Ophthalmic compositions

Abstract

An ophthalmic composition containing a divalent salt and a non-steroidal anti-inflammatory agent as a precipitate. The composition reduces or eliminates the risk of stinging and burning the eye from topical application. Additionally a preservative system comprising a perborate salt, a polyphosphonic acid peroxy stabilizer and EDTA provides stable preservation of a variety of aqueous ophthalmic compositions.

We claim:  
     
         1 . An ophthalmic composition comprising an aqueous medium containing an effective amount of a non-steroidal anti-inflammatory agent, wherein at least about 80 mol. % of said agent is in the form of a precipitate, and at least about 0.5 mole equivalents of a pharmacologically acceptable divalent cation per mole of said non-steroidal anti-inflammatory agent precipitate; said aqueous medium having a pH in the range of from 4.0 to 6.7.  
     
     
         2 . The composition according to    claim 1   , wherein said non-steroidal anti-inflammatory agent is selected from the group consisting of diclofenac, suprofen, and flurbiprofen.  
     
     
         3 . The composition according to    claim 2   , wherein said non-steroidal anti-inflammatory agent is diclofenac.  
     
     
         4 . The composition according to    claim 1   , wherein said pharmacologically acceptable divalent cation is a Group IIA metal.  
     
     
         5 . The composition according to    claim 4   , wherein said Group IIA divalent metal cation is calcium or magnesium.  
     
     
         6 . The composition according to    claim 1   , wherein said precipitate is in a free-acid form.  
     
     
         7 . The composition according to    claim 6   , wherein said divalent cation is present as a solute in said aqueous medium.  
     
     
         8 . The composition according to    claim 7   , wherein said divalent cation is present from 1 to 5 times the stoichiometric amount equivalent to the molar amount of said non-steroidal anti-inflammatory agent precipitate.  
     
     
         9 . The composition according to    claim 8   , wherein 85 to 95% of said non-steroidal anti-inflammatory agent is in said precipitate form.  
     
     
         10 . The composition according to    claim 9   , wherein said NSAI agent is diclofenac and said divalent cation is Mg ++ .  
     
     
         11 . The composition according to    claim 1   , further comprising a polymer.  
     
     
         12 . The composition according to    claim 11   , wherein said polymer is water insoluble and water swellable.  
     
     
         13 . The composition according to    claim 12   , wherein said polymer is a crosslinked carboxy-containing polymer.  
     
     
         14 . The composition according to    claim 13   , wherein said polymer is a polycarbophil.  
     
     
         15 . The composition according to    claim 13   , wherein said polymer is a Carbopol.  
     
     
         16 . The composition according to    claim 15   , wherein said polymer is Carbopol 974P  
     
     
         17 . The composition according to    claim 13   , further comprising EDTA.  
     
     
         18 . The composition according to    claim 1   , wherein said aqueous medium has a pH of from 4.0 to 6.5.  
     
     
         19 . The composition according to    claim 1   , wherein said non-steroidal anti-inflammatory agent is contained in an amount of from 0.01 to 5.0% by weight of the entire composition.  
     
     
         20 . The composition according to    claim 1   , further comprising a perborate salt.  
     
     
         21 . A method for treating an eye, which comprises administering to an eye in need thereof an effective amount of the composition according to    claim 1   .  
     
     
         22 . A method for making the composition according to    claim 1   , which comprises: 
 combining a non-steroidal anti-inflammatory agent and a divalent cation source in an aqueous medium to form a precipitate-containing solution.    
     
     
         23 . The method according to    claim 22   , wherein said non-steroidal anti-inflammatory agent is added to an aqueous solution containing a polymer dispersed therein and said divalent cation source.  
     
     
         24 . The method according to    claim 23   , wherein said aqueous solution further comprises EDTA and said dispersed polymer is a water insoluble, water-swellable crosslinked carboxy-containing polymer.  
     
     
         25 . The method according to    claim 24   , wherein said non-steroidal anti-inflammatory agent comprises diclofenac and said divalent cation source is CaCl 2  MgCl 2  or MgSO 4 .  
     
     
         26 . An ophthalmic composition obtained by combining at least (1) sodium diclofenac, (2) a divalent metal salt, (3) a water insoluble, water-swellable polymer, and (4) water.  
     
     
         27 . The composition according to    claim 26   , which further comprises EDTA and wherein said divalent metal salt is CaCl 2 , MgCl 2  or MgSO 4 .  
     
     
         28 . The composition according to    claim 26   , wherein said sodium diclofenac is added to an aqueous suspension comprising said divalent metal salt, said water-swellable polymer and said water.  
     
     
         29 . The composition according to    claim 1   , further comprising benzalkonium chloride.  
     
     
         30 . An ophthalmic composition comprising an aqueous suspension of a crosslinked carboxyl-containing polymer, solid diclofenac in free-acid form, dissolved diclofenac, and dissolved Mg ++  or Ca ++  cations in an amount of from about 1 to 5 times the stoichiometric equivalent amount per mole of said solid diclofenac; said composition having a pH of from about 4.0 to about 6.7 and the total amount of diclofenac being a pharmaceutically effective amount and said solid diclofenac comprising 85 to 95 mol % of the total amount of diclofenac.  
     
     
         31 . The composition according to    claim 30   , further comprising 0.03 to 0.3 wt. % sodium perborate, 0.003 to 0.03 wt. % polyphosphonic acid peroxy stabilizer and 0.01 to 0.1 wt. % EDTA.  
     
     
         32 . The composition according to    claim 31   , wherein said sodium perborate is contained in an amount of about 0.28 wt. % and said polyphosphonic acid peroxy stabilizer is diethylene triamine penta(methylene-phosphonic acid).  
     
     
         33 . A preserved ophthalmic composition comprising water, about 0.01 to 0.5 wt. % of a perborate salt, about 0.001 to 0.06 wt. % of a polyphosphonic acid peroxy stabilizer, and about 0.01 to 0.1 wt. % of ethylenediaminetetraacetic acid.  
     
     
         34 . The composition according to    claim 33   , wherein said water is sterile water, said perborate is sodium perborate contained in an amount of from 0.03 to 0.3 wt. %, and said polyphosphonic acid peroxy stabilizer is a compound of formula I or II:  
                   
       wherein x is an integer of 0 to 3 and k, m, n, o, and p are each independently an integer of 1 to 4;  
                 
 
       wherein q, r, s, and t are each independently an integer of 0 to 4.