Topical formulations of PDE-4 inhibitors and their methods of use
View Patent ↗Embodiments herein are directed to topical formulations of a compound represented by the formula (I), salt, metabolite, prodrug, or hydrate thereof along with a solvent, and a base. The compound is a PDE4 inhibitor and the topical formulations may be used to treat dermatological conditions such as, but not limited to, atopic dermatitis, seborrheic dermatitis, alopecia, contact dermatitis, psoriasis, urticaria, eczema, burns, sunburn, pancreatitis, hepatitis, lichen planus, scleritis, scleroderma, dermatomyositis, itching associated with any of the preceding conditions or a combination thereof.
1. A topical formulation comprising an effective amount of a compound represented by the formula (I), a salt thereof, or hydrate thereof,
wherein R represents hydroxyl, C1-6 alkoxy optionally substituted with C1-6 alkoxy, or amino optionally substituted with C1-6 alkyl,
a bleeding preventing agent, a solvent, and a base;
wherein the topical formulation comprises about 30% to about 60% by weight of a solvent.
2. The topical formulation of claim 1 , wherein the base is in an amount of about 0.001% to less than about 10% by weight of the topical formulation.
3. The topical formulation of claim 1 , wherein the compound represented by formula (I) is in an amount of about 0.2% to about 0.9% by weight of the topical formulation.
4. The topical formulation of claim 1 , wherein the compound represented by formula (I) is in an amount of about 0.5% by weight of the topical formulation.
5. The topical formulation of claim 1 , further comprising an absorption enhancer, water, or a combination thereof.
6. The topical formulation of claim 1 , wherein the bleeding preventing agent is two or more bleeding preventing agents.
7. The topical formulation of claim 1 , wherein a total amount of the bleeding preventing agent is greater than about 40% by weight of the topical formulation.
8. The topical formulation of claim 5 , wherein the absorption enhancer is in an amount of about 5% to about 20% by weight of the topical formulation.
9. The topical formulation of claim 5 , wherein the sum of the solvent and absorption enhancer is about 35% to about 70% by weight of the topical formulation.
10. The topical formulation of claim 1 , wherein the base is selected from the group consisting of petrolatum, paraffin, liquid paraffin, microcrystalline wax, carnauba wax, white beeswax, and any combination thereof.
11. The topical formulation of claim 1 , wherein the solvent is selected from the group consisting of polyethylene glycol having an average molecular weight of about 200 to about 600, dipropylene glycol, benzyl alcohol, polyoxyethylene sorbitan fatty acid ester, diethylene glycol monoethyl ether, propylene glycol, polyoxyethylene oleyl ether, polyoxyethylene octyl phenyl ether, polyoxyethylene lauryl ether, polyoxyethylene castor oil, oleic acid, and any combination thereof.
12. The topical formulation of claim 1 , wherein the solvent is polyethylene glycol having an average molecular weight of about 200 to about 600.
13. The topical formulation of claim 1 , wherein the solvent is polyethylene glycol having an average molecular weight of about 400.
14. The topical formulation of claim 5 , wherein the absorption enhancer is selected from the group consisting of isopropyl myristate, ethyl myristate, octyldodecyl myristate, isopropyl palmitate, isostearyl palmitate, isopropyl isostearate, butyl stearate, ethyl oleate, decyl oleate, diisopropyl sebacate, diethyl sebacate, diisopropyl adipate, diethyl adipate, diethyl phthalate, and any combination thereof.
15. The topical formulation of claim 1 , wherein the bleeding preventing agent is selected from the group consisting of polyethylene glycol having an average molecular weight of 1000 to 50000, polyoxyethylene hydrogenated castor oil, stearic acid, oleic acid, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, glycerol esters of fatty acids, and any combination thereof.
16. The topical formulation of claim 1 , wherein the bleeding preventing agent is polyethylene glycol with an average molecular weight of about 3600 to about 4400.
17. The topical formulation of claim 1 , wherein the bleeding preventing agent is polyethylene glycol with an average molecular weight of about 4000.
18. The topical formulation of claim 15 , wherein the glycerol esters of fatty acids is selected from the group consisting of glycerol monostearate 40-55, monoglycerides, diglycerides, monoglycerol stearates, diglycerol stearates, triglycerol stearates, diglyceryl isostearate, hexaglyceryl polyricinoleate, and any combination thereof.
19. The topical formulation of claim 6 , wherein the two or more bleeding preventing agents are polyethylene glycol having an average molecular weight of 1000 to 50000 and glycerol esters of fatty acids.
20. The topical formulation of claim 1 , wherein the solvent is in an amount of about 50% by weight, the base is in an amount of about 4.4% by weight, the bleeding preventing agent is in an amount of about 33% by weight, and the topical formulation further comprises an absorption enhancer in an amount of about 10% by weight.
21. The topical formulation of claim 1 , wherein the compound represented by the formula (I) is:
22. The topical formulation of claim 21 , wherein the base is in an amount of about 0.001% to less than about 10% by weight of the topical formulation.
23. The topical formulation of claim 21 , wherein the compound represented by formula (I) is in an amount of about 0.2% to about 0.9% by weight of the topical formulation.
24. The topical formulation of claim 21 , wherein the compound represented by formula (I) is in an amount of about 0.5% by weight of the topical formulation.
25. The topical formulation of claim 21 , further comprising an absorption enhancer, water, or a combination thereof.
26. The topical formulation of claim 21 , wherein the bleeding preventing agent is two or more bleeding preventing agents.
27. The topical formulation of claim 21 , wherein a total amount of the bleeding preventing agent is greater than about 40% by weight of the topical formulation.
28. The topical formulation of claim 25 , wherein the absorption enhancer is in an amount of about 5% to about 20% by weight of the topical formulation.
29. The topical formulation of claim 25 , wherein the sum of the solvent and absorption enhancer is about 35% to about 70% by weight of the topical formulation.
30. The topical formulation of claim 21 , wherein the base is selected from the group consisting of petrolatum, paraffin, liquid paraffin, microcrystalline wax, carnauba wax, white beeswax, and any combination thereof.
31. The topical formulation of claim 21 , wherein the solvent is selected from the group consisting of polyethylene glycol having an average molecular weight of about 200 to about 600, dipropylene glycol, benzyl alcohol, polyoxyethylene sorbitan fatty acid ester, diethylene glycol monoethyl ether, propylene glycol, polyoxyethylene oleyl ether, polyoxyethylene octyl phenyl ether, polyoxyethylene lauryl ether, polyoxyethylene castor oil, oleic acid, and any combination thereof.
32. The topical formulation of claim 21 , wherein the solvent is polyethylene glycol having an average molecular weight of about 200 to about 600.
33. The topical formulation of claim 21 , wherein the solvent is polyethylene glycol having an average molecular weight of about 400.
34. The topical formulation of claim 25 , wherein the absorption enhancer is selected from the group consisting of isopropyl myristate, ethyl myristate, octyldodecyl myristate, isopropyl palmitate, isostearyl palmitate, isopropyl isostearate, butyl stearate, ethyl oleate, decyl oleate, diisopropyl sebacate, diethyl sebacate, diisopropyl adipate, diethyl adipate, diethyl phthalate, and any combination thereof.
35. The topical formulation of claim 21 , wherein the bleeding preventing agent is selected from the group consisting of polyethylene glycol having an average molecular weight of 1000 to 50000, polyoxyethylene hydrogenated castor oil, stearic acid, oleic acid, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, glycerol esters of fatty acids, and any combination thereof.
36. The topical formulation of claim 21 , wherein the bleeding preventing agent is polyethylene glycol with an average molecular weight of about 3600 to about 4400.
37. The topical formulation of claim 21 , wherein the bleeding preventing agent is polyethylene glycol with an average molecular weight of about 4000.
38. The topical formulation of claim 35 , wherein the glycerol esters of fatty acids is selected from the group consisting of glycerol monostearate 40-55, monoglycerides, diglycerides, monoglycerol stearates, diglycerol stearates, triglycerol stearates, diglyceryl isostearate, hexaglyceryl polyricinoleate, and any combination thereof.
39. The topical formulation of claim 26 , wherein the two or more bleeding preventing agents are polyethylene glycol having an average molecular weight of 1000 to 50000 and glycerol esters of fatty acids.
40. The topical formulation of claim 21 , wherein the solvent is in an amount of about 50% by weight, the base is in an amount of about 4.4% by weight, the bleeding preventing agent is in an amount of about 33% by weight, and the topical formulation further comprises an absorption enhancer in an amount of about 10% by weight.