Stabilized compositions comprising a therapeutically active agent and an oxidizing preservative

Abstract

Citric acid and conjugate bases thereof are useful for stabilizing stabilized chlorine dioxide in the presence of therapeutically active agents and excipients in a composition. Ophthalmic compositions and methods related thereto are also disclosed herein.

1 . An ophthalmic composition comprising an effective amount of a therapeutically active agent having an oxidizable functional group, an effective amount of stabilized chlorine dioxide to act as a preservative, and an effective amount of citric acid and/or conjugate bases thereof to stabilize said therapeutically active agent in the presence of said stabilized chlorine dioxide.  
   
   
       2 . The composition of  claim 1  wherein said therapeutically active agent comprises a sulfur atom.  
   
   
       3 . The composition of  claim 1  wherein said therapeutically active agent comprises a carboxylic acid, a carboxylic acid ester, or a carboxylic acid amide.  
   
   
       4 . The composition of  claim 1  comprising a prostaglandin or a prostamide.  
   
   
       5 . The composition of  claim 1  which comprises bimatoprost.  
   
   
       6 . The composition of  claim 1  comprising a borate/boric acid buffer.  
   
   
       7 . The composition of  claim 1  comprising from 0.01% to 0.10% bimatoprost.  
   
   
       8 . The composition of  claim 1  comprising from 0.001% to 0.10% citric acid and/or conjugate bases thereof.  
   
   
       9 . The composition of  claim 7  comprising about 0.02% citric acid and/or conjugate bases thereof.  
   
   
       10 . The composition of  claim 8  comprising 0.03% bimatoprost, 0.39% sodium chloride, 0.6% boric acid, 0.045% sodium borate decahydrate, 0.014% citric acid monohydrate, 0.5% carboxymethylcellulose, and 0.005% stabilized chlorine dioxide, wherein the pH is adjusted to 7.3 by the addition of hydrochloric acid or sodium hydroxide.  
   
   
       11 . A method of stabilizing incompatible components of a composition comprising adding an effective amount of citric acid and/or conjugate bases thereof to said composition, 
 wherein said incompatible components comprise stabilized chlorine dioxide and a second component.    
   
   
       12 . The method of  claim 11  wherein said second component is a therapeutically active agent.  
   
   
       13 . The method of  claim 12  wherein said therapeutically active agent is a prostaglandin or a prostamide.  
   
   
       14 . The method of  claim 13  wherein said therapeutically active agent is bimatoprost.  
   
   
       15 . The method of  claim 14  wherein bimatoprost has a concentration of about 0.03%.  
   
   
       16 . A method of preserving an ophthalmic composition comprising providing an effective amount of citric acid and/or conjugate bases thereof and stabilized chlorine dioxide to said composition.  
   
   
       17 . The composition of  claim 8  comprising about 0.03% bimatoprost, about 0.27% sodium phosphate dibasic heptahydrate, about 0.014% citric acid monohydrate, about 0.83% sodium chloride, and about 0.01% Purite®, wherein the pH is adjusted to 7.3 by the addition of hydrochloric acid and/or sodium hydroxide.  
   
   
       18 . The composition of  claim 8  consisting essentially of about 0.03% bimatoprost, about 0.27% sodium phosphate dibasic heptahydrate, about 0.014% citric acid monohydrate, about 0.83% sodium chloride, and about 0.01% Purite®, water, and a sufficient quantity of hydrochloric acid and/or sodium hydroxide to adjust the pH is adjusted to 7.3.  
   
   
       19 . The composition of  claim 8  consisting of about 0.03% bimatoprost, about 0.27% sodium phosphate dibasic heptahydrate, about 0.014% citric acid monohydrate, about 0.83% sodium chloride, and about 0.01% Purite®, water, and a sufficient quantity of hydrochloric acid and/or sodium hydroxide to adjust the pH is adjusted to 7.3.  
   
   
       20 . The composition of  claim 8  comprising from 30 ppm to 500 ppm Purite®.