Claims for Patent: 10,660,908

Summary for Patent: 10,660,908

Title:	Pharmaceutical spray composition comprising a vitamin D analogue and a corticosteroid
Abstract:	The present invention relates to a topical spray composition comprising a biologically active vitamin D derivative or analogue and a corticosteroid, and its use in the treatment of dermal diseases and conditions.
Inventor(s):	Lind; Marianne (Bagsv.ae butted.rd, DK), Rasmussen; Gritt (Virum, DK), Sonne; Mette Rydahl (Brondby Strand, DK), Hansen; Jens (Virum, DK), Petersson; Karsten (Ballerup, DK)
Assignee:	LEO Pharma A/S (Ballerup, DK)
Application Number:	16/135,366
Patent Claims:	1. A substantially anhydrous topical composition comprising calcipotriol or calcipotriol monohydrate, betamethasone dipropionate, a pharmaceutically acceptable propellant, and a pharmaceutically acceptable lipid carrier, wherein the calcipotriol or calcipotriol monohydrate and the betamethasone dipropionate are dissolved in the pharmaceutically acceptable propellant, wherein upon application of the composition to skin and evaporation of the pharmaceutically acceptable propellant, the pharmaceutically acceptable lipid carrier forms a semi-solid and occlusive layer at the site of application, and wherein the composition does not include propylene glycol. 2. The composition of claim 1, wherein the pharmaceutically acceptable propellant is present in an amount sufficient to completely dissolve the calcipotriol or calcipotriol monohydrate, and the betamethasone dipropionate. 3. The composition of claim 1, wherein the content of free water in the composition does not exceed about 1% by weight of the composition. 4. The composition of claim 1, wherein the calcipotriol or calcipotriol monohydrate is present in an amount of about 0.00001-0.05% w/w of the composition and the betamethasone dipropionate is present in an amount of about 0.0005-1% w/w of the composition. 5. The composition of claim 4, wherein the calcipotriol or calcipotriol monohydrate is present in amount of about 0.002% w/w of the composition and the betamethasone dipropionate is present in an amount of about 0.02-0.03% w/w of the composition. 6. The composition of claim 1, wherein no more than about 10% of the calcipotriol or calcipotriol monohydrate and no more than about 10% of the betamethasone dipropionate degrades during storage of the composition at 40.degree. C. for at least two months. 7. The composition of claim 6, wherein no more than about 10% of the calcipotriol or calcipotriol monohydrate and no more than about 10% of the betamethasone dipropionate degrades during storage of the composition at 40.degree. C. for three months. 8. The composition of claim 1 wherein the calcipotriol or calcipotriol monohydrate, and the betamethasone dipropionate do not precipitate from the pharmaceutically acceptable propellant during storage of the composition for at least 12 months at 25.degree. C. 9. The composition of claim 1, wherein the pharmaceutically acceptable propellant comprises dimethyl ether, methylethyl ether, or both. 10. The composition of claim 1, wherein the pharmaceutically acceptable propellant comprises dimethyl ether. 11. The composition of claim 1, wherein the pharmaceutically acceptable lipid carrier comprises at least one hydrocarbon. 12. The composition of claim 1, wherein the pharmaceutically acceptable lipid carrier comprises a paraffin. 13. The composition of claim 1, wherein the pharmaceutically acceptable lipid carrier comprises a wax. 14. A substantially anhydrous topical composition comprising calcipotriol or calcipotriol monohydrate, betamethasone dipropionate, a first pharmaceutically acceptable propellant and a second pharmaceutically acceptable propellant, and a pharmaceutically acceptable lipid carrier, wherein the calcipotriol or calcipotriol monohydrate and the betamethasone dipropionate are dissolved in the first propellant, or are dissolved in the first propellant and in the second propellant, wherein upon application of the composition to skin and evaporation of the first propellant and the second propellant, the lipid carrier forms a semi-solid and occlusive layer at the site of application, and wherein the composition does not include propylene glycol. 15. The composition of claim 14, wherein the first pharmaceutically acceptable propellant comprises dimethyl ether and the calcipotriol or calcipotriol monohydrate, and the betamethasone dipropionate are dissolved in the dimethyl ether. 16. The composition of claim 14, wherein the first pharmaceutically acceptable propellant comprises dimethyl ether and the calcipotriol or calcipotriol monohydrate, and the betamethasone dipropionate are dissolved in the mixture of dimethyl ether and the second propellant. 17. The composition of claim 14, wherein the second propellant comprises a C.sub.3-5 alkane, hydrofluoroalkane, hydrochloroalkane, fluoroalkane, or chlorofluoroalkane. 18. The composition of claim 17, wherein the second propellant comprises a C.sub.3-5 alkane. 19. The composition of claim 18, wherein the C.sub.3-5 alkane is propane, isopropane, n-butane, or isobutane. 20. The composition of claim 19, wherein the C.sub.3-5 alkane is n-butane. 21. The composition of claim 1, wherein the pharmaceutically acceptable lipid carrier is solubilized or suspended in the pharmaceutically acceptable propellant. 22. The composition of claim 1, wherein the pharmaceutically acceptable lipid carrier comprises white soft paraffin. 23. The composition of claim 1 wherein the pharmaceutically acceptable lipid carrier further comprises liquid paraffin. 24. The composition of claim 1, wherein the composition further comprises an oily co-solvent. 25. The composition of claim 24, wherein the oily co-solvent comprises one or more of: (a) a compound of general formula I: H(OCH.sub.2C(CH.sub.3)H).sub.xOR.sup.1 wherein R.sup.1 is a straight or branched chain C.sub.1-20 alkyl, and x is an integer from 2 to 60 inclusive; (b) an isopropyl ester of a straight or branched chain C.sub.10-18 alkanoic or alkenoic acid; (c) a propylene glycol diester of a C.sub.8-14 alkanoic or alkenoic acid; (d) a straight or branched C.sub.8-24 alkanol or alkenol; (e) a highly purified vegetable oil; or (f) an N-alkylpyrrolidone or N-alkylpiperidone. 26. The composition of claim 25, wherein the compound of general formula I is polyoxypropylene-15-stearyl ether, polyoxypropylene-11-stearyl ether, polyoxypropylene-14-butyl ether, polyoxypropylene-10-cetyl ether, or polyoxypropylene-3-myristyl ether. 27. The composition of claim 25, wherein the isopropyl ester of a straight or branched chain C.sub.10-18 alkanoic or alkenoic acid is isopropyl myristate, isopropyl palmitate, isopropyl isostearate, isopropyl linolate, or isopropyl monooleate. 28. The composition of claim 25, wherein the propylene glycol diester of a C.sub.8-14 alkanoic acid is propylene glycol dipelargonate. 29. The composition of claim 25, wherein: the straight C.sub.8-24 alkanol is capryl alcohol, lauryl alcohol, cetyl alcohol, stearyl alcohol, or myristyl alcohol; the straight C.sub.8-24 alkenol is oleyl alcohol or linoleyl alcohol; or the branched C.sub.8-24 alkanol is a branched C.sub.18-24 alkanol. 30. The composition of claim 29, wherein the straight C.sub.8-24 alkanol is myristyl alcohol, or the straight C.sub.8-24 alkenol is oleyl alcohol. 31. The composition of claim 25, wherein the N-alkylpyrrolidone is N-methylpyrrolidone. 32. The composition of claim 25, wherein the highly purified vegetable oil comprises medium chain triglycerides. 33. The composition of claim 25, wherein the oily co-solvent comprises polyoxypropylene-11-stearyl ether. 34. The composition of claim 1, wherein the pharmaceutically acceptable propellant comprises dimethyl ether and wherein the pharmaceutically acceptable lipid carrier comprises white soft paraffin and liquid paraffin, wherein the calcipotriol or calcipotriol monohydrate is present in an amount of about 0.002% w/w of the composition, wherein the betamethasone dipropionate is present in an amount of about 0.02-03% w/w of the composition, and wherein the composition further comprises n-butane. 35. The composition of claim 34 wherein the composition further comprises an oily co-solvent. 36. The composition of claim 35, wherein the oily co-solvent comprises polyoxypropylene-11-stearyl ether, or polyoxypropylene-15-stearyl ether. 37. The composition of claim 35, wherein the oily co-solvent comprises oleyl alcohol or myristyl alcohol. 38. The composition of claim 35, wherein the oily co-solvent comprises medium chained triglycerides. 39. The composition of claim 1, wherein the composition, when applied to skin, results in an approximately two-fold or more increase in penetration of the calcipotriol or the calcipotriol monohydrate, and the betamethasone dipropionate into the skin's dermis, epidermis, or dermis and epidermis, after at least about 6 hours from application, as compared to an identical composition that does not comprise a propellant. 40. The composition of claim 1, wherein the pharmaceutically acceptable propellant is present in an amount of about 45-95% w/w of the composition. 41. The composition of claim 1, wherein the pharmaceutically acceptable propellant is present in an amount of about 45-70% w/w of the composition. 42. The composition of claim 1, wherein the pharmaceutically acceptable propellant is present in an amount of about 50-70% w/w of the composition. 43. The composition of claim 18, wherein the ratio of the C.sub.3-5 alkane to the dimethyl ether is in the range of about 6:1-0:1 v/v. 44. The composition of claim 18, wherein the ratio of the C.sub.3-5 alkane to the dimethyl ether is in the range of about 5:1-1:2 v/v. 45. The composition of claim 18, wherein the ratio of the C.sub.3-5 alkane to the dimethyl ether is in the range of about 4:1-1:1 v/v. 46. The composition of claim 18, wherein the ratio of the C.sub.3-5 alkane to the dimethyl ether is in the range of about 4:2-1:1 v/v. 47. The composition of claim 18, wherein the ratio of the C.sub.3-5 alkane to the dimethyl ether is in the range of about 4:2-4:3 v/v. 48. The composition of claim 18, wherein the ratio of the C.sub.3-5 alkane to the dimethyl ether is in the range of about 4:3-1:1 v/v. 49. The composition of claim 1, wherein (a) the calcipotriol or calcipotriol monohydrate is present in an amount of about 0.00001-0.05% w/w of the composition, (b) the betamethasone dipropionate is present in an amount of about 0.0005-1% w/w of the composition, (c) the pharmaceutically acceptable lipid carrier is present in an amount of about 5-55% w/w of the composition, and (d) the pharmaceutically acceptable propellant is present in an amount of about 45-95% w/w of the composition. 50. The composition of claim 49, wherein the calcipotriol or calcipotriol monohydrate is present in an amount of about 0.002% w/w of the composition. 51. The composition of claim 50, wherein the betamethasone dipropionate is present in an amount of about 0.026% w/w of the composition. 52. The composition of claim 49, wherein the pharmaceutically acceptable lipid carrier is present in an amount of about 20-40% w/w of the composition. 53. The composition of claim 49, wherein the pharmaceutically acceptable propellant is present in an amount of about 55-70% w/w of the composition. 54. The composition of claim 49, wherein the composition further comprises an oily co-solvent in an amount of about 0.1-10% w/w of the composition. 55. The composition of claim 49, wherein the composition further comprises an oily co-solvent in an amount of about 0.5-3% w/w of the composition. 56. The composition of claim 49, wherein the composition further comprises an oily co-solvent in an amount of about 1-2.5% w/w of the composition. 57. The composition of claim 49, wherein the composition further comprises an oily co-solvent in an amount of about 1.5-2% w/w of the composition. 58. The composition of claim 11, wherein the pharmaceutically acceptable lipid carrier comprises hydrocarbons with chain lengths of at least five carbons and no greater than sixty carbons, and wherein the hydrocarbons exhibit a peak at one or more chain lengths of C.sub.14-16, C.sub.18-22, C.sub.20-22, C.sub.20-26, C.sub.28-40, and C.sub.40-44 as determined by gas chromatography. 59. The composition of claim 1, wherein the pharmaceutically acceptable lipid carrier comprises an isoparaffin. 60. The composition of claim 1, wherein the pharmaceutically acceptable lipid carrier comprises a microcrystalline wax, a silicone wax, or both. 61. The composition of claim 4, wherein the composition comprises calcipotriol or calcipotriol monohydrate in an amount of about 0.00001% w/w to less than 0.005% w/w of the composition and betamethasone dipropionate in an amount of about 0.0005% w/w to less than 0.064% w/w of the composition, and wherein upon application of the composition to skin and evaporation of the pharmaceutically acceptable propellant, the calcipotriol or calcipotriol monohydrate is present in an amount of about 0.005% w/w of the composition, and the betamethasone dipropionate is present in amount of about 0.064% w/w of the composition. 62. The composition of claim 5, wherein upon application of the composition to skin and evaporation of the pharmaceutically acceptable propellant, the calcipotriol or calcipotriol monohydrate is present in an amount of about 0.005% w/w of the composition, and the betamethasone dipropionate is present in amount of about 0.064% w/w of the composition. 63. The composition of claim 49, wherein the composition comprises calcipotriol or calcipotriol monohydrate in an amount of about 0.00001% w/w to less than 0.005% w/w of the composition and betamethasone dipropionate in an amount of about 0.0005% w/w to less than 0.064% w/w of the composition, and wherein upon application of the composition to skin and evaporation of the pharmaceutically acceptable propellant, the calcipotriol or calcipotriol monohydrate is present in an amount of about 0.005% w/w of the composition, and the betamethasone dipropionate is present in amount of about 0.064% w/w of the composition. 64. The composition of claim 51, wherein upon application of the composition to skin and evaporation of the pharmaceutically acceptable propellant, the calcipotriol or calcipotriol monohydrate is present in an amount of about 0.005% w/w of the composition, and the betamethasone dipropionate is present in amount of about 0.064% w/w of the composition. 65. The composition of claim 51, wherein upon application of the composition to skin and evaporation of the pharmaceutically acceptable propellant, the calcipotriol or calcipotriol monohydrate is present in an amount of about 0.005% w/w of the composition, and the betamethasone dipropionate is present in amount of about 0.064% w/w of the composition. 66. A method of treating psoriasis in a patient in need thereof, comprising topically administering to skin of the patient a composition of claim 1.