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.

What is claimed is: 
     
         1 . 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, 
         wherein 
         n is an integer from 0 to 15, 
         R 1  and R 2  are each independently hydrogen, halogen, an aliphatic group, a heteroaliphatic group, an aryl, a heteroaryl; —OR A ; —C(O)R A ; —C(O)N(R A ) 2 ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N(R A ) 2 ; —NHR A ; —NR A C(O)R A ; or —C(R A ) 3 ; and wherein R A  for each occurrence is, independently, a hydrogen, an aliphatic group, a heteroaliphatic group, an acyl moiety, an aryl moiety, a heteroaryl moiety, alkoxy; aryloxy; alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio moiety. 
       
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the at least one acidifying agent is selected from the groups 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. 
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein the at least one acidifying agent is selected from citric acid, acetic acid, and phosphoric acid. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the at least one pharmaceutically acceptable non-aqueous solvent is selected from the groups consisting of ethanol, acetone, benzyl alcohol, 2-(2-ethoxyethoxy)ethanol, diethylene glycol monoethyl ether, glycerin, propylene glycol, propylene carbonate, acetone, hexylene glycol, isopropyl alcohol, polyethylene glycols (PEGs), methoxypolyethylene glycols, diethyl sebacate, dimethyl isosorbide, propylene carbonate, dimethyl sulfoxide (DMSO), diisopropyl adipate, isopropyl myristate, vegetable oils, a mineral oil, and isopropyl palmitate. 
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein the at least one pharmaceutically acceptable non-aqueous solvent is selected from ethanol, benzyl alcohol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, hexylene glycol and diisopropyl adipate. 
     
     
         6 . The pharmaceutical composition of  claim 1 , further including at least one humectant. 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein the at least one humectant is selected from the groups 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 pharmaceutical composition of  claim 6 , wherein the at least one humectant is selected from glycerin and hexylene glycol. 
     
     
         9 . The pharmaceutical composition of  claim 1 , further including at least one emollient. 
     
     
         10 . The pharmaceutical composition of  claim 3 , wherein the at least one emollient is selected from the groups 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 pharmaceutical composition of  claim 9 , wherein the at least one emollient is selected from diisopropyl adipate and oleyl alcohol. 
     
     
         12 . The pharmaceutical composition of  claim 1 , further including at least one humectant and at least one emollient. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the at least one humectant is selected from glycerin and hexylene glycol and wherein the at least one emollient is selected from diisopropyl adipate and oleyl alcohol. 
     
     
         14 . The pharmaceutical composition of  claim 1 , further including at least one skin permeation enhancer. 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein the at least one permeation enhancer is selected from one or more of oleyl alcohol, proypylene glycol, and ethanol. 
     
     
         16 . The pharmaceutical composition of  claim 1 , further including at least one gelling agent. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the at least one gelling agent is a hydroxypropylcellulose. 
     
     
         18 . The pharmaceutical composition of  claim 1 , further including at least one antioxidant. 
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the antioxidant is selected from the groups 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 pharmaceutical composition of  claim 19 , wherein the antioxidant is the butylated hydroxytoluene (BHT). 
     
     
         21 . The pharmaceutical composition of  claim 1 , comprising at least 0.01% by weight of the API. 
     
     
         22 . The pharmaceutical composition of  claim 21 , comprising at least 0.1% by weight of the API. 
     
     
         23 . The pharmaceutical composition of  claim 21 , comprising at least 0.5% by weight of the API. 
     
     
         24 . The pharmaceutical composition of  claim 1 , wherein the measured pH is about 7. 
     
     
         25 . The pharmaceutical composition of  claim 1 , wherein the measured pH is from about 3 to about 6. 
     
     
         26 . The pharmaceutical composition of  claim 1 , wherein the measured pH is from about 3 to about 5. 
     
     
         27 . The pharmaceutical composition of  claim 1 , comprising at least 0.5% by weight of the API,
 wherein the vehicle base comprises a mixture of ethanol and propylene glycol; and   wherein the measured pH of the pharmaceutical composition is from about 3 to 4.   
     
     
         28 . The pharmaceutical composition of  claim 27 , wherein the at least one acidifying agent is selected from citric acid and phosphoric acid. 
     
     
         29 . The pharmaceutical composition of  claim 27 , further including at least one humectant selected from glycerin and hexylene glycol. 
     
     
         30 . The pharmaceutical composition of  claim 27 , further including at least one emollient selected from diisopropyl adipate and oleyl alcohol. 
     
     
         31 . The pharmaceutical composition of  claim 27 , further including at least one permeation enhancer is selected from ethanol, propylene glycol, or oleyl alcohol. 
     
     
         32 . The pharmaceutical composition of  claim 27 , further including a hydroxypropylcellulose gelling agent. 
     
     
         33 . The pharmaceutical composition of  claim 1 , wherein n is 5, 6 or 7. 
     
     
         34 . The pharmaceutical composition of  claim 33 , wherein n is 6. 
     
     
         35 . The pharmaceutical composition of  claim 1 , wherein R 2  is hydrogen and R 1  is selected from:
 a halogen, —OR A , N(R A ) 2 , —NHR A , —C 1 -C 6  alkyl, —C(O)R A , —C(O)OR A , —C(O)N(R A ) 2 , —C(O)NH 2 , —CHO and —NHC(O)R A ,   wherein R A  is hydrogen or a C 1 -C 12  alkyl.   
     
     
         36 . The pharmaceutical composition of  claim 1 , wherein:
 n is 6;   R 2  is hydrogen and R 1  is —C(O)OR A ; and   R A  is a C 1 -C 12  alkyl.   
     
     
         37 . A pharmaceutical composition, comprising:
 at least 0.01% by weight of an active pharmaceutical ingredient (API) compound represented by the following structural formula   
       
         
           
           
               
               
           
         
         at least one acidifying agent; and 
         at least one pharmaceutically acceptable non-aqueous solvent, wherein: 
         n is 6, R 2  is hydrogen and R 1  is —C(O)OR A , R A  is a C 1 -C 12  alkyl; 
         the at least one pharmaceutically acceptable non-aqueous solvent is a mixture of ethanol and propylene glycol; 
         the at least one acidifying agent is selected from one or more of citric acid and phosphoric acid and the measured pH of the pharmaceutical composition is from about 3 to about 5, 
         the pharmaceutical composition further optionally including one or more of the following:
 at least one humectant selected from glycerin and hexylene glycol; 
 at least one emollient selected from diisopropyl adipate and oleyl alcohol; 
 at least one permeation enhancer selected from ethanol, propylene glycol, or oleyl alcohol a hydroxypropylcellulose gelling agent; and 
 a butylated hydroxytoluene as an antioxidant. 
 
       
     
     
         38 . The pharmaceutical composition of  claim 37 , wherein the API is a compound represented by the following structural formula