Carboxylvinyl polymer-containing nanoparticle suspensions

Abstract

The present invention generally relates to suspension compositions having a carboxyvinyl polymer such as a carbomer, a galactomannan such as guar, and a borate compound. A sparingly soluble particulate compound such as nepafenac is also included in the compositions. The sparingly soluble particulate compound has a small particle size to enhance bioavailability of the compound.

What is claimed is: 
     
         1 . A topically administrable aqueous ophthalmic suspension composition comprising:
 a carboxyvinyl polymer at a concentration of 0.1 to 0.5 w/v %;   a galactomannan at a concentration of 0.1 to 0.4 w/v %;   borate at a concentration of 0.4 to 2.0 w/v %; and   a sparingly soluble particulate compound, said compound having a solubility in water at 25° C. of 0.001 to 0.1 w/v % and a particle size of 50 to 700 nm.   
     
     
         2 . A composition according to  claim 1 , further comprising a pH-adjusting agent in an amount sufficient to cause the composition to have a pH of 5.0 to 7.2. 
     
     
         3 . A composition according to  claim 1 , further comprising a tonicity-adjusting agent in an amount sufficient to cause the composition to have an osmolality of 250 to 350 mOsm/kg. 
     
     
         4 . A composition according to  claim 1  wherein said sparingly soluble particulate compound is nepafenac at a concentration of 0.1 to 1.0 w/v %. 
     
     
         5 . A composition according to  claim 1  wherein said carboxyvinyl polymer is carbomer at a concentration of 0.4 w/v %. 
     
     
         6 . A composition according to  claim 1  further comprising a milling agent at a concentration of 0.005 to 0.1 w/v %. 
     
     
         7 . A composition according to  claim 6  wherein said milling agent is a surfactant or polymer. 
     
     
         8 . A composition according to  claim 7  wherein said milling agent is sodium carboxylmethylcellulose. 
     
     
         9 . A composition according to  claim 1  further comprising a metal chloride salt tonicity-adjusting agent. 
     
     
         10 . A composition according to  claim 9  wherein said metal chloride salt is sodium chloride at a concentration of 0.4 w/v %. 
     
     
         11 . A composition according to  claim 1  further comprising a non-ionic hydroxyl compound as a tonicity-adjusting agent. 
     
     
         12 . A composition according to  claim 1  further comprising both a preservative and a chelating agent. 
     
     
         13 . A composition according to  claim 12  wherein the preservative is benzalkonium chloride at a concentration of 0.005 w/v % and the chelating agent is edetate disodium at a concentration of 0.01 w/v %. 
     
     
         14 . A composition according to  claim 1  wherein said carboxyvinyl polymer is carbomer, said galactomannan is guar, said borate is boric acid, and said sparingly soluble particulate compound is nepafenac at a concentration of 0.1 to 1.0 w/v %. 
     
     
         15 . A composition according to  claim 14  comprising 0.4 w/v % carbomer, 0.2 w/v % guar, 0.5 w/v % boric acid, and 0.3 w/v % nepafenac. 
     
     
         16 . A composition according to  claim 15  wherein said nepafenac has an average particle size of 400 nm. 
     
     
         17 . A method of treating ophthalmic disorders in a patient comprising topically administering to the patient a composition according to  claim 1 . 
     
     
         18 . A method according to  claim 17  wherein said ophthalmic disorder is selected from the group consisting of:
 ocular surface and retinal disorders, glaucoma, dry eye, ocular surface pain, uveitis, scleritis, episcleritis, keratitis, surgically-induced inflammation, endophthalmitis, iritis, atrophic macular degeneration, retinitis pigmentosa, iatrogenic retinopathy, retinal tears and holes, macular edema, cystoid macular edema, diabetic macular edema, diabetic retinopathy, sickle cell retinopathy, retinal vein and artery occlusion, optic neuropathy, exudative macular degeneration, neovascular glaucoma, corneal neovascularization, cyclitis, sickle cell retinopathy, and pterygium. 
 
     
     
         19 . A topically administrable ophthalmic suspension composition consisting essentially of
 a) 0.3 w/v % nepafenac having a particle size of 50 to 700 nm;   b) 0.4 w/v % carbomer;   c) 0.2 w/v % guar;   d) 0.5 w/v % boric acid;   e) 0.06 w/v % sodium carboxymethylcellulose;   f) 0.4 w/v % sodium chloride;   g) 0.5 w/v % propylene glycol;   h) a pH-adjusting agent in an amount sufficient to cause the composition to have a pH of 7.0;   i) 0.005% (w/v) benzalkonium chloride;   j) 0.01% edetate disodium; and   k) purified water.   
     
     
         20 . A method for maintaining the viscosity of a topical ophthalmic composition comprising 0.1 to 0.5 w/v % carbomer when said composition is topically applied to the eye, the method comprising:
 adding galactomannan sufficient to provide a concentration of 0.1 w/v % to 0.4 w/v % galactomannan in said composition, and borate sufficient to provide a concentration of 0.4 w/v % to 0.6 w/v % in said composition.   
     
     
         21 . A method according to  claim 20 , wherein said composition has a pH of 5.0 to 7.2. 
     
     
         22 . A method according to  claim 20 , wherein said composition further comprises a sparingly soluble particulate compound. 
     
     
         23 . A method according to  claim 22 , wherein said sparingly soluble particulate compound is nepafenac at a concentration of 0.3 w/v %.