Pharmaceutical compositions with phosphonium antimicrobial agents

Abstract

The present invention is related to pharmaceutical compositions that include a phosphonium antimicrobial agent. In a preferred embodiment, the present invention relates to an otic, nasal or ophthalmic composition (e.g., an aqueous ophthalmic solution) that includes a phosphonium salt compound as an antimicrobial agent. The compositions typically possess sufficient antimicrobial activity to satisfy USP preservative efficacy requirements and/or similar preservative standards (e.g., EP and JP).

1 . A pharmaceutical composition, comprising:
 an phosphonium antimicrobial agent according to the following formula:   
       
         
           
           
               
               
           
         
         wherein: 
         R 1 , R 2 , R 3  and R 4  are independently selected from the group consisting of H, o alkyl, aryl, alkoxy, hydroxyl, hydroxyalkyl or alcohol; and 
         X −  is a counterion; and 
         water; 
         wherein the phosphonium antimicrobial agent is at least 0.0001 w/w % of the composition and is no greater than 0.5 w/w %; and 
         wherein the composition is suitable for parenteral, oral or topical administration to a human being; and 
         wherein either:
 i. at least two of R 1 , R 2 , R 3  and R 4  are selected from one or more hydroxyalkyl groups; or 
 ii. at least one of R 1 , R 2 , R 3  and R 4  is a long alkyl chain of at least 8 carbons; or 
 iii. both. 
 
       
     
     
         2 . A pharmaceutical composition as in  claim 1  wherein the phosphonium antimicrobial agent is selected from the group consisting of: Tetrakis(hydroxymethyl)phosphonium chloride, Tributyl-tetradecylphosphonium chloride, Tributyldodecylphosphonium bromide, Tributylhexadecylphosphonium bromide, Triphenyltetradecylphosphonium bromide, Triphenyldodecylphosphomium bromide, Trihexyltetradecylphosphonium, Trihexyltetradecylphosphonium chloride, Benzyldimethyldodecylphosphonium chloride, Benzyldimethyltetradecylphosphonium chloride, Benzyldihydroxymethyldodecylphosphonium chloride, Benzyldihydroxymethyltetradecylphosphonium chloride, Trihydroxymethyldodecylphosphonium chloride, and Trihydroxymethyltetradecylphosphonium chloride, or any combinations thereof. 
     
     
         3 . A pharmaceutical composition as in  claim 2  wherein the phosphonium antimicrobial agent is tetrakishydroxymethyl phosphonium chloride. 
     
     
         4 . A pharmaceutical composition as in  claim 1  wherein the composition is an ophthalmic composition disposed within a dispenser. 
     
     
         5 . A pharmaceutical composition as in  claim 4 , wherein the dispenser contains at least 0.5 ml. but no greater than 10,000 ml. 
     
     
         6 . A pharmaceutical composition as in  claim 5  wherein the composition is a contact lens disinfecting solution or an ophthalmic pharmaceutical solution and the composition is sterile within the container. 
     
     
         7 . A pharmaceutical composition as in  claim 1  wherein the composition has a pH of at least 5 but no greater than 9. 
     
     
         8 . A pharmaceutical composition as in  claim 1  wherein the composition has an osmolality of at least 200, but no greater than 330. 
     
     
         9 . A pharmaceutical composition as in  claim 1  wherein the composition satisfies Ph. Eur. A, Ph. Eur. B or both. 
     
     
         10 . A pharmaceutical composition as in  claim 1  wherein X −  is a halogen. 
     
     
         11 . A pharmaceutical composition as in  claim 1  wherein the composition is an aqueous ophthalmic solution and wherein X −  is a chloride. 
     
     
         12 . A pharmaceutical composition as in  claim 1  wherein each of R 1 , R 2 , R 3  and R 4  selected from one or more hydroxyalkyl groups and the one or more hydroxyl alkyl groups are selected from hydroxylmethyl, hydroxyethyl and hydroxypropyl. 
     
     
         13 . A pharmaceutical composition, comprising:
 an phosphonium antimicrobial agent according to the following formula:   
       
         
           
           
               
               
           
         
         wherein: 
         R 1 , R 2 , R 3  and R 4  are selected from one or more hydroxyalkyl groups and the one or more hydroxyl alkyl groups are selected from hydroxylmethyl, hydroxyethyl and hydroxypropyl; and 
         X −  is a counterion and a halogen; and 
         water; 
         wherein the phosphonium antimicrobial agent is at least 0.0001 w/w % of the composition and is no greater than 0.5 w/w %; and 
         wherein the composition is a contact lens disinfecting solution or an ophthalmic pharmaceutical solution and the composition is sterile within a container. 
       
     
     
         14 . A pharmaceutical composition as in  claim 13  wherein the phosphonium antimicrobial agent is tetrakishydroxymethyl phosphonium chloride. 
     
     
         15 . A pharmaceutical composition as in  claim 14  wherein the composition is an ophthalmic composition disposed within an eye dropper. 
     
     
         16 . A pharmaceutical composition as in  claim 14  wherein the composition is a contact lens disinfecting solution or an ophthalmic pharmaceutical solution and the composition is sterile within the container. 
     
     
         17 . A pharmaceutical composition as in  claim 16 , wherein the container is a dispenser contains at least 0.5 ml, but no greater than 1000 ml of the composition. 
     
     
         18 . A pharmaceutical composition as in  claim 17  wherein the composition has a pH at least 6 but no greater than 8. 
     
     
         19 . A pharmaceutical composition as in  claim 18  wherein the composition has an osmolality of at least 240 but no greater than 360. 
     
     
         20 . A pharmaceutical composition as in  claim 19  wherein the composition satisfies Ph. Eur. A, Ph. Eur. B or both.