Use of small molecules for the treatment of clostridium difficile toxicity

Abstract

Disclosed are methods and compositions for reducing toxicity associated with infection by Clostridium difficile by inhibiting Clostridium difficile toxin B (TcdB) and/or toxin A (TcdA). Such compounds include ebselen compounds, namely ebselen and its salts, ebselen functional analogues and ebselen structural analogues, as well as certain amide derivatives. This includes Formula I, e.g. 1-methyl-3-phenylpropylamine, Formula II, e.g., 2,2′-diselane-1,2-diylbis[N-(2,4-difluorophenyl)benzamide]; and Formula III, e.g. 2-(2-methoxy-5-methylphenyl)-1, 2-benzoselenazol-3-one. The present compositions may be comprised in a colon-retentive formulation that increases residence of and/or release of the compound in the area where the infection is active.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising ebselen and one or more enteric polymers as an oral formulation. 
     
     
         2 . The composition of  claim 1 , wherein the composition includes two or more enteric polymers soluble at different pHs. 
     
     
         3 . The composition of  claim 1 , wherein one or more of the enteric polymers are selected from the group consisting of cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, and cellulose acetate propionate. 
     
     
         4 . The composition of  claim 1 , wherein one or more of the enteric polymers are selected from the group consisting of copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), and ethyl methyacrylate-methylmethacrylatechlorotrimethylammonium ethyl acrylate copolymer. 
     
     
         5 . The composition of  claim 1 , wherein one or more of the enteric polymers are a natural resin. 
     
     
         6 . The composition of  claim 5 , wherein the resin is selected from the group consisting of zein, shellac and copal collophorium. 
     
     
         7 . The composition of  claim 1 , wherein one or more of the enteric polymers are selected from the group consisting of Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric. 
     
     
         8 . The composition of  claim 1 , wherein the formulation releases ebselen into solution at pH 5.5 to 6.5. 
     
     
         9 . The composition of  claim 1 , wherein the formulation releases ebselen into solution at pH 6 to 7. 
     
     
         10 . The composition of  claim 1 , wherein the formulation releases ebselen into solution at pH 7 to 7.5.