Self-Preserved Aqueous Pharmaceutical Compositions

Abstract

The present invention is directed to the provision of multi-dose, self-preserved ophthalmic compositions. The compositions possess sufficient antimicrobial activity to satisfy USP preservative efficacy requirements, as well as similar preservative standards (e.g., EP and JP), without requiring the presence of conventional anti-microbial preservative agents, such as benzalkonium chloride. The compositions are effectively preserved by a balanced ionic buffer system containing zinc ions at a concentration of 0.04 to 0.9 mM, preferably 0.04 to 0.4 mM. One aspect of the balanced buffer system is limitation of the amount of buffering anions present to a concentration of 15 mM or less, preferably 5 mM or less. In a preferred embodiment, the compositions also contain borate or, most preferably, one or more borate/polyol complexes. The use of propylene glycol as the polyol in such complexes is strongly preferred. Limiting the amount of divalent metals other than zinc and the amount of ionized salts present has also been determined to be important to maximize the antimicrobial activity of the balanced buffer systems.

1 - 18 . (canceled) 
     
     
         19 . A multi-dose, self-preserved ophthalmic composition, comprising:
 a therapeutically effective amount of an ophthalmic therapeutic agent selected from the group consisting of bimatoprost, latanoprost and travoprost;   water; and   a zinc/borate/polyol system consisting essentially of:   i. zinc ions at a concentration of 0.04 to 0.4 mM;   ii. borate; and   iii. polyol comprising sorbitol and propylene glycol;   wherein the composition has a concentration of anionic species less than 15 mM.   
     
     
         20 . A composition according to  claim 19  wherein the composition satisfies USP 27 preservative efficacy requirements. 
     
     
         21 . A composition according to  claim 19  wherein the sorbitol is in the composition at a concentration of 0.05 to 0.75% w/v. 
     
     
         22 . A composition according to  claim 19  wherein the sorbitol is in the composition at a concentration of 0.25 to 0.75% w/v. 
     
     
         23 . A composition according to  claim 19  wherein the propylene glycol is in the composition at a concentration of 0.25 to 2.5% w/v. 
     
     
         24 . A composition according to  claim 19  wherein the borate is in the composition at a concentration of 0.3 to 1.5% w/v. 
     
     
         25 . A composition according to  claim 19  wherein the zinc ions are provided by zinc chloride, the zinc chloride being present in the composition at a concentration of 0.001 to 0.005 w/v %. 
     
     
         26 . A composition according to  claim 19  wherein the ophthalmic therapeutic agent is travoprost. 
     
     
         27 . A composition according to  claim 19  wherein the composition has a concentration of multivalent buffering anions that is less than 5 mM. 
     
     
         28 . A composition according to  claim 19  wherein: (i) the composition has a concentration of multivalent buffering anions that is less than 5 mM; and (ii) the composition has a concentration of multivalent metal cations other than zinc that is less than 5 mM. 
     
     
         29 . A composition according to  claim 19  further comprising polyoxyl 40 hydrogenated castor oil wherein the composition has a pH from 5.5 to 5.9 and wherein the zinc ions are provided by zinc chloride, the zinc chloride being present in the composition at a concentration of 0.001 to 0.005 w/v %. 
     
     
         30 . A composition according to  claim 19  wherein the propylene glycol is present in the composition at a concentration of 0.75 w/v %, the borate is boric acid and is present in the composition at a concentration of 1.0 w/v % and the zinc ions are provided by zinc chloride, the zinc chloride being present in the composition at a concentration of 0.0025 w/v %. 
     
     
         31 . A composition according to  claim 19  wherein the composition has a pH from 5.5 to 5.9. 
     
     
         32 . A composition according to  claim 31  further comprising polyoxyl 40 hydrogenated castor oil. 
     
     
         33 . A composition according to  claim 19  wherein the zinc ions are in the composition at a concentration of 0.1 to 0.4 mM. 
     
     
         34 . A multi-dose, self-preserved ophthalmic composition, comprising:
 a therapeutically effective amount of an ophthalmic therapeutic agent selected from the group consisting of bimatoprost, latanoprost and travoprost;   water; and   a zinc/borate/polyol system consisting essentially of:   i. zinc ions at a concentration of 0.04 to 0.4 mM;   ii. borate at a concentration of 0.3 to 1.5% w/v; and   iii. polyol comprising sorbitol at a concentration of 0.05 to 0.75% w/v and propylene glycol at a concentration of 0.25 to 2.5% w/v;   
       wherein the composition has a concentration of anionic species less than 15 mM. 
     
     
         35 . A composition according to  claim 34  wherein the sorbitol is in the composition at a concentration of 0.25 to 0.75% w/v. 
     
     
         36 . A composition according to  claim 35  wherein the zinc ions are provided by zinc chloride, the zinc chloride being present in the composition at a concentration of 0.001 to 0.005 w/v %. 
     
     
         37 . A composition according to  claim 36  wherein the therapeutic agent is travoprost. 
     
     
         38 . A composition according to  claim 37  wherein: (i) the composition has a concentration of multivalent buffering anions that is less than 5 mM; and (ii) the composition has a concentration of multivalent metal cations other than zinc that is less than 5 mM. 
     
     
         39 . A composition according to  claim 38  wherein the composition has a pH from 5.5 to 5.9. 
     
     
         40 . A composition according to  claim 39  wherein the zinc ions are in the composition at a concentration of 0.1 to 0.4 mM. 
     
     
         41 . A composition according to  claim 40  wherein the propylene glycol is present in the composition at a concentration of 0.75 w/v %, the borate is boric acid and is present in the composition at a concentration of 1.0 w/v % and the zinc ions are provided by zinc chloride at a concentration of 0.0025 w/v %. 
     
     
         42 . A composition according to  claim 41  further comprising polyoxyl 40 hydrogenated castor oil.