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 topical pharmaceutical oil-in-water emulsion composition comprising:
an effective amount of 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, wherein the effective amount is about 0.5% to about 2% by weight, based on the total weight of the composition,
an oil phase in an amount of about 5% to about 25% by weight, based on the total weight of the composition, wherein the oil phase is selected from the group consisting of fatty acids, esters, esters of glycerin, fatty alcohols, waxes, sterols, unsaponifiables, siloxanes, silanes, lanolin, hydrocarbons, essential oils, vegetable oils, mineral oils, animal oils and edible oils, and mixtures thereof,
a water phase in an amount of about 55% to about 75% by weight, based upon the total weight of the composition,
a non-ionic surfactant in an amount of about 1% to about 20% by weight, based on the total weight of the composition, wherein the non-ionic surfactant is selected from the group consisting of ethoxylated fatty alcohol ethers, PEG castor oils, PEG esters, propylene glycol esters, glyceryl esters and derivatives, polymeric ethers, sorbitan derivatives, fatty alcohols, emulsifying waxes, and mixtures thereof, and
an antioxidant,
and optionally comprising an additional excipient selected from the group consisting of a preservative, a pH adjusting agent, a chelating agent, a co-solvent, a penetration enhancer, a humectant, a viscosity building agent, a fragrance, a colorant and combinations thereof,
wherein the topical pharmaceutical oil-in-water emulsion composition is substantially free of petrolatum, is stable under ICH conditions up to 6 months, and is a lotion or a cream,
wherein the 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase, and
wherein the oil phase contains droplets with a D90 of the average droplet size of about 0.5 microns to about 1 micron.
2. The topical pharmaceutical oil-in-water emulsion composition of claim 1 , wherein the topical pharmaceutical oil-in-water emulsion composition is a cream.
3. The topical pharmaceutical oil-in-water emulsion composition of claim 1 , wherein the effective amount of 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, is about 0.5% by weight, based on the total weight of the composition.
4. The topical pharmaceutical oil-in-water emulsion composition of claim 1 , wherein the effective amount of 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, is about 1% by weight, based on the total weight of the composition.
5. The topical pharmaceutical oil-in-water emulsion composition of claim 1 , wherein the surfactant is at an amount of about 5% to about 15% by weight, based on the total weight of the composition and the oil phase is at an amount of about 5% to about 15% by weight, based on the total weight of the composition.
6. The topical pharmaceutical oil-in-water emulsion composition of claim 1 , wherein the oil phase comprises medium chain triglycerides of a carbon length from six to twelve carbons.
7. The topical pharmaceutical oil-in-water emulsion composition of claim 1 , wherein the surfactant comprises at least one non-ionic emulsifying wax NF.
8. The topical pharmaceutical oil-in-water emulsion composition of claim 1 , wherein the 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is the only active ingredient in the oil phase.
9. The topical pharmaceutical oil-in-water emulsion composition of claim 1 , wherein the oil phase is substantially free of mineral oil.
10. The topical pharmaceutical oil-in-water emulsion composition of claim 1 , wherein the antioxidant is in an amount of 0.001% to 5% by weight, based on the total weight of the composition.
11. The topical pharmaceutical oil-in-water emulsion composition of claim 1 , wherein the pH is from 4 to 7.
12. The topical pharmaceutical oil-in-water emulsion composition of claim 1 , wherein the pH adjusting agent is present and the pH adjusting agent is in an amount of 0.01% to 10% by weight, based on the total weight of the composition.
13. The topical pharmaceutical oil-in-water emulsion composition of claim 12 , 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.
14. The topical pharmaceutical oil-in-water emulsion composition of claim 12 , wherein the pH adjusting agent is a buffer and 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.
15. The topical pharmaceutical oil-in-water emulsion composition of claim 1 , wherein the chelating agent is present, and the chelating agent is in an amount of 0.01% to 1% by weight, or 0.1% by weight, based on the total weight of the composition.
16. The topical pharmaceutical oil-in-water emulsion composition of claim 15 , 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.
17. The topical pharmaceutical oil-in-water emulsion composition of claim 1 , wherein the preservative is present and the preservative is in an amount of 0.01% to 2% by weight, or 0.25% by weight, based on the total weight of the composition.
18. The topical pharmaceutical oil-in-water emulsion composition of claim 17 , 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.
19. The topical pharmaceutical oil-in-water emulsion composition of claim 1 , wherein the co-solvent is present and the co-solvent is in an amount of 5% to 20% by weight, based on the total weight of the composition.
20. The topical pharmaceutical oil-in-water emulsion composition of claim 19 , wherein the co-solvent is a mixture of propylene glycol and diethylene glycol monoethyl ether.
21. The topical pharmaceutical oil-in-water emulsion composition of claim 1 , wherein the non-ionic surfactant comprises at least one non-ionic emulsifying wax NF.
22. The topical pharmaceutical oil-in-water emulsion composition of claim 1 , wherein at least about 75% of the droplets have a droplet size of 0.1 micron to 0.75 microns.
23. The topical pharmaceutical oil-in-water emulsion composition of claim 1 , wherein at least about 80% of the droplets have a droplet size of 0.1 micron to 0.75 microns.
24. The topical pharmaceutical oil-in-water emulsion composition of claim 1 , wherein at least about 85% of the droplets have a droplet size of 0.1 micron to 0.75 microns.
25. The topical pharmaceutical oil-in-water emulsion composition of claim 1 , wherein at least about 95% of the droplets have a droplet size of 0.1 micron to 0.75 microns.
26. The topical pharmaceutical oil-in-water emulsion composition of claim 1 , wherein at least about 75% to about 95% of the droplets have a droplet size of 0.5 micron to 0.75 microns.
27. The topical pharmaceutical oil-in-water emulsion composition of claim 1 , wherein the composition comprises:
about 0.5 to about 2% of 3,5-Dihydroxy-4-isopropyl-trans-stilbene, based on the total weight of the composition,
an oil phase in an amount of about 5% to about 15% by weight, based on the total weight of the composition, wherein the oil phase is a mixture of a vegetable oil and a mineral oil,
a water phase in an amount of about 55% to about 75% by weight, based upon the total weight of the composition,
a non-ionic surfactant in an amount of about 1% to about 20% by weight, based on the total weight of the composition, wherein the non-ionic surfactant is selected from the group consisting of ethoxylated fatty alcohol ethers, PEG castor oils, PEG esters, propylene glycol esters, glyceryl esters and derivatives, polymeric ethers, sorbitan derivatives, fatty alcohols, emulsifying waxes, and mixtures thereof, and
an antioxidant in an amount of about 0.1% by weight, based on the total weight of the composition, wherein the antioxidant is butylated hydroxytoluene,
a preservative in the amount of about 0.25% by weight, based on the total weight of the composition, wherein the preservative is benzoic acid;
a pH adjusting agent, wherein the pH adjusting agent is a buffer;
a chelating agent in the amount of about 0.1% by weight, based on the total weight of the composition, wherein the chelating agent is disodium edetate;
a gelling agent in the amount of about 0.2% to about 1%, based on the total weight of the composition, wherein the gelling agent is a carbomer;
and a co-solvent in the amount of about 1% to about 30% by weight, based on the total weight of the composition, wherein the co-solvent is a mixture of dietheylene glycol monoethyl ether, propylene glycol and dimethyl sulfoxide;
wherein the composition is a lotion.
28. The topical pharmaceutical oil-in-water emulsion composition of claim 27 , wherein the mineral oil is mineral oil light and the vegetable oil is castor oil.
29. The topical pharmaceutical oil-in-water emulsion composition of claim 1 , wherein the composition comprises:
about 0.5 to about 2% of 3,5-Dihydroxy-4-isopropyl-trans-stilbene, based on the total weight of the composition,
an oil phase in an amount of about 10%, based on the total weight of the composition, wherein the oil phase is diethyl sebacate,
a water phase in an amount of about 30% to about 80% by weight, based upon the total weight of the composition,
a non-ionic surfactant in an amount of about 1% to about 20% by weight, based on the total weight of the composition, wherein the non-ionic surfactant is polysorbate 20, and
an antioxidant in an amount of about 0.01% to about 1% by weight, based on the total weight of the composition, wherein the antioxidant is propyl gallate,
a preservative in the amount of about 0.01% to about 2% by weight, based on the total weight of the composition, wherein the preservative is phenoxyethanol;
a gelling agent in the amount of about 0.1% to about 2%, based on the total weight of the composition, wherein the gelling agent is hydroxyethylcellulose; and
a penetration enhancer in the amount of about 0.5% to about 40%, based upon the total weight of the composition, wherein the penetration enhancer is isopropyl myristate.