Injectable sustained release composition and method of using the same for treating inflammation in joints and pain associated therewith

Abstract

Described herein are injectable corticosteroid-loaded microparticles, pharmaceutical composition thereof and methods for reducing inflammation or pain in a body compartment such as a joint, an epidural space, a vitreous body of an eye, a surgically created space, or a space adjacent to an implant.

We claim: 
     
         1 . A pharmaceutical composition comprising: a plurality of microparticles, each microparticle including:
 (1) a drug core including one or more crystals of fluticasone or a pharmaceutically acceptable salt or ester thereof; and   (2) a polymeric shell encapsulating the drug core, the polymeric shell being in contact but immiscible with the drug core,   wherein, each microparticle comprises 90-98% w/w of drug core and 2-10% w/w of polymeric shell; and wherein the polymer shell is at least partially crystalline.   
     
     
         2 . The pharmaceutical composition of  claim 1  wherein the plurality of microparticles have a mean diameter in the range of 80 μm to 150 μm and a standard deviation of less than 50% of the mean diameter. 
     
     
         3 . The pharmaceutical composition of  claim 1  wherein the plurality of microparticles have a mean diameter of 50-100 μm. 
     
     
         4 . The pharmaceutical composition of  claim 1  wherein the drug core comprises fluticasone, fluticasone furoate, or fluticasone propionate, or a combination thereof. 
     
     
         5 . The pharmaceutical composition of  claim 1  wherein the polymeric shell comprises one or more polymers selected from the group consisting of polyvinyl alcohol (PVA), ethylene vinyl acetate(EVA), poly(p-xylylene) polymers, poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), poly(ε-caprolactone) (PCL), poly(valerolactone) (PVL), poly(ε-decalactone) (PDL), poly(1,4-dioxane-2,3-dione), poly(1,3-dioxane-2-one), poly(para-dioxanone) (PDS), poly(hydroxybutyric acid) (PHB), poly(hydroxyvaleric acid) (PHV), and poly(β-malic acid) (PMLA). 
     
     
         6 . The pharmaceutical composition of  claim 1  wherein, when dissolution tested using United States Pharmacopoeia Type II apparatus, said plurality of microparticles release dissolved fluticasone or a pharmaceutically acceptable salt or ester thereof at a dissolution half-life of 12-20 hours, wherein the dissolution conditions are: 3 milligrams of microparticles in 200 milliliters of dissolution medium of 70% v/v methanol and 30% v/v of water at 25° C. 
     
     
         7 . The pharmaceutical composition of  claim 1  wherein each microparticle comprises drug core of fluticasone propionate and a polymer shell comprising polyvinyl alcohol (PVA). 
     
     
         8 . A unit dosage form of a corticosteroid for injecting into a body compartment, comprising:
 an injectable formulation having a plurality of microparticles and a pharmaceutically acceptable excipient, each microparticle comprising (1) a drug core including one or more crystals of a corticosteroid; and (2) a polymeric shell encapsulating the drug core, the polymeric shell being in contact but immiscible with the drug core,   wherein, each microparticle comprises 90-98% w/w of drug core and 2-10% w/w of polymeric shell; and wherein the polymer shell comprises one or more polymers; and   wherein the unit dosage form is capable of sustained-release of the corticosteroid over a period of 2-12 months while maintaining a minimum therapeutically effective concentration of the corticosteroid within the body compartment.   
     
     
         9 . The unit dosage form of  claim 8  wherein the body compartment is a joint, an epidural space, intravitreal space, a surgically created space, or a space adjacent to an implant. 
     
     
         10 . The unit dosage form of  claim 9  wherein the body compartment is a knee joint. 
     
     
         11 . The unit dosage form of  claim 8  wherein, within the sustained release period of 2-12 months, the corticosteroid is released locally within the body compartment and provides below a quantifiable limit of plasma corticosteroid 7 days after injection. 
     
     
         12 . The unit dosage form of  claim 8  wherein the plurality of microparticles have a mean diameter in the range of 50 μm to 150 μm and a standard deviation of less than 50% of the mean diameter. 
     
     
         13 . The unit dosage form of  claim 8  wherein the corticosteroid is fluticasone or a pharmaceutically acceptable salt or ester thereof. 
     
     
         14 . The unit dosage form of  claim 13  wherein the corticosteroid is fluticasone propionate. 
     
     
         15 . The unit dosage form of  claim 8  wherein the polymeric shell comprises one or more polymers selected from the group consisting of polyvinyl alcohol (PVA), ethylene vinyl acetate (EVA), poly(p-xylylene) polymers, poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), poly(ε-caprolactone) (PCL), poly(valerolactone) (PVL), poly(ε-decalactone) (PDL), poly(1,4-dioxane-2,3-dione), poly(1,3-dioxane-2-one), poly(para-dioxanone) (PDS), poly(hydroxybutyric acid) (PHB), poly(hydroxyvaleric acid) (PHV), and poly(β-malic acid) (PMLA). 
     
     
         16 . An injectable formulation comprising: a plurality of microparticles and a pharmaceutically acceptable excipient, wherein each microparticle comprises heat-treated PVA-coated corticosteroid, wherein the corticosteroid is fluticasone or a pharmaceutically acceptable salt or ester thereof. 
     
     
         17 . The injectable formulation of  claim 16  wherein the plurality of microparticles have a mean diameter in the range of 80 μm to 150 μm and a standard deviation of less than 50% of the mean diameter. 
     
     
         18 . The injectable formulation of  claim 16  wherein the plurality of microparticles have a mean diameter of 50-100 μm. 
     
     
         19 . The injectable formulation of  claim 16  wherein the corticosteroid is fluticasone propionate. 
     
     
         20 . The injectable formulation of  claim 16  wherein the PVA-coated corticosteroid is heat-treated at a temperature range of 100-250° C.