Topical pharmaceutical compositions
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.
1. A method of improving residency time of an active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof in the skin of a patient in need thereof, the method comprising topically administering to the skin of said patient up to twice daily a homogenous oil-in-water emulsion composition comprising:
the active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof in an amount of about 0.5% to about 2% by weight based on the total weight of the composition,
a first oil phase, wherein the active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the first oil phase, and wherein the first oil phase does not contain mineral oil or petrolatum,
optionally, a second oil phase selected from the group consisting of mineral oil, petrolatum, and a combination thereof,
wherein the first oil phase and, if present, the second oil phase, combined are present in an amount of about 5% to about 25% by weight based on the total weight of the composition,
a water phase in an amount of about 30% to about 80% by weight,
a non-ionic surfactant in an amount of about 5% to about 15% by weight, based on the total weight of the composition, wherein the non-ionic surfactant is an emulsifying wax, and
an antioxidant in an amount of about 0.01% to about 1% by weight, based on the total weight of the composition, and
wherein the oil-in-water emulsion composition has a D90 of about 0.1 μm to about 1 μm, and has an improved residency time,
wherein the improved residency time is measured as a ratio of the active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene in the dermis to the cumulative amount of the active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene in the receiving fluid and wherein the ratio is about 909.3:1 at about 12 hours or about 1044.0:1 at about 15 hours.
2. The method of claim 1 , wherein the improved residency time is measured as an in vitro skin flux.
3. The method of claim 2 , wherein the in vitro skin flux is about 1,000 to about 5,000 ng/cm 2 /hour.
4. The method of claim 1 , wherein the improved residency time appears as early as 3 hours post application and continues over 15 hours.
5. The method of claim 1 , wherein the homogenous oil-in-water emulsion composition further comprises one or more additional surfactants.
6. The method of claim 1 , wherein the homogenous oil-in-water emulsion composition does not comprise the second oil phase.
7. The method of claim 1 , wherein the second oil phase is present and wherein the second oil phase comprises ≤3% petrolatum.
8. A method of improving residency time of an active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof in the skin of a patient in need thereof, the method comprising topically administering to the skin of said patient up to twice daily a homogenous oil-in-water emulsion composition comprising:
the active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof in an amount of about 0.5% to about 2% by weight based on the total weight of the composition,
a first oil phase, wherein the active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the first oil phase, and wherein the first oil phase does not contain mineral oil or petrolatum,
optionally, a second oil phase selected from the group consisting of mineral oil, petrolatum, and a combination thereof,
wherein the first oil phase and, if present, the second oil phase, combined are present in an amount of about 5% to about 25% by weight based on the total weight of the composition,
a water phase in an amount of about 30% to about 80% by weight,
a non-ionic surfactant in an amount of about 5% to about 15% by weight, based on the total weight of the composition, wherein the non-ionic surfactant is an emulsifying wax, and
an antioxidant in an amount of about 0.01% to about 1% by weight, based on the total weight of the composition, and
wherein the oil-in-water emulsion composition has a D90 of about 0.1 μm to about 1 μm, and has an improved residency time,
and wherein the improved residency time is demonstrated by an area under the curve (AUC) of the active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof below about 50 ng*h/mL.
9. The method of claim 8 , wherein the improved residency time is demonstrated by an AUC of the active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof below about 42.5 ng*h/mL.
10. The method of claim 8 , wherein the improved residency time is demonstrated by an AUC of the active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof below about 30 ng*h/mL.
11. The method of claim 8 , wherein the improved residency time is demonstrated by an AUC of the active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof below about 23.5 ng*h/mL.
12. The method of claim 8 , wherein the improved residency time is demonstrated by an AUC (0-8 h) of the active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof below about 16 ng*h/mL.
13. The method of claim 8 , wherein the improved residency time is demonstrated by an AUC (0-8 h) of the active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof below about 14 ng*h/mL.
14. The method of claim 8 , wherein the improved residency time is demonstrated by an AUC (0-8 h) of the active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof below about 11 ng*h/mL.
15. The method of claim 8 , wherein the homogenous oil-in-water emulsion composition does not comprise the second oil phase.
16. The method of claim 8 , wherein the second oil phase is present and wherein the second oil phase comprises ≤3% petrolatum.
17. The method of claim 8 , wherein the homogenous oil-in-water emulsion composition further comprises one or more additional surfactants.
18. A method of improving residency time of an active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof in the skin of a patient in need thereof, the method comprising topically administering to the skin of said patient up to twice daily a homogenous oil-in-water emulsion composition comprising:
the active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof in an amount of about 0.5% to about 2% by weight based on the total weight of the composition,
a first oil phase, wherein the active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the first oil phase, and wherein the first oil phase does not contain mineral oil or petrolatum,
optionally, a second oil phase selected from the group consisting of mineral oil, petrolatum, and a combination thereof,
wherein the first oil phase and, if present, the second oil phase, combined are present in an amount of about 5% to about 25% by weight based on the total weight of the composition,
a water phase in an amount of about 30% to about 80% by weight,
a non-ionic surfactant in an amount of about 5% to about 15% by weight, based on the total weight of the composition, wherein the non-ionic surfactant is an emulsifying wax, and
an antioxidant in an amount of about 0.01% to about 1% by weight, based on the total weight of the composition, and
wherein the oil-in-water emulsion composition has a D90 of about 0.1 μm to about 1 μm, and has an improved residency time,
and wherein the improved residency time is demonstrated by a C max of the active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof below about 15 ng/mL.
19. The method of claim 18 , wherein the improved residency time is demonstrated by a C max of the active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof below about 12.5 ng/mL.
20. The method of claim 18 , wherein the improved residency time is demonstrated by a C max of the active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof below about 11.3 ng/mL.
21. The method of claim 18 , wherein the improved residency time is demonstrated by a C max of the active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof below about 5 ng/mL.
22. The method of claim 18 , wherein the improved residency time is demonstrated by a C max of the active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof below about 4 ng/mL.
23. The method of claim 18 , wherein the improved residency time is demonstrated by a C max of the active ingredient 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof below about 3 ng/mL.
24. The method of claim 18 , wherein the homogenous oil-in-water emulsion composition does not comprise the second oil phase.
25. The method of claim 18 , wherein the second oil phase is present and wherein the second oil phase comprises ≤3% petrolatum.
26. The method of claim 18 , wherein the homogenous oil-in-water emulsion composition further comprises one or more additional surfactants.