Pharmaceutical compositions of 5-alpha-reductase inhibitors and methods of use thereof

Abstract

Non-occlusive compositions for transdermal delivery of 5-alpha-reductase inhibitors, and more particularly finasteride or dutasteride or pharmaceutically acceptable salts or derivatives thereof, and methods of making same. The composition may, for example, be a gel suitable for transdermal or transmucosal applications. The compositions of the present invention typically include a mixture of water and alcohol, and a solvent system having a mono alkyl ether of diethylene glycol and a glycol present in specified ratios and in specific amounts, wherein the pH of the gel is usually between about pH 4.5 and about pH 8. The compositions may include further components, for example, the hydroalcoholic vehicle may further include additional penetration enhancer(s), buffering agent(s), antioxidant(s), stabilizer(s) and/or gelling agent(s). Also, a method for the sustained delivery of 5-alpha-reductase inhibitors to treat a variety of conditions and disorders.

1 . A transdermal or transmucosal non-occlusive, semi-solid pharmaceutical formulation comprising: at least one active ingredient which is a 5-alpha-reductase inhibitor; and a permeation enhancing solvent system present in an amount sufficient to solubilize the active ingredient and characterized in that it includes: (i) a pharmaceutically acceptable monoalkyl ether of diethylene glycol present in an amount of between about 1% and 30% by weight of the solvent system; (ii) a pharmaceutically acceptable glycol present in an amount of between about 1% and 30% by weight of the solvent system, wherein the monoalkyl ether of diethylene glycol and the glycol in combination are present in an amount of at least 15% and no more than 60% by weight of the formulation; and (iii) a mixture of a C 2  to C 4  alcohol and water, which mixture is present in an amount of between about 40% and 98% by weight of the solvent system, wherein the C 2  to C 4  alcohol is present in an amount of about 5% to 80% by weight of the mixture, and the water is present in an amount of about 20% to 95% by weight of the mixture; so that, compared to formulations not containing the present permeation enhancing solvent system, the present formulation (a) inhibits crystallization of the at least one active ingredient on a skin or mucosal surface of a mammal, (b) reduces or prevents transfer of the formulation to clothing or to another being, (c) modulates biodistribution of the at least one active agent within different layers of skin, (d) facilitates absorption of the at least one active agent by a skin or a mucosal surface of a mammal, or (e) provides a combination of one or more of (a) through (d). 
   
   
       2 . The pharmaceutical formulation of  claim 1 , wherein the monoalkyl ether of diethylene glycol and the glycol are present in a weight ratio of 10:1 to 1:10. 
   
   
       3 . The pharmaceutical formulation of  claim 1 , wherein the monoalkyl ether of diethylene glycol is selected from the group consisting of diethylene glycol monomethyl ether, and diethylene glycol monoethyl ether or mixtures thereof. 
   
   
       4 . The pharmaceutical formulation of  claim 1 , wherein the glycol is selected from the group consisting of propylene glycol, dipropylene glycol or mixtures thereof. 
   
   
       5 . The pharmaceutical formulation of  claim 1 , wherein the C 2  to C 4  alcohol is selected from the group consisting of ethanol, propanol, isopropanol, 1-butanol, 2-butanol, or mixtures thereof. 
   
   
       6 . The pharmaceutical formulation of  claim 1 , wherein the formulation further includes a saturated fatty alcohol or fatty acid, or mixtures thereof, wherein said fatty alcohol and/or said fatty acid have the formula CH 3 —(CH 2 ) n —CH 2 OH or CH 3 —(CH 2 ) n —H 2 COOH, respectively, in which n is an integer from 8 to 22, preferably 8 to 12, most preferably 10; or an unsaturated fatty alcohol or fatty acid, or mixtures thereof, wherein said unsaturated fatty alcohol and/or fatty acid have the formula CH 3 —(C n H 2(n-x) )—OH or CH 3 —(C n H 2(n-x) )—COOH, respectively, in which n is an integer from 8 to 22. 
   
   
       7 . The pharmaceutical formulation of  claim 1 , wherein the formulation further includes lauryl alcohol or myristyl alcohol present in an amount from 0.1 to 2% by weight of the total formulation. 
   
   
       8 . The pharmaceutical formulation of  claim 1 , wherein the at least one active ingredient is an azasteroid compound. 
   
   
       9 . The pharmaceutical formulation of  claim 1 , wherein the azasteroid compound is used to treat benign prostate hyperplasia; prostate cancer; or androgenetic alopecia. 
   
   
       10 . The pharmaceutical formulation of  claim 9 , wherein the azasteroid compound is selected from the group consisting of finasteride and pharmaceutically acceptable salts thereof. 
   
   
       11 . The pharmaceutical formulation of  claim 9 , wherein the azasteroid compound is selected from the group consisting of dutasteride and pharmaceutically acceptable salts thereof. 
   
   
       12 . The pharmaceutical formulation of  claim 1 , further comprising an agent selected from the group consisting of gelling agents; permeation enhancers, preservatives, anti-oxidants, buffers, humectants, sequestering agents, moisturizers, surfactants, emollients, film-forming agents, solubilizers, flavors, fragrances, stabilizers, solubilizers, and any combination thereof. 
   
   
       13 . The pharmaceutical formulation of  claim 1 , comprising dutasteride in an amount of between about 0.01% and 5% by weight; a monoethyl ether of diethylene glycol in an amount of between about 1% and 30% by weight; propylene glycol in an amount of between about 1% and 30% by weight; a C 2  to C 4  alcohol in an amount of between about 10% and 70% by weight; a fatty permeation enhancer selected from the group of lauryl alcohol, myristyl alcohol, oleyl alcohol, lauric acid, myristic acid, or oleic acid in an amount of between about 0.1% to about 2% by weight; water; and an agent selected from the group consisting of gelling agents; permeation enhancers, preservatives, anti-oxidants, buffers, humectants, sequestering agents, moisturizers, surfactants, emollients, film-forming agents, solubilizers, flavors, fragrances, stabilizers, solubilizers, and any combination thereof.