WO2019045994A1 – March 7, 2019 – PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF OPHTHALMIC CONDITIONS

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Inventors :

CHANG, Ping - 11 Trumbull Road, Waterford, CT 06385; HU, Zhenze - 12665 SW 20th Street, Davie, FL 33325; TAO, Yuanyuan - 446 Turner Avenue, Drexel Hill, PA 19026

Owner :

RHODES TECHNOLOGIES

Application Number :

WOUS18046331

Document Number :

WO2019045994A1

Priority Date :

January 1, 1970

Filing Date :

August 10, 2018

Date of Grant/ Publication :

March 7, 2019

Class :

A61K31 / 352; A61K9 / 00; A61K9 / 10; A61K9 / 107; A61K31 / 00

Abstract

The invention provides emulsion compositions comprising at least one cannabinoid compound, and methods for making the same. The emulsion compositions are stable, well tolerated and are capable of delivering therapeutically effective amounts of cannabiniods to target sites, including sites on the surface of and/or within an eye. Also provided are methods of using the compositions to provide ocular neuroprotection and/or to treat ophthalmic conditions such as glaucoma.

Claim(s)

1. An emulsion composition comprising: tetrahydrocannabinol (THC), or a derivative thereof; an oil; a surfactant; and water, wherein the emulsion comprises an oil phase component comprising a plurality of oil droplets, dispersed with an aqueous phase component, the emulsion remains stable after being stored at a condition selected from the group consisting of: at least two years at about -18 °C; at least three months at about 4 °C; and at least one month at about 23 °C, such that there is an absence of visible phase separation between the oil phase component and the aqueous phase component after such storage condition.;
2. The emulsion composition of claim 1, wherein the emulsion is an oil-in-water type emulsion.;
3. The emulsion composition of claim 1, wherein the composition is a topical formulation suitable for administration to the eye.;
4. The emulsion composition of claim 1, wherein the composition is an eye drop solution.;
5. The emulsion composition of claim 1, wherein the ratio (w/w) of oil to water in the composition is in the range of about 1 : 10 to about 1 : 1000.;
6. The emulsion composition of claim 5, wherein the ratio (w/w) of oil to water in the composition is in the range of about 1 :20 to about 1 : 100.;
7. The emulsion composition of claim 1, wherein the emulsion is substantially free of antimicrobial preservative agents.;
8. The emulsion composition of claim 7, wherein the antimicrobial preservative agent is selected from the group consisting of benzalkonium chloride; thimerosal; chlorobutanol; methyl paraben; propyl paraben; phenylethyl alcohol; EDTA; and sorbic acid.;
9. The emulsion composition of claim 1, which is a micro-emulsion.;
10. The emulsion composition of claim 1, wherein at least about 90% of the oil droplets in the emulsion are less than about 200 nm in diameter;
11. The emulsion composition of claim 1, wherein the diameter of the oil droplets in the emulsion is in the range of about 30 nm to about 300 nm.;
12. The emulsion composition of claim 1, wherein the particle size distribution of the oil droplets remains essentially constant after being stored at one or more of the storage conditions.;
13. The emulsion composition of claim 1, wherein the THC is (-)-trans- 9 – tetrahydrocannabinol .;
14. The emulsion composition of claim 1, comprising about 0.005 % (w/w) to about 0.5% (w/w) THC.;
15. The emulsion composition of claim 1, comprising about 0.05% (w/w) to about 0.5% (w/w) THC.;
16. The emulsion composition of claim 1, comprising about 0.05% (w/w) THC.;
17. The emulsion composition of claim 1, wherein the THC remains chemically stable in the composition such that at least about 90% (w/w) of the initial THC content in the emulsion is present after the emulsion is being stored at one or more of the storage conditions.;
18. The emulsion composition of claim 1, wherein the THC remains chemically stable in the composition such that at least about 95% (w/w) of the initial THC content in the emulsion is present after the emulsion is being stored at one or more of the said storage conditions.;
19. The emulsion composition of claim 1, wherein the oil is a vegetable oil.;
20. The emulsion composition of claim 19, wherein the vegetable oil is selected from the group consisting of sesame oil, castor oil, soybean oil, olive oil, cotton seed oil, and peanut oil, or a combination thereof.;
claim 21: 21. The emulsion composition of claim 19, wherein the vegetable oil is selected from sesame oil, castor oil, and a combination thereof.;
claim 22: 22. The emulsion composition of claim 19, wherein the vegetable oil is sesame oil.;
claim 23: 23. The emulsion composition of claim 1, comprising about 1.5% (w/w) to about 5.0% (w/w) oil.;
claim 24: 24. The emulsion composition of claim 1, wherein the surfactant is selected from the group consisting of Tween ® 80 (polyoxyethylene (20) sorbitan monooleate); Tween ® 20 (polyoxyethylene (20) sorbitan monolaurate); Tyloxapol (4-(l,l,3,3-Tetramethylbutyl)phenol polymer with formaldehyde and oxirane); Span 80 (Sorbitane monooleate); Kollipher ® HS 15 (polyoxyethylated 12-hydroxystearic acid); polyoxyl 35 castor oil; polyoxyl 40 hydrogenated castor oil; and polyoxyl 40 sterate, or a combination thereof.;
claim 25: 25. The emulsion composition of claim 1, wherein the surfactant is Tween ® 80 (Polyoxyethylene (20) sorbitan monooleate) or tyloxapol.;
claim 26: 26. The emulsion composition of claim 1, wherein the surfactant is Tween ® 80 (Polyoxyethylene (20) sorbitan monooleate).;
claim 27: 27. The emulsion composition of claim 1, comprising about 0.5% (w/w) to about 5% (w/w) surfactant.;
claim 28: 28. The emulsion composition of claim 1, further comprising a co-solvent.;
claim 29: 29. The emulsion composition of claim 28, wherein the co-solvent is a polyol compound.;
claim 30: 30. The emulsion composition of claim 29, wherein the polyol compound is glycerin.;
claim 31: 31. The emulsion composition of claim 28, comprising about 1% (w/w) to about 10% (w/w) co-solvent.;
claim 32: 32. The emulsion composition of claim 28, comprising about 2.5% (w/w) co-solvent.;
claim 33: 33. The emulsion composition of claim 1, further comprising an antioxidant.;
claim 34: 34. The emulsion composition of claim 33, wherein the antioxidant is butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT).;
claim 35: 35. The emulsion composition of claim 33, comprising about 0.001%) (w/w) to about 0.5% (w/w) antioxidant.;
claim 36: 36. The emulsion composition of claim 33, comprising about 0.06% (w/w) antioxidant.;
claim 37: 37. The emulsion composition of claim 1, further comprising a pH adjusting agent.;
claim 38: 38. The emulsion composition of claim 37, wherein the pH adjusting agent is selected from the group consisting of lactic acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydrogen carbonate.;
claim 39: 39. The emulsion composition of claim 37, wherein the pH adjusting agent is sodium hydroxide.;
claim 40: 40. The emulsion composition of claim 1, having a pH value of about 6.5 to about 7.5.;
claim 41: 41. The emulsion composition of claim 1, having a pH value of about 6.8 to about 7.2.;
claim 42: 42. An emulsion composition comprising: a tetrahydrocannabinol (THC), or a derivative thereof; an oil; a surfactant; and water, wherein the emulsion comprises an oil phase component comprising a plurality of oil droplets dispersed with an aqueous phase component, wherein the osmolarity of the emulsion is substantially similar to human tear fluid osmolarity.;
claim 43: 43. The emulsion composition of claim 42, having an osmolarity of about 250 mOsm/L to about 330 mOsm/L.;
claim 44: 44. The emulsion composition of claim 42, having an osmolarity of about 290 mOsm/L to about 315 mOsm/L.;
claim 45: 45. The emulsion composition of claim 42, having an osmolarity of about 300 mOsm/L to about 340 mOsm/L.;
claim 46: 46. An emulsion composition comprising: (-)-trans-A 9 -tetrahydrocannabinol ; an oil selected from sesame oil, castor oil, or a combination thereof; a surfactant selected from the group consisting of Tween ® 80 (polyoxyethylene (20) sorbitan monooleate); Tween ® 20 (polyoxyethylene (20) sorbitan monolaurate); Tyloxapol (4- (l,l,3,3-Tetramethylbutyl)phenol polymer with formaldehyde and oxirane); Span 80 (Sorbitane monooleate); Kollipher ® HS 15 (polyoxyethylated 12-hydroxystearic acid); polyoxyl 35 castor oil; polyoxyl 40 hydrogenated castor oil; and polyoxyl 40 sterate, or a combination thereof; and water, wherein the ratio (w/w) of oil to water in the composition is in the range of about 1 :20 to about 1 : 100, the emulsion comprises an oil phase component comprising a plurality of oil droplets dispersed with an aqueous phase component, wherein at least about 90% of the oil droplets in the emulsion are less than about 200 nm in diameter.;
claim 47: 47. The emulsion composition of claim 46, wherein the emulsion remains stable after being stored at a condition selected from the group consisting of: at least two years at about -18 °C; at least three months at about 4 °C; and at least one month at about 23 °C, such that there is an absence of visible phase separation between the oil phase component and the aqueous phase component after such storage condition, the emulsion being suitable for topical administration to the eye of a subj ect.;
claim 48: 48. The emulsion composition of claim 47, wherein the emulsion is substantially free antimicrobial preservative agents.;
claim 49: 49. The emulsion composition of claim 48, wherein the antimicrobial preservative agent is selected from the group consisting of benzalkonium chloride; thimerosal; chlorobutanol; methyl paraben; propyl paraben; phenylethyl alcohol; EDTA; and sorbic acid.;
claim 50: 50. The emulsion composition of claim 46, comprising about 0.005 % (w/w) to about 0.5% (w/w) (-)-tra«5-A 9 -tetrahydrocannabinol .;
claim 51: 51. The emulsion composition of claim 46, comprising about 0.05 % (w/w) to about 0.5% (w/w) (-)-tra«5-A 9 -tetrahydrocannabinol .;
claim 52: 52. The emulsion composition of claim 46, wherein the (-)-tra«s-A 9 -tetrahydrocannabinol remains chemically stabile in the composition such that at lease about 90% (w/w) of the initial (- )-tra«5-A 9 -tetrahydrocannabinol content in the emulsion is present after the emulsion is being stored at one or more of the storage conditions.;
claim 53: 53. The emulsion composition of claim 46, wherein the oil is sesame oil.;
claim 54: 54. The emulsion composition of claim 46, comprising about 1.5% (w/w) to about 5.0% (w/w) vegetable oil.;
claim 55: 55. The emulsion composition of claim 46, wherein the surfactant is Tween ® 80 (Polyoxyethylene (20) sorbitan monooleate).;
claim 56: 56. The emulsion composition of claim 46, comprising about 0.5% (w/w) to about 5% (w/w) surfactant.;
claim 57: 57. The emulsion composition of claim 46, further comprising a co-solvent.;
claim 58: 58. The emulsion of claim 57, wherein the co-solvent is glycerin.;
claim 59: 59. The emulsion composition of claim 57, comprising about 1 % (w/w) to about 10% (w/w) co-solvent.;
claim 60: 60. The emulsion composition of claim 57, comprising about 2.5% (w/w) co-solvent.;
claim 61: 61. The emulsion composition of claim 46, further comprising an antioxidant.;
claim 62: 62. The emulsion composition of claim 61, wherein the antioxidant is selected from butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and a combination thereof.;
claim 63: 63. The emulsion composition of claim 46, comprising about 0.001%) (w/w) to about 0.5% (w/w) antioxidant.;
claim 64: 64. The emulsion composition of claim 46, comprising about 0.06% (w/w) antioxidant.;
claim 65: 65. The emulsion composition of claim 46, having a pH of about 6.8 to about 7.2.;
claim 66: 66. The emulsion composition of claim 46, comprising: about 0.005 %> (w/w) to about 0.5 %> (w/w) of (-)-trans-A 9 -tetrahydrocannabinol; about 1.5%) (w/w) to about 2.0%> (w/w) of sesame oil; about 0.5%) (w/w) to about 2%> (w/w) of Tween ® 80 (polyoxyethylene (20) sorbitan monooleate); about 2.5% (w/w) glycerin; about 0.03% (w/w) BHT and/or 0.03% (w/w) BHA; and water, wherein the ratio (w/w) of oil to water in the composition is in the range of about 1 :20 to about 1 : 100, the emulsion comprises an oil phase component comprising a plurality of oil droplets dispersed with an aqueous phase component, wherein at least about 90%> of the oil droplets in the emulsion are less than about 200 nm in diameter, wherein the emulsion remains stable after being stored at a condition selected from the group consisting of: at least two years at about -18 °C; at least three months at about 4 °C; and at least one month at about 23 °C, such that there is an absence of visible phase separation between the oil phase component and the aqueous phase component after such storage condition, the (-)-tram , -A 9 -tetrahydrocannabinol remains chemically stabile in the composition such that at lease about 90%> (w/w) of the initial {-)-trans- ? 9 -tetrahydrocannabinol content in the emulsion is present after exposure of the emulsion to the storage condition.;
claim 67: 67. A method of treating or preventing an ophthalmic condition in a subject in need thereof, the method comprising administering to the eye of the subject a therapeutically effective amount of the emulsion composition of any one of claims 1, 42 and 46, wherein said method provides ocular neuroprotection to the subject.;
claim 68: 68. The method of claim 67, wherein said method decreases or reverses ocular neurodegeneration in said subject.;
claim 69: 69. The method of claim 67, comprising administering between 1 to 5 drops of the emulsion composition of any one of claims 1, 42 and 46 to the eye of the subject.;
claim 70: 70. The method of claim 67, wherein the administering comprises topical administration of the emulsion composition.;
claim 71: 71. The method of claim 67, wherein the emulsion composition is administered topically as liquid drops, liquid wash, gel, ointment, or a spray, or a combination thereof.;
claim 72: 72. The method of claim 67, wherein the administering comprises topical administration by infusing the emulsion composition via a device selected from the group consisting of a pump- catheter system, a continuous or selective release device, and a contact lens, or a combination thereof.;
claim 73: 73. The method of claim 67, the emulsion composition is administered in an injectable form.;
claim 74: 74. The method of claim 67, wherein the injectable form is injected behind the eye.;
claim 75: 75. The method of claim 67, wherein the subject is suffering from or is at substantial risk of developing a neuropathic condition.;
claim 76: 76. The method of claim 75, wherein the neuropathic condition is a blinding eye disease.;
claim 77: 77. The method of claim 74, wherein the neuropathic condition is a disease selected from the group consisting of macular degeneration, retinitis pigmentosa, and glaucoma.;
claim 78: 78. The method of claim 74, wherein the neuropathic condition is neuropathic pain.;
claim 79: 79. The method of claim 67, wherein the administering is once a day administration.;
claim 80: 80. The method of claim 67, wherein the administering is twice a day administration.;
claim 81: 81. A method of treating or preventing an ophthalmic condition in a subject identified in need of such treatment, the method comprising administering to the eye of the subject a therapeutically effective amount of the emulsion composition of any one of claims 1, 42 and 46.;
claim 82: 82. The method of claim 81, comprising administering between 1 to 5 drops of the emulsion composition of any one of claims 1, 42 and 46 to the eye of the subject.;
claim 83: 83. The method of claim 81, wherein the administering is once a day administration.;
claim 84: 84. The method of claim 81, wherein the administering is twice a day administration.;
claim 85: 85. The method of claim 81, wherein the administering comprises topical administration of the emulsion composition.;
claim 86: 86. The method of claim 81, wherein the emulsion composition is administered topically as liquid drops, liquid wash, gel, ointment, or a spray, or a combination thereof.;
claim 87: 87. The method of claim 81, wherein the administering comprises topical administration by infusing the emulsion composition via a device selected from the group consisting of a pump- catheter system, a continuous or selective release device, and a contact lens, or a combination thereof.;
claim 88: 88. The method of claim 81, wherein the emulsion composition is administered in an injectable form.;
claim 89: 89. The method of claim 81, wherein the ophthalmic condition is selected from the group consisting of glaucoma, age-related macular degeneration (AMD), ophthalmitis, and conjunctivitis.;
claim 90: 90. The method of claim 81, wherein the ophthalmic condition is glaucoma.;
claim 91: 91. The method of claim 81, wherein the method decreases intraocular pressure (IOP) for a period of at least about 1 hour after administering the emulsion composition to the eye.;
claim 92: 92. The method of claim 81, wherein the method decreases intraocular pressure (IOP) for a period of at least about 4 hours after administering the emulsion composition to the eye.;
claim 93: 93. The method of claim 81, wherein the method increases aqueous outflow facility in the eye of the subject.;
claim 94: 94. The method of claim 81, wherein the ophthalmic condition is an inflammatory eye disease or disorder.;
claim 95: 95. The method of claim 94, wherein the inflammatory eye disease is selected from the group consisting of dry eye disease; posterior uveitis; retinitis; uveoretinitis; proliferative vitreoretinopathy; anterior uveitis; episcleritis; scleritis; ocular neuropathic pain; and ocular inflammation caused by a non-infectious condition.;
claim 96: 96. The method of claim 94, wherein the ocular neuropathic pain arises from dry eye, trauma, a corneal abrasion, a corneal burn, a corneal transplant, an autoimmune disease or an allergen.;
claim 97: 97. A method of preparing the emulsion composition of claim 1, comprising: combining tetrahydrocannabinol (THC), an oil, a surfactant, and a first portion of water to form a premix; homogenizing the premix to form a homogenized premix; adding a second portion of water after the homogenization step to form a bulk sample; filtering the bulk sample over a membrane to afford the emulsion composition.;
claim 98: 98. The method of claim 97, wherein the homogenizing the premix occurs at a speed of about 5000 rpm for about 2 minutes.;
claim 99: 99. The method of claim 97, wherein the homogenizing the premix occurs at a speed of about 5000 rpm for about 20 minutes.;
claim 100: 100. The method of claim 97, wherein the ratio (w/w) of oil to water in the premix is in the range of about 1 : 10 to about 1 : 1000.;
claim 101: 101. The method of claim 97, wherein the ratio (w/w) of oil to water in the premix is in the range of about 1 :20 to about 1 : 100.;
claim 102: 102. The method of claim 97, wherein the oil is a vegetable oil.;
claim 103: 103. The method of claim 97, wherein the vegetable oil is selected from the group consisting of sesame oil, castor oil, soybean oil, olive oil, cotton seed oil, and peanut oil, or a combination thereof.;
claim 104: 104. The method of claim 97, wherein the vegetable oil is selected from sesame oil, castor oil, and a combination thereof.;
claim 105: 105. The method of claim 97, wherein the vegetable oil is sesame oil.;
claim 106: 106. The method of claim 97, wherein the amount of oil in the premix is about 1.5% (w/w) to about 5.0% (w/w) oil.;
claim 107: 107. The method of claim 97, wherein the surfactant is selected from the group consisting of Tween ® 80 (polyoxyethylene (20) sorbitan monooleate); Tween ® 20 (polyoxyethylene (20) sorbitan monolaurate); Tyloxapol (4-(l,l,3,3-Tetramethylbutyl)phenol polymer with formaldehyde and oxirane); Span 80 (Sorbitane monooleate); Kollipher ® HS 15 (polyoxyethylated 12-hydroxy stearic acid); polyoxyl 35 castor oil; polyoxyl 40 hydrogenated castor oil; and polyoxyl 40 sterate, or a combination thereof.;
claim 108: 108. The method of claim 97, wherein the surfactant is T ween 80 (Polyoxy ethylene (20) sorbitan monooleate) or tyloxapol.;
claim 109: 109. The method of claim 97, wherein the surfactant is Tween ® 80 (Polyoxy ethylene (20) sorbitan monooleate).;
claim 110: 110. The method of claim 97, wherein the amount of surfactant in the premix is about 0.5% (w/w) to about 5% (w/w) surfactant.;
claim 111: 111. The method of claim 97, wherein the membrane comprises a polyvinylidene fluoride (PVDF) filter.;
claim 112: 112. The method of claim 97, wherein the membrane comprises a polytetrafluoroethylene (PTFE) filter.;
claim 113: 113. The method of claim 97, wherein the membrane comprises a Poly(ether sulfonej (T^ES) filter.;
claim 114: 114. A method of preparing the emulsion composition of claim 1, comprising: combining tetrahydrocannabinol (THC), an oil, a surfactant, and a first portion of water to form a premix; homogenizing the premix at a speed of about 3000 rpm to about 5000 rpm for a time period of about 2 minutes to about 20 minutes to form a homogenized premix; adjusting the pH of the homogenized premix solution to about 6.5 to about 7.5 to form a neutralized premix; adding a second portion of water to the neutralized premix to form a bulk sample; filtering the bulk sample over a membrane having a maximum pore size of about 200 nm to afford the emulsion composition.;
claim 115: 115. A kit comprising a therapeutically effective amount of the emulsion composition of any one of claims 1, 42, and 46, and instructional material for administering the composition to a patient having an ophthalmic condition.;
claim 116: 116. The kit of claim 115, wherein the ophthalmic condition is selected from the group consisting of glaucoma, age-related macular degeneration (AMD), ophthalmitis, and conjunctivitis.;
claim 117: 117. The kit of claim 115, wherein the ophthalmic condition is associated with ocular neurodegenerati on .;
claim 118: 118. The kit of claim 115, wherein the ophthalmic condition is neuropathic pain.;
claim 119: 119. The kit of claim 115, further comprising a second medication useful for treating or preventing an ophthalmic condition.

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