Claims for Patent: 10,426,743

Summary for Patent: 10,426,743

Title:	Topical pharmaceutical compositions
Abstract:	The present invention relates to topical pharmaceutical emulsion compositions comprising a therapeutically effective amount of 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, a water phase, a surfactant, and an antioxidant, and wherein the emulsion composition is homogeneous and/or the active is solubilized in the oil phase. The invention also relates to methods of treating a dermatological condition or disorder in a patient by administering the present compositions to the skin of the patient.
Inventor(s):	Sonti; Sujatha D. (Collegeville, PA), Thomas; Joey Roger (Clayton, NC), Lenn; Jon (Durham, NC), Santos; Leandro (King of Prussia, PA), Whiteman; Justin (Raleigh, NC), Doherty; Michael Quinn (Hillsborough, NC), Bedard; Mary (King of Prussia, PA), Jain; Piyush (Chester Springs, PA)
Assignee:	DERMAVANT SCIENCES GMBH (Basel, CH)
Application Number:	16/255,121
Patent Claims:	1. A method of treating an inflammatory disease or disorder in a patient in need thereof, the method comprising administering to said patient a topical pharmaceutical oil-in-water emulsion composition comprising: 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof in an amount of about 0.05% to about 2% by weight, based on the total weight of the composition; an oil phase comprising medium chain triglycerides of a carbon length from six to twelve carbons in an amount of about 2% to about 30% by weight, based on the total weight of the composition; a water phase; a surfactant in an amount of about 1% to about 20% by weight, based on the total weight of the composition, wherein the surfactant comprises at least one non-ionic emulsifying wax NF; and a dermatologically acceptable excipient selected from the group consisting of an antioxidant, a pH adjusting agent, a chelating agent, a preservative, a co-solvent and combinations thereof; wherein the 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase and is the only active ingredient in the oil phase; wherein the oil phase is substantially free of petrolatum and mineral oil; wherein the oil-in-water emulsion is homogeneous; and wherein the average droplet size of the oil phase is from about 0.1 microns to about 35 microns. 2. The method according to claim 1, wherein the inflammatory disease or disorder is psoriasis, atopic dermatitis, or acne. 3. The method of claim 1, wherein the topical pharmaceutical oil-in-water emulsion is administered once per day. 4. The method of claim 1, wherein the topical pharmaceutical oil-in-water emulsion is administered twice per day. 5. The method of claim 1, wherein the 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt thereof, is in an amount of about 2% by weight, based on the total weight of the composition. 6. The method of claim 1, wherein the 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt thereof, is in an amount of about 1% by weight, based on the total weight of the composition. 7. The method of claim 1, wherein the 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt thereof, is in an amount of about 0.50% by weight, based on the total weight of the composition. 8. The method of claim 1, wherein the medium chain triglyceride carbon length is from C.sub.6 to C.sub.8. 9. The method of claim 1, wherein the medium chain triglycerides are in an amount of about 5% to about 20% by weight, based on the total weight of the composition. 10. The method of claim 1, wherein the medium chain triglycerides are in an amount of about 5% to about 15% by weight, based on the total weight of the composition. 11. The method of claim 1, wherein the medium chain triglycerides are in an amount of about 10% by weight, based on the total weight of the composition. 12. The method of claim 1, wherein the water phase is in an amount of about 30% to about 80% by weight, based on the total weight of the composition. 13. The method of claim 1, wherein the water phase is in an amount of about 55% to about 75% by weight, based on the total weight of the composition. 14. The method of claim 1, wherein the surfactant is in an amount of about 5% to about 15% by weight, based on the total weight of the composition. 15. The method of claim 1, wherein the at least one non-ionic emulsifying wax NF is a mixture of cetostearyl alcohol and a polysorbate. 16. The method of claim 1, wherein the surfactant comprises a mixture of the at least one non-ionic emulsifying wax NF and a surfactant selected from the group consisting of ethoxylated fatty alcohol ethers, a sorbitan derivative, and combinations thereof. 17. The method of claim 1, wherein the surfactant comprises a mixture of the at least one non-ionic emulsifying wax NF and a surfactant selected from the group consisting of steareth-2, steareth-20, polysorbate 80, and combinations thereof. 18. The method of claim 1, wherein the surfactant is a mixture of the at least one non-ionic emulsifying wax NF, steareth-2, steareth-20, and polysorbate 80. 19. The method of claim 1, wherein the dermatologically acceptable excipient is an antioxidant. 20. The method of claim 19, wherein the antioxidant is in an amount of about 0.001% to about 5% by weight, based on the total weight of the composition. 21. The method of claim 19, wherein the antioxidant is in an amount of about 0.01% to 1% by weight, based on the total weight of the composition. 22. The method of claim 19, wherein the antioxidant is in an amount of about 0.05% by weight, based on the total weight of the composition. 23. The method of claim 19, wherein the antioxidant is in an amount of about 0.1% by weight, based on the total weight of the composition. 24. The method of claim 19, wherein the antioxidant is selected from the group consisting of propyl gallate, butylated hydroxytoluene, and tocopherol. 25. The method of claim 19, wherein the antioxidant is butylated hydroxytoluene. 26. The method of claim 19, wherein the antioxidant is butylated hydroxytoluene in an amount of about 0.1% by weight, based on the total weight of the composition. 27. The method of claim 1, wherein the dermatologically acceptable excipient is a pH adjusting agent. 28. The method of claim 27, wherein the pH adjusting agent is selected from an acid, an acid salt, or a mixture thereof. 29. The method of claim 27, wherein the pH adjusting agent is selected from the group consisting of lactic acid, acetic acid, maleic acid, succinic acid, citric acid, benzoic acid, boric acid, sorbic acid, tartaric acid, edetic acid, phosphoric acid, nitric acid, sulphuric acid and hydrochloric acid, and mixtures thereof. 30. The method of claim 27, wherein the pH adjusting agent is a buffer. 31. The method of claim 30, wherein the buffer is selected from the group consisting of citrate/citric acid, acetate/acetic acid, phosphate/phosphoric acid, propionate/propionic acid, lactate/lactic acid, ammonium/ammonia, and edetate/edetic acid. 32. The method of claim 27, wherein the pH adjusting agent is a citrate/citric acid buffer. 33. The method of claim 27, wherein the pH adjusting agent is a citrate/citric acid buffer in an amount of about 0.27% by weight, based on the total weight of the composition. 34. The method of claim 27, wherein the pH adjusting agent is in an amount of from about 0.01% to about 10% by weight, based on the total weight of the composition. 35. The method of claim 1, wherein the dermatologically acceptable excipient is a chelating agent. 36. The method of claim 35, wherein the chelating agent is selected from the group consisting of citric acid, glucuronic acid, sodium hexametaphosphate, zinc hexametaphosphate, ethylene diamine tetraacetic acid, phosphonates, salts thereof, and mixtures thereof. 37. The method of claim 35, wherein the chelating agent is ethylene diamine tetraacetic acid or a salt thereof. 38. The method of claim 35, wherein the chelating agent is in an amount of about 0.01% to about 1% by weight, based on the total weight of the composition. 39. The method of claim 35, wherein the chelating agent is in an amount of about 0.1% by weight, based on the total weight of the composition. 40. The method of claim 1, wherein the dermatologically acceptable excipient is a preservative. 41. The method of claim 40, wherein the preservative is selected from the group consisting of benzyl alcohol, imidazolidinyl urea, diazolidinyl urea, dichlorobenzyl alcohol, chloroxylenol, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, phenoxyethanol, sorbic acid, benzoic acid, salts thereof, and mixtures thereof. 42. The method of claim 40, wherein the preservative is benzoic acid. 43. The method of claim 40, wherein the preservative is benzoic acid in an amount of about 0.25% by weight, based on the total weight of the composition. 44. The method of claim 40, wherein the preservative is in an amount of about 0.01% to about 2% by weight, based on the total weight of the composition. 45. The method of claim 40, wherein the preservative is in an amount of about 0.25% by weight, based on the total weight of the composition. 46. The method of claim 1, wherein the dermatologically acceptable excipient is a co-solvent. 47. The method of claim 46, wherein the co-solvent is in an amount of about 5% to about 20% by weight, based on the total weight of the composition. 48. The method of claim 46, wherein the co-solvent is a mixture of propylene glycol and diethylene glycol monoethyl ether. 49. The method of claim 48, wherein the propylene glycol is in an amount of about 10% by weight, based on the total weight of the composition. 50. The method of claim 48, wherein the diethylene glycol monoethyl ether is in an amount of about 2% by weight, based on the total weight of the composition. 51. The method of claim 1 further comprising a second dermatologically acceptable excipient selected from the group consisting of a penetration enhancer, a humectant, a thickening agent, a gelling agent, a viscosity building agent, a fragrance, a colorant, and combinations thereof. 52. The method of claim 1, wherein the pH is from about 2 to about 6. 53. The method of claim 1, wherein the pH is from about 4 to about 7. 54. The method of claim 1, wherein the pH is from about 4.5 to about 6.5. 55. The method of claim 1, wherein the average droplet size of the oil phase is about 0.1 microns to less than 15 microns. 56. The method of claim 1, wherein the average droplet size of the oil phase is about 0.1 microns to about 5 microns. 57. The method of claim 1, wherein the average droplet size of the oil phase is about 0.1 microns to about 0.75 microns. 58. The method of claim 1, wherein the average droplet size of the oil phase is about 0.5 microns. 59. The method of claim 1, wherein the composition comprises: 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof in an amount of about 0.05% to about 2% by weight, based on the total weight of the composition; an oil phase comprising medium chain triglycerides of a carbon length from six to twelve carbons in an amount of about 2% to about 30% by weight, based on the total weight of the composition; a water phase; a surfactant in an amount of about 1% to about 20% by weight, based on the total weight of the composition, wherein the surfactant comprises a mixture of the at least one non-ionic emulsifying wax NF and a surfactant selected from the group consisting of steareth-2, steareth-20, polysorbate 80, and combinations thereof; an antioxidant; a pH adjusting agent; a chelating agent; a preservative; and a co-solvent; wherein the 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase and is the only active ingredient in the oil phase; wherein the oil phase is substantially free of petrolatum and mineral oil; wherein the emulsion is homogeneous; and wherein the average droplet size of the oil phase is from about 0.1 microns to about 35 microns. 60. The method of claim 59, wherein the 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is in an amount of about 2% by weight, based on the total weight of the composition. 61. The method of claim 59, wherein the 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is in an amount of about 1% by weight, based on the total weight of the composition. 62. The method of claim 59, wherein the 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is in an amount of about 0.50% by weight, based on the total weight of the composition. 63. The method of claim 59, wherein the medium chain triglyceride carbon length is from C6 to C8. 64. The method of claim 59, wherein the medium chain triglycerides are in an amount of about 5% to about 20% by weight, based on the total weight of the composition. 65. The method of claim 59, wherein the medium chain triglycerides are in an amount of about 5% to about 15% by weight, based on the total weight of the composition. 66. The method of claim 59, wherein the medium chain triglycerides are in an amount of about 10% by weight, based on the total weight of the composition. 67. The method of claim 59, wherein the water phase is in an amount of about 30% to about 80% by weight, based on the total weight of the composition. 68. The method of claim 59, wherein the water phase is in an amount of about 55% to about 75% by weight, based on the total weight of the composition. 69. The method of claim 59, wherein the surfactant is in an amount of about 5% to about 15% by weight, based on the total weight of the composition. 70. The method of claim 59, wherein the at least one non-ionic emulsifying wax NF is a mixture of cetostearyl alcohol and a polysorbate. 71. The method of claim 59, wherein the surfactant is a mixture of the at least one non-ionic emulsifying wax NF, steareth-2, steareth-20, and polysorbate 80. 72. The method of claim 59, wherein the antioxidant is in an amount of about 0.001% to about 5% by weight, based on the total weight of the composition. 73. The method of claim 59, wherein the antioxidant is in an amount of about 0.01% to about 1% by weight, based on the total weight of the composition. 74. The method of claim 59, wherein the antioxidant is in an amount of about 0.05% by weight, based on the total weight of the composition. 75. The method of claim 59, wherein the antioxidant is in an amount of about 0.1% by weight, based on the total weight of the composition. 76. The method of claim 59, wherein the antioxidant is selected from the group consisting of propyl gallate, butylated hydroxytoluene, and tocopherol. 77. The method of claim 59, wherein the antioxidant is butylated hydroxytoluene. 78. The method of claim 59, wherein the antioxidant is butylated hydroxytoluene in an amount of about 0.1% by weight, based on the total weight of the composition. 79. The method of claim 59, wherein the pH adjusting agent is selected from an acid, an acid salt, or a mixture thereof. 80. The method of claim 59, wherein the pH adjusting agent is selected from the group consisting of lactic acid, acetic acid, maleic acid, succinic acid, citric acid, benzoic acid, boric acid, sorbic acid, tartaric acid, edetic acid, phosphoric acid, nitric acid, sulphuric acid and hydrochloric acid, and mixtures thereof. 81. The method of claim 59, wherein the pH adjusting agent is a buffer. 82. The method of claim 81, wherein the buffer is selected from the group consisting of citrate/citric acid, acetate/acetic acid, phosphate/phosphoric acid, propionate/propionic acid, lactate/lactic acid, ammonium/ammonia, and edetate/edetic acid. 83. The method of claim 59, wherein the pH adjusting agent is a citrate/citric acid buffer. 84. The method of claim 59, wherein the pH adjusting agent is a citrate/citric acid buffer in an amount of about 0.27% by weight, based on the total weight of the composition. 85. The method of claim 59, wherein the pH adjusting agent is in an amount of about 0.01% to about 10% by weight, based on the total weight of the composition. 86. The method of claim 59, wherein the chelating agent is selected from the group consisting of citric acid, glucuronic acid, sodium hexametaphosphate, zinc hexametaphosphate, ethylene diamine tetraacetic acid, phosphonates, salts thereof, and mixtures thereof. 87. The method of claim 59, wherein the chelating agent is ethylene diamine tetraacetic acid or a salt thereof. 88. The method of claim 59, wherein the chelating agent is in an amount of about 0.01% to about 1% by weight, based on the total weight of the composition. 89. The method of claim 59, wherein the chelating agent is in an amount of about 0.1% by weight, based on the total weight of the composition. 90. The method of claim 59, wherein the preservative is selected from the group consisting of benzyl alcohol, imidazolidinyl urea, diazolidinyl urea, dichlorobenzyl alcohol, chloroxylenol, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, phenoxyethanol, sorbic acid, benzoic acid, salts thereof, and mixtures thereof. 91. The method of claim 59, wherein the preservative is benzoic acid. 92. The method of claim 59, wherein the preservative is benzoic acid in an amount of about 0.25% by weight, based on the total weight of the composition. 93. The method of claim 59, wherein the preservative is in an amount of about 0.01% to about 2% by weight, based on the total weight of the composition. 94. The method of claim 59, wherein the preservative is in an amount of about 0.25% by weight, based on the total weight of the composition. 95. The method of claim 59, wherein the co-solvent is in an amount of about 5% to about 20% by weight, based on the total weight of the composition. 96. The method of claim 59, wherein the co-solvent is a mixture of propylene glycol and diethylene glycol monoethyl ether. 97. The method of claim 96, wherein the propylene glycol is in an amount of about 10% by weight, based on the total weight of the composition. 98. The method of claim 96, wherein the diethylene glycol monoethyl ether is in an amount of about 2% by weight, based on the total weight of the composition. 99. The method of claim 59 further comprising a second dermatologically acceptable excipient selected from the group consisting of a penetration enhancer, a humectant, a thickening agent, a gelling agent, a viscosity building agent, a fragrance, a colorant, and combinations thereof. 100. The method of claim 59, wherein the pH is from about 2 to about 6. 101. The method of claim 59, wherein the pH is from about 4 to about 7. 102. The method of claim 59, wherein the pH is from about 4.5 to about 6.5. 103. The method of claim 59, wherein the average droplet size of the oil phase is about 0.1 microns to less than 15 microns. 104. The method of claim 59, wherein the average droplet size of the oil phase is about 0.1 microns to about 5 microns. 105. The method of claim 59, wherein the average droplet size of the oil phase is about 0.1 microns to about 0.75 microns. 106. The method of claim 59, wherein the average droplet size of the oil phase is about 0.5 microns. 107. The method of claim 1, wherein the composition comprises: 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof in an amount of about 0.5% by weight, based on the total weight of the composition; an oil phase comprising medium chain triglycerides of a carbon length from six to twelve carbons in an amount of about 10% by weight, based on the total weight of the composition; a water phase in an amount of about 65.18% by weight, based on the total weight of the composition; a surfactant, wherein the surfactant is a mixture of about 7.20% of the at least one non-ionic emulsifying wax NF by weight, about 1.80% steareth-2 by weight, about 1.10% steareth-20 by weight, and 1.5% polysorbate 80 by weight, based upon the total weigh of the composition; an antioxidant in an amount of about 0.10%, based upon the total weight of the composition, wherein the antioxidant is butylated hydroxytoluene; a pH adjusting agent in an amount of about 0.27% by weight, based upon the total weight of the composition, wherein the pH adjusting agent is a citrate/citric acid buffer; a chelating agent in an amount of about 0.10% by weight, based upon the total weight of the composition, wherein the chelating agent is disodium ethylene diamine tetraacetic acid; a preservative in an amount of about 0.25% by weight, based upon the total weight of the composition, wherein the preservative is benzoic acid; and a co-solvent, wherein the co-solvent is a mixture of about 10% propylene glycol by weight, and about 2% diethylene glycol monoethyl ether by weight, based upon the total weight of the composition; wherein the 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase and is the only active ingredient in the oil phase; wherein the oil phase is substantially free of petrolatum and mineral oil; wherein the emulsion is homogeneous; and wherein the average droplet size of the oil phase is from about 0.1 microns to about 35 microns. 108. The method of claim 107, wherein the average droplet size of the oil phase is about 0.1 microns to less than 15 microns. 109. The method of claim 107, wherein the average droplet size of the oil phase is about 0.1 microns to about 5 microns. 110. The method of claim 107, wherein the average droplet size of the oil phase is about 0.1 microns to about 0.75 microns. 111. The method of claim 107, wherein the average droplet size of the oil phase is about 0.5 microns. 112. The method of claim 1, wherein the composition comprises: 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof in an amount of about 1.0% by weight, based on the total weight of the composition; an oil phase comprising medium chain triglycerides of a carbon length from six to twelve carbons in an amount of about 10% by weight, based on the total weight of the composition; a water phase in an amount of about 64.68% by weight, based on the total weight of the composition; a surfactant, wherein the surfactant is a mixture of about 7.20% of the at least one non-ionic emulsifying wax NF by weight, about 1.80% steareth-2 by weight, about 1.10% steareth-20 by weight, and 1.5% polysorbate 80 by weight, based upon the total weight of the composition; an antioxidant in an amount of about 0.10%, based upon the total weight of the composition, wherein the antioxidant is butylated hydroxytoluene; a pH adjusting agent in an amount of about 0.27% by weight, based upon the total weight of the composition, wherein the pH adjusting agent is a citrate/citric acid buffer; a chelating agent in an amount of about 0.10% by weight, based upon the total weight of the composition, wherein the chelating agent is disodium ethylene diamine tetraacetic acid; a preservative in an amount of about 0.25% by weight, based upon the total weight of the composition, wherein the preservative is benzoic acid; and a co-solvent, wherein the co-solvent is a mixture of about 10% propylene glycol by weight, and about 2% diethylene glycol monoethyl ether by weight, based upon the total weight of the composition; wherein the 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase and is the only active ingredient in the oil phase; wherein the oil phase is substantially free of petrolatum and mineral oil; wherein the emulsion is homogeneous; and wherein the average droplet size of the oil phase is from about 0.1 microns to about 35 microns. 113. The method of claim 112, wherein the average droplet size of the oil phase is about 0.1 microns to less than 15 microns. 114. The method of claim 112, wherein the average droplet size of the oil phase is about 0.1 microns to about 5 microns. 115. The method of claim 112, wherein the average droplet size of the oil phase is about 0.1 microns to about 0.75 microns. 116. The method of claim 112, wherein the average droplet size of the oil phase is about 0.5 microns.