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.

1 . A long-term controlled or sustained release preparation of a Class B corticosteroid comprising a lactic acid-glycolic acid copolymer microparticle containing the Class B corticosteroid, wherein the Class B corticosteroid comprises between 5% to 15% of the lactic acid-glycolic acid copolymer microparticle matrix, and wherein the lactic acid-glycolic acid copolymer microparticle releases the Class B corticosteroid for a period of at least 90 days. 
     
     
         2 . A formulation comprising long-term controlled- or sustained-release microparticles comprising a Class B corticosteroid and a lactic acid-glycolic acid copolymer matrix, wherein the lactic acid-glycolic acid copolymer microparticles release the Class B corticosteroid for a period of at least 90 days, wherein the lactic acid-glycolic acid copolymer microparticles comprise a mixture of lactic acid-glycolic acid copolymers, wherein the Class B corticosteroid comprises between 5% to 15% of the microparticles and wherein the mixture of lactic acid-glycolic acid copolymer comprises a first lactic acid-glycolic acid copolymer having one of more of the following characteristics: (i) a molecular weight in the range of about 110 to 150 kDa; (ii) an inherent viscosity in the range of 0.6 to 1.0 dL/g; or (iii) a lactide:glycolide molar ratio of 80:20 to 60:40 or a lactide:glycolide molar ratio of 80:20 to 50:50 and a second lactic acid-glycolic acid copolymer having 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 0.2 to 0.5 dL/g; or (iii) a lactide:glycolide molar ratio of 80:20 to 60:40 a lactide:glycolide molar ratio of 80:20 to 50:50. 
     
     
         3 . The preparation of  claim 1 , wherein the copolymer is biodegradable. 
     
     
         4 . The preparation of  claim 1 , wherein the lactic acid-glycolic acid copolymer is a poly(lactic-co-glycolic) acid copolymer (PLGA). 
     
     
         5 . The preparation of  claim 1 , wherein the Class B corticosteroid is triamcinolone acetonide or a commercially available chemical analogue or a pharmaceutically-acceptable salt thereof. 
     
     
         6 . The preparation of  claim 1 , wherein the microparticles have a mean diameter of between 10 μm to 100 μm. 
     
     
         7 . The preparation of  claim 1 , wherein the lactic acid-glycolic acid copolymer, the first lactic acid-glycolic acid copolymer or the second lactic acid-glycolic acid copolymer has a molar ratio of lactic acid:glycolic acid from the range of about 80:20 to 60:40. 
     
     
         8 . The preparation of  claim 1 , wherein the lactic acid-glycolic acid copolymer, the first lactic acid-glycolic acid copolymer or the second lactic acid-glycolic acid copolymer has a molar ratio of lactic acid:glycolic acid of 75:25. 
     
     
         9 . The preparation 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. 
     
     
         10 . The preparation of  claim 1 , wherein the Class B corticosteroid is released for at least 90 days. 
     
     
         11 . The preparation of  claim 1 , wherein the lactic acid-glycolic acid copolymer comprises an ester endcap. 
     
     
         12 . A population of microparticles comprising a Class B corticosteroid or a pharmaceutically acceptable salt thereof incorporated in a lactic acid-glycolic acid copolymer matrix, wherein the Class B corticosteroid comprises between 22% to 28% of the microparticles, and wherein the Class B corticosteroid is budesonide or a commercially available chemical analogue or a pharmaceutically-acceptable salt thereof. 
     
     
         13 . A controlled or sustained release preparation of a Class B corticosteroid comprising a lactic acid-glycolic acid copolymer microparticle containing the Class B corticosteroid, wherein the Class B corticosteroid comprises between 22% to 28% of the lactic acid-glycolic acid copolymer microparticle matrix, and wherein the Class B corticosteroid is budesonide or a commercially available chemical analogue or a pharmaceutically-acceptable salt thereof. 
     
     
         14 . A formulation comprising controlled- or sustained-release microparticles comprising a Class B corticosteroid and a lactic acid-glycolic acid copolymer matrix, wherein the Class B corticosteroid is budesonide or a commercially available chemical analogue or a pharmaceutically-acceptable salt thereof, wherein the budesonide 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 0.35 to 0.5 dL/g; or (iii) a lactide:glycolide molar ratio of 80:20 to 60:40 or a lactide:glycolide molar ratio of 80:20 to 50:50. 
     
     
         15 . The population of  claim 12 , wherein the copolymer is biodegradable. 
     
     
         16 . The population of  claim 12 , wherein the lactic acid-glycolic acid copolymer is a poly(lactic-co-glycolic) acid copolymer (PLGA). 
     
     
         17 . The population of  claim 12 , wherein the lactic acid-glycolic acid copolymer comprises an acid endcap. 
     
     
         18 . The population of  claim 12 , wherein the microparticles have a mean diameter of between 10 μm to 100 μm. 
     
     
         19 . The population of  claim 12 , 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. 
     
     
         20 . The population of  claim 12 , wherein the lactic acid-glycolic acid copolymer has a molar ratio of lactic acid:glycolic acid of 75:25. 
     
     
         21 . The population of  claim 12 , wherein the microparticles further comprise a polyethylene glycol (PEG) moiety, wherein the PEG moiety comprises between 25% to 0% weight percent of the microparticle. 
     
     
         22 . The population of  claim 12 , wherein the budesonide or commercially available chemical analogue or pharmaceutically acceptable salt thereof is released for between 14 days and 90 days. 
     
     
         23 . A method of treating pain or inflammation in a patient comprising administering to said patient a therapeutically effective amount of the controlled or sustained release preparation of  claim 1 . 
     
     
         24 . A method of treating pain or inflammation in a patient comprising administering to said patient a therapeutically effective amount of the controlled or sustained release preparation of  claim 1 , wherein the controlled or sustained release preparation releases the corticosteroid for at least 14 days at a rate that does not adversely suppress the hypothalamic-pituitary-adrenal axis (HPA axis). 
     
     
         25 . 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 controlled or sustained release preparation of  claim 1 . 
     
     
         26 . 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 controlled or sustained release preparation of  claim 1 , wherein the controlled or sustained release preparation releases the corticosteroid for at least 14 days at a rate that does not adversely suppress the hypothalamic-pituitary-adrenal axis (HPA axis). 
     
     
         27 . The method of any one of  claim 23 , wherein the controlled or sustained release preparation is administered as one or more injections. 
     
     
         28 . The method of any one of  claim 23 , wherein the patient has osteoarthritis, rheumatoid arthritis, acute gouty arthritis, and synovitis. 
     
     
         29 . A method of manufacturing the controlled or sustained release preparation 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. 
     
     
         30 . The method of manufacture of  claim 29 , wherein the solvent evaporation process utilizes a spray drying or fluid bed apparatus to remove the solvent and produce microparticles. 
     
     
         31 . The method of manufacture of  claim 29 , wherein the solvent evaporation process utilizes a spinning disk.