WO2014153384A1

WO2014153384A1 - Corticosteroid formulations for the treatment of joint pain and methods of use thereof

Info

Publication number: WO2014153384A1
Application number: PCT/US2014/031167
Authority: WO
Inventors: Neil Bodick
Original assignee: Flexion Therapeutics, Inc.
Priority date: 2013-03-19
Filing date: 2014-03-19
Publication date: 2014-09-25

Abstract

TCA/PLGA 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. TCA/PLGA microparticle formulations are administered locally as a sustained release dosage form that results in efficacy accompanied by clinically insignificant or no measurable effect on endogenous Cortisol production.

Description

CORTICOSTEROID FORMULATIONS FOR THE TREATMENT OF JOINT PAIN AND METHODS OF USE THEREOF

RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.

61/803,129, filed March 19, 2013, U.S. Provisional Application No. 61/822,654, filed May 13, 2013, and U.S. Provisional Application No. 61/831,030, filed June 4, 2013, each of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] This invention relates to the use of corticosteroids to treat pain, including pain caused by inflammatory diseases such as osteoarthritis or rheumatoid arthritis, and to slow, arrest or reverse 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. More specifically, a formulation of triamcinolone acetonide (TCA) is 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.

BACKGROUND OF THE INVENTION

[0003] Corticosteroids influence all tissues of the body and produce various cellular effects. These steroids regulate carbohydrate, lipid, protein biosynthesis and metabolism, and water and electrolyte balance. Corticosteroids influencing cellular biosynthesis or metabolism are referred to as glucocorticoids while those affecting water and electrolyte balance are mineralocorticoids. Both glucocorticoids and mineralocorticoids are released from the cortex of the adrenal gland.

[0004] The administration of corticosteroids, particularly for extended periods of time, can have a number of unwanted side effects. The interdependent feedback mechanism between the hypothalamus, which is responsible for secretion of corticotrophin-releasing factor, the pituitary gland, which is responsible for secretion of adrenocorticotropic hormone, and the adrenal cortex, which secretes Cortisol, is termed the hypothalamic- pituitary-adrenal (HP A) axis. The HPA axis may be suppressed by the administration of corticosteroids, leading to a variety of unwanted side effects.

[0005] Accordingly, there is a medical need to extend the local duration of action of corticosteroids, while reducing the systemic side effects associated with that administration. Thus, there is a need in the art for methods and compositions for the sustained local treatment of pain and inflammation, such as joint pain, with corticosteroids that results in clinically insignificant or no measurable HPA axis suppression. In addition, there is a medical need to slow, arrest, reverse or otherwise inhibit structural damage to tissues caused by inflammatory diseases such as damage to articular tissues resulting from osteoarthritis or rheumatoid arthritis.

SUMMARY OF THE INVENTION

[0006] Described herein are compositions and methods for the treatment of pain and inflammation using corticosteroids. The compositions and methods provided herein use one or more corticosteroids in a microparticle formulation. Preferably, the corticosteroid is triamcinolone acetonide (TCA) and the microparticle is made from a poly(lactic-co- glycolic) acid copolymer (PLGA). These TCA containing PLGA microparticles and formulations thereof are collectively referred to herein as "TCA/PLGA microparticles" and "TCA/PLGA microparticle formulations," where these terms are used interchangeably. The target for the TCA/PLGA microparticles and microparticle formulations described herein is about 24% to 26% triamcinolone acetonide, e.g., about 25% triamcinolone acetonide, in 75:25 PLGA with molecular weight of 50-54 kDa, inherent viscosity 0.40-0.46 dL/g, and the volumetric particle size of the microparticles is typically in the range of about 29-75 μιη. TCA PLGA microparticles and formulations described herein include one or more

TCA/PLGA microparticles that have these specific properties, or a population of

TCA/PLGA microparticles having an average of around 25% triamcinolone acetonide in 75:25 PLGA with molecular weight of 50-54 kDa, inherent viscosity 0.40-0.46 dL/g, and the volumetric particle size of the microparticles is typically in the range of about 29-75 μιη.

[0007] In some embodiments, TCA/PLGA microparticle formulations are administered at a TCA dose in the range of about 10 mg to about 50 mg. In some

embodiments, the TCA/PLGA microparticle formulations are administered at a TCA dose in the range of about 30 mg to about 50 mg. In some embodiments, the TCA/PLGA microparticle formulations are administered at a TCA dose in the range of about 31 mg to about 50 mg, about 32 mg to about 50 mg, about 33 mg to about 50 mg, about 34 mg to about 50 mg, about 35 mg to about 50 mg, about 36 mg to about 50 mg, about 37 mg to about 50 mg, about 38 mg to about 50 mg, about 39 mg to about 50 mg, about 40 mg to about 50 mg, about 41 mg to about 50 mg, about 42 mg to about 50 mg, about 43 mg to about 50 mg, about 44 mg to about 50 mg, about 45 mg to about 50 mg, about 46 mg to about 50 mg, about 47 mg to about 50 mg, about 48 mg to about 50 mg, or about 49 mg to about 50 mg. In some embodiments, the TCA PLGA microparticle formulations are administered at a TCA dose in the range of about 30 mg to about 40 mg, about 31 mg to about 40 mg, about 32 mg to about 40 mg, about 33 mg to about 40 mg, about 34 mg to about 40 mg, about 35 mg to about 40 mg, about 36 mg to about 40 mg, about 37 mg to about 40 mg, about 38 mg to about 40 mg, or about 39 mg to about 40 mg. In some embodiments, the TCA/PLGA microparticle formulations are administered at a TCA dose of about 40 mg.

[0008] In some embodiments, the TCA/PLGA microparticles are administered in a formulation having a viscosity in the range of about 2.7 centipoise (cP) to about 3.5 cP. In some embodiments, the TCA/PLGA microparticles are administered in a formulation having a viscosity in the range of about 2.8 cP to about 3.5 cP, about 2.9 cP to about 3.5 cP, about 3.0 cP to about 3.5 cP, about 3.1 cP to about 3.5 cP, about 3.2 cP to about 3.5 cP, about 3.3 cP to about 3.5 cP, about 3.4 cP to about 3.5 cP, about 2.8 cP to about 3.2 cP, about 2.9 cP to about 3.2 cP, about 3.0 cP to about 3.2 cP, about 2.8 cP to about 3.1 cP, about 2.9 cP to about 3.1 cP, about 3.0 cP to about 3.1 cP, about 2.8 cP to about 3.0 cP, or about 2.9 cP to about 3.0 cP. In some embodiments, TCA/PLGA microparticle formulations are administered at a TCA dose in the range of about 10 mg to about 50 mg and in a formulation having a viscosity in the range of about 2.7 cP to about 3.5 cP. In some embodiments, TCA/PLGA microparticle formulations are administered at a TCA dose in the range of about 10 mg to about 50 mg and in a formulation having a viscosity of in the range of about 2.8 cP to about 3.5 cP, about 2.9 cP to about 3.5 cP, about 3.0 cP to about 3.5 cP, about 3.1 cP to about 3.5 cP, about 3.2 cP to about 3.5 cP, about 3.3 cP to about 3.5 cP, about 3.4 cP to about 3.5 cP, about 2.8 cP to about 3.2 cP, about 2.9 cP to about 3.2 cP, about 3.0 cP to about 3.2 cP, about 2.8 cP to about 3.1 cP, about 2.9 cP to about 3.1 cP, about 3.0 cP to about 3.1 cP, about 2.8 cP to about 3.0 cP, or about 2.9 cP to about 3.0 cP. In some embodiments, TCA/PLGA microparticle formulations are administered at a TCA dose in the range of about 10 mg to about 50 mg and in a formulation having a viscosity of about 3.0 cP.

[0009] In some embodiments, the TCA PLGA microparticles are administered as a suspension having a viscosity in the range of about 2.7 centipoise (cP) to about 3.5 cP. In some embodiments, the TCA/PLGA microparticles are administered as a suspension having a viscosity in the range of about 2.8 cP to about 3.5 cP, about 2.9 cP to about 3.5 cP, about 3.0 cP to about 3.5 cP, about 3.1 cP to about 3.5 cP, about 3.2 cP to about 3.5 cP, about 3.3 cP to about 3.5 cP, about 3.4 cP to about 3.5 cP, about 2.8 cP to about 3.2 cP, about 2.9 cP to about 3.2 cP, about 3.0 cP to about 3.2 cP, about 2.8 cP to about 3.1 cP, about 2.9 cP to about 3.1 cP, about 3.0 cP to about 3.1 cP, about 2.8 cP to about 3.0 cP, or about 2.9 cP to about 3.0 cP. In some embodiments, TCA/PLGA microparticle formulations are

administered at a TCA dose in the range of about 10 mg to about 50 mg and as a suspension having a viscosity in the range of about 2.7 cP to about 3.5 cP. In some embodiments, TCA/PLGA microparticle formulations are administered at a TCA dose in the range of about 10 mg to about 50 mg and as a suspension having a viscosity of in the range of about 2.8 cP to about 3.5 cP, about 2.9 cP to about 3.5 cP, about 3.0 cP to about 3.5 cP, about 3.1 cP to about 3.5 cP, about 3.2 cP to about 3.5 cP, about 3.3 cP to about 3.5 cP, about 3.4 cP to about 3.5 cP, about 2.8 cP to about 3.2 cP, about 2.9 cP to about 3.2 cP, about 3.0 cP to about 3.2 cP, about 2.8 cP to about 3.1 cP, about 2.9 cP to about 3.1 cP, about 3.0 cP to about 3.1 cP, about 2.8 cP to about 3.0 cP, or about 2.9 cP to about 3.0 cP. In some embodiments, TCA/PLGA microparticle formulations are administered at a TCA dose in the range of about 10 mg to about 50 mg and as a suspension having a viscosity of about 3.0 cP.

[00010] The TCA/PLGA microparticle formulations provided herein, when administered at a TCA dose in the range of about 10 mg to about 60 mg, exhibit similar time to onset of pain relief as the currently approved and marketed dose for immediate release TCA (TCA IR) formulations, i.e., 40 mg TCA IR. For example, TCA/PLGA microparticle formulations administered at a TCA dose in the range of about 30 mg to about

50 mg, e.g., about 40 mg, exhibit similar time to onset of pain relief as a 40 mg TCA IR formulation. Onset of pain relief is largely independent of the dose and/or formulation of

TCA. The TCA/PLGA microparticle formulations provided herein, when administered at a

TCA dose in the range of about 10 mg to about 60 mg, are able to provide pain relief in patients with moderate to severe osteoarthritis pain at much lower concentrations, e.g., plasma and/or systemic concentrations, of TCA than the concentration of TCA IR that is associated with providing the same time to onset of pain relief in patients with moderate to severe OA pain.

[00011] The TCA/PLGA microparticle formulations provided herein, when administered at a TCA dose in the range of about 30 mg to about 50 mg, e.g., about 40 mg, exhibit a better peak effect on pain in patients with moderate to severe osteoarthritis pain as compared to the effect of 40 mg TCA IR formulation. In some embodiments, the peak effect on pain in patients who receive a TCA/PLGA microparticle formulation of the disclosure is improved at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%), 75%), 80%), 85%o, 90%>, 95% or more as compared to the peak effect in patients who receive 40 mg TCA IR formulation. In some embodiments, the peak effect on pain in patients who receive a TCA PLGA microparticle formulation of the disclosure is improved at least 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, two-fold, 2.5-fold, three-fold, 3.5-fold, four- fold, 4.5-fold, five-fold, ten- fold or more as compared to the peak effect in patients who receive 40 mg TCA IR formulation.

[00012] The TCA/PLGA microparticle formulations provided herein, when administered at a TCA dose in the range of about 30 mg to about 50 mg, e.g., about 40 mg, exhibit an improvement in continued pain relief in patients with moderate to severe osteoarthritis pain as compared to the effect of 40 mg TCA IR formulation. Continued pain relief is measured, in some embodiments, by comparing pain relief at a first time point post- administration to at least a second time point post-administration. In some embodiments, the first time point and the second time point are independently selected from the group consisting of 12 hours post-administration, 24 hours post- administration, 48 hours post- administration, 72 hours post- administration, 96 hours post- administration, one week post- administration, two weeks post- administration, three weeks post- administration, four weeks post- administration, five weeks post- administration, six weeks post- administration, seven weeks post- administration, eight weeks post- administration, nine weeks post- administration, ten weeks post- administration, 11 weeks post- administration, , 12 weeks post- administration, 13 weeks post- administration, 14 weeks post- administration, 15 weeks post- administration, 16 weeks post- administration, 17 weeks post- administration, 18 weeks post- administration, 19 weeks post- administration, 20 weeks post- administration, 21 weeks post- administration, 22 weeks post- administration, 23 weeks post- administration, 24 weeks post- administration or longer , provided that the first time point and second time point are not the same time point. In some embodiments, the improvement in continued pain relief for at least a first time point in patients who receive a TCA/PLGA microparticle formulation of the disclosure is at least 5%, 10%, 15%, 20%>, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more as compared to the continued pain relief for the corresponding time point(s) in patients who receive 40 mg TCA IR formulation. In some embodiments, the improvement in continued pain relief for at least a first time point in patients who receive a TCA/PLGA microparticle formulation of the disclosure is at least 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, two-fold, 2.5-fold, three-fold, 3.5-fold, four-fold, 4.5- fold, five- fold, ten-fold or more as compared to the continued pain relief r the corresponding time point(s)in patients who receive 40 mg TCA IR formulation.

[00013] The TCA PLGA microparticle formulations provided herein, when administered at a TCA dose in the range of about 30 mg to about 50 mg, e.g., about 40 mg, exhibit an improved duration of therapeutic effect on pain in patients with moderate to severe osteoarthritis pain as compared to the effect of 40 mg TCA IR formulation. In some embodiments, the improvement in duration of therapeutic effect on pain in patients who receive a TCA/PLGA microparticle formulation of the disclosure is at least 5%, 10%>, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more as compared to the duration of therapeutic effect on pain in patients who receive 40 mg TCA IR formulation. In some embodiments, the improvement in duration of therapeutic effect on pain in patients who receive a TCA/PLGA microparticle formulation of the disclosure is at 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, two-fold, 2.5-fold, three-fold, 3.5-fold, four-fold, 4.5-fold, five-fold, ten-fold or more as compared to the duration of therapeutic effect on pain in patients who receive 40 mg TCA IR formulation. In some embodiments, the duration of therapeutic effect on pain is a timeframe selected from the group consisting of 12 hours post-administration, 24 hours post- administration, 48 hours post- administration, 72 hours post- administration, 96 hours post- administration, one week post- administration, two weeks post- administration, three weeks post- administration, four weeks post- administration, five weeks post- administration, six weeks post- administration, seven weeks post- administration, eight weeks post- administration, nine weeks post- administration, ten weeks post- administration, 11 weeks post- administration, , 12 weeks post- administration, 13 weeks post- administration, 14 weeks post- administration, 15 weeks post- administration, 16 weeks post- administration, 17 weeks post- administration, 18 weeks post- administration, 19 weeks post- administration, 20 weeks post- administration, 21 weeks post- administration, 22 weeks post- administration, 23 weeks post- administration, 24 weeks post- administration or longer.

[00014] The TCA/PLGA microparticle formulations provided herein, when administered at a TCA dose in the range of about 30 mg to about 50 mg, e.g., about 40 mg, exhibit an improved pain level as measured for at least a first time point in patients with moderate to severe osteoarthritis pain as compared to the effect seen for the corresponding time point(s) in patients who received the 40 mg TCA IR formulation when measured on the WOMAC A scale. In some embodiments, the improvement in pain level in patients who receive a TCA/PLGA microparticle formulation of the disclosure is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more as compared to the pain level in patients who receive 40 mg TCA IR formulation. In some embodiments, the improvement in pain level in patients who receive a TCA PLGA microparticle formulation of the disclosure is at least 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, two-fold, 2.5-fold, three-fold, 3.5-fold, four-fold, 4.5- fold, five-fold, ten-fold or more as compared to the pain level in patients who receive 40 mg TCA IR formulation. In some embodiments, the first time point and any subsequent time points at which improvement in pain level is measured is selected from the group consisting of 12 hours post-administration, 24 hours post- administration, 48 hours post- administration, 72 hours post- administration, 96 hours post- administration, one week post- administration, two weeks post- administration, three weeks post- administration, four weeks post- administration, five weeks post- administration, six weeks post- administration, seven weeks post- administration, eight weeks post- administration, nine weeks post- administration, ten weeks post- administration, 11 weeks post- administration, , 12 weeks post- administration, 13 weeks post- administration, 14 weeks post- administration, 15 weeks post- administration, 16 weeks post- administration, 17 weeks post- administration, 18 weeks post- administration, 19 weeks post- administration, 20 weeks post- administration, 21 weeks post- administration, 22 weeks post- administration, 23 weeks post- administration, 24 weeks post- administration or longer.

[00015] The TCA/PLGA microparticle formulations provided herein, when administered at a TCA dose in the range of about 30 mg to about 50 mg, e.g., about 40 mg, exhibit an improved level of joint function as measured for at least a first time point in patients with moderate to severe osteoarthritis pain as compared to the effect seen for the corresponding time point(s) in patients who received the 40 mg TCA IR formulation when measured on the WO MAC C scale. In some embodiments, the improvement in level of joint function in patients who receive a TCA/PLGA microparticle formulation of the disclosure is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%), 80%), 85%), 90%), 95% or more as compared to the level of joint function in patients who receive 40 mg TCA IR formulation. In some embodiments, the improvement in level of joint function in patients who receive a TCA/PLGA microparticle formulation of the disclosure is at least 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9- fold, two-fold, 2.5-fold, three-fold, 3.5-fold, four-fold, 4.5-fold, five-fold, ten-fold or more as compared to the level of joint function in patients who receive 40 mg TCA IR

formulation. In some embodiments, the first time point and any subsequent time points at which improvement in level of joint function is measured is selected from the group consisting of 12 hours post-administration, 24 hours post- administration, 48 hours post- administration, 72 hours post- administration, 96 hours post- administration, one week post- administration, two weeks post- administration, three weeks post- administration, four weeks post- administration, five weeks post- administration, six weeks post- administration, seven weeks post- administration, eight weeks post- administration, nine weeks post- administration, ten weeks post- administration, 11 weeks post- administration, , 12 weeks post- administration, 13 weeks post- administration, 14 weeks post- administration, 15 weeks post- administration, 16 weeks post- administration, 17 weeks post- administration, 18 weeks post- administration, 19 weeks post- administration, 20 weeks post- administration, 21 weeks post- administration, 22 weeks post- administration, 23 weeks post- administration, 24 weeks post- administration or longer.

[00016] The TCA PLGA microparticle formulations provided herein, when administered at a TCA dose in the range of about 30 mg to about 50 mg, e.g., about 40 mg, exhibit an improved percent of OMERACT-OARSI responders as measured for at least a first time point in patients with moderate to severe osteoarthritis pain as compared to the effect for the corresponding time point(s) in patients who received the 40 mg TCA IR formulation. In some embodiments, the improvement in percent of OMERACT-OARSI responders in patients who receive a TCA/PLGA microparticle formulation of the disclosure is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more as compared to the percent of OMERACT- OARSI responders in patients who receive 40 mg TCA IR formulation. In some

embodiments, the improvement in the percent of OMERACT-OARSI responders in patients who receive a TCA/PLGA microparticle formulation of the disclosure is at least 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, two-fold, 2.5-fold, threefold, 3.5-fold, four- fold, 4.5-fold, five-fold, ten- fold or more as compared to the percent of OMERACT-OARSI responders in patients who receive 40 mg TCA IR formulation. In some embodiments, the first time point and any subsequent time points at which the percent of OMERACT-OARSI responders is measured is selected from the group consisting of 12 hours post-administration, 24 hours post- administration, 48 hours post- administration, 72 hours post- administration, 96 hours post- administration, one week post- administration, two weeks post- administration, three weeks post- administration, four weeks post- administration, five weeks post- administration, six weeks post- administration, seven weeks post- administration, eight weeks post- administration, nine weeks post- administration, ten weeks post- administration, 11 weeks post- administration, , 12 weeks post- administration, 13 weeks post- administration, 14 weeks post- administration, 15 weeks post- administration, 16 weeks post- administration, 17 weeks post- administration, 18 weeks post- administration, 19 weeks post- administration, 20 weeks post- administration, 21 weeks post- administration, 22 weeks post- administration, 23 weeks post- administration, 24 weeks post- administration or longer.

[00017] The TCA/PLGA microparticle formulations provided herein, when administered at a TCA dose in the range of about 30 mg to about 50 mg, e.g., about 40 mg, exhibit an improved effect on patient global impression of change as measured for at least a first time point in patients with moderate to severe osteoarthritis pain as compared to the effect seen for the corresponding time point(s) in patients who received the 40 mg TCA IR formulation. In some embodiments, the improvement in the effect on global impression of change in patients who receive a TCA/PLGA microparticle formulation of the disclosure is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%), 80%), 85%), 90%), 95% or more as compared to the effect on patient global impression of change in patients who receive 40 mg TCA IR formulation. In some embodiments, the improvement in the effect on global impression of change in patients who receive a

TCA/PLGA microparticle formulation of the disclosure is at least 1.2-fold, 1.3-fold, 1.4- fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, two-fold, 2.5-fold, three-fold, 3.5-fold, four-fold, 4.5-fold, five-fold, ten-fold or more as compared to the effect on global impression of change in patients who receive 40 mg TCA IR formulation. In some embodiments, the first time point and any subsequent time points at which patient global impression of change is measured is selected from the group consisting of 12 hours post- administration, 24 hours post- administration, 48 hours post- administration, 72 hours post- administration, 96 hours post- administration, one week post- administration, two weeks post- administration, three weeks post- administration, four weeks post- administration, five weeks post- administration, six weeks post- administration, seven weeks post- administration, eight weeks post- administration, nine weeks post- administration, ten weeks post- administration, 11 weeks post- administration, , 12 weeks post- administration, 13 weeks post- administration, 14 weeks post- administration, 15 weeks post- administration, 16 weeks post- administration, 17 weeks post- administration, 18 weeks post- administration, 19 weeks post- administration, 20 weeks post- administration, 21 weeks post- administration, 22 weeks post- administration, 23 weeks post- administration, 24 weeks post- administration or longer.

[00018] The TCA/PLGA microparticle formulations provided herein, when administered at a TCA dose in the range of about 30 mg to about 50 mg, e.g., about 40 mg, exhibit an improved effect on a clinical observer's global impression of change as measured for at least a first time point in patients with moderate to severe osteoarthritis pain as compared to the effect seen for the corresponding time point(s) in patients who received the 40 mg TCA IR formulation. In some embodiments, the improvement in the effect on a clinical observer's global impression of change in patients who receive a TCA/PLGA microparticle formulation of the disclosure is at least 5%, 10%, 15%, 20%>, 25%, 30%>, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more as compared to the effect on a clinical observer's global impression of change in patients who receive 40 mg TCA IR formulation. In some embodiments, the improvement in the effect on a clinical observer's global impression of change in patients who receive a TCA PLGA microparticle formulation of the disclosure is at least 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7- fold, 1.8-fold, 1.9-fold, two-fold, 2.5-fold, three-fold, 3.5-fold, four-fold, 4.5-fold, five-fold, ten-fold or more as compared to the effect on a clinical observer's global impression of change in patients who receive 40 mg TCA IR formulation. In some embodiments, the first time point and any subsequent time points at which clinical observer's global impression of change is measured is selected from the group consisting of 12 hours post-administration, 24 hours post- administration, 48 hours post- administration, 72 hours post- administration, 96 hours post- administration, one week post- administration, two weeks post- administration, three weeks post- administration, four weeks post- administration, five weeks post- administration, six weeks post- administration, seven weeks post- administration, eight weeks post- administration, nine weeks post- administration, ten weeks post- administration, 11 weeks post- administration, , 12 weeks post- administration, 13 weeks post- administration, 14 weeks post- administration, 15 weeks post- administration, 16 weeks post- administration, 17 weeks post- administration, 18 weeks post- administration, 19 weeks post- administration, 20 weeks post- administration, 21 weeks post- administration, 22 weeks post- administration, 23 weeks post- administration, 24 weeks post- administration or longer.

[00019] In some embodiments, the TCA/PLGA microparticle formulations, when administered at a TCA dose in the range of about 30 mg to about 50 mg, e.g., about 40 mg, provide clinically meaningful therapeutic effect on pain in patients with moderate to severe osteoarthritis pain for at least 5 weeks post-administration, least 6 weeks post- administration, least 7 weeks post-administration, least 8 weeks post-administration, least 9 weeks post-administration, for at least 10 weeks post-administration, for at least 11 weeks post-administration, for at least 12 weeks post-administration, for at least 13 weeks post- administration, for at least 14 weeks post-administration, for at least 15 weeks post- administration, for at least 16 weeks post-administration, for at least 17 weeks post- administration, for at least 18 weeks post-administration, for at least 19 weeks post- administration, for at least 20 weeks post-administration, for at least 21 weeks post- administration, for at least 22 weeks post-administration, for at least 23 weeks post- administration, for at least 24 weeks post-administration, or longer. Clinically meaningful therapeutic effect on pain is measured, for example, against a baseline level of pain in patients with moderate to severe osteoarthritis.

[00020] The specific combination of desirable properties such as rapid time to onset of pain relief, the prolonged duration of clinically meaningful pain relief, and the magnitude of the peak response was unexpectedly seen when the TCA/PLGA microparticle

formulations were administered at a TCA dose in the range of about 30 mg to about 50 mg, e.g., about 40 mg.

[00021] The TCA PLGA microparticle formulations provided herein are effective at treating pain and/or inflammation with minimal long-term side effects of corticosteroid administration, including for example, prolonged suppression of the HPA axis. The

TCA/PLGA microparticle formulations are suitable for administration, for example, local administration by injection into a site at or near the site of a patient's pain and/or inflammation. The TCA/PLGA microparticle formulations provided herein are effective in slowing, arresting, reversing or otherwise inhibiting structural damage to tissues associated with progressive disease with minimal long-term side effects of TCA/PLGA administration, including for example, prolonged suppression of the HPA axis. The TCA/PLGA

microparticle formulations are suitable for administration, for example, local administration by injection into a site at or near the site of structural tissue damage. As used herein, "prolonged" suppression of the HPA axis refers to levels of Cortisol suppression greater than 40%, preferably greater than 35% by day 14 post-administration, for example post- injection. The TCA/PLGA microparticle formulations provided herein deliver the TCA in a dose and in a controlled or sustained release manner such that the levels of Cortisol suppression are at or below 40%>, preferably 35% by day 14 post-administration, for example post-injection. In some embodiments, the TCA/PLGA microparticle formulations provided herein deliver the TCA in a dose and in a controlled or sustained release manner such that the levels of Cortisol suppression are negligible, clinically

insignificant/inconsequential and/or undetectable by 14 post-administration, for example post-injection. In some embodiments, the TCA/PLGA microparticle formulations provided herein deliver the TCA in a dose and in a controlled or sustained release manner such that the levels of Cortisol suppression are negligible at any time post-injection. Thus, the

TCA/PLGA microparticle formulations in these embodiments are effective in the absence of any significant HPA axis suppression. Administration of the TCA/PLGA microparticle formulations provided herein can result in initial HPA axis suppression, for example, within the first few days, within the first two days and/or within the first 24 hours post-injection, but by day 14 post-injection, suppression of the HPA axis is less than 40%, preferably 35%.

[00022] In certain embodiments, a sustained release form of TCA/PLGA

microparticles is administered locally to treat pain and inflammation. Local administration of a TCA/PLGA microparticle formulation can occur, for example, by injection into the intra-articular space or peri-articular space at or near the site of a patient's pain. In certain embodiments, the formulation additionally contains an immediate release component. In certain preferred embodiments of the invention, a sustained release form of TCA/PLGA microparticles is administered (e.g., by single injection or as sequential injections) into an intra-articular space for the treatment of pain, for example, due to osteoarthritis, rheumatoid arthritis, gouty arthritis and/or other joint disorders, or into local tissues affected by bursitis, tenosynovitis, epicondylitis, synovitis and/or other disorders. In certain preferred

embodiments of the invention, a sustained release form of TCA/PLGA microparticles is administered (e.g., by single injection or as sequential injections) into an intra-articular space to slow, arrest, reverse or otherwise inhibit structural damage to tissues associated with progressive disease such as, for example, the damage to cartilage associated with progression of osteoarthritis. The TCA PLGA microparticles described herein are also useful in the treatment of a systemic disorder for which TCA treatment would be required or otherwise therapeutically beneficial.

[00023] In one aspect, a TCA/PLGA microparticle formulation is provided the

TCA/PLGA microparticle formulation provides at least two weeks, preferably at least three weeks, including up to and beyond 30 days, or 60 days, or 90 days of a sustained, steady state release of TCA. In one aspect, a TCA/PLGA microparticle formulation is provided wherein the TCA/PLGA microparticle formulation provides at least two weeks, preferably at least three weeks, including up to and beyond 30 days, or 60 days, or 90 days of a sustained, steady state release of TCA at a rate that does not adversely suppress the HPA axis. The duration of the release of TCA from the TCA/PLGA microparticles can vary in relation to the total number of TCA/PLGA microparticles contained in a given formulation. In the TCA/PLGA microparticle formulations described herein, when administered at a dose around 10 mg, the TCA/PLGA microparticles provide at least 6 weeks of a sustained, steady state release of TCA.

[00024] In some embodiments, the TCA/PLGA microparticle formulation retains sustained efficacy even after the TCA is no longer resident at the site of administration, for example, in the intra-articular space, and/or after the TCA is no longer detected in the systemic circulation. The TCA/PLGA microparticle formulation retains sustained efficacy even after the TCA/PLGA microparticle formulation is no longer resident at the site of administration, for example, in the intra-articular space, and/or the released TCA is no longer detected in the systemic circulation. The TCA/PLGA microparticle formulation retains sustained efficacy even after the TCA/PLGA microparticle formulation ceases to release therapeutically effective amounts of TCA. For example, in some embodiments, the

TCA released by the TCA/PLGA microparticle formulation retains efficacy for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, at least twelve weeks, or more than twelve-weeks post-administration. In some embodiments, the TCA released by the TCA/PLGA microparticle formulation retains efficacy for a time period that is at least 1.1 times as long, at least 1.2 times as long, at least 1.3 times as long, at least 1.4 times as long, at least 1.5 times as long, at least 1.6 times as long, at least 1.7 times as long, at least 1.8 times as long, at least 1.9 times as long, twice as long, at least 2.5 times as long, at least three times as long, or more than three times as long as the residency period for the TCA and/or the TCA/PLGA microparticle formulation. In some

embodiments, the sustained, steady state release of TCA will not adversely suppress the HP A axis.

[00025] In some embodiments, a controlled or sustained-release TCA/PLGA formulation is provided wherein formulation may or may not exhibit an initial rapid release in addition to the sustained, steady state release of TCA for a second length of time of at least two weeks, preferably at least three weeks, including up to and beyond 30 days, or 60 days, or 90 days. The initial rapid release can be, for example, an initial "burst" of release within 1 hour of administration the TCA/PLGA microparticle formulation. The initial rapid release can be within the first 24 hours post-administration. In some embodiments, the

TCA/PLGA formulation is provided wherein formulation may or may not exhibit an initial rapid release within the first 24 hours post-administration. In some embodiments, the

TCA/PLGA formulation is provided wherein formulation may or may not exhibit an initial

"burst" of rapid release within 1 hour post-administration. It should be noted that when

TCA levels are measured in vitro, an initial rapid release or burst of TCA release from the

TCA/PLGA microparticle formulation can be seen, but this initial rapid release or burst may or may not be seen in vivo. In some embodiments, the TCA/PLGA formulations may or may not exhibit an initial rapid release, and the sustained, steady state release of TCA occurs at a rate that does not suppress the HPA axis at a level greater than 50% at day 14 post-administration. In some embodiments, the sustained, steady state release of TCA will not adversely suppress the HPA axis, for example, the level of HPA axis suppression at or less than 40%, preferably 35% by day 14 post-administration. In some embodiments, the sustained, steady state release of TCA does not significantly suppress the HPA axis, for example, the level of HPA axis suppression is negligible, clinically

insignificant/inconsequential and/or undetectable by day 14 post-injection. In some embodiments, the sustained, steady state release of TCA does not significantly suppress the HPA axis, for example, the level of HP A axis suppression is negligible at all times post- injection. In some embodiments, the length of sustained release is between 21 days and 90 days. In some embodiments, the length of sustained release is between 21 days and 60 days. In some embodiments, the length of sustained release is between 14 days and 30 days. In some embodiments, the length of the initial "burst" release is between 0 and 1 hour post- administration. In some embodiments, the length of the initial release is between 0 and 24 hours.

[00026] The TCA/PLGA microparticle formulations provided herein can be used in combination with any of a variety of therapeutics, also referred to herein as "co -therapies."

[00027] For example, the TCA/PLGA microparticle formulations can be used in combination with an immediate release TCA (or other corticosteroid) solution or

suspension, which provides high local exposures for between 1 day and 14 days following administration and which produce systemic exposures that may be associated with transient suppression of the HPA axis. In some embodiments, the same corticosteroid, i.e., TCA, is used in both the immediate release and sustained release components. In some

embodiments, the immediate release component contains a corticosteroid that is different from that of the sustained release component, i.e., the immediate release component does not include TCA. In some embodiments, the sustained, steady state release of TCA will not adversely suppress the HPA axis. In some embodiments, the period of sustained release is between 21 days and 90 days. In some embodiments, the period of sustained release is between 21 days and 60 days. In some embodiments, the period of sustained release is between 14 days and 30 days. In some embodiments, the high local exposure attributable to the immediate release component lasts for between 1 day and 14 days. In some

embodiments, the high local exposure attributable to the immediate release component lasts for between 1 day and 10 days. In some embodiments, the high local exposure attributable to the immediate release component lasts between 1 days and 8 days. In some embodiments, the high local exposure attributable to the immediate release component lasts between 1 days and 6 days. In some embodiments, the high local exposure attributable to the immediate release component lasts for between 1 day and 4 days.

[00028] Suitable additional agents for use in combination with the TCA PLGA microparticle formulations provided herein include hyaluronic acid preparations including but not limited to Synvisc One, Gel 200 and Supartz; NSAIDS including but not limited to aspirin, celecoxib (Celebrex), diclofenac (Voltaren), diflunisal (Dolobid), etodolac (Lodine), ibuprofen (Motrin), indomethacin , Indocin), ketoprofen (Orudis), ketorolac (Toradol), nabumetone (Relafen), naproxen (Aleve, Naprosyn), oxaprozin (Daypro), piroxicam

(Feldene), salsalate (Amigesic), sulindac (Clinoril), tolmetin (Tolectin); biologies including but not limited to Actemra (tocilizumab), Enbrel (etanercept), Humira (adalimumab), Kineret (anakinra), Orencia (abatacept), Remicade (infliximab), Rituxan (rituximab), Cimzia (certolizumab), and Simponi (golimumab); disease modifying agents including but not limited to Methotrexate, Plaquenil (hydroxychloroquine) and Azulfidine (sulfasalazine), Minocin (minocycline); and other analgesic and anti-inflammatory agents including but not limited to p38 inhibitors JAC inhibitors, opioids, other corticosteroids, lidocaine, bupivacaine, ropivacaine, botulinum toxin A.

[00029] In some embodiments, the TCA/PLGA microparticle formulation and additional agent are formulated into a single therapeutic composition, and the TCA/PLGA microparticle formulation and additional agent are administered simultaneously.

Alternatively, the TCA/PLGA microparticle formulation and additional agent are separate from each other, e.g., each is formulated into a separate therapeutic composition, and the TCA/PLGA microparticle formulation and the additional agent are administered

simultaneously, or the TCA/PLGA microparticle formulation and the additional agent are administered at different times during a treatment regimen. For example, the TCA/PLGA microparticle formulation is administered prior to the administration of the additional agent, the TCA/PLGA microparticle formulation is administered subsequent to the administration of the additional agent, or the TCA/PLGA microparticle formulation and the additional agent are administered in an alternating fashion. As described herein, the TCA/PLGA microparticle formulation and additional agent are administered in single doses or in multiple doses.

[00030] In some embodiments, the TCA/PLGA microparticle formulation and the additional agent are administered by the same route. In some embodiments, the TCA/PLGA microparticle formulation and the additional agent are administered via different routes.

[00031] The invention provides populations of microparticles including

triamcinolone acetonide (TCA) or a pharmaceutically acceptable salt thereof incorporated in, admixed, encapsulated or otherwise associated with a poly(lactic-co-glycolic) acid (PLGA) copolymer matrix, wherein the TCA is between 22% to 28% of the microparticles. In a preferred embodiment, the TCA is about 25% of the microparticle. [00032] The invention also provides controlled or sustained release preparation of

TCA that include a poly(lactic-co-glycolic) acid copolymer microparticle containing the TCA, wherein the TCA is between 22% to 28% of the lactic acid-glycolic acid copolymer microparticle matrix. In a preferred embodiment, the TCA is about 25% of the

microparticle.

[00033] The invention also provides formulations that include (a) controlled- or sustained- release microparticles comprising TCA and a poly(lactic-co-glycolic) acid copolymer matrix, wherein the TCA comprises about 25% of the microparticles, wherein the microparticles have a mean volumetric particle size in the range of about 29-75 μιη, and wherein the PLGA copolymer has one of more of the following characteristics: (i) a molecular weight in the range of about 50 to 54 kDa; (ii) an inherent viscosity in the range of 0.4 to 0.46 dL/g; (iii) a poly(lactic-co-glycolic) acid molar ratio of about 75:25; and/or (iv) the PLGA copolymer is carboxylic acid endcapped.

[00034] In some embodiments, the microparticles have a mean diameter in the range of 10-100 μιη, for example, as detected by laser light scattering methods. In some embodiments, the microparticles have a mean diameter in the range of 20-100 μιη, 20-90 μιη, 30-100 μιη, 30-90 μιη, or 10-90 μιη. It is understood that these ranges refer to the mean diameter of all microparticles in a given population. The diameter of any given individual microparticle could be within a standard deviation above or below the mean diameter.

[00035] These TCA/PLGA microparticle formulations, preparations, and populations thereof, when administered to a patient, exhibit an improved benefit or other therapeutic outcome in the treatment of a disease, for example a joint related disorder, as compared to the administration, for example administration into the intra-articular space of a joint, of an equivalent amount of the TCA absent any microparticle or other type of incorporation, admixture, or encapsulation. The improved benefit can be any of a variety of laboratory or clinical results. For example, administration of a TCA PLGA microparticle formulation is considered more successful than administration of TCA absent any microparticle if, following administration of the TCA/PLGA microparticles, one or more of the symptoms associated with the disease is alleviated, reduced, inhibited or does not progress to a further, i.e., worse, state, to a greater extent than the level that is observed after administration of

TCA absent any microparticle. Administration of a TCA/PLGA microparticle formulation is considered more successful than administration of TCA absent any microparticle if, following administration of the TCA/PLGA microparticles, anti-inflammatory activity is sustained for a longer period than the level that is observed after administration of TCA absent any microparticle.

[00036] In some embodiments, the total dose of TCA or a commercially available chemical analogue or a pharmaceutically-acceptable salt thereof, is about 10 mgs, where the TCA is about 25% of the TCA/PLGA microparticle, the PLGA is about 30 mg and the total weight of the TCA PLGA microparticle is about 40 mg. In some embodiments, the total dose of TCA or a commercially available chemical analogue or a pharmaceutically- acceptable salt thereof, is about 40 mgs, where the TCA is about 25% of the TCA/PLGA microparticle, the PLGA is about 120 mg and the total weight of TCA/PLGA microparticle is about 160 mg. In some embodiments, the total dose of TCA or a commercially available chemical analogue or a pharmaceutically-acceptable salt thereof, is about 60 mgs, where the TCA is about 25% of the TCA/PLGA microparticle, the PLGA is about 180 mg and the total weight of TCA/PLGA microparticle is about 240 mg. In some embodiments, the TCA is released for at least 14 days, at least 20 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, at least 50 days, at least 55 days, at least 60 days, at least 65 days, at least 70 days, at least 75 days, at least 80 days, at least 85 days, at least 90 days or longer. In some embodiments, the TCA is released for between at least 14 days and at least 90 days or longer.

[00037] The invention provides methods of treating pain or inflammation in a patient comprising administering to said patient a therapeutically effective amount of any of the

TCA/PLGA microparticles formulations described herein. In some embodiments, the population of microparticles releases TCA for at least 14 days at a rate that does not adversely suppress the hypothalamic-pituitary-adrenal axis (HP A axis). In some

embodiments, the population of microparticles releases TCA in a controlled or sustained release manner such that the levels of Cortisol suppression are at or below 40%, preferably

35% by, for example day 14 post-administration. In some embodiments, the population of microparticles releases TCA in a controlled or sustained release manner such that the levels of Cortisol suppression are negligible, clinically insignificant/inconsequential and/or undetectable by 14 post-administration. In some embodiments, the population of

TCA/PLGA microparticles releases TCA in a controlled or sustained release manner such that the levels of Cortisol suppression are negligible at any time post-administration.

Therapeutically effective amounts of TCA are released for a period of time at a rate that does not suppress (e.g., adversely and/or measurably) the HPA axis. [00038] In some embodiments, the methods include the initial step of identifying a selected patient population for treatment with a TCA/PLGA microparticle formulation of the disclosure. In some embodiments, the patient population is identified based on pain level. On the 10 point Numerical Rating scale where 0 is no pain and 10 is the worst pain imaginable, patients with a score of 5 or above are an identified patient population. In some embodiments, the patient population is identified based on level joint movement. In some embodiments, the patient population is identified based on level of joint deterioration.

Patients with Osteoarthrits with scores of 2 and 3 in the Kellgren & Lawrence system for classification of knee radiographs are an identified population. In some embodiments, the patient population is identified based on the occurrence of prior joint injury leading to deterioration of joint tissues.

[00039] In some embodiments, the population of TCA/PLGA microparticles, the controlled or sustained release TCA/PLGA microparticle preparation or formulation is administered as one or more intra-articular injections. In some embodiments, the population of TCA/PLGA microparticles, the controlled or sustained release TCA/PLGA microparticle preparation or formulation is administered as one or more local injections at the site of pain. In some embodiments, the patient has osteoarthritis, rheumatoid arthritis, acute gouty arthritis, and/or synovitis. In some embodiments, the patient has acute bursitis, sub-acute bursitis, acute nonspecific tenosynovitis, and/or epicondylitis.

[00040] The invention also provides methods of slowing, arresting or reversing progressive structural tissue damage associated with chronic inflammatory disease in a patient by administering to said patient a therapeutically effective amount of a population of TCA/PLGA microparticles described herein.

[00041] It is contemplated that whenever appropriate, any embodiment of the present invention can be combined with one or more other embodiments of the present invention, even though the embodiments are described under different aspects of the present invention.

BRIEF DESCRIPTION OF THE FIGURES

[00042] Figure 1 is a graph depicting TCA concentrations through day 43 for all patient groups, i.e., those receiving TCA/PLGA microparticle formulation at a dose selected from 10 mg, 40 mg or 60 mg, and those receiving an injectable suspension of TCA at a dose of 40 mg (TCA-IR). [00043] Figure 2 is a graph depicting TCA concentrations through day 4 for patient groups receiving TCA/PLGA microparticle formulation at a dose selected from 10 mg, 40 mg or 60 mg.

[00044] Figure 3 is a graph depicting TCA levels in synovial fluids for all patient groups, i.e., those receiving TCA PLGA microparticle formulation at a dose selected from 10 mg, 40 mg or 60 mg, and those receiving an injectable suspension of TCA at a dose of 40 mg (TCA-IR).

[00045] Figure 4 is a graph depicting the weekly mean of average daily pain intensity in patients with moderate to severe osteoarthritis pain (n = 228).

[00046] Figure 5 is a graph depicting the time to onset of pain relief using Kaplan-

Meier estimates. The TCA/PLGA microparticle formulations administered at 10 mg, 40 mg, and 60 mg doses exhibit a similar time to onset of pain relief as the 40 mg TCA IR formulation.

[00047] Figure 6 is a graph depicting the continuous response curve at week 8 for the

TCA/PLGA microparticle formulations (10 mg, 40 mg, or 60 mg) or 40 mg TCA IR formulation, plotted as a function of the percentage of patients exhibiting improved pain relief as the percentage of improvement from the baseline pain level.

[00048] Figure 7 is a graph depicting the LS mean change of pain level from baseline level of pain using the WOMAC A pain scale. The baseline level of pain for patients is calculated by the average pain level of a patient for the 7 days prior to administration of the TCA/PLGA microparticle formulations (10 mg, 40 mg, or 60 mg) or 40 mg TCA IR formulation.

[00049] Figure 8 is a graph depicting the LS mean change of the level of joint function from a baseline level of function using the WOMAC C function scale. The baseline level of joint function for patients is calculated by the average joint function level of a patient for the 7 days prior to administration of the TCA/PLGA microparticle formulations (10 mg, 40 mg, or 60 mg) or 40 mg TCA IR formulation.

[00050] Figure 9 is a graph depicting the proportion of OMERACT-0 ARSI responders, defined as patients with high improvement in pain or function) according to the OMERACT-OARSI criteria (available on the Osteoarthritis Research Society International website), at 1, 2, 4, 8 and 12 weeks after administration of the TCA/PLGA microparticle formulations (10 mg, 40 mg, or 60 mg) or 40 mg TCA IR formulation. [00051] Figure 10 is a graph depicting the LS mean change in patient global impression of change from a baseline level of global impression of change post- administration of the TCA/PLGA microparticle formulations (10 mg, 40 mg, or 60 mg) or 40 mg TCA IR formulation.

[00052] Figure 11 is a graph depicting the LS mean change in a clinical observer's global impression of change from a baseline level of global impression of change.

[00053] Figure 12 is a graph depicting the LS mean change in average rescue medication usage post-administration of the TCA/PLGA microparticle formulations (10 mg, 40 mg, or 60 mg) or 40 mg TCA IR formulation.

[00054] Figure 13 is a graph depicting the mean plasma concentration-time profiles of various TCA formulations using semi-log analysis.

DETAILED DESCRIPTION OF THE INVENTION

[00055] The invention provides compositions and methods for the treatment of pain and inflammation using TCA/PLGA microparticle formulations. The compositions and methods provided herein TCA in a PLGA microparticle formulation. The TCA/PLGA microparticle formulations provided herein are effective at treating pain and/or

inflammation with minimal prolonged suppression of the HPA axis and/or other long term side effects of TCA administration. The TCA/PLGA microparticle formulations provided herein are effective in slowing, arresting, reversing or otherwise inhibiting structural damage to tissues associated with progressive disease with minimal prolonged suppression of the HPA axis and/or other long term side effects of TCA administration. The TCA/PLGA microparticle formulations provided herein deliver TCA in a dose and in a sustained release manner such that the levels of Cortisol suppression are at or below 40%, preferably 35% by day 14 post-injection. In some embodiments, the TCA/PLGA microparticle formulations provided herein deliver TCA in a dose and in a controlled or sustained release manner such that the levels of Cortisol suppression are negligible, clinically insignificant/inconsequential and/or undetectable by 14 post-injection. Thus, the TCA/PLGA microparticle formulations in these embodiments are effective in the absence of any significant HPA axis suppression. Administration of the TCA/PLGA microparticle formulations provided herein can result in initial HPA axis suppression, for example, within the first few days, within the first two days and/or within the first 24 hours post-injection, but by day 14 post-injection, suppression of the HPA axis is less than 40%, preferably 35%.

[00056] The administration of corticosteroids such as TCA, particularly for extended periods of time, can have a number of unwanted side effects. The HPA axis, the

interdependent feedback mechanism between the hypothalamus, the pituitary gland and the adrenal cortex, may be suppressed by the administration of corticosteroids including TCA, leading to a variety of unwanted side effects.

[00057] In some embodiments, TCA/PLGA microparticle formulations are administered at a TCA dose in the range of about 10 mg to about 50 mg. In some embodiments, the TCA/PLGA microparticle formulations are administered at a TCA dose in the range of about 30 mg to about 50 mg. In some embodiments, the TCA/PLGA microparticle formulations are administered at a TCA dose in the range of about 31 mg to about 50 mg, about 32 mg to about 50 mg, about 33 mg to about 50 mg, about 34 mg to about 50 mg, about 35 mg to about 50 mg, about 36 mg to about 50 mg, about 37 mg to about 50 mg, about 38 mg to about 50 mg, about 39 mg to about 50 mg, about 40 mg to about 50 mg, about 41 mg to about 50 mg, about 42 mg to about 50 mg, about 43 mg to about 50 mg, about 44 mg to about 50 mg, about 45 mg to about 50 mg, about 46 mg to about 50 mg, about 47 mg to about 50 mg, about 48 mg to about 50 mg, or about 49 mg to about 50 mg. In some embodiments, the TCA/PLGA microparticle formulations are administered at a TCA dose in the range of about 30 mg to about 40 mg, about 31 mg to about 40 mg, about 32 mg to about 40 mg, about 33 mg to about 40 mg, about 34 mg to about 40 mg, about 35 mg to about 40 mg, about 36 mg to about 40 mg, about 37 mg to about 40 mg, about 38 mg to about 40 mg, or about 39 mg to about 40 mg. In some embodiments, the TCA/PLGA microparticle formulations are administered at a TCA dose of about 40 mg.

[00058] In some embodiments, the TCA/PLGA microparticles are administered in a formulation having a viscosity in the range of about 2.7 centipoise (cP) to about 3.5 cP. In some embodiments, the TCA/PLGA microparticles are administered in a formulation having a viscosity in the range of about 2.8 cP to about 3.5 cP, about 2.9 cP to about 3.5 cP, about 3.0 cP to about 3.5 cP, about 3.1 cP to about 3.5 cP, about 3.2 cP to about 3.5 cP, about 3.3 cP to about 3.5 cP, about 3.4 cP to about 3.5 cP, about 2.8 cP to about 3.2 cP, about 2.9 cP to about 3.2 cP, about 3.0 cP to about 3.2 cP, about 2.8 cP to about 3.1 cP, about 2.9 cP to about 3.1 cP, about 3.0 cP to about 3.1 cP, about 2.8 cP to about 3.0 cP, or about 2.9 cP to about 3.0 cP. In some embodiments, TCA/PLGA microparticle formulations are administered at a TCA dose in the range of about 10 mg to about 50 mg and in a formulation having a viscosity in the range of about 2.7 cP to about 3.5 cP. In some embodiments, TCA/PLGA microparticle formulations are administered at a TCA dose in the range of about 10 mg to about 50 mg and in a formulation having a viscosity of in the range of about 2.8 cP to about 3.5 cP, about 2.9 cP to about 3.5 cP, about 3.0 cP to about 3.5 cP, about 3.1 cP to about 3.5 cP, about 3.2 cP to about 3.5 cP, about 3.3 cP to about 3.5 cP, about 3.4 cP to about 3.5 cP, about 2.8 cP to about 3.2 cP, about 2.9 cP to about 3.2 cP, about 3.0 cP to about 3.2 cP, about 2.8 cP to about 3.1 cP, about 2.9 cP to about 3.1 cP, about 3.0 cP to about 3.1 cP, about 2.8 cP to about 3.0 cP, or about 2.9 cP to about 3.0 cP. In some embodiments, TCA/PLGA microparticle formulations are administered at a TCA dose in the range of about 10 mg to about 50 mg and in a formulation having a viscosity of about 3.0 cP.

[00059] In some embodiments, the TCA/PLGA microparticles are administered as a suspension having a viscosity in the range of about 2.7 centipoise (cP) to about 3.5 cP. In some embodiments, the TCA/PLGA microparticles are administered as a suspension having a viscosity in the range of about 2.8 cP to about 3.5 cP, about 2.9 cP to about 3.5 cP, about 3.0 cP to about 3.5 cP, about 3.1 cP to about 3.5 cP, about 3.2 cP to about 3.5 cP, about 3.3 cP to about 3.5 cP, about 3.4 cP to about 3.5 cP, about 2.8 cP to about 3.2 cP, about 2.9 cP to about 3.2 cP, about 3.0 cP to about 3.2 cP, about 2.8 cP to about 3.1 cP, about 2.9 cP to about 3.1 cP, about 3.0 cP to about 3.1 cP, about 2.8 cP to about 3.0 cP, or about 2.9 cP to about 3.0 cP. In some embodiments, TCA/PLGA microparticle formulations are

[00060] The TCA/PLGA microparticle formulations provided herein, when administered at a TCA dose in the range of about 10 mg to about 60 mg, exhibit similar time to onset of pain relief as the currently approved and marketed dose for immediate release TCA (TCA IR) formulations, i.e., 40 mg TCA IR. For example, TCA PLGA microparticle formulations administered at a TCA dose in the range of about 30 mg to about 50 mg, e.g., about 40 mg, exhibit similar time to onset of pain relief as a 40 mg TCA IR formulation. Onset of pain relief is largely independent of the dose and/or formulation of TCA. The TCA/PLGA microparticle formulations provided herein, when administered at a TCA dose in the range of about 10 mg to about 60 mg, are able to provide pain relief in patients with moderate to severe osteoarthritis pain at much lower concentrations, e.g., plasma and/or systemic concentrations, of TCA than the concentration of TCA IR that are associated with providing the same time to onset of pain relief in patients with moderate to severe OA pain.

[00061] The TCA/PLGA microparticle formulations provided herein, when administered at a TCA dose in the range of about 30 mg to about 50 mg, e.g., about 40 mg, exhibit a better peak effect on pain in patients with moderate to severe osteoarthritis pain as compared to the effect of 40 mg TCA IR formulation.

[00062] The TCA/PLGA microparticle formulations provided herein, when administered at a TCA dose in the range of about 30 mg to about 50 mg, e.g., about 40 mg, exhibit an improvement in continued pain relief as measured, in some embodiments, by comparing pain relief at a first time point post-administration to at least a second time point post-administration in patients with moderate to severe osteoarthritis pain as compared to the effect of 40 mg TCA IR formulation.

[00063] The TCA/PLGA microparticle formulations provided herein, when administered at a TCA dose in the range of about 30 mg to about 50 mg, e.g., about 40 mg, exhibit an improved duration of therapeutic effect on pain as measured for at least a first time point in patients with moderate to severe osteoarthritis pain as compared to the effect for the corresponding time point(s) in patients who receive the 40 mg TCA IR formulation.

[00064] The TCA/PLGA microparticle formulations provided herein, when administered at a TCA dose in the range of about 30 mg to about 50 mg, e.g., about 40 mg, exhibit an improved pain level as measured for at least a first time point in patients with moderate to severe osteoarthritis pain as compared to the effect seen for the corresponding time point(s) in patients who received the 40 mg TCA IR formulation when measured on the WOMAC A scale.

[00065] The TCA/PLGA microparticle formulations provided herein, when administered at a TCA dose in the range of about 30 mg to about 50 mg, e.g., about 40 mg, exhibit an improved level of joint function as measured for at least a first time point in patients with moderate to severe osteoarthritis pain as compared to the effect seen for the corresponding time point(s) in patients who received the 40 mg TCA IR formulation when measured on the WOMAC C scale.

[00066] The TCA/PLGA microparticle formulations provided herein, when administered at a TCA dose in the range of about 30 mg to about 50 mg, e.g., about 40 mg, exhibit an improved percent of OMERACT-OARSI responders as measured for at least a first time point in patients with moderate to severe osteoarthritis pain as compared to the effect for the corresponding time point(s) in patients who received the 40 mg TCA IR formulation.

[00067] The TCA PLGA microparticle formulations provided herein, when administered at a TCA dose in the range of about 30 mg to about 50 mg, e.g., about 40 mg, exhibit an improved effect on patient global impression of change as measured for at least a first time point in patients with moderate to severe osteoarthritis pain as compared to the effect seen for the corresponding time point(s) in patients who received the 40 mg TCA IR formulation.

[00068] The TCA/PLGA microparticle formulations provided herein, when administered at a TCA dose in the range of about 30 mg to about 50 mg, e.g., about 40 mg, exhibit an improved effect on a clinical observer's global impression of change as measured for at least a first time point in patients with moderate to severe osteoarthritis pain as compared to the effect seen for the corresponding time point(s) in patients who received the 40 mg TCA IR formulation.

[00069] In some embodiments, the TCA/PLGA microparticle formulations, when administered at a TCA dose in the range of about 30 mg to about 50 mg, e.g., about 40 mg, provide clinically meaningful therapeutic effect on pain as measured for at least a first time point in patients with moderate to severe osteoarthritis pain for at least 5 weeks post- administration, least 6 weeks post-administration, least 7 weeks post-administration, least 8 weeks post-administration, least 9 weeks post-administration, for at least 10 weeks post- administration, , for at least 11 weeks post-administration, for at least 12 weeks post- administration, for at least 13 weeks post-administration, for at least 14 weeks post- administration, for at least 15 weeks post-administration, for at least 16 weeks post- administration, for at least 17 weeks post-administration, for at least 18 weeks post- administration, for at least 19 weeks post-administration, for at least 20 weeks post- administration, for at least 21 weeks post-administration, for at least 22 weeks post- administration, for at least 23 weeks post-administration, for at least 24 weeks post- administration, or longer. Clinically meaningful therapeutic effect on pain is measured, for example, against a baseline level of pain in patients with moderate to severe osteoarthritis.

[00070] The specific combination of desirable properties such as rapid time to onset of pain relief, the prolonged duration of clinically meaningful pain relief, and the magnitude of the peak response was unexpectedly seen when the TCA/PLGA microparticle

[00071] The details of one or more embodiments of the invention are set forth in the accompanying description below. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the case of conflict, the present Specification will control.

[00072] An amount of TCA that does not "suppress the hypothalamic-pituitary- adrenal axis (HPA axis)" refers to the amount of the sustained release TCA/PLGA microparticle delivered locally to relieve pain due to inflammation, which provides a systemic concentration that will not have a clinically significant effect or "adverse effect" on the HPA axis. Suppression of the HPA axis is generally manifested by a reduction in endogenous glucocorticoid production. It is useful to consider both basal and augmented production of endogenous glucocorticoids. Under ordinary, "unstressed" conditions, glucocorticoid production occurs at a normal, basal level. There is some natural variation of production during the course of the 24-hour day. Under extraordinary, "stressed" conditions associated with, e.g., infection or trauma and the like, augmented endogenous production of glucocorticoids occurs. Endogenous Cortisol production may be determined by measuring glucocorticoid concentrations in plasma, saliva, urine or by any other means known in the art. It is known that systemic concentrations of corticosteroids can suppress the HPA axis.

[00073] In embodiments of the present invention, administration of the formulation may result in a clinically acceptable HPA suppression, particularly during the initial 14 days of therapy. In some embodiments of the present invention, administration of the

TCA/PLGA formulation will not result in any significant level of HPA suppression, including no detectable HPA suppression, particularly during the initial 14 days of therapy.

During the subsequent or sustained release period of the therapy, additional TCA may be released into the plasma. However, the plasma levels during this period will generally be less than those during the initial release period, if any TCA release occurs, and will not be associated with HPA axis suppression. Further, the adverse events associated with exogenous TCA administration, e.g., hyperglycemia, hypertension, altered mood, etc. will generally not be observed. Preferably, the number of clinical adverse events during this period will not substantially exceed the number achieved by an immediate release formulation alone or by KENALOG™ or its bioequivalent and will, preferably, be fewer than during the prior, initial release period of the therapy, if any TCA release occurs.

Alternatively, one can determine the suppression of the formulation on HPA by measuring endogenous Cortisol production. Thus, the formulation can be considered as avoiding clinically significant (or adverse) suppression of the HPA axis where the endogenous

Cortisol level is substantially the same in the steady state between a patient population receiving a therapeutically beneficial amount of an immediate release formulation and those receiving a therapeutically beneficial amount of a sustained release formulation. Such a formulation would be deemed to have a tolerable effect on the HPA axis. Alternatively or additionally, a small but measurable reduction in steady-state glucocorticoid production can result from the formulation during the sustained release period of the therapy with adequate preservation of the augmented, stress response needed during infection or trauma can be deemed a clinically insignificant suppression of the HPA axis. Endogenous glucocorticoid production may be assessed by administering various doses of adreno corticotropin hormone or by other tests known to those skilled in the art. Embodiments of the current invention provide for controlling the release of TCA, as may be desired, to achieve either no measurable effect on endogenous glucocorticoid production or a target, or a measurable effect that is, however, without adverse clinical consequence. In this regard, it has been found that intra-articular doses of TCA that suppress Cortisol production by 20-40%, e.g., by

20-35%, and sometimes more, provide very useful sustained anti-inflammatory and analgesic activity. These benefits are achieved without acute risks of hypoadrenalism and without excessive risks, after sustained intra-articular dosing, of developing an adrenal unresponsiveness in times of stress or of developing frank adrenal failure.

[00074] As shown further below, the studies presented herein have demonstrated that the HPA axis sensitivity appears to diminish with time, steroid, and dose.

[00075] "Patient" refers to a human diagnosed with a disease or condition that can be treated in accordance to the inventions described herein. In some embodiments it is contemplated that the formulations described herein may also be used in horses and other animals.

[00076] "Delivery" refers to any means used to place the drug into a patient. Such means may include without limitation, placing matrices into a patient that release the drug into a target area. One of ordinary skill in the art recognizes that the matrices may be delivered by a wide variety of methods, e.g., injection by a syringe, placement into a drill site, catheter or canula assembly, or forceful injection by a gun type apparatus or by placement into a surgical site in a patient during surgery.

[00077] The terms "treatment" and "treating" a patient refer to reducing, alleviating, stopping, blocking, delaying the progression, or preventing the symptoms of pain and/or inflammation in a patient. As used herein, "treatment" and "treating" includes partial alleviation of symptoms as well as complete alleviation of the symptoms for a time period. The time period can be hours, days, months, or even years.

[00078] By an "effective" amount or a "therapeutically effective amount" of a drug or pharmacologically active agent is meant a nontoxic but sufficient amount of the drug or agent to provide the desired effect, e.g., analgesia. An appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[00079] "Site of a patient's pain" refers to any area within a body causing pain, e.g., a knee joint with osteoarthritis, nerve root causing sciatic pain, nerve fibers growing into annular tears in discs causing back pain, temporomandibular joint (TMJ) pain, for example TMJ pain associated with temporomandibular joint disorder (TMD) or pain radiating from epidural or perineural spaces. The pain perceived by the patient may result from inflammatory responses, mechanical stimuli, chemical stimuli, thermal stimuli, as well as allodynia.

[00080] Additionally, the site of a patient's pain can comprise one or multiple sites in the spine, such as between the cervical, thoracic, or lumbar vertebrae, or can comprise one or multiple sites located within the immediate area of inflamed or injured joints such as the shoulder, hip, or other joints.

[00081] A "biocompatible" material refers to a material that is not toxic to the human body, it is not carcinogenic and it should induce limited or no inflammation in body tissues. A "biodegradable" material refers to a material that is degraded by bodily processes (e.g., enzymatic) to products readily disposable by the body or absorbed into body tissue. The biodegraded products should also be biocompatible with the body. In the context of intraarticular drug delivery systems for TCA and other corticosteroids, such polymers may be used to fabricate, without limitation: microparticles, micro-spheres, matrices, microparticle matrices, micro-sphere matrices, capsules, hydrogels, rods, wafers, pills, liposomes, fibers, pellets, or other appropriate pharmaceutical delivery compositions that a physician can administer into the joint. The biodegradable polymers degrade into non-toxic residues that the body easily removes or break down or dissolve slowly and are cleared from the body intact. The polymers may be cured ex-vivo forming a solid matrix that incorporates the drug for controlled release to an inflammatory region. Suitable biodegradable polymers may include, without limitation natural or synthetic biocompatible biodegradable material.

[00082] Descriptions of various embodiments of the invention are given below.

Although these embodiments are exemplified with reference to treat joint pain associated with osteoarthritis, rheumatoid arthritis and other joint disorders, it should not be inferred that the invention is only for these uses. Rather, it is contemplated that embodiments of the present invention will be useful for treating other forms of joint pain by administration into articular and periarticular spaces. In addition, it will be understood that for some embodiments injection near a joint may be equivalent to injections in that joint. Any and all uses of specific words and references are simply to detail different embodiments of the present invention.

[00083] Local administration of a TCA/PLGA microparticle formulation can occur, for example, by injection into the intra-articular space or peri-articular space at or near the site of a patient's pain and/or structural tissue damage. Local injection of the formulations described herein into articular or periarticular spaces may be useful in the treatment of, for example, juvenile rheumatoid arthritis, sciatica and other forms of radicular pain (e.g., arm, neck, lumbar, thorax), psoriatic arthritis, acute gouty arthritis, Morton's neuroma, acute and subacute bursitis, acute and subacute nonspecific tenosynovitis and epicondylitis, and ankylosing spondylitis.

[00084] In one embodiment, the TCA/PLGA microparticle formulations provided herein are useful in treating, alleviating a symptom of, ameliorating and/or delaying the progression of sciatica. In one embodiment, TCA PLGA microparticle formulations provided herein are useful in treating, alleviating a symptom of, ameliorating and/or delaying the progression of temporomandibular joint disorder (TMD).

[00085] Administration of a TCA/PLGA microparticle formulation to a patient suffering from an inflammatory disease such as osteoarthritis or rheumatoid arthritis, is considered successful if any of a variety of laboratory or clinical results is achieved. For example, administration of a TCA/PLGA microparticle formulation is considered successful if one or more of the symptoms associated with the disease is alleviated, reduced, inhibited or does not progress to a further, i.e., worse, state. Administration of a TCA/PLGA microparticle formulation is considered successful if the disease, e.g., an arthritic or other inflammatory disease, or any symptom thereof enters remission or does not progress to a further, i.e., worse, state.

[00086] Also, any and all alterations and further modifications of the invention, as would occur to one of ordinary skill in the art, are intended to be within the scope of the invention.

[00087] TCA and Drug Dosage

[00088] Triamcinolone acetonide (TCA) associated with embodiments of the present invention has the following basic structure:

[00089] For the present invention non- limiting examples of TCA may include triamcinolone acetonide and/or pharmaceutically acceptable salts thereof.

[00090] Embodiments of the invention include using sustained release TCA/PLGA microparticles delivered to treat pain at dosages that do not adversely suppress the HPA axis. Such amounts delivered locally to relieve pain due to inflammation, will provide a systemic concentration that does not have a measurable adverse effect on the HPA axis (differences if any are not significant because any such differences are within normal assay variability) or, as desired, may have a measurable but clinically insignificant effect on the HPA axis (basal Cortisol is suppressed to some measurable extent but stress responses are adequately preserved). Further embodiments of the invention may include doses during a second period of time selected to adjust for a change in sensitivity of the HPA axis to suppression following exposure during a first period of time to TCA.

[00091] In one preferred embodiment, a single component TCA/PLGA microparticle sustained release formulation releases a TCA dose (in mg/day) that suppresses the HPA axis by no more than between 5 - 40% at steady state, more preferably no more than between 10 - 35% at steady state. These doses are therapeutically effective without adverse side effects.

[00092] In another preferred embodiment, a single component TCA PLGA microparticle sustained release formulation releases a dose (in mg/day) that does not measurably suppress the HPA axis at steady state. These doses are therapeutically effective without adverse side effects.

[00093] Sustained Release Delivery Platforms

[00094] The manufacture of PLGA microparticles or methods of making

biodegradable polymer microparticles are known in the art. PLGA microparticles are commercially available from a number of sources and/or can be made by, but not limited to, spray drying, solvent evaporation, phase separation, fluidized bed coating or combinations thereof.

[00095] If not purchased from a supplier, then the biodegradable PLGA copolymers may be prepared by the procedure set forth in U.S. Pat. No. 4,293,539 (Ludwig, et al), the disclosure of which is hereby incorporated by reference in its entirety. Ludwig prepares such copolymers by condensation of lactic acid and glycolic acid in the presence of a readily removable polymerization catalyst (e.g., a strong acid ion-exchange resin such as Dowex HCR-W2-H). However, any suitable method known in the art of making the polymer can be used.

[00096] In the coacervation process, a suitable biodegradable polymer is dissolved in an organic solvent. Suitable organic solvents for the polymeric materials include, but are not limited to acetone, halogenated hydrocarbons such as chloroform and methylene chloride, aromatic hydrocarbons such as toluene, halogenated aromatic hydrocarbons such as chlorobenzene, and cyclic ethers such as dioxane. The organic solvent containing a suitable biodegradable polymer is then mixed with a non-solvent such as silicone based solvent. By mixing the miscible non -solvent in the organic solvent, the polymer precipitates out of solution in the form of liquid droplets. The liquid droplets are then mixed with another non- solvent, such as heptane or petroleum ether, to form the hardened microparticles. The microparticles are then collected and dried. Process parameters such as solvent and non- solvent selections, polymer/solvent ratio, temperatures, stirring speed and drying cycles are adjusted to achieve the desired particle size, surface smoothness, and narrow particle size distribution.

[00097] In the phase separation or phase inversion procedures entrap dispersed agents in the polymer to prepare microparticles. Phase separation is similar to coacervation of a biodegradable polymer. By addition of a nonsolvent such as petroleum ether, to the organic solvent containing a suitable biodegradable polymer, the polymer is precipitates from the organic solvent to form microparticles.

[00098] In the salting out process, a suitable biodegradable polymer is dissolved in an aqueous miscible organic solvent. Suitable water miscible organic solvents for the polymeric materials include, but are not limited to acetone, as acetone, acetonitrile, and tetrahydrofuran. The water miscible organic solvent containing a suitable biodegradable polymer is then mixed with an aqueous solution containing salt. Suitable salts include, but are not limited to electrolytes such as magnesium chloride, calcium chloride, or magnesium acetate and non-electrolytes such as sucrose. The polymer precipitates from the organic solvent to form microparticles, which are collected and dried. Process parameters such as solvent and salt selection, polymer/solvent ratio, temperatures, stirring speed and drying cycles are adjusted to achieve the desired particle size, surface smoothness, and narrow particle size distribution.

[00099] Alternatively, the microparticles may be prepared by the process of

Ramstack et al, 1995, described in published international patent application WO 95/13799, the disclosure of which is incorporated herein in its entirety. The Ramstack et al. process essentially provides for a first phase, including an active agent and a polymer, and a second phase, that are pumped through a static mixer into a quench liquid to form microparticles containing the active agent. The first and second phases can optionally be substantially immiscible and the second phase is preferably free from solvents for the polymer and the active agent and includes an aqueous solution of an emulsifier.

[000100] In the spray drying process, a suitable biodegradable polymer is dissolved in a suitable solvent and then sprayed through nozzles into a drying environment provided with sufficient elevated temperature and/or flowing air to effectively extract the solvent.

[000101] Alternatively, a suitable biodegradable polymer can be dissolved or dispersed in supercritical fluid, such as carbon dioxide. The polymer is either dissolved in a suitable organic solvent, such as methylene chloride, prior to mixing in a suitable supercritical fluid or directly mixed in the supercritical fluid and then sprayed through a nozzle. Process parameters such as spray rate, nozzle diameter, polymer/solvent ratio, and temperatures, are adjusted to achieve the desired particle size, surface smoothness, and narrow particle size distribution.

[000102] In a fluidized bed coating, the drug is dissolved in an organic solvent along with the polymer. The solution is then processed, e.g., through a Wurster air suspension coating apparatus to form the final microcapsule product.

[000103] The microparticles can be prepared in a size distribution range suitable for local infiltration or injection. The diameter and shape of the microparticles can be manipulated to modify the release characteristics. In addition, other particle shapes, such as, for example, cylindrical shapes, can also modify release rates of a sustained release

TCA/PLGA microparticle by virtue of the increased ratio of surface area to mass inherent to such alternative geometrical shapes, relative to a spherical shape. The microparticles have a volumetric mean diameter ranging between about 0.5 to 500 microns. In a preferred embodiment, the microparticles have a volumetric mean diameter of between 10 to about 100 microns.

[000104] Biodegradable polymer microparticles that deliver sustained release TCA may be suspended in suitable aqueous or non-aqueous carriers which may include, but is not limited to water, saline, pharmaceutically acceptable oils, low melting waxes, fats, lipids, liposomes and any other pharmaceutically acceptable substance that is lipophilic, substantially insoluble in water, and is biodegradable and/or eliminatable by natural processes of a patient's body. Oils of plants such as vegetables and seeds are included. Examples include oils made from corn, sesame, cannoli, soybean, castor, peanut, olive, arachis, maize, almond, flax, safflower, sunflower, rape, coconut, palm, babassu, and cottonseed oil; waxes such as carnoba wax, beeswax, and tallow; fats such as triglycerides, lipids such as fatty acids and esters, and liposomes such as red cell ghosts and phospholipid layers.

[000105] TCA Loading of and Release from Biodegradable PLGA Microparticles

[000106] When intra-articularly delivered TCA is incorporated into a PLGA biodegradable polymer for sustained release into a joint at a dosage that does not suppress the HPA axis, preferred loadings of the TCA are about 25% (w/w) of the microparticle.

[000107] As the biodegradable PLGA polymers undergo gradual bio-erosion within the joint, the TCA is released to the inflammatory site. The pharmacokinetic release profile of TCA by the biodegradable PLGA polymer may be first order, zero order, bi- or multiphasic, to provide desired treatment of inflammatory related pain. In any pharmacokinetic event, the bio-erosion of the polymer and subsequent release of TCA may result in a controlled release of TCA from the polymer matrix. The rate of release at dosages that do not suppress the HPA axis are described above.

[000108] Excipients

[000109] The release rate of TCA from a PLGA biodegradable polymer matrix can be modulated or stabilized by adding a pharmaceutically acceptable excipient to the formulation. An excipient may include any useful ingredient added to the biodegradable polymer depot that is not a corticosteroid or a biodegradable polymer. Pharmaceutically acceptable excipients may include without limitation lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, micro crystalline cellulose, PEG, polysorbate 20, polysorbate 80,

polyvinylpyrrolidone, cellulose, water, saline, syrup, methyl cellulose, and carboxymethyl cellulose. An excipient for modulating the release rate of TCA from the biodegradable PLGA drug depot may also include without limitation pore formers, pH modifiers, solubility enhancers, reducing agents, antioxidants, and free radical scavengers. [000110] Delivery of TCA/PLGA Microparticles

[000111] Parenteral administration of TCA/PLGA formulations of the invention can be effected by intra-articular injection or other injection using a needle. To inject the TCA/PLGA microparticles into a joint, needles having a gauge of about 14-28 gauge are suitable. It will be appreciated by those skilled in the art that TCA/PLGA formulations of the present invention may be delivered to a treatment site by other conventional methods, including catheters, infusion pumps, pens devices, injection guns and the like.

[000112] All references, patents, patent applications or other documents cited are hereby incorporated by reference.

EXAMPLES

[000113] The present invention is further defined in the following Examples. It should be understood that these Examples, while indicating preferred embodiments of the invention, are given by way of illustration only. From the above discussion and these Examples, one skilled in the art can ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various uses and conditions.

EXAMPLE 1: Sustained Release TCA Microparticles Prolong the Residency of Triamcinolone Acetonide in the Synovial Tissues of Patients with Knee Osteoarthritis

[000114] Intra-articular (IA) administration of triamcinolone acetonide injectable suspension (TCA IR) is commonly used to treat pain and inflammation associated with osteoarthritis (OA) of the knee. The TCA/PLGA microparticles used in this study are an extended-release IA formulation of TCA at a load dose of about 25% in 75:25 poly(lactic- co-glycolic acid) (PLGA) microspheres that is intended to deliver TCA to the synovial and peri-synovial tissues for a period of up to 3 months. The purposes of this study included the evaluation of safety and tolerability and the characterization of pharmacokinetics (PK) and pharmacodynamics (PD) of the TCA/PLGA microparticle formulations relative to TCA IR.

[000115] Methods: In this double blind, randomized, parallel group, active comparator study, 24 patients were randomized (1 : 1 : 1 : 1) to receive a single IA injection of 10 mg, 40 mg or 60 mg of the TCA/PLGA microparticle formulation or 40 mg of TCA IR. Each patient was followed for 6 weeks. Safety, PK and PD were evaluated during three in-patient periods and seven out-patient visits. This study is referred to herein as FX006-2011-002.

[000116] Results: As expected, injection of TCA IR produced high peak plasma concentrations within hours of administration, which dropped rapidly over the ensuing 7 days (Figure 1). IA administration of the TCA/PLGA microparticle formulation produced a distinctly different profile; peak concentrations were achieved approximately 24h after injection, remained constant over the 4 days post injection and thereafter declined slowly (Figures 1 and 2). The C_max associated with 40 mg TCA IR was nearly 30-fold that observed with 40 mg of the TCA/PLGA microparticle formulation, and the exposure over the first 24h (AUCo-24) was 21 -fold higher. The total exposure (AUC₀__∞) to TCA with 40 mg TCA IR was 2-fold greater than that achieved with 40 mg of the TCA/PLGA microparticle formulation.

[000117] Synovial fluid concentration measurements of (non-encapsulated) TCA demonstrated a 200 to 500-fold multiple over corresponding plasma levels for all doses of FX006 at Day 43.

[000118] Administration of 40 mg FX006 resulted in approximately 2000x more TCA in the joint when compared to TCA IR on Day 43 (82673 pg/mL / 38.6 pg/mL).

[000119] All treatments were well tolerated. There were no serious adverse events or discontinuations due to an adverse event (AE). The majority of AE's were mild and considered unrelated to study drug. Local knee-related AE's were also similar across treatments. Laboratory assessments, ECG's and vital signs were unremarkable and similar across all treatments.

[000120] The TCA/PLGA microparticle formulation maintains a gradient between synovial and systemic concentrations for the duration of this 6-week study. Even at the lowest dose of the TCA/PLGA microparticle formulation, synovial concentrations of TCA are consistent with biologic activity at 6 weeks; at this time point, the synovial

concentrations associated with the approved dose of TCA IR are below levels associated with biological activity. Relative to TCA IR, the TCA/PLGA microparticle formulation has the potential to provide prolonged suppression of the synovitis of OA, an effect that may prove beneficial to patients in the extension of symptomatic relief. EXAMPLE 2: Cumulative Cortisol Suppression following Intra-Articular

Administration of TCA/PLGA Microparticle Formulations or Commercially

Available Triamcinolone Acetonide Injectable Suspension

[000121] Cumulative Cortisol suppression (CCS%) on days 1, 14 and 42 following intra-articular injection of the TCA/PLGA microparticle formulations are described herein for a formulation of triamcinolone acetonide (TCA) designed to deliver therapeutically effective glucocorticoid concentrations to the synovial and peri-synovial tissues for 1 to 3 months. Pharmacokinetic data from a study in patients with osteoarthritis of the knee showed that the new sustained release product greatly reduced the magnitude of peak plasma TCA concentrations compared to the currently available TCA immediate release (TCA-IR) injectable suspension product. To assess systemic glucocorticoid activity, serial serum Cortisol levels were measured before treatment, immediately following injection and at 2 and 6 weeks following injection. Endogenous Cortisol secretion shows diurnal fluctuation and serial serum Cortisol profiles collected over 24-h are generally considered reliable and sensitive measures of exogenous systemic corticosteroid activity (Derendorf, H., et al, Optimized therapeutic ratio of inhaled corticosteroids using retrometabolism. Die Pharmazie, 2000. 55(3): p. 223-7). CCS% values were calculated from serial serum Cortisol profiles as a surrogate marker to quantify and compare overall systemic corticosteroid effects with other corticosteroid products (Meibohm, B., et al, A

pharmacokinetic/pharmacodynamic approach to predict the cumulative Cortisol suppression of inhaled corticosteroids. Journal of pharmacokinetics and biopharmaceutics, 1999. 27(2): p. 127-47).

[000122] Individual serum Cortisol concentrations from 24 patients with osteoarthritis of the knee were provided from clinical studies described above in Example 1. In these studies, patients received a single intra-articular injection of TCA PLGA microparticle formulation at doses of 10 mg (n=5), 40 mg (n=7) or 60 mg (n=7) or TCA-IR (n=5) and serum Cortisol profiles were obtained beginning 24 h before treatment (Day -1), 0 to 24 h after treatment (Day 1) and on Day 14 and Day 42 after treatment. Samples for serum Cortisol were obtained at 0, 1, 2, 4, 6, 8, 12, and 24 h beginning at approximately 8:00 am each day of sampling.

[000123] CCS% is based on the difference between the area under the curve for Cortisol measured at baseline (AUC^CORBaseiine) and area under the curve for Cortisol measured after corticosteroid exposure (AUC Treatment). AUC was calculated using the trapezoid rule for each 24 h sampling period. For patients where zero timepoints were not available for baseline profiles, AUC was calculated from 1 to 24 hours for all sample days. The following equation was used to calculate CCS% (Xu, J., et al, Assessment of the impact of dosing time on the pharmacokinetics/pharmacodynamics of prednisolone. The AAPS journal, 2008. 10(2): p. 331-41):

AUC -,COR

ccs% = BASELINE - AUC •COR

TREATMENT

A TjrCOR * 100%

SI U U BnASELINE

[000124] Median CCS% values followed the expected dose and time dependent pattern as shown in Table 1.

Table 1. Median CCS% for groups of 4-7 subjects calculated from 24 h serum Cortisol profiles on days 1, 14 and 42 following intra-articular injection with FX006 at 3 dose levels or 40 mg TCA-IR. The range of CCS% values for each group is also listed.

[000125] The largest median CCS% values were confirmed on Day 1 for all treatment groups with the highest overall value identified for reference TCA-IR 40 mg dose group. Cortisol suppression was less than 40% of baseline for all treatments at day 14. Cortisol suppression was less than 20%> of baseline for all groups on Day 42. Median CCS%> values on Days 1 and 14 increased with increasing dose of TCA/PLGA microparticle. On Day 42, there was no apparent dose related effect on CCS%, which is consistent with low and variable values.

[000126] Calculated CCS%> values varied considerably within dosing groups for each day, which is reflected in the wide range of values listed in Table 1. Consequently, corresponding calculated CV% were large with values of 43 to 350% for groups with 4 to 7 subjects. The terms subject and patient are used interchangeably throughout.

[000127] Although CCS%> values were accompanied with considerable variability within each Day for all four treatment groups, median values showed the expected pattern of increase for increasing TCA/PLGA microparticle dose that decreased with time. These data support a dose-related increase in corticosteroid activity after TCA PLGA

microparticle. It should be noted that pharmacokinetic parameters for triamcinolone were also associated with considerable variability within each treatment group. CV% values for pharmacokinetic parameters most often exceeded 40% and exceeded 100% in several cases.

[000128] For purposes of comparison and interpretation, published CCS%> values are listed in Table 2 for several marketed corticosteroid products formulated for systemic or local (inhaled) drug delivery. Table 2 shows increasing CCS%> with increasing dose of all products. Essentially complete suppression of Cortisol secretion is associated with high oral methylprednisolone doses.

Table 2. Reported CCS%> values calculated from clinical studies after single and multiple dosing with oral, intravenous (iv) or inhaled commercially available corticosteroid products

Flunisolide inhaled 1.0 11-26 Meibohm 1997

Fluticasone propionate inhaled 0.5 24-26 Meibohm 1997

Fluticasone propionate inhaled 1.0 25-40 Rohatagi 1996

Methylpredniso lone Oral (BID) 1 53.3 Meibohm 1999

Methylpredniso lone Oral (BID) 2 67.6 Meibohm 1999

Methylpredniso lone Oral (BID) 5 82.6 Meibohm 1999

Methylpredniso lone Oral (BID) 10 90.0 Meibohm 1999

TCA inhaled (QID) 0.2 20.7 Meibohm 1999

TCA inhaled (QID) 0.4 34.1 Meibohm 1999

TCA inhaled (BID) 1 33.1 Meibohm 1999

* single dose unless noted as BID (twice daily), QID (4 times daily)

Xu 2008: Xu, J., et al, Assessment of the impact of dosing time on the

pharmacokinetics/ pharmacodynamics of prednisolone. The AAPS journal, 2008. 10(2): p. 331-41

Meibohm 1997: Meibohm, B., et al, Dependency of Cortisol suppression on the administration time of inhaled corticosteroids. Journal of clinical pharmacology, 1997. 37(8): p. 704-10

Rohatagi 1996: Rohatagi, S., et al, Dynamic modeling of Cortisol reduction after inhaled administration of fluticasone propionate. Journal of clinical pharmacology, 1996. 36(10): p. 938-41

Meibohm 1999: Meibohm, B., et al, A pharmacokinetic/pharmacodynamic approach to predict the cumulative Cortisol suppression of inhaled corticosteroids. Journal of pharmacokinetics and biopharmaceutics, 1999. 27(2): p. 127-47.

[000129] On Day 1, both the 60 mg dose of the TCA/PLGA microparticle formulation and Inter-articular delivery of 40 mg of Triamcinolone are transiently associated with Cortisol suppression of approximately 60%. The 40 mg of TCA IR is known to induce transient hyperglycemia in diabetics and cause transient increases in blood pressure in hypertensive patients. The 60 mg dose of the microparticle formulation is likely to produce similar transient effects. The 10 mg dose of the TCA/PLGA the microparticle formulation produces a %CCS of 18.8% on Day 1 and is likely to have a superior systemic safety profile to that of 40 mg of TCA IR in the days following injection. The CCS% of 40 mg of the TCA/PLGA the microparticle formulation on day is 43.3% and likely will have an advantaged safety profile relative to 40 mg TCA IR but the definitive characterization of the transient effects on glycemic control blood pressure will require further study.

[000130] Inhaled steroids, such as Fluticasone propionate have benign safety profiles in adults and are associated with a suppression of the HPA axis of 40%> or less (Derendorf, FL, et al, Bioavailability and disposition of azelastine and fluticasone propionate when delivered by MP29-02, a novel aqueous nasal spray. British journal of clinical

pharmacology, 2012. 74(1): p. 125-33). At week 2, the CCS% for all doses of the microparticle formulation is below 40%, and it is expected that at two weeks post injection, the effects of all doses of the microparticle formulation on the HPA axis will not be of clinical consequence in patients with HPA function that is otherwise intact.

[000131] At Week 6, CCS% for all treatments are near baseline and it is reasonable to conclude that administration of 10, 40, and 60 mg of the microparticle formulation is without clinical relevant effect at 6 weeks on the HPA axis in adults with otherwise intact HPA axis function.

[000132] Those of ordinary skill in the art will appreciate that there are several ways to calculate Cortisol suppression, for example, by determining the median % of CCS as described above or by determining the change from baseline in weighted mean of serum Cortisol levels. The Least Squares (LS) means are back transformed to obtain the ratio of on treatment response to baseline and then converted to percentage change from baseline as (ratio ¹ )x 100% within each treatment group.

Table 3. % Change from Baseline - Weighted mean serum Cortisol (LS Means)

EXAMPLE 3: Dose Ranging Study of TCA/PLGA Microparticle Formulations

[000133] The studies described herein were a double-blind, randomized, parallel group, dose-ranging study (n = up to 224 patients with confirmed knee osteoarthritis) comparing TCA/PLGA microparticle to a commercially available triamcinolone acetonide injectable suspension in patients with osteoarthritis of the knee. In these studies, the TCA PLGA microparticle formulation was administered at a dose selected from 10 mg single intra-articular (IA) injection, 40 mg single IA injection, and 60 mg single IA injection, while the commercially available TCA was administered at40 mg single IA dose.

[000134] Each patient was evaluated for a total of 12 weeks following a single IA injection. Following screening, safety and efficacy and PK was evaluated at 7 out-patient visits (Days 1 [Baseline], 2, 8, 15, 29, 57 and 85). Analgesic effect was assessed using weekly average of daily (24 hour) pain intensity score, Western Ontario & McMaster University Osteoarthritis Index (WO MAC®, available on the WO MAC website) and patient and clinical global impression of change.

[000135] The following data were collected and measured for each patient:

Primary endpoint:

• Change from Baseline ("Δ from BS") to each of Weeks 8, 10 and 12 in

weekly mean of the average daily (24-hour) pain intensity score, also referred to herein as Average Daily Pain Score (ADPS), analyzed by longitudinal mixed effects model (LMEM).

Secondary endpoints:

• Incidence of treatment emergent adverse events through 12 weeks

• Change from Baseline to each of Weeks 1, 2, 3, 4, 5, 6, 7, 9 and 11 in weekly mean of the average (24-hour) pain intensity score through 12, analyzed by LMEM

• Time of onset of pain relief, weekly through 12 weeks as indicated by a first daily pain score showing greater than 30% improvement from weekly ADPS at baseline, analyzed by Kaplan-Meier and log rank test

• Continuous responder at each study week, weekly through 12 weeks, where responders are based on ADPS at a given week, analyzed by logistic regression: • > 30% improvement from baseline ADPS;

• > 20% improvement from baseline ADPS;

• > 50% improvement from baseline ADPS

• WO MAC A (pain subscale) change from Baseline at 1, 2, 4, 8 and 12 weeks, analyzed by LMEM

• WO MAC B (stiffness subscale) change from Baseline at 1, 2, 4, 8 and 12 weeks, analyzed by LMEM

• WO MAC C (function subscale) change from Baseline at 1, 2, 4, 8 and 12 weeks, analyzed by LMEM

• WO MAC (total) change from Baseline at 1, 2, 4, 8 and 12 weeks, analyzed by LMEM

• Percent of responders (defined as patients with high improvement in pain or function) according to OMERACT-OARSI (available on the Osteoarthritis Research Society International website) criteria at 1, 2, 4, 8 and 12 weeks, analyzed by logistic regression

• Change in patient's and clinical observer's global impression of change

scores at 1, 2, 4, 8 and 12 weeks, analyzed by LMEM

• Average weekly and total consumption of rescue medications, weekly

through 12 weeks, analyzed by LMEM

• Pharmacokinetic profile through 12 weeks

• WO MAC Al (pain on walking question) change from Baseline at 1, 2, 4, 8 and 12 weeks, analyzed by LMEM

[000136] The primary endpoint for these studies will be a decrease in pain at 8, 10 and 12 weeks. No safety concerns have been identified in these studies, and the two serious adverse events (AE's) that have been reported were both unrelated to the drug study.

EXAMPLE 4: Single Injection Study Comparing TCA/PLGA Microparticle

Formulations and Immediate Release TCA Formulations

[000137] A single injection study of 3 different TCA doses of FX006 (10 mg, 40 mg and 60 mg of sustained release TCA microparticle formulation) compared with the currently approved and marketed dose of immediate release TCA (40 mg) (TCA IR) was performed in patients with moderate to severe osteoarthritis (OA) pain (n = 228 for patients who receive TCA IR or TCA/PLGA microparticles, have a baseline pain level and at least one post-dose pain evaluation). A baseline pain level was calculated by averaging the pain level of a patient for the 7 days prior to administration of the TCA/PLGA microparticle formulations (10 mg, 40 mg, or 60 mg) or 40 mg TCA IR formulation. The objective of the study was to identify a safe and well tolerated dose of FX006 which demonstrated superiority to immediate release TCA in magnitude and duration of pain relief over 12 weeks.

[000138] As shown in Figure 4, the 40 mg dose of FX006 provided clinically meaningful and statistically significant improvement over TCA IR beginning at week 5. Pre-specified secondary endpoints that measured function, responder status and rescue medicine consumption also supported 40 mg as the optimal dose. As seen in Figure 4, the pain relief provided by the 40 mg TCA IR formulation peaked at week 4 and diminished through week 12. In contrast, the 40 mg TCA PLGA microparticle formulation exhibited an ongoing amplification of pain relief through week 7. Moreover, the 40 mg TCA/PLGA microparticle formulation provided a statistically significant improvement in pain relief, as compared to the 40 mg TCA IR formulation, at weeks 5, 6, 7, 8, 9 and 10.

[000139] As shown in Figure 5, the time to onset of pain relief in patients, indicated by greater than 30% pain relief in a patient, is similar for all TCA/PLGA microparticle formulations (e.g., 10 mg, 40 mg, and 60 mg) and for the 40 mg TCA IR formulation. Onset of pain relief is largely independent of dose and/or formulation of TCA that is administered. Figure 5 demonstrates the unexpected effect that the TCA/PLGA microparticles, which have much lower concentrations, e.g., plasma and/or systemic concentrations, of TCA than the 40 mg TCA IR formulation, are able to achieve substantially similar results in the onset of pain relief.

[000140] As shown in Figure 6, the percentage of patients with an improvement in pain relief over the baseline level of pain, as measured at week 8, was consistently larger for the TCA/PLGA microparticle formulations (10 mg, 40 mg, and 60 mg) as compared to the TCA IR formulation.

[000141] Figures 7 and 8 demonstrate that the 10 mg TCA/PLGA microparticle formulation and the 40 mg TCA/PLGA microparticle formulation provide a statistically significant improvement in pain as measured by the WOMAC A scale (Fig. 7) and a statistically significant improvement in joint function as measured by the WOMAC C scale

(Fig 8.) as compared to the 40 mg TCA IR formulation. [000142] Figure 9 demonstrates that by week 8, all TCA/PLGA microparticle formulations (10 mg, 40 mg, and 60 mg) consistently outperformed the 40 mg TCA IR formulation in the proportion of OMERACT-OARSI responders. The 10 mg TCA/PLGA microparticle formulation and the 40 mg TCA PLGA microparticle formulation provide a statistically significant improvement in the percentage of responders as compared to the 40 mg TCA IR formulation.

[000143] Figures 10 and 11 demonstrate that at week 8, the 10 mg TCA/PLGA microparticle formulation and the 40 mg TCA/PLGA microparticle formulation provide a statistically significant improvement in the patient global impression of change (Fig. 10) and in clinical observer's global impression of change (Fig. 11) as compared to the 40 mg TCA IR formulation.

[000144] Figure 12 demonstrates that for most weeks, patients who received the TCA/PLGA microparticle formulations (10 mg, 40 mg, and 60 mg) used fewer tablets of rescue medication than the patients who received the 40 mg TCA IR formulation.

[000145] Figure 13 indicates that the unexpected properties of the TCA/PLGA microparticle formulations (10 mg, 40 mg and 60 mg), e.g., those shown in Figures 4-12, could not have been predicted based on the pharmacokinetic analysis and comparison of the TCA/PLGA microparticle formulations (10 mg, 40 mg and 60 mg) and the 40 mg TCA IR formulation in this study, referred to as FX006-2011-001, and in the FX006-2011-002 study shown in Figure 1.

[000146] Although particular embodiments have been disclosed herein in detail, this has been done by way of example for purposes of illustration only, and is not intended to be limiting with respect to the scope of the appended claims, which follow. In particular, it is contemplated by the inventors that various substitutions, alterations, and modifications may be made to the invention without departing from the spirit and scope of the invention as defined by the claims. Other aspects, advantages, and modifications are considered to be within the scope of the following claims. The claims presented are representative of the inventions disclosed herein. Other, unclaimed inventions are also contemplated. Applicants reserve the right to pursue such inventions in later claims.

Claims

What is claimed is:

1. A population of microparticles comprising triamcinolone acetonide (TCA) or a pharmaceutically acceptable salt thereof incorporated in a poly(lactic-co-glycolic) acid (PLGA) copolymer matrix, wherein the TCA comprises about 25% of the microparticles.

2. A population of microparticles comprising triamcinolone acetonide (TCA) or a pharmaceutically acceptable salt thereof incorporated in a poly(lactic-co-glycolic) acid (PLGA) copolymer matrix, wherein the TCA comprises about 25% of the microparticles and wherein the TCA dose is in a range of about 30 mg to about 50 mg.

3. A controlled or sustained release preparation of triamcinolone acetonide (TCA) comprising a poly(lactic-co-glycolic) acid (PLGA) copolymer microparticle containing the TCA, wherein the TCA comprises about 25% of the PLGA copolymer microparticle matrix.

4. A controlled or sustained release preparation of triamcinolone acetonide (TCA) comprising a poly(lactic-co-glycolic) acid (PLGA) copolymer microparticle containing the TCA, wherein the TCA comprises about 25% of the PLGA copolymer microparticle matrix and wherein the TCA dose is in a range of about 30 mg to about 50 mg.

5. A formulation comprising (a) controlled- or sustained- release microparticles comprising triamcinolone acetonide (TCA) and poly(lactic-co-glycolic) acid (PLGA) copolymer matrix, wherein the TCA comprises about 25% of the microparticles, wherein the microparticles have a mean volumetric particle size in the range of about 29 to about 75 μΜ, and wherein the PLGA copolymer has one of more of the following characteristics: (i) a molecular weight in the range of about 50 to 54 kDa; (ii) an inherent viscosity in the range of 0.4 to 0.46 dL/g; or (iii) a lactide:glycolide molar ratio of 75:25.

6. A formulation comprising (a) controlled- or sustained- release microparticles comprising triamcinolone acetonide (TCA) and poly(lactic-co-glycolic) acid (PLGA) copolymer matrix, wherein the TCA comprises about 25% of the microparticles is in a range of about 30 mg to about 50 mg, wherein the microparticles have a mean volumetric particle size in the range of about 29 to about 75 μΜ , and wherein the PLGA copolymer has one of more of the following characteristics: (i) a molecular weight in the range of about 50 to 54 kDa; (ii) an inherent viscosity in the range of 0.4 to 0.46 dL/g; or (iii) a

lactide:glycolide molar ratio of 75:25.

7. The population of claim 1 or claim 2, the preparation of claim 3 or claim 4, or the formulation of claim 5 or claim 6, wherein the PLGA is biodegradable.

8. The population of claim 1 or claim 2, the preparation of claim 3 or claim 4, or the formulation of claim 5 or claim 6, wherein the TCA is released for between 14 days and 90 days.

9. The population of claim 1 or claim 2, the preparation of claim 3 or claim 4, or the formulation of claim 5 or claim 6, wherein the PLGA copolymer comprises an ester endcap.

10. The population of claim 1 or claim 2, the preparation of claim 3 or claim 4, or the formulation of claim 5 or claim 6, wherein the TCA dose is about 40 mg.

11 A method of treating pain or inflammation in a patient comprising administering to said patient a therapeutically effective amount of the population of claim 1 or claim 2, the preparation of claim 3 or claim 4, or the formulation of claim 5 or claim 6.

12. A method of treating pain or inflammation in a patient comprising administering to said patient a therapeutically effective amount of the population of claim 1 or claim 2, the preparation of claim 3 or claim 4, or the formulation of claim 5 or claim 6, wherein the population, the preparation or the formulation releases TCA for at least 14 days at a rate that does not adversely suppress the hypothalamic-pituitary-adrenal axis (HPA axis).

13. 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 population of claim 1 or claim 2, the preparation of claim 3 or claim 4, or the formulation of claim 5 or claim 6.

14. 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 population of claim 1 or claim 2, the preparation of claim 3 or claim 4, or the formulation of claim 5 or claim 6, wherein the population, the preparation or the formulation releases TCA for at least 14 days at a rate that does not adversely suppress the hypothalamic-pituitary-adrenal axis (HPA axis).

15. A method of slowing, arresting, reversing loss of or improving joint function in a patient with chronic inflammatory disease comprising administering to said patient a therapeutically effective amount of the population of claim 1 or claim 2, the preparation of claim 3 or claim 4, or the formulation of claim 5 or claim 6.

16. The method of any one of claims 11 to 15, wherein the population, the preparation or the formulation is administered as one or more injections.

17. The method of claim 16, wherein the injection is one or more local injections at a site of pain.

18. The method of claim 16, wherein the injection is one or more intra-articular or periarticular injections.

19. The method of any one of claims 11 to 18, wherein the patient has osteoarthritis, rheumatoid arthritis, acute gouty arthritis, and/or synovitis.

20. The method of any one of claims 11 to 18, wherein the population, the preparation or the formulation comprises a TCA dose in of about 40 mg.