Corticosteroids for the treatment of joint pain

Abstract

Corticosteroid microparticle formulations are provided for use for treating pain, including pain caused by inflammatory diseases such as osteoarthritis or rheumatoid arthritis, and for slowing, arresting or reversing structural damage to tissues caused by an inflammatory disease, for example damage to articular and/or peri-articular tissues caused by osteoarthritis or rheumatoid arthritis. Corticosteroid microparticle formulations are administered locally as a sustained release dosage form (with or without an immediate release component) that results in efficacy accompanied by clinically insignificant or no measurable effect on endogenous cortisol production.

What is claimed is: 
     
         1 . A formulation comprising controlled- or sustained-release microparticles comprising a combination of a corticosteroid and a lactic acid-glycolic acid copolymer matrix selected from the group consisting of:
 (a) controlled- or sustained-release microparticles comprising a Class B corticosteroid and a lactic acid-glycolic acid copolymer matrix, wherein the Class B corticosteroid comprises between 22% to 28% of the microparticles and wherein the lactic acid-glycolic acid copolymer has one of more of the following characteristics: (i) a molecular weight in the range of about 40 to 70 kDa; (ii) an inherent viscosity in the range of 0.3 to 0.5 dL/g; or (iii) a lactide:glycolide molar ratio of 80:20 to 60:40;   (b) controlled- or sustained-release microparticles comprising a Class A corticosteroid and a lactic acid-glycolic acid copolymer matrix, wherein the Class A corticosteroid comprises between 15% to 30% of the microparticles and wherein the lactic acid-glycolic acid copolymer has one of more of the following characteristics: (i) a molecular weight in the range of about 40 to 70 kDa; (ii) an inherent viscosity in the range of 0.35 to 0.5 dL/g; or (iii) a lactide:glycolide molar ratio of 60:40 to 45:55;   (c) controlled- or sustained-release microparticles comprising a Class C corticosteroid and a lactic acid-glycolic acid copolymer matrix, wherein the Class C corticosteroid comprises between 15% to 30% of the microparticles and wherein the lactic acid-glycolic acid copolymer has one of more of the following characteristics: (i) a molecular weight in the range of about 40 to 70 kDa; (ii) an inherent viscosity in the range of 0.35 to 0.5 dL/g; or (iii) a lactide:glycolide molar ratio of 60:40 to 45:55; and   (d) controlled- or sustained-release microparticles comprising a Class D corticosteroid and a lactic acid-glycolic acid copolymer matrix, wherein the Class D corticosteroid comprises between 8% to 20% of the microparticles and wherein the lactic acid-glycolic acid copolymer has one of more of the following characteristics: (i) a molecular weight in the range of about 40 to 70 kDa; (ii) an inherent viscosity in the range of 0.35 to 0.5 dL/g; or (iii) a lactide:glycolide molar ratio of 60:40 to 45:55.   
     
     
         2 . The formulation of  claim 1 , wherein the copolymer is biodegradable. 
     
     
         3 . The formulation of  claim 1 , wherein the lactic acid-glycolic acid copolymer is a poly(lactic-co-glycolic) acid copolymer (PLGA). 
     
     
         4 . The formulation of  claim 1 , wherein the Class B corticosteroid is triamcinolone acetonide or a commercially available chemical analogue or a pharmaceutically-acceptable salt thereof. 
     
     
         5 . The formulation of  claim 1 , wherein the Class A corticosteroid is prednisolone or a commercially available chemical analogue or a pharmaceutically-acceptable salt thereof. 
     
     
         6 . The formulation of  claim 1 , wherein the Class C corticosteroid is betamethasone or a commercially available chemical analogue or a pharmaceutically-acceptable salt thereof. 
     
     
         7 . The formulation of  claim 1 , wherein the Class D corticosteroid is fluticasone propionate, fluticasone, or a commercially available chemical analogue or a pharmaceutically-acceptable salt thereof. 
     
     
         8 . The formulation of  claim 1 , wherein the microparticles have a mean diameter of between 10 μm to 100 μm. 
     
     
         9 . The formulation of  claim 1 , wherein the corticosteroid is a Class B corticosteroid, and wherein the lactic acid-glycolic acid copolymer has a molar ratio of lactic acid: glycolic acid from the range of about 80:20 to 60:40. 
     
     
         10 . The formulation of  claim 1 , wherein the corticosteroid is a Class B corticosteroid, and wherein the lactic acid-glycolic acid copolymer has a molar ratio of lactic acid: glycolic acid of 75:25. 
     
     
         11 . The formulation of  claim 1 , wherein the corticosteroid is a Class A corticosteroid, and wherein the lactic acid-glycolic acid copolymer has a molar ratio of lactic acid: glycolic acid from the range of about 60:40 to 45:55. 
     
     
         12 . The formulation of  claim 1 , wherein the corticosteroid is a Class A corticosteroid, and wherein the lactic acid-glycolic acid copolymer has a molar ratio of lactic acid: glycolic acid of 50:50. 
     
     
         13 . The formulation of  claim 1 , wherein the corticosteroid is a Class C corticosteroid, and wherein the lactic acid-glycolic acid copolymer has a molar ratio of lactic acid: glycolic acid from the range of about 60:40 to 45:55. 
     
     
         14 . The formulation of  claim 1 , wherein the corticosteroid is a Class C corticosteroid, and wherein the lactic acid-glycolic acid copolymer has a molar ratio of lactic acid: glycolic acid of 50:50. 
     
     
         15 . The formulation of  claim 1 , wherein the corticosteroid is a Class D corticosteroid, and wherein the lactic acid-glycolic acid copolymer has a molar ratio of lactic acid: glycolic acid from the range of about 60:40 to 45:55. 
     
     
         16 . The formulation of  claim 1 , wherein the corticosteroid is a Class D corticosteroid, and wherein the lactic acid-glycolic acid copolymer has a molar ratio of lactic acid: glycolic acid of 50:50. 
     
     
         17 . The formulation of  claim 1 , wherein the microparticles further comprise a polyethylene glycol (PEG) moiety, wherein the PEG moiety comprises between 25% to 0% weight percent of the microparticle. 
     
     
         18 . The formulation of  claim 1 , wherein the corticosteroid is released for between 14 days and 90 days. 
     
     
         19 . A method of treating pain or inflammation in a patient comprising administering to said patient a therapeutically effective amount of the formulation of  claim 1 . 
     
     
         20 . The method of  claim 19 , wherein the formulation releases the corticosteroid for at least 14 days at a rate that does not adversely suppress the hypothalamic-pituitary-adrenal axis (HPA axis). 
     
     
         21 . The method of  claim 19 , wherein the formulation is administered as one or more injections. 
     
     
         22 . The method of  claim 19 , wherein the patient has osteoarthritis, rheumatoid arthritis, acute gouty arthritis, or synovitis. 
     
     
         23 . A method of slowing, arresting or reversing progressive structural tissue damage associated with chronic inflammatory disease in a patient comprising administering to said patient a therapeutically effective amount of the formulation of  claim 1 . 
     
     
         24 . The method of  claim 23 , wherein the formulation releases the corticosteroid for at least 14 days at a rate that does not adversely suppress the hypothalamic-pituitary-adrenal axis (HPA axis). 
     
     
         25 . The method of  claim 23 , wherein the formulation is administered as one or more injections. 
     
     
         26 . The method of  claim 23 , wherein the patient has osteoarthritis, rheumatoid arthritis, acute gouty arthritis, or synovitis. 
     
     
         27 . A method of manufacturing the formulation of  claim 1 , wherein the microparticles are manufactured using a solvent evaporation process wherein the Class B corticosteroid is dispersed in a lactic acid-glycolic acid copolymer organic solution and the mixture is treated to remove the solvent from the mixture, thereby producing microparticles. 
     
     
         28 . The method of manufacture of  claim 27 , wherein the solvent evaporation process utilizes a spray drying or fluid bed apparatus to remove the solvent and produce microparticles. 
     
     
         29 . The method of manufacture of  claim 27 , wherein the solvent evaporation process utilizes a spinning disk. 
     
     
         30 . A method of manufacturing the formulation of  claim 1 , wherein the microparticles are manufactured using a solid in oil in water emulsion process wherein the Class A corticosteroid is dispersed in a lactic acid-glycolic acid copolymer organic solution and added to an aqueous solvent to produce microparticles. 
     
     
         31 . A method of manufacturing the formulation of  claim 1 , wherein the microparticles are manufactured using a solid in oil in water emulsion process wherein the Class C corticosteroid is dispersed in a lactic acid-glycolic acid copolymer organic solution and added to an aqueous solvent to produce microparticles. 
     
     
         32 . A method of manufacturing the formulation of  claim 1 , wherein the microparticles are manufactured using a solid in oil in water emulsion process wherein the Class D corticosteroid is dispersed in a lactic acid-glycolic acid copolymer organic solution and added to an aqueous solvent produce microparticles.