Corticosteroids for the treatment of joint pain
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 formulation comprising long-term controlled- or sustained-release microparticles comprising triamcinolone acetonide (TCA) or a commercially available chemical analogue or a pharmaceutically-acceptable salt thereof and a mixture of poly(lactic-co-glycolic) acid (PLGA) copolymers, wherein the microparticles release the TCA for a period of at least 90 days, wherein the TCA comprises between 5% to 10% of the microparticles, and wherein the mixture of PLGA copolymers comprises a first PLGA copolymer having the following characteristics: a molecular weight in the range of about 110 to 150 kDa and a lactide:glycolide molar ratio of 80:20 to 60:40 and a second PLGA copolymer having the following characteristics: a molecular weight in the range of about 40 to 70 kDa and a lactide:glycolide molar ratio of 80:20 to 60:40.
2. The formulation of claim 1 , wherein the microparticles have a mean diameter of between 10 μm to 100 μm.
3. The formulation of claim 1 , wherein the first PLGA copolymer has a molar ratio of lactic acid:glycolic acid of 75:25.
4. The formulation of claim 1 , wherein the second PLGA copolymer has a molar ratio of lactic acid:glycolic acid of 75:25.
5. The formulation of claim 1 , wherein the first PLGA copolymer has an inherent viscosity in the range of 0.6 to 1.0 dL/g.
6. The formulation of claim 1 , wherein the second PLGA copolymer has an inherent viscosity in the range of 0.2 to 0.5 dL/g.
7. The formulation of claim 1 , wherein the first PLGA copolymer has an inherent viscosity in the range of 0.6 to 1.0 dL/g, and the second PLGA copolymer has an inherent viscosity in the range of 0.2 to 0.5 dL/g.
8. The formulation of claim 1 , wherein the first PLGA copolymer has a molar ratio of lactic acid:glycolic acid of 75:25, and the second PLGA copolymer has a molar ratio of lactic acid:glycolic acid of 75:25.
9. 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.
10. The formulation of claim 1 , wherein the mixture of PLGA copolymers comprises an ester endcap.
11. 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 formulation of claim 1 .
12. The method of claim 11 , wherein the controlled or sustained release formulation is administered as one or more injections.
13. The method of claim 11 , wherein the patient has osteoarthritis, rheumatoid arthritis, acute gouty arthritis, or synovitis.
14. 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 formulation of claim 1 , wherein the controlled or sustained release formulation releases the corticosteroid for at least 14 days at a rate that does not adversely suppress the hypothalamic-pituitary-adrenal axis (HPA axis).
15. The method of claim 14 , wherein the controlled or sustained release formulation is administered as one or more injections.
16. The method of claim 14 , wherein the patient has osteoarthritis, rheumatoid arthritis, acute gouty arthritis, or synovitis.
17. 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 formulation of claim 1 .
18. The method of claim 17 , wherein the controlled or sustained release formulation is administered as one or more injections.
19. The method of claim 17 , wherein the patient has osteoarthritis, rheumatoid arthritis, acute gouty arthritis, or synovitis.
20. 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 formulation of claim 1 , wherein the controlled or sustained release 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 20 , wherein the controlled or sustained release formulation is administered as one or more injections.
22. The method of claim 20 , wherein the patient has osteoarthritis, rheumatoid arthritis, acute gouty arthritis, or synovitis.
23. A method of manufacturing the controlled or sustained release formulation of claim 1 , wherein the microparticles are manufactured using a solvent evaporation process wherein the TCA 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.
24. The method of manufacture of claim 23 , wherein the solvent evaporation process utilizes a spray drying or fluid bed apparatus to remove the solvent and produce microparticles.
25. The method of manufacture of claim 23 , wherein the solvent evaporation process utilizes a spinning disk.