53, wherein each crosslinking moiety comprises thioctic acid. 55. The composition of claim 53 or 54, wherein each cationic moiety comprises diethylenetriamine. 56. The composition of any one of claims 53 to 55, wherein the first amphiphilic copolymer comprises the amphiphilic copolymer of claim 12; the second amphiphilic copolymer comprises the amphiphilic copolymer of claim 24; and the at least one biologically active substance comprises paclitaxel and let-7 mimic with the paclitaxel being associated with hydrophobic portions of the vitamin E units, and let-7 mimic being associated with cationic portions of the diethylenetriamine groups. 57. The composition of any one of claims 53 to 56, wherein the first amphiphilic copolymer and the second amphiphilic copolymer are present at a weight ratio of from about 1:1 to about 16:1. 58. The composition of any one of claims 53 to 57, wherein the first amphiphilic copolymer and the second amphiphilic copolymer are present at a weight ratio of about 8:1. 59. The composition of any one of claims 36 to 58, further comprising water. 60. The composition of any one of claims 36 to 59, further comprising one or more additional components selected from the group consisting of sodium phosphate, sodium chloride, glucose, HEPES, mannitol, and combinations thereof. 61. The composition of any one of claims 36 to 60, wherein said composition does not contain any organic solvents or surfactants. 62. The composition of any one of claims 36 to 61, wherein each amphiphilic copolymer is present in any amount of up to about 20 mg/mL. 63. The composition of any one of claims 36 to 62, wherein each biologically active substance is present in any amount of up to about 6.0 mM. 64. A method of making the amphiphilic copolymer of any one of claims 1 to 33, the nanocarrier of claim 34 or 35, or the composition of any one of embodiments 36 to 63, said method comprising:
covalently bonding three or more vitamin E units to the polyethylene glycol. 65. The method of claim 64, wherein the covalently bonding step comprises:
reacting a functionalized polyethylene glycol having a terminal amine end group and a terminal carboxyl end group with one or more divalent linkages; and reacting functional groups on the one or more divalent linkages with the three or more vitamin E units. 66. The method of claim 65, wherein the covalently bonding step further comprises:
reacting one or more crosslinking moieties with either the polyethylene glycol, the one or more divalent linkages, or both. 67. The method of any one of claims 64 to 66, further comprising:
combining the at least one biologically active substance with the amphiphilic copolymer or the nanocarrier. 68. The method of claim 67, wherein the at least one biologically active substance comprises paclitaxel, docetaxel, carbazitaxel, ixabepilone, eribulin, topotecan, irinotecan, SN-38, doxorubicin, daunorubicin, idarubicin, epirubicin, etoposide, omacetaxine, or any combination thereof. 69. The method of claim 67 or 68, wherein the at least one biologically active substance comprises paclitaxel. 70. The method of any one of claims 67 to 69, wherein the at least one biologically active substance comprises let-7 mimic. 71. The method of any one of claims 67 to 70, wherein the at least one biologically active substance comprises a combination of paclitaxel and let-7 mimic. 72. The method of claim 71, wherein the combination of paclitaxel and let-7 mimic is combined with the amphiphilic copolymer of claim 24 so that the paclitaxel is associated with hydrophobic portions of the vitamin E units, and the let-7 mimic is associated with cationic portions of the diethylenetriamine groups. 73. The method of any one of claims 64 to 72, said method comprising:
forming a composition comprising (1) a first amphiphilic copolymer of any one of claims 1 to 10, 15 to 16, 19 to 21, 25 to 26 and 30 to 31, and (2) a second amphiphilic copolymer of any one of claims 11 to 14 and 17 to 33, the at least one biologically active substance being incorporated within or along at least the second amphiphilic copolymer. 74. The method of claim 73, wherein the first amphiphilic copolymer comprises the amphiphilic copolymer of claim 10; the second amphiphilic copolymer comprises the amphiphilic copolymer of claim 24; and the at least one biologically active substance comprises paclitaxel and let-7 mimic with the paclitaxel being associated with hydrophobic portions of the vitamin E units, and let-7 mimic being associated with cationic portions of the diethylenetriamine groups. 75. The method of claim 73 or 74, wherein the first amphiphilic copolymer and the second amphiphilic copolymer are present at a weight ratio of from about 1:1 to about 16:1. 76. The method of any one of claims 73 to 75, wherein the first amphiphilic copolymer and the second amphiphilic copolymer are present at a weight ratio of about 8:1. 77. The method of any one of claims 73 to 76, further comprising:
forming the composition with a third amphiphilic copolymer comprising the amphiphilic copolymer of any one of claims 11 to 12, 19 to 23, 25 to 27 and 30 to 33, wherein R represents a crosslinking moiety. 78. The method of claim 77, wherein each R represents thioctic acid. 79. The method of claim 77 or 78, wherein the third amphiphilic copolymer comprises the amphiphilic copolymer of claim 12. 80. The method of any one of claims 77 to 79, wherein a weight ratio of (i) a combined weight of the first amphiphilic copolymer and the third amphiphilic copolymer to (ii) the second amphiphilic copolymer is from about 1:1 to about 16:1. 81. The method of any one of claims 77 to 80, wherein a weight ratio of (i) a combined weight of the first amphiphilic copolymer and the third amphiphilic copolymer to (ii) the second amphiphilic copolymer is from about 8:1. 82. The method of any one of claims 64 to 72, said method comprising:
forming a composition comprising (1) a first amphiphilic copolymer of any one of claims 11 to 12, 19 to 23, 25 to 27 and 30 to 33, wherein R represents a crosslinking moiety, and (2) a second amphiphilic copolymer of any one of claims 11 to 14 and 17 to 33, wherein R represents a cationic moiety, the at least one biologically active substance being incorporated within or along at least the second amphiphilic copolymer. 83. The method of claim 82, wherein each crosslinking moiety comprises thioctic acid. 84. The method of claim 82 or 83, wherein each cationic moiety comprises diethylenetriamine. 85. The method of any one of claims 82 to 84, wherein the first amphiphilic copolymer comprises the amphiphilic copolymer of claim 12; the second amphiphilic copolymer comprises the amphiphilic copolymer of claim 24; and the at least one biologically active substance comprises paclitaxel and let-7 mimic with the paclitaxel being associated with hydrophobic portions of the vitamin E units, and let-7 mimic being associated with cationic portions of the diethylenetriamine groups. 86. The method of any one of claims 82 to 85, wherein the first amphiphilic copolymer and the second amphiphilic copolymer are present at a weight ratio of from about 1:1 to about 16:1. 87. The method of any one of claims 82 to 86, wherein the first amphiphilic copolymer and the second amphiphilic copolymer are present at a weight ratio of about 8:1. 88. The method of any one of claims 64 to 87, further comprising:
incorporating the at least one biologically active substance and each amphiphilic copolymer or nanocarrier into an aqueous solution. 89. A method of delivering one or more drugs to a patient, said method comprising:
administering an effective amount of the amphiphilic copolymer of any one of claims 1 to 33, the nanocarrier of claim 34 or 35, or the composition of any one of claims 36 to 63 to the patient. | 1,600 |
1,198 | 16,456,177 | 1,642 | The present invention relates to duocarmycin-containing antibody-drug conjugates (ADCs) for use in the treatment of human solid tumours and haematological malignancies expressing HER2, in particular breast cancer, gastric cancer, bladder cancer, ovarian cancer, lung cancer, prostate cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell cancer or osteosarcoma, and acute lymphoblastic leukaemia. In particular, the present invention relates to duocarmycin-containing ADCs for use in the treatment of human solid tumours with HER2 IHC 2+ or 1+ and HER2 FISH negative tissue status. Advantageously, the present invention relates to duocarmycin-containing ADCs for use in the treatment of triple negative breast cancer (TNBC). | 1-15. (canceled) 16. A method of treating bladder cancer in a human patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I)
wherein
anti-HER2 Ab is an anti-HER2 antibody or antibody fragment able to bind HER2,
n is 0, 1, 2, or 3,
m represents an average DAR of from 1 to 4,
R1 is selected from the group consisting of
y is 1-16, and
R2 is selected from the group consisting of
and
wherein the patient has HER2 expressing bladder cancer. 17. The method according to claim 16, wherein
n is 0 or 1, R1 is selected from the group consisting of
and
R2 is 18. The method according to claim 17, wherein
anti-HER2 Ab is an anti-HER2 monoclonal antibody, m represents an average DAR of from 2 to 3, R1 is
and
y is 1, 2, 3, or 4. 19. The method according to claim 16, wherein said bladder cancer is HER2 positive. 20. The method according to claim 19, wherein said bladder cancer is IHC 3+. 21. The method according to claim 16, wherein said anti-HER2 Ab is trastuzumab. 22. The method according to claim 16, wherein the compound of formula (I) is a compound of formula (II) 23. The method according to claim 22, wherein the compound of formula (II) has an average DAR of from 2.5 to 2.9. 24. The method according to claim 22, wherein the compound of formula (II) has an average DAR of from 2.6 to 2.9. 25. The method according to claim 16, further comprising administering an effective amount of a therapeutic antibody or a chemotherapeutic agent, or a combination thereof. 26. The method according to claim 25, wherein the therapeutic antibody is pertuzumab and the chemotherapeutic agent is a taxane or an anthracycline. | The present invention relates to duocarmycin-containing antibody-drug conjugates (ADCs) for use in the treatment of human solid tumours and haematological malignancies expressing HER2, in particular breast cancer, gastric cancer, bladder cancer, ovarian cancer, lung cancer, prostate cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell cancer or osteosarcoma, and acute lymphoblastic leukaemia. In particular, the present invention relates to duocarmycin-containing ADCs for use in the treatment of human solid tumours with HER2 IHC 2+ or 1+ and HER2 FISH negative tissue status. Advantageously, the present invention relates to duocarmycin-containing ADCs for use in the treatment of triple negative breast cancer (TNBC).1-15. (canceled) 16. A method of treating bladder cancer in a human patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I)
wherein
anti-HER2 Ab is an anti-HER2 antibody or antibody fragment able to bind HER2,
n is 0, 1, 2, or 3,
m represents an average DAR of from 1 to 4,
R1 is selected from the group consisting of
y is 1-16, and
R2 is selected from the group consisting of
and
wherein the patient has HER2 expressing bladder cancer. 17. The method according to claim 16, wherein
n is 0 or 1, R1 is selected from the group consisting of
and
R2 is 18. The method according to claim 17, wherein
anti-HER2 Ab is an anti-HER2 monoclonal antibody, m represents an average DAR of from 2 to 3, R1 is
and
y is 1, 2, 3, or 4. 19. The method according to claim 16, wherein said bladder cancer is HER2 positive. 20. The method according to claim 19, wherein said bladder cancer is IHC 3+. 21. The method according to claim 16, wherein said anti-HER2 Ab is trastuzumab. 22. The method according to claim 16, wherein the compound of formula (I) is a compound of formula (II) 23. The method according to claim 22, wherein the compound of formula (II) has an average DAR of from 2.5 to 2.9. 24. The method according to claim 22, wherein the compound of formula (II) has an average DAR of from 2.6 to 2.9. 25. The method according to claim 16, further comprising administering an effective amount of a therapeutic antibody or a chemotherapeutic agent, or a combination thereof. 26. The method according to claim 25, wherein the therapeutic antibody is pertuzumab and the chemotherapeutic agent is a taxane or an anthracycline. | 1,600 |
1,199 | 16,090,692 | 1,612 | The invention provides liquid cleansing composition comprising having mild surfactant, specifically salts of N-acyl polycarboxylic acid where pH of composition is preferably 6.5 and below. By combining with particular defibrillated cell wall materials, the mild surfactants can be structured and also have surprisingly good foam stability. | 1. A cleansing composition comprising:
1) 0.5 to 35% by wt. of total composition of a surfactant system which contains:
a) 0.5 to 25% by wt. of total composition anionic surfactant and
b) 0 to 20% by wt. of a co-surfactant selected from the group consisting of non-ionic surfactant, cationic surfactant, amphoteric surfactant and mixtures thereof; where an N-acyl salt of polycarboxylic acid is present at a level of 50% or more of all surfactant (both (a) and (b)); or is present at a level of 50% or more of anionic surfactant (a);
2) 0 to 30% by wt. of a hair or skin benefit agent; 3) 0.05 to 4.0 wt. % of a primary cell wall material comprising microfibers wherein:
a) the primary cell wall material is sourced from plant pararchymal tissue;
b) 80% or more (80% to 100% or 85% to 100%) of the microfibrils have a diameter of less than 50 nanometers (nm); and
4) balance of water wherein the primary cell wall material is defibrillated. 2. A composition according to claim 1 having homogeneity parameter (CHP) of 0.030 and greater, according to the protocol as defined herein. 3. (canceled) 4. A composition according to claim 1, wherein the cell wall material has a fiber homogeneity parameter (FHP) of 0.030 and greater, according to the protocol as defined herein. 5. A composition according to claim 1, wherein the cell wall has a fiber defibrillation parameter (FDP) of 0.10 Hz or greater, according to the protocol as defined herein. 6. A composition according to claim 1, wherein the salt of polycarboxylic acid is a salt of dicarboxylic acid. 7. A composition according to claim 6, wherein the salt of dicarboxylic acid is a salt of glutamate. 8. A composition according to claim 7, wherein pH of the composition is 3 to 6.5. | The invention provides liquid cleansing composition comprising having mild surfactant, specifically salts of N-acyl polycarboxylic acid where pH of composition is preferably 6.5 and below. By combining with particular defibrillated cell wall materials, the mild surfactants can be structured and also have surprisingly good foam stability.1. A cleansing composition comprising:
1) 0.5 to 35% by wt. of total composition of a surfactant system which contains:
a) 0.5 to 25% by wt. of total composition anionic surfactant and
b) 0 to 20% by wt. of a co-surfactant selected from the group consisting of non-ionic surfactant, cationic surfactant, amphoteric surfactant and mixtures thereof; where an N-acyl salt of polycarboxylic acid is present at a level of 50% or more of all surfactant (both (a) and (b)); or is present at a level of 50% or more of anionic surfactant (a);
2) 0 to 30% by wt. of a hair or skin benefit agent; 3) 0.05 to 4.0 wt. % of a primary cell wall material comprising microfibers wherein:
a) the primary cell wall material is sourced from plant pararchymal tissue;
b) 80% or more (80% to 100% or 85% to 100%) of the microfibrils have a diameter of less than 50 nanometers (nm); and
4) balance of water wherein the primary cell wall material is defibrillated. 2. A composition according to claim 1 having homogeneity parameter (CHP) of 0.030 and greater, according to the protocol as defined herein. 3. (canceled) 4. A composition according to claim 1, wherein the cell wall material has a fiber homogeneity parameter (FHP) of 0.030 and greater, according to the protocol as defined herein. 5. A composition according to claim 1, wherein the cell wall has a fiber defibrillation parameter (FDP) of 0.10 Hz or greater, according to the protocol as defined herein. 6. A composition according to claim 1, wherein the salt of polycarboxylic acid is a salt of dicarboxylic acid. 7. A composition according to claim 6, wherein the salt of dicarboxylic acid is a salt of glutamate. 8. A composition according to claim 7, wherein pH of the composition is 3 to 6.5. | 1,600 |
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