Pharmaceutical Formulation for Histone Deacetylase Inhibitors

Abstract

A pharmaceutical composition, comprising a therapeutically effective amount of an active pharmaceutical ingredient (API) compound represented by the following structural formula at least one acidifying agent; and a vehicle base comprising at least one pharmaceutically acceptable non-aqueous solvent. Values and preferred values of the variables in structural formula (I) are defined herein.

1 . A method of treating a proliferative disorder in a subject in need thereof, said method comprising cutaneously administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising
 an active pharmaceutical ingredient (API) compound represented by the following structural formula   
       
         
           
           
               
               
           
         
         at least one acidifying agent; and 
         a vehicle base comprising at least one pharmaceutically acceptable non-aqueous solvent, 
         wherein the pharmaceutical composition has a measured pH of from about 3 to about 5; 
         the API is present in an amount of 0.1 to 5.0% (w/w); and 
         the at least one non-aqueous solvent comprises ethanol. 
       
     
     
         2 . The method of  claim 1  wherein the proliferative disorder is selected from cutaneous T cell lymphoma, and a skin cancer. 
     
     
         3 . The method of  claim 1  wherein the proliferative disorder is selected from cutaneous T-cell lymphoma, and, basal cell carcinoma. 
     
     
         4 . The method of  claim 3 , wherein the at least one acidifying agent of the pharmaceutical composition is selected from the group consisting of acetic acid, dehydro acetic acid, ascorbic acid, benzoic acid, boric acid, citric acid, edetic acid, hydrochloric acid, isostearic acid, stearic acid, lactic acid, nitric acid, oleic acid, phosphoric acid, sorbic acid, sulfuric acid, tartaric acid, and undecylenic acid. 
     
     
         5 . The method of  claim 4  wherein the at least one acidifying agent of the pharmaceutical composition is selected from citric acid, acetic acid, and phosphoric acid. 
     
     
         6 . The method of  claim 4  wherein the pharmaceutical composition further comprises at least one humectant. 
     
     
         7 . The method of  claim 6 , wherein the at least one humectant is selected from the group consisting of hexylene glycol, glycerin, propylene glycol, sorbitol, lactic acid, sodium lactate, mannitol, butylene glycol, panthenol, hyaluronic acid, urea, chitosan, polyols, methyl gluceth-10, methyl gluceth-20, and polyethylene glycols. 
     
     
         8 . The method of  claim 6 , wherein the at least one humectant is selected from glycerin and hexylene glycol. 
     
     
         9 . The method of  claim 4  wherein the pharmaceutical composition further comprises at least one emollient. 
     
     
         10 . The method of  claim 9  wherein the at least one emollient of the pharmaceutical composition is selected from the group consisting of diisopropyl adipate, isopropyl myristate, isopropyl palmitate, cetearyl octonoate, isopropyl isostearate, myristyl lactate, octyldodecanol, oleyl alcohol, a mineral oil, petrolatum, a vegetable oil, PPG-15 stearyl ether, PEG-4 dilaurate, lecithin, lanolin, lanolin alcohol, polyoxyl 75 lanolin, cholesterol, cetyl esters wax, cetostearyl alcohol, glyceryl monostearate, triglycerides of capric and caprylic acids, dimethicone, and cyclomethicone. 
     
     
         11 . The method of  claim 9  wherein the at least one emollient of the pharmaceutical composition is selected from diisopropyl adipate and oleyl alcohol. 
     
     
         12 . The method of  claim 4  wherein the pharmaceutical composition further comprises at least one humectant and at least one emollient. 
     
     
         13 . The method of  claim 12  wherein the at least one humectant of the pharmaceutical composition is selected from glycerin and hexylene glycol and wherein the at least one emollient is selected from diisopropyl adipate and oleyl alcohol. 
     
     
         14 . The method of  claim 4  wherein the pharmaceutical composition further comprises at least one skin permeation enhancer. 
     
     
         15 . The method of  claim 14  wherein the at least one permeation enhancer of the pharmaceutical composition is selected from one or more of oleyl alcohol, propylene glycol, and ethanol. 
     
     
         16 . The method of  claim 4  wherein the pharmaceutical composition further comprises at least one gelling agent. 
     
     
         17 . The method of  claim 16 , wherein the at least one gelling agent of the pharmaceutical composition is a hydroxypropylcellulose. 
     
     
         18 . The method of  claim 4  wherein the pharmaceutical composition further comprises at least one antioxidant. 
     
     
         19 . The method of  claim 18 , wherein the antioxidant of the pharmaceutical composition is selected from the group consisting of alpha tocopherol, beta tocopherol, delta tocopherol, gamma tocopherol, tocopherols, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisol (BHA), butylated hydroxytoluene (BHT), fumaric acid, malic acid, methionine, propyl gallate, sodium ascorbate, sodium metabisulfate, sodium thiosulfate, sodium bisulfate. 
     
     
         20 . The method of  claim 18 , wherein the antioxidant is the butylated hydroxytoluene (BHT). 
     
     
         21 . The method of  claim 4  wherein the pharmaceutical composition comprises at least 0.5% by weight of the API. 
     
     
         22 . The method of  claim 21  wherein the pharmaceutical composition comprises at least 1.0% by weight of the API. 
     
     
         23 . The method of  claim 21 , wherein the ethanol is present in an amount of about 50% (w/w); and wherein the measured pH of the pharmaceutical composition is from about 3 to about 4. 
     
     
         24 . The method of  claim 22 , wherein the ethanol is present in an amount of about 50% (w/w); and wherein the measured pH of the pharmaceutical composition is from about 3 to about 4.