United States Patent:   5,985,310

Assignee:  Alcon Laboratories, Inc. (Fort Worth, TX)

Filed:  March 10, 1998

Disclosed are preservative systems useful in aqueous pharmaceutical compositions containing an active agent and a cyclodextrin. The preservative systems comprise boric acid and one or more compounds selected from the group consisting of C₁₆ benzalkonium halide compounds, polymeric quatemary ammonium compounds, and quatemary ammonium alkylene glycol phospholipid derivatives of the following structure

where a+b=3; R¹ is C₈ -C₂₂ alkyl or alkene; X is NH, O, or CH₂ ; R² is C₂ -C₆ alkyl; each R³ is independently C₁ -C₁₂ alkyl or alkene; and Y is nothing or C₁ -C₆ alkyl or alkene; and pharmaceutically acceptable salts thereof.

SUMMARY OF THE INVENTION

According to the present invention, aqueous pharmaceutical compositions containing a pharmaceutically active compound and a cyclodextrin can be preserved using a preservative system comprising a combination of boric acid and one or more compounds selected from the group consisting of C₁₆ benzalkonium halide compounds, polymeric quaternary ammonium compounds, and quaternary ammonium alkylene glycol phospholipid derivatives.

Thus, the present invention relates to aqueous compositions containing a pharmaceutically active drug compound, a cyclodextrin, and a preservative system selected as described above. The present invention also relates to a method of preserving aqueous pharmaceutical compositions containing a cyclodextrin, wherein the method comprises adding to the composition a preservative system of the type described above.

Among other factors, the present invention is based on the discovery that, unlike BAC, C₁₆ benzalkonium halide compounds, polymeric quaternary ammonium compounds and quaternary ammonium alkylene glycol phospholipid derivatives do not interact with cylodextrins in a way that significantly reduces or eliminates their antimicrobial preservative activity.

Claim 1 of 13 Claims

1. In a preserved aqueous pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically active agent, a chelating agent, a cyclodextrin and an antimicrobial preservative, the improvement wherein the preservative comprises a combination of boric acid and an antimicrobial preservative compound consisting essentially of a compound selected from the group consisting of C₁₆ benzalkanium halide compounds in an amount from about 0.01-0.5% by weight and polymeric quaternary ammonium compounds in an amount from about 0.001-3% by weight.

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