Aqueous pharmaceutical compositions containing borate-polyol complexes

Abstract

The present invention is directed to the provision of multi-dose, 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). The compositions include at two different polyols in conjunction with borate and a low concentration of benzalkonium chloride.

We claim: 
     
         1 . A multi-dose ophthalmic composition, comprising:
 a first polyol, the first polyol being selected from mannitol, sorbitol or a combination thereof;   a second polyol, the second polyol being selected from propylene glycol, glycerine or a combination thereof;   an effective amount of borate, the effective amount being less than about 0.5 w/v % of the overall composition;   BAC as an anti-microbial preservative, the concentration of BAC in the composition being greater than 0.00001 w/v % but less than 0.0035 w/v %; and   water.   
     
     
         2 . A composition as in  claim 1  wherein the composition satisfies Ph. Eur. A, Ph. Eur. B or both. 
     
     
         3 . A composition as in  claim 1  wherein the concentration of the first polyol is at least 0.01 w/v % but is less than about 0.35 w/v %. 
     
     
         4 . A composition as in  claim 1  wherein concentration of the BAC is less than 0.0025 w/v % of the composition. 
     
     
         5 . A composition as in  claim 1  wherein concentration of the BAC is less than 0.0015 w/v % of the composition. 
     
     
         6 . A composition as in  claim 1  wherein the first polyol is mannitol and the second polyol is propylene glycol. 
     
     
         7 . A composition as in  claim 1  wherein the composition is substantially free of any preservatives other than benzalkonium chloride. 
     
     
         8 . A composition as in  claim 1  wherein the resistance provided by the composition to normalization of tear pH after instillation in the eye is less than 25 μl of 1 M NaOH/mL of composition. 
     
     
         9 . A composition as in  claim 1  wherein the pH of the composition is from about 6.2 to about 7.7. 
     
     
         10 . A composition as in  claim 1  further comprising therapeutic agent wherein the therapeutic agent is brinzolamide, brimonidine or a combination thereof. 
     
     
         11 . A composition as in  claim 1  further comprising an anionic polymer. 
     
     
         12 . A composition as in  claim 11  wherein the anionic polymer is selected from xanthan gum or a carboxyvinyl polymer. 
     
     
         13 . A composition as in  claim 11  wherein the composition is a suspension with a therapeutic agent suspended in solution. 
     
     
         14 . A composition as in  claims 1  wherein the composition is free of any anti-infective or anti-biotic therapeutic agent. 
     
     
         15 . A composition as in  claim 13  wherein the suspension is redispersed with no more than 15 seconds of vigorous shaking. 
     
     
         16 . A multi-dose ophthalmic composition, comprising:
 a first polyol, the first polyol being selected from mannitol, sorbitol or a combination thereof and wherein the concentration of the first polyol is at least 0.01 w/v % but no greater than 0.5 w/v %;   a second polyol, the second polyol being selected from propylene glycol, glycerine or a combination thereof wherein the second polyol is at least about 0.1 but less than about 5 w/v % of the composition;   an effective amount of borate, the effective amount being less than about 0.5 w/v % of the overall composition;   therapeutic agent;   anionic polymer;   BAC as an anti-microbial preservative, the concentration of BAC in the composition being greater than 0.00001 w/v % but less than 0.0035 w/v %; and   water.   wherein the composition is substantially free of any preservatives other than benzalkonium chloride   
     
     
         17 . A composition as in  claim 16  wherein the resistance provided by the composition to normalization of tear pH after instillation in the eye is less than 15 μl of 1 M NaOH/mL of composition. 
     
     
         18 . A composition as in  claim 16  wherein the composition is a suspension with a therapeutic agent suspended in solution and wherein the viscosity of the suspension is greater than 20 cps but less than 500 cps with the viscosity of the suspension being measured at a high shear rate of 120 sec-1 at room temperature. 
     
     
         19 . A composition as in  claim 18  wherein the suspension is redispersed with no more than 15 seconds of vigorous shaking. 
     
     
         20 . A composition as in  claim 16  wherein the composition is free of any anti-infective or anti-biotic therapeutic agent. 
     
     
         21 . A composition as in  claim 16  wherein the composition is configured for administration to the eye of the mammal repeatedly for an extend period of time of and is administered at least once a week and wherein the eye of the mammal has been diagnosed with an eye disorder that is suitably treated with chronic administration of the therapeutic agent. 
     
     
         22 . A composition as in  claim 21  wherein the eye disorder is elevated intraocular pressure. 
     
     
         23 . A multi-dose ophthalmic composition, comprising:
 mannitol wherein the concentration of the mannitol is at least 0.01 w/v % but no greater than 0.5 w/v %;   propylene glycol wherein the concentration of the mannitol is at least 0.01 w/v % but no greater than 0.5 w/v %;   an effective amount of borate, the effective amount being less than about 0.5 w/v % of the overall composition;   therapeutic agent selected from brinzolamide, brimonidine or a combination thereof;   carboxyvinyl polymer that is at least about 0.1 w/v % but less than about 1.2 w/v % of the composition;   BAC as an anti-microbial preservative, the concentration of BAC in the composition being greater than 0.00001 w/v % but less than 0.0035 w/v %; and   water;   wherein:
 i. the composition is substantially free of any preservatives other than benzalkonium chloride;