Liposomal composition of intra-articular corticosteroid for pain control

Abstract

A method for treating joint pain in an individual chronically afflicted with osteoarthritis, the method comprising administering to the osteoarthritis individual repeat doses of a liposomal composition comprising an effective amount of an intra-articular corticosteroid or a pharmaceutically acceptable salt thereof, in an intra-articular administration manner. A robust and long-lasting intra-articular corticosteroid treatment efficacy response is achieved for more than one year, without any signs or symptoms of adrenal insufficiency in the individual.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480070561.0 (22) Application Date 2024.11.01 (30) Priority Data 63 / 547,217 2023.11.03 US 63 / 633,336 2024.04.12 US (85) PCT International Application Entering National Phase Date 2026.05.06 (86) PCT International Application Application Data PCT / US2024 / 054126 2024.11.01 (87) PCT International Application Publication Data WO2025 / 096949 EN 2025.05.08 (71) Applicant Taiwan Liposome Co., Ltd. Address 11F-1, No. 3, Yuanqu Street, Nangang District, Taipei City, Taiwan Applicant: TLC Biopharmaceuticals, Inc. (72) Inventors: Shi Xuefang, Dai Tianci, Gao Kailin, Huang Xiaoning, George Spencer-Green (74) Patent Agency: Shanghai Patent & Trademark Agency Co., Ltd. 31100 Patent Attorney: Tao Qichang (51) Int.Cl. A61K 31 / 56 (2006.01) A61K 31 / 57 (2006.01) A61K 47 / 28 (2006.01) A61K 47 / 06 (2006.01) (54) Invention Title: Liposome Composition of Intra-articular Corticosteroid for Pain Control (57) Abstract: A method for treating joint pain in an individual suffering from chronic osteoarthritis, the method comprising administering repeated doses of a liposome composition to the individual in an intra-articular manner, the liposome composition comprising an effective amount of an intra-articular corticosteroid or a pharmaceutically acceptable salt thereof. Achieving a robust and long-lasting response to intra-articular corticosteroid treatment for over a year, with the individual showing no signs or symptoms of adrenal insufficiency. Claims 2 pages, Description 20 pages, Drawings 6 pages. CN 122349429 A 2026.07.07 CN 1 22 34 94 29 A 1. A method for treating joint pain in a human individual with long-term osteoarthritis, comprising repeatedly administering, intra-articularly, doses of a liposomal composition to the human individual, each dose comprising an effective amount of an intra-articular corticosteroid or a pharmaceutically acceptable salt thereof, and a lipid mixture, wherein the repeated doses of the liposomal composition do not induce signs and / or symptoms of adrenal insufficiency in the human individual. 2. The method of claim 1.The liposome composition was administered at repeated doses at intervals selected from the following groups: 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, and 36 weeks. 3. The method of claim 1, wherein the intra-articular corticosteroid or a pharmaceutically acceptable salt thereof is released during a period selected from the group consisting of: weeks 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, and 80. 4. The method of claim 1, wherein the intra-articular corticosteroid or a pharmaceutically acceptable salt thereof is released at a rate that does not adversely inhibit the hypothalamic-pituitary-adrenal (HPA) axis. 5. The method of claim 1, wherein the intra-articular corticosteroid or a pharmaceutically acceptable salt thereof is released at a rate that does not adversely inhibit the cortisol levels of the human individual. 6. The method of claim 1, wherein the intra-articular corticosteroid or a pharmaceutically acceptable salt thereof is selected from the group consisting of: dexamethasone sodium phosphate, dexamethasone, betamethasone, betamethasone sodium phosphate, betamethasone acetate, betamethasone dipropionate, betamethasone valerate, mometasone furoate, triamcinolone, hexamethasone diacetate, triamcinolone diacetate, methylprednisolone sodium succinate, methylprednisolone acetate, hydrocortisone butyrate, hydrocortisone acetate, aclomethasone dipropionate, halcinonide, fluocinolone, fluocinolone acetonide, and combinations thereof. 7. The method of claim 1, wherein the intra-articular corticosteroid is dexamethasone sodium phosphate (DSP) and has an effective amount of about 6 mg to 18 mg. 8. The method of claim 7, wherein the effective amount of DSP is about 12 mg. 9. The method of claim 1, wherein the lipid mixture comprises dioleoylphosphatidylcholine (DOPC) and dioleoylphosphatidylglycerol (DOPG). 10. The method of claim 9, wherein, based on the total amount of the lipid mixture, the lipid mixture further comprises about 10 to 33 mol% cholesterol. 11. The method of claim 1,The osteoarthritis mentioned therein is knee osteoarthritis. 12. A dosing regimen for the long-term treatment of joint pain, comprising: repeated doses of a liposomal composition administered intra-articularly to the joint of a patient with osteoarthritis, each dose comprising an effective amount of an intra-articular corticosteroid and a lipid mixture, wherein the dosing regimen does not induce signs and / or symptoms of adrenal insufficiency in the patient with osteoarthritis. 13. The dosing regimen of claim 12, wherein repeated doses of the liposome composition are administered at dosing intervals selected from the group consisting of: 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, and 36 weeks. 14. The dosing regimen of claim 12, wherein the intra-articular corticosteroid or a pharmaceutically acceptable salt thereof (see claim 1 / 2 page 2 CN 122349429 A) is released during a period selected from the group consisting of: 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, and 80 weeks. 15. The dosing regimen of claim 12, wherein the intra-articular corticosteroid or a pharmaceutically acceptable salt thereof is released at a rate that does not adversely inhibit the hypothalamic-pituitary-adrenal (HPA) axis. 16. The dosing regimen of claim 12, wherein the intra-articular corticosteroid or a pharmaceutically acceptable salt thereof is released at a rate that does not adversely inhibit the cortisol levels of the individual human. 17. The dosing regimen of claim 12, wherein the intra-articular corticosteroid or a pharmaceutically acceptable salt thereof is selected from the group consisting of: dexamethasone sodium phosphate, dexamethasone, betamethasone, betamethasone sodium phosphate, betamethasone acetate, betamethasone dipropionate, betamethasone valerate, mometasone furoate, triamcinolone acetonide, hexamethylenetetramine, triamcinolone diacetate, methylprednisolone sodium succinate, methylprednisolone acetate, hydrocortisone butyrate, hydrocortisone acetate, aclomethasone dipropionate, halcinonide, fluocinolone, fluocinolone acetonide, and combinations thereof. 18. The dosing regimen of claim 12, wherein the intra-articular corticosteroid is dexamethasone sodium phosphate (DSP).And has an effective amount of about 6 mg to 18 mg. 19. The dosing regimen of claim 18, wherein the effective amount of DSP is about 12 mg. 20. The dosing regimen of claim 12, wherein the lipid mixture comprises dioleoylphosphatidylcholine (DOPC) and dioleoylphosphatidylglycerol (DOPG). 21. The dosing regimen of claim 20, wherein, based on the total amount of the lipid mixture, the lipid mixture further comprises about 10 to 33 mol% cholesterol. 22. The dosing regimen of claim 12, wherein the osteoarthritis patient is a patient with knee osteoarthritis. Claims 2 / 2 Page 3 CN 122349429 A Liposome Composition of Intra-articular Corticosteroids for Pain Control

[0001] Cross-Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 547,217, filed November 3, 2023, and U.S. Provisional Application No. 63 / 633,336, filed April 12, 2024, the entire disclosure of which is incorporated herein by reference. Technical Field

[0003] This disclosure relates to a method for treating chronic pain or inflammation using a lipid-based delivery system to deliver a therapeutic agent to a patient with osteoarthritis. This disclosure also relates to a dosing regimen for administering a liposome composition to an osteoarthritis patient requiring chronic joint pain treatment. Background Art

[0004] Osteoarthritis (OA) is a common degenerative joint disease of articular cartilage associated with hypertrophic bone changes. Treatment of osteoarthritis (OA) primarily involves a combination of nonpharmacological treatments, including exercise and lifestyle modifications; pharmacological treatments (e.g., nonsteroidal anti-inflammatory drugs, intra-articular corticosteroids); glucosamine or chondroitin sulfate supplementation; and joint replacement surgery.

[0005] Intra-articular (IA) corticosteroid injections are an existing treatment recommendation for individuals with osteoarthritis (OA) according to the 2019 Osteoarthritis Research Society International (OARSI) guidelines (Bannuru RR et al., Osteoarthritis and Cartilage, 2019; 27(11): 1578-1589). Although intra-articular corticosteroid injections are known to relieve osteoarthritis-related pain, reduce inflammation, and improve mobility, their average duration of benefit is usually short.It can only last for 2 to 4 weeks (Jüni P. et al. Cochrane Database Syst Rev. 2015; (10) Art. No.: CD005328). Considering that osteoarthritis is a chronic and usually progressive disease that leads to joint incapacitation and long-term pain, patients almost always need to receive long-term treatment with multiple doses to maintain their quality of life.

[0006] Repeated injections can be made in the same joint, but there is limited data on the safety and duration of effectiveness of this procedure. It has been reported that repeated injections of corticosteroids (especially long-term injections) may increase the risk of local and systemic side effects, including pericapsular calcification, tendon rupture, skin atrophy / discoloration, steroid arthropathy, joint infection, facial flushing, allergies, and hyperglycemia. For example, chronic use of corticosteroids may lead to suppression of the hypothalamic-pituitary-adrenal axis (HPA axis) through negative feedback, which may further lead to secondary adrenal insufficiency. Therefore, the general practice is to use IA corticosteroids no more than once every 3 months; however, this may lead to intermittent treatment effects between IA injections and worsen arthritis symptoms.

[0007] Although sustained-release, lipid-based formulations of dexamethasone sodium phosphate (DSP) have been used for IA injections in the treatment of pain caused by knee osteoarthritis (international publication number WO2020 / 056399 A1), considering the potential risks associated with repeated dosing, there remains an unmet need for robustness of efficacy response to IA corticosteroid injections in long-term treatment while minimizing or reducing side effects.

[0008] According to some embodiments, this disclosure provides a method for treating joint pain in a human individual suffering from chronic osteoarthritis, comprising administering repeated doses of a liposomal composition to the human individual via intra-articular injection, each dose comprising an effective amount of an intra-articular corticosteroid (IACS) or a pharmaceutically acceptable salt thereof, and a lipid mixture, wherein the repeated doses of the liposomal composition do not cause signs and / or symptoms of adrenal insufficiency in the human individual.

[0009] In some embodiments, a dosing regimen for treating chronic joint pain is provided, comprising administering repeated doses of a liposomal composition to the joint of a patient with osteoarthritis via intra-articular injection, each dose comprising an effective amount of an intra-articular corticosteroid and a lipid mixture.The aforementioned dosing regimen does not induce signs and / or symptoms of adrenal insufficiency in the osteoarthritis patients.

[0010] In some embodiments, a method for treating joint pain in a patient with long-term osteoarthritis is provided, comprising administering repeated doses of intra-articular corticosteroids to the osteoarthritis patient via intra-articular administration, wherein at least one dose of the intra-articular corticosteroid is prepared in liposome form, or in a liposomal composition containing an intra-articular corticosteroid or a pharmaceutically acceptable mixture of its salts and lipids, and the effective amount of the intra-articular corticosteroid in the liposomal composition is from about 6 mg to about 18 mg.

[0011] In some embodiments, the repeated dose may be administered at intervals consisting of the following groups: 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, and 36 weeks.

[0012] In some embodiments, the repeated intra-articular administration of intra-articular corticosteroids is released during periods selected from the group consisting of: weeks 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, and 80.

[0013] In some embodiments, the osteoarthritis is graded as Kellgren-Lawrence grade 2 or 3. In some embodiments, the severity of osteoarthritis is assessed based on the presence of multiple osteophytes observed within the joints of the individual, using radiography or magnetic resonance imaging of the joints.

[0014] In some embodiments, the individual is female. In some embodiments, the individual is between 50 and 65 years of age, or 65 years of age or older. In other embodiments, the individual has a body mass index (BMI) greater than 30, approximately 30, or not less than 30.

[0015] In some embodiments, the individual suffers from unilateral or bilateral osteoarthritis. In some embodiments, the joint pain is knee pain.

[0016] In some embodiments,The average daily pain (ADP) score of the human individuals is 5 to 9.

[0017] In some embodiments, the intra-articular corticosteroid or a pharmaceutically acceptable salt thereof is released at a rate that does not adversely inhibit the hypothalamic-pituitary-adrenal (HPA) axis. In other embodiments, the intra-articular corticosteroid or a pharmaceutically acceptable salt thereof is released at a rate that does not adversely inhibit cortisol levels in the human individual. In other embodiments, the intra-articular corticosteroid or a pharmaceutically acceptable salt thereof is released at a rate that does not induce adrenal insufficiency in the human individual.

[0018] In some embodiments, the liposome composition comprises: (a) a lipid mixture comprising one or more phospholipids; and (b) an intra-articular corticosteroid or a pharmaceutically acceptable salt thereof. An exemplary intra-articular corticosteroid according to this disclosure is dexamethasone sodium phosphate (DSP). An exemplary lipid mixture comprises dioleoylphosphatidylic choline (DOPC) and dioleoylphosphatidylic glycerol (DOPG).

[0019] In some embodiments, the intra-articular corticosteroid content in the liposome composition is from about 6 mg to about 18 mg, or about 12 mg. In other embodiments, the intra-articular corticosteroid content is from about 6 mg to about 18 mg, or about 12 mg per milliliter of the liposome composition.

[0020] In some embodiments, the individual has knee osteoarthritis assessed as grade 2 or 3 on the Kellgren-Lawrence scale. The effective amount of IACS or a pharmaceutically acceptable salt thereof in the liposome composition is about 12 mg per milliliter. The liposome composition comprises: (a) IACS or a pharmaceutically acceptable salt thereof; and (b) a mixture of DOPC, DOPG, and cholesterol, wherein the molar percentages of DOPC, DOPG, and cholesterol, based on the total molar number of the mixture, are 56.25 to 72.5: 7.5 to 18.75: 10 to 33.

[0021] Based on changes in pain relative to baseline, the sustained-release liposome composition according to some embodiments of this disclosure is used to treat osteoarthritis in human individuals by single or multiple injections.This demonstrates the safety and robustness of efficacy response in long-term treatment with IACS (especially Coopman Group B and Group C steroids in the liposome compositions of this disclosure).

[0022] Other objects, advantages, and novel features of the invention will become clearer from the following detailed description taken in conjunction with the accompanying drawings. Brief Description of the Drawings

[0023] Figure 1 is a schematic diagram illustrating the design of the Phase III study in this disclosure.

[0024] Figure 2 is an overview of the number of patients who completed injection phase 1 and injection phase 2.

[0025] Figure 3 is a graph illustrating the change in the mean least squares (LS) pain score from baseline in the TLC599 treatment group and the placebo group during the first injection period.

[0026] Figure 4 is a graph illustrating the change in the mean WOMAC function score from baseline in all treatment groups during the first injection period.

[0027] Figure 5 is a graph illustrating the total cumulative weekly emergency drug consumption in all treatment groups from week 1 to week 24.

[0028] Figure 6 is a graph illustrating the mean change in weekly ADP values ​​relative to baseline for all treatment groups during the first injection period (from week 0 to week 24). The abbreviation “NRS” stands for Numerical Rating Scale.

[0029] Figure 7 is a graph illustrating the change in ADP values ​​for all treatment groups from baseline to week 52. The first injection was administered at baseline (week 0), and the second injection was administered at week 24. Detailed Description

[0030] Unless otherwise specified, the following terms are to be understood to have the following meanings as used above and throughout this disclosure.

[0031] Unless the context clearly indicates otherwise, the singular forms “a” and “described” as used herein include plural references.

[0032] Unless otherwise stated, all numerical values ​​herein are to be understood to be modified by “about”. When referring to measurable values ​​such as amount or duration, the word "about" means a variable that includes ±10%, preferably ±5%, more preferably ±1%, and even more preferably ±0.1% of the specified value; these variables are suitable for obtaining the required amount of the liposomal drug.

[0033] The terms "treating," "treated," and "treatment" as used herein include prevention (e.g., preventative medication), mitigation, prevention, or reversal of progressive structural tissue damage that causes joint pain. The term "treatment" may also refer to a composition or agent. Throughout this disclosure, treatment refers to a method of reducing, alleviating, suppressing, or delaying the symptoms or signs of one or more osteoarthritis, or improving joint pain detected by known techniques.Or reduce the use of pain control medications. These methods include, but are not limited to, clinical examination, imaging, or analysis of serum or joint aspirates (e.g., rheumatoid factor, erythrocyte sedimentation rate).

[0034] Pain and its symptoms can be assessed using methods known in the art. These methods include, but are not limited to, the 6-point descriptive pain rating scale, the 11-point NPRS, the visual analog scale, average daily pain (ADP), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Wisconsin Brief Pain Questionnaire, the Brief Pain Inventory, the McGill Pain Questionnaire and the short-form, the McGill Pain Questionnaire, and other scoring methods including the Patient Overall Assessment (PGA) of pain control methods. Human individuals can use self-reporting to determine pain levels, for example, using a rating scale from (0) no pain to (10) maximum pain. For instance, the ADP measures daily pain intensity using a numeric rating scale (NRS) from 0 to 10. Alternatively, the WOMAC index is a self-administered questionnaire comprising three subscales (each subscale scored from 0 to 4): pain (5 items), stiffness (2 items), and physical function (17 items). Functional magnetic resonance imaging (fMRI) can be used on individuals, as needed, to identify pain reduction following administration of the liposomal composition disclosed herein. For example, if an individual experiences a reduction in joint pain of approximately or at least 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to an individual before treatment or a control individual,The disclosed method is considered a treatment. Treatment includes a single joint injection or multiple joint injections at required intervals.

[0035] The term "joint pain" refers to a joint disorder or condition involving inflammation and / or pain in one or more joints. As used herein, the term "joint pain" includes all types and subtypes of arthritis of known or unknown etiologies and causes, including but not limited to: rheumatoid arthritis, osteoarthritis, infectious arthritis, psoriatic arthritis, gouty arthritis and lupus-related arthritis, or localized tissue pain caused by bursitis, tenosynovitis, epicondylitis, synovitis and / or other conditions.

[0036] The pharmaceutically acceptable salts of intra-articular corticosteroids (IACS) disclosed herein are salts formed by acidic IACS and a base, i.e., base addition salts, such as alkali metal salts and alkaline earth metal salts (e.g., sodium, lithium, potassium, calcium, magnesium salts), and ammonium salts (e.g., ammonium salts, trimethylammonium salts, diethylammonium salts, tri-(hydroxymethyl)methylammonium salts). Similarly, acid addition salts, such as mineral acids, organic carboxylic acids, and organic sulfonic acids (e.g., hydrochloric acid, methanesulfonic acid, maleic acid), may also be provided to basic IACS.

[0037] As used herein, a “long-term” treatment or administration regimen generally refers to a treatment or administration regimen that lasts for at least 52 weeks when a therapeutic agent is administered to a patient to provide its therapeutic effect. This includes administering a therapeutic agent to a patient in a single dose, multiple doses, or repeated doses over a period of at least 52 weeks (or for a duration of at least 52 weeks). In many cases, the duration of long-term treatment or dosing regimens can be extended to 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80 weeks or longer, depending on the patient's need for improvement, cure or recovery from their original disease state.

[0038] The term "HPA axis" refers to the hypothalamus-pituitary-adrenal axis, which is an important endocrine system for regulating the body's stress response and cortisol release. Cortisol is the primary adrenal glucocorticoid.Furthermore, it plays a central role in regulating glucose metabolism and the body's response to stress. Cortisol produced by the adrenal cortex generates negative feedback inhibition of the hypothalamus and pituitary gland. This effect reduces the secretion of corticotropin-releasing hormone (CRH) and vasopressin, and directly reduces the breakdown of proopiomelanocortin (POMC) to produce adrenocorticotropic hormone (ACTH) and β-endorphins. It is known that the use of exogenous glucocorticoids can cause suppression of the HPA axis. Therefore, chronic use of glucocorticoids for potent anti-inflammatory and pharmacological effects may exacerbate secondary adrenal insufficiency due to long-term exposure (Younes A. (2017). Translational Pediatrics, 17; 6 (4), 269-273).

[0039] The term "adrenal insufficiency" is clinically classified into primary, secondary, and tertiary causes. "Primary adrenal insufficiency" occurs due to lesions affecting the adrenal glands themselves. "Secondary adrenal insufficiency" is caused by a decrease in the level of adrenocorticotropic hormone (ACTH) released by the pituitary gland, and "tertiary adrenal insufficiency" is caused by a decrease in the level of corticotropin-releasing hormone (CRH) released by the hypothalamus. It is known that glucocorticoid therapy may prolong the inhibition of CRH production, causing suppression of the HPA axis through negative feedback, and further leading to secondary adrenal insufficiency. Some clinical manifestations of secondary adrenal insufficiency include pale skin without obvious anemia, amenorrhea, decreased libido and sexual function, sparse axillary and pubic hair, small testes, secondary hypothyroidism, prepubertal growth retardation, delayed puberty, headache, visual symptoms, and diabetic diabetes insipidus (Oelkers W. (1996). The New England Journal of Medicine, 335 (16), 1206–1212). The diagnosis of adrenal insufficiency is based on clinical features and confirmed by biochemical tests (e.g., insulin resistance test (ITT), metyrapone stimulation test, or ACTH stimulation test). Characteristics of adrenal insufficiency include fever, hypoglycemia, chronic fatigue, anorexia, diarrhea, weight loss, muscle weakness, abdominal pain, nausea, vomiting, low blood pressure that worsens upon standing and causes dizziness or fainting, irritability and depression, craving for salty foods, irregular or absent menstruation, and loss of interest in sexual activity.Or other potential clinical signs and symptoms.

[0040] Lipid mixture and liposome composition containing said mixture

[0041] In some embodiments, this disclosure provides a sustained-release liposome composition comprising a lipid mixture and an effective amount of an articular endothelial steroid (IACS) or a pharmaceutically acceptable salt thereof, wherein said lipid mixture comprises one or more phospholipids, and the sustained-release liposome composition contains phospholipids in an amount of about 20 micromoles (μmol) to about 150 μmol per milliliter (mL).

[0042] In some embodiments, the liposome composition described herein and administered in a single or repeated dose can maintain the release of IACS for 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 19.5 months, 20 months, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 35 weeks, 36 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 35 weeks, 36 weeks, 37 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 35 weeks, 36 weeks, 37 weeks, 28 weeks, 3 ...6 weeks, Weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, 80 weeks, half a year, one year, or 1.5 years.

[0043] In some embodiments, the liposome compositions disclosed herein have increased efficacy compared to liposome compositions with a phospholipid content exceeding 150 μmol per 1 mL of liposome composition. In another embodiment, the liposome composition disclosed herein is able to maintain the therapeutic effect of IACS and reduce IACS-related side effects. Specification 5 / 20 pages 8 CN 122349429 A

[0044] In some embodiments, the total amount of phospholipids is about 50 μmol to about 140 μmol per 1 mL of liposome composition. In another embodiment, the total amount of phospholipids is about 45 μmol to about 135 μmol per 1 mL of liposome composition. In another embodiment, the total amount of phospholipids is about 70 μmol to about 150 μmol per 1 mL of liposome composition. In another embodiment,The total amount of phospholipids is about 90 μmol to about 150 μmol per 1 mL of liposome composition. In another embodiment, the total amount of phospholipids is about 50 μmol to about 120 μmol per 1 mL of liposome composition. In another embodiment, the total amount of phospholipids is about 60 μmol to about 110 μmol per 1 mL of liposome composition.

[0045] In some embodiments, the liposome composition further comprises at least one pharmaceutically acceptable excipient, diluent, vehicle, carrier, active ingredient medium, preservative, cryoprotectant, or combination thereof.

[0046] In some embodiments, the liposome composition of the present disclosure is prepared by: mixing one or more phospholipids with one or more buffers, in the presence or absence of cholesterol, to form liposomes; freeze-drying the liposomes with one or more building agents to form a cake-like lipid mixture; and rehydrating the lipid mixture cake with a solution containing IACS to form an aqueous suspension.

[0047] In some embodiments, the liposome composition of this disclosure is prepared by: mixing one or more phospholipids in a solvent, with or without cholesterol; subsequently removing the solvent to form a lipid mixture in powder or film form; and rehydrating the lipid mixture powder or film with a solution containing IACS to form an aqueous suspension. In another embodiment, the liposome composition of this disclosure is prepared by: mixing one or more phospholipids in a solvent, with or without cholesterol; and then injecting the dissolved lipid solution into an aqueous solution to form liposomes. The size of the liposomes is reduced by filtration through track-etched polycarbonate membranes. The solvent is removed by diafiltration of the buffer solution using a semi-automatic tangential-flow filtration (TFF) system. The dialyzed liposome solution is then freeze-dried into a powder, and the lipid mixture powder or film is rehydrated with a solution containing IACS to form an aqueous suspension.

[0048] In some embodiments, the liposome compositions of this disclosure comprise about 10% to about 50% of lipid-associated IACS, or about 50% to about 90% of non-associated IACS. The term "non-associated form" refers to a form that can be filtered through a gel.IACS molecules are isolated from the phospholipid / cholesterol fraction of the liposome composition and are intended to provide immediate release. In other embodiments, the weight ratio of the phospholipid and cholesterol combination to the IACS is about 5 to 80:1. In another embodiment, the weight ratio of the phospholipid and cholesterol combination to the IACS is about 5 to 40:1. For example, the weight ratio of the phospholipid and cholesterol combination to the IACS can be about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80:1.

[0049] In some embodiments, the IACS concentration in the liposome composition of this disclosure is at least or about 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, 24 mM, 25 mM, 26 mM, 27 mM, 28 mM, 29 mM, 30 mM, 31 mM, 32 mM, 33 mM, 34 mM, or 35 mM; or about 10 mM to about 40 mM, about 15 mM to about 40 mM, about 20 mM to about 40 mM, about 15 mM to about 35 mM, about 15 mM to about 30 mM, about 15 mM to about 25 mM, or about 20 mM to about 25 mM. mM.

[0050] In some embodiments, the total amount of liposome composition administered each time is from about 0.5 mL to about 1.5 mL, preferably about 1.0 mL.

[0051] The lipid mixture of the liposome composition provided herein refers to phospholipids or phospholipid mixtures. The lipid mixture may be in the form of a film, cake, granules or powder before being added to the liposome composition, but is not limited thereto.

[0052] In some embodiments, with or without cholesterol, the phospholipids or phospholipid mixture is pre-formed into liposomes before further processing into a lipid mixture.

[0053] In some embodiments, with or without cholesterol, the phospholipids or phospholipid mixture is not pre-formed into liposomes before further processing into a lipid mixture.

[0054] The liposomes may be nanoscale,It comprises a lipid bilayer encapsulating an internal aqueous agent-carrying component. Non-limiting examples of liposomes include small unilamellar vesicles (SUVs), large unilamellar vesicles (LUVs), multivesicular liposomes (MVLs), and multilayer vesicles (MLVs).

[0055] The lipid mixture can be prepared from a variety of lipids capable of forming or incorporating a single-layer or bilayer structure. The lipids used in this disclosure include one or more phospholipids, including but not limited to phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidic acid (PA), phosphatidylinositol (PI), or combinations thereof. In some embodiments, the lipid mixture comprises egg phosphatidylcholine (EPC), egg phosphatidylglycerol (EPG), egg phosphatidylethanolamine (EPE), egg phosphatidylserine (EPS), egg phosphatidic acid (EPA), egg phosphatidylinositol (EPI), soy phosphatidylcholine (SPC), soy phosphatidylglycerol (SPG), soy phosphatidylethanolamine (SPE), soy phosphatidylserine (SPS), soy phosphatidic acid (SPA), and soy phosphatidylinositol (EPI). Phosphatidylinositol (SPI) or combinations thereof. In other embodiments, the lipid mixture comprises dipalmitoylphosphatidylcholine (SPI).DPPC), 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC), dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylglycero (DPPG), dioleoylphosphatidyl lycerol (DOPG), dimyristoylphosphatidylglycerol (DMPG), hexadecylphosphocholine (HEPC), hydrogenated soybean phosphatidylcholine (HPC). Phosphatidylcholine (HSPC), distearoylphosphatidylcholine (DSPC), distearoylphosphatidylglycerol (DSPG), dioleoylphosphatidylethanolamine (DOPE), palmitoylstearoylphosphatidylcholine (PSPC), palmitoylstearoylphosphatidylglyc erol (PSPG), monooleoylphosphatidylethanolamine (MOPE), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine,POPC), polyethylene glycol distearoylphosphatidylethanolamine (PEG-DSPE), dipalmitoylphosphatidylserine (DPPS), 1,2-dioleoyl-sn-glycero-3-phosphatidylserine (DOPS), dimyristoylphosphatidylserine (DMPS), distearoylphosphatidylserine (DSPS), dipalmitoylphosphatidic acid (DPPA), 1,2-dioleoyl-sn-glycero-3-phosphatidylserine (DPPS). Phosphatidic acid (1,2-dioleoyl-sn-glycero-3-phosphatidic acid, DOPA), dimyristoylphosphatidic acid (DMPA), distearoylphosphatidic acid (DSPA), dipalmitoylphosphatidylinositol (DPPI), 1,2-dioleoyl-sn-glycero-3-phosphatidylinositol (DOPI), dimyristoylphosphatidylinositol (DMPI), distearoylphosphatidylinositol (DSPI), or combinations thereof.

[0056] In some embodiments, the lipid mixture comprises a first phospholipid and a second phospholipid. In some embodiments, the first phospholipid is selected from the group consisting of: EPC, EPE, SPC, SPE, DPPC, DOPC, DMPC, HEPC, HSPC, DSPC, DOPE, PSPC, MOPE, POPC, and mixtures thereof; and the second phospholipid is selected from the group consisting of: PG, PS, PA, PI, and mixtures thereof. In some embodiments,The first phospholipid is EPC, EPE, SPC, SPE, DPPC, DOPC, DMPC, HEPC, HSPC, DSPC, DOPE, PSPC, MOPE, POPC, or a mixture thereof; and the second phospholipid is selected from the group consisting of: EPG, EPS, EPA, EPI, SPG, SPE, SPS, SPA, SPI, DPPG, DOPG, DMPG, DSPG, PSPG, DPPS, DOPS, DMPS, DSPS, DPPA, DOPA, DMPA, DSPA, DPPI, DOPI, DMPI, DSPI, hydrophilic polymers having long chains of highly hydrated flexible neutral polymers attached to phospholipid molecules, and mixtures thereof. Examples of hydrophilic polymers include, but are not limited to, polyethylene glycol (PEG), methoxy PEG (mPEG), ganglioside GM1, polysialic acid, polylactic acid (also known as polylactic acid ester), polyglycolic acid (also known as polyglycolide), polylactic-polyglycolic acid, polyvinyl alcohol, polyvinylpyrrolidone, polymethoxazoline, polyethyloxazoline, polyhydroxyethyloxazoline, polyhydroxypropyloxazoline, polyaspartamide, polyhydroxypropyl methacrylamide, polymethacrylamide, polydimethylacrylamide, polyvinylmethyl ether, and polyhydroxyethyl acrylate, with molecular weights from about 2,000 to about 5,000 Daltons. Acrylates), derived celluloses (e.g., hydroxymethyl cellulose or hydroxyethyl cellulose), and synthetic polymers.

[0057] In some embodiments, the lipid mixture further comprises sterols. There are no particular limitations on the sterols used in this disclosure.Examples include cholesterol, phytosterols (sitosterol, stigmasterol, phytosterol, spinach sterol, brassicasterol, etc.), ergosterol, cholesterolanone, cholesterolenone, cloprostenol, cholesterolyl-2'-hydroxyethyl ether, and cholesterolyl-4'-hydroxybutyl ether. The sterol component in the lipid mixture (if present) can be any sterol conventionally used in the preparation of liposomes, lipid vesicles, or lipid particles. In other embodiments, the lipid mixture contains about 10 mol% to about 33 mol% cholesterol, about 15 mol% to about 30 mol% cholesterol, about 18 mol% to about 28 mol% cholesterol, or about 20 mol% to about 25 mol% cholesterol.

[0058] In some embodiments, the lipid mixture comprises a first phospholipid, a second phospholipid, and a sterol in a molar percentage of 29.5% to 87%: 3% to 37.5%: 10% to 33%. Specification 8 / 20 pages 11 CN 122349429 A

[0059] In some embodiments, the first phospholipid is DOPC, POPC, SPC, or EPC, and the second phospholipid is PEG-DSPE or DOPG.

[0060] In some embodiments, the first phospholipid is DOPC, and the second phospholipid is DOPG.

[0061] In some embodiments,The lipid mixture does not contain fatty acids or cationic lipids (i.e., lipids with a net positive charge under physiological pH conditions).

[0062] The liposome compositions prepared in this disclosure can be prepared by conventional techniques for vesicle preparation. These techniques include ether injection (Deamer et al., Acad. Sci. (1978) 308: 250), surfactant method (Brunner et al., Biochim. Biophys. Acta. (1976) 455: 322), freeze-thaw method (Pick et al., Arch. Biochim. Biophys. (1981) 212: 186), reverse evaporation method (Szoka et al., Biochim. Biophys. Acta. (1980) 601: 559-571), ultrasonic treatment method (Huang et al., Biochemistry (1969) 8: 344), ethanol injection method (Kremer et al., Biochemistry (1977) 16: 3932), and extrusion method (Hope et al., Biochim. Biophys. Acta. (1985)). The methods described above include 812: 55-65, the French press method (Barenholz et al., FEBS Lett. (1979) 99: 210), and the method described in Szoka, F., Jr., et al., Ann. Rev. Biophys. Bioeng. 9: 467 (1980). All of the above processing techniques are fundamental to vesicle formation and are incorporated herein by reference. After sterilization, the preformed liposomes are aseptically placed in a container and then freeze-dried to form a powder or cake. In embodiments where the lipid mixture comprises preformed liposomes, the liposomes are prepared by solvent injection and then freeze-dried with or without fillers and / or buffers to obtain the lipid mixture. In some embodiments, the lipid mixture comprises one or more volume-expanding agents. In some embodiments, the lipid mixture further comprises one or more buffers.

[0063] The volume-expanding agents include, but are not limited to: polyols or sugar alcohols, such as mannitol, glycerol, sorbitol, dextrose, sucrose and / or trehalose; and,Amino acids such as histidine or glycine. A preferred volume-expanding agent is mannitol.

[0064] Buffers include, but are not limited to, sodium phosphate monobasic dihydrate and anhydrous sodium hydrogen phosphate.

[0065] In some embodiments where the lipid mixture comprises lipids that are not pre-formed into liposomes, the lipid mixture can be prepared by dissolving it in a suitable organic solvent (including, but not limited to, ethanol, methanol, tert-butanol, diethyl ether, and chloroform) and drying it using heating, vacuum evaporation, nitrogen evaporation, freeze-drying, or other conventional solvent removal methods.

[0066] Specific embodiments supporting the preparation of lipid mixtures of this disclosure will be described below.

[0067] Intra-articular corticosteroids

[0068] Intra-articular corticosteroids (IACS) are the current treatment recommendations for the non-surgical management of osteoarthritis in individuals with knee, hip and multi-joint osteoarthritis as outlined in the International Osteoarthritis Research Society (OARSI) guidelines (Bannuru RR et al. Osteoarthritis and Cartilage (2019) 27: 1578-1589).

[0069] IACS that can be used in this disclosure include any naturally occurring corticosteroid hormone, synthetic steroid and its derivatives. Examples of IACS, its derivatives or pharmaceutically acceptable salts include, but are not limited to, corticosteroids according to Coopman classification groups B and C (S. Coopman et al., “Identification of cross-reaction patterns in allergic contact dermatitis from topical corticosteroids” Br J Dermatol. 1989 Jul; 121 (1):27-34).

[0070] Pharmaceutically acceptable salts for IACS include non-toxic salts formed from non-toxic inorganic or organic bases. For example, non-toxic salts can be formed from: inorganic bases, such as hydroxides of alkali metals or alkaline earth metals (e.g., potassium, sodium, lithium, calcium, or magnesium); and organic bases.For example, amines, etc.

[0071] Pharmaceutically acceptable salts for IACS also include non-toxic salts formed from non-toxic inorganic or organic acids. Examples of organic and inorganic acids include hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, succinic acid, citric acid, lactic acid, maleic acid, fumaric acid, palmitic acid, cholic acid, pamoic acid, mucoic acid, D-glutamic acid, glutaric acid, glycolic acid, phthalic acid, tartaric acid, lauric acid, stearic acid, salicylic acid, sorbic acid, benzoic acid, etc.

[0072] In some embodiments, IACS includes, but is not limited to, hydrocortisone acetate, methylprednisolone acetate, dexamethasone sodium acetate, dexamethasone sodium phosphate, betamethasone acetate, prednisolone, triamcinolone acetonide, and triamcinolone hexacetonide, which can be administered in the following doses: about 0.1 mg to about 300 mg per milliliter of liposome composition, about 0.1 mg to about 100 mg, about 0.1 mg to about 20 mg, about 0.1 mg to about 18 mg, about 1 mg to about 300 mg, about 1 mg to about 100 mg, about 1 mg to about 20 mg, about 1 mg to about 18 mg, about 4 mg About 300 mg, about 4 mg to about 100 mg, about 4 mg to about 20 mg, about 4 mg to about 18 mg, about 6 mg to about 18 mg, about 6 mg to about 16 mg, about 8 mg to about 16 mg, about 6 mg to about 12 mg.

[0073] In one embodiment, the IACS is dexamethasone sodium phosphate (DSP). DSP is in solution form, and as the above-mentioned solution containing IACS, the cake-shaped lipid mixture is rehydrated to obtain the liposome composition of this disclosure.The IACS concentration of the liposome composition is such that it is about 2 mg / mL to about 100 mg / mL, about 4 mg / mL to about 80 mg / mL, about 5 mg / mL to about 60 mg / mL, about 6 mg / mL to about 40 mg / mL, about 8 mg / mL to about 20 mg / mL, or about 10 mg / mL to about 16 mg / mL.

[0074] The effective dose of IACS in humans in this disclosure may be higher than the recommended or standard doses known in the art; see, for example, Wernecke, C. et al. Orthop J Sports Med., 3 (5), 2325967115581163 (DOI: 10.1177 / 2325967115581163), which is incorporated herein by reference. For example, while the recommended and tolerable dose of hexamethylenetetramine cortisol as an IACS is 20 mg, the dose of IACS in the compositions and methods of the present invention can be at least 20 mg or higher.

[0075] The dose of IACS administered also depends on the severity of the condition being treated, the specific prescription, and other clinical factors, such as the recipient's weight and general condition, and the severity of side effects.

[0076] In some embodiments, the liposome composition may further comprise targeting molecules, including but not limited to TNF-α and B cell surface antigens (e.g., CD20). Other antigens may also be used, such as CD19, HER-3, GD2, Gp75, CS1 protein, mesothelin, cMyc, CD22, CD4, CD44, CD45, CD28, CD3, CD123, CD138, CD52, CD56, CD74, CD30, Gp75, CD38, CD33, GD2, VEGF, or TGF. The targeting molecule can be in the form of a lipid-conjugate of an antibody or peptide. The antibody or peptide acts as a targeting portion capable of specifically binding to target cells carrying the targeting molecule, thereby delivering IACS to the desired microenvironment to achieve the desired disease-modifying therapy to improve disease progression.

[0077] Administration of the liposome composition

[0078] The liposome composition can be administered intra-articularly in a single-dose or multiple-dose regimen during the treatment period. The liposome composition can be conveniently administered at an appropriate dosing frequency.For example: once a week, once every two weeks, once every six weeks, once a month, once every two months, at least once every three months, at least once every six months, at least once every nine months, or until the symptoms and signs of the condition (i.e., joint pain) are relieved, improved or cured.

[0079] In some embodiments, the liposome composition can be administered at multiple doses, selected from the group consisting of: 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, and 36 weeks.

[0080] In one set of embodiments, the liposome composition can be administered according to a multi-dosing regimen, which includes, but is not limited to, at least two joint injections at an interval selected from the following groups: 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, and 36 weeks.

[0081] In some embodiments, the multi-dose regimen includes administering at least two joint injections at dosing intervals of at least 12 weeks (e.g., 13 weeks to 6 months). In another set of embodiments, provided that no adverse reaction occurs after exposure to the liposome composition, the above multi-dose regimen may further include one, two, three, four or more additional joint injections at suitable dosing intervals after the two joint injections.

[0082] In some embodiments, the multi-dose regimen includes administering at least two joint injections at dosing intervals of at least 24 weeks (e.g., 25 weeks to 36 weeks or longer). In another set of embodiments, provided that no adverse reaction occurs after exposure to the liposome composition, the above multi-dose regimen may further include one, two, three, four or more additional joint injections at suitable dosing intervals after the two joint injections.

[0083] In some embodiments,The dosage of the liposome composition for each joint injection is about 0.5 mL to about 1.5 mL, about 0.6 mL to about 1.2 mL, about 0.8 mL to about 1.2 mL, or about 1.0 mL.

[0084] In an exemplary embodiment, the liposome composition is administered in a single therapeutic dose, wherein the effective amount of intra-articular corticosteroid is about 6 mg to about 18 mg, about 10 mg to about 18 mg, about 12 mg to about 18 mg, about 10 mg to about 15 mg, about 11 mg to about 13 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg. The lipid mixture comprises a first phospholipid, a second phospholipid, and a sterol in a molar ratio of 29.5% to 87%: 3% to 37.5%: 10% to 33%; and the total amount of phospholipids is about 50 μmol to about 140 μmol, about 45 μmol to about 135 μmol, about 50 μmol to about 120 μmol, or about 60 μmol to about 110 μmol.

[0085] In some embodiments, the liposome composition is administered in multiple doses, wherein the effective amount of intra-articular corticosteroid in each dose is about 6 mg to about 18 mg, about 10 mg to about 18 mg, about 12 mg to about 18 mg, about 10 mg to about 15 mg, about 11 mg to about 13 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg. The lipid mixture comprises a first phospholipid, a second phospholipid, and a sterol in a molar ratio of 29.5% to 87%: 3% to 37.5%: 10% to 33%; while the total amount of phospholipids is about 50 μmol to about 140 μmol, about 45 μmol to about 135 μmol, about 50 μmol to about 120 μmol, or about 60 μmol to about 110 μmol.

[0086] In some embodiments, during multiple-dose treatment, the liposomal composition is administered as a dose independent of the non-liposomal composition, wherein the effective amount of intra-articular corticosteroid in the non-liposomal composition is about 0.1 mg to about 300 mg.

[0087] Method of treating joint pain, 11 / 20 pages, 14 CN 122349429 A

[0088] One aspect of this disclosure is a method of treating individual joint pain.It comprises administering an effective amount of the liposome composition described herein to individuals in need, thereby reducing adverse reactions caused by IACS compared to individuals administered with immediate release or a standard IACS formulation; and / or improving the therapeutic efficacy and release rate of the liposome composition for IACS compared to the efficacy and release rate of liposome compositions with a phospholipid content exceeding 150 μmol per milliliter of liposome composition.

[0089] In some embodiments, the individual suffers from arthritis, such as osteoarthritis, rheumatoid arthritis, acute gouty arthritis, psoriatic arthritis, reactive arthritis, arthritis caused by the following diseases: Ehlers-Danlos Syndrome, hemochromatosis, hepatitis, Lyme disease, Sjogren's disease, Hashimoto's thyroiditis, celiac disease, non-celiac gluten sensitivity, inflammatory bowel disease, allergic purpura, hyperimmune globulin D with recurrent fever, sarcoidosis, Whipple's disease, tumor necrosis factor receptor-associated periodic fever syndrome, granulomatous polyangiitis, familial Mediterranean fever, or systemic lupus erythematosus.

[0090] Planar radiography or magnetic resonance imaging (MRI) of the knee joint can be used to assess patients with knee osteoarthritis. MRI is the preferred diagnostic tool for assessing bone and soft tissue changes in knee osteoarthritis. The Kellgren-Lawrence (K-L) classification of osteoarthritis can be assessed based on knee radiographs.

[0091] The Kellgren and Lawrence classification system has been widely used to classify the severity of osteoarthritis. The following is the original description: Grade 0 (None): No obvious X-ray changes of osteoarthritis; Grade 1 (Suspicious): Suspicious narrowing of the joint space, possibly with osteophyte lip deformity; Grade 2 (Mild): Obvious osteophytes are visible on posteroanterior weight-bearing radiographs, and the joint space may be narrowed; Grade 3 (Moderate): Moderate multiple osteophytes, significant narrowing of the joint space, partial sclerosis of the bone ends, possibly accompanied by deformity; Grade 4 (Severe): Numerous osteophytes, significant narrowing of the joint space, severe sclerosis of the bone ends and obvious deformity.

[0092] Patients classified as Grade 2 based on the lowest diagnosed severity are considered to have osteoarthritis. This classification was proposed by Kellgren and Lawrence in 1957 and subsequently adopted by the World Health Organization (WHO) in 1961 as the radiological definition of osteoarthritis (OA) for epidemiological research purposes.

[0093] Efficacy refers to the ability of IACS to induce a beneficial clinical response in the disease. Efficacy also includes relief of clinical symptoms, such as joint pain, joint tenderness, transient morning stiffness, and crepitus that lead to unstable and impaired physical function. In some implementations,The efficacy of IACS can be assessed using indicators such as the WOMAC osteoarthritis index, ADP score, and VAS score. In some embodiments, the IACS in the liposome composition described herein is released continuously and stably without inducing adverse reactions, including but not limited to articular cartilage damage or destruction, such as chondrocyte apoptosis, proteoglycan loss, articular cartilage cysts, articular cartilage degradation, joint injury, suppression of serum cortisol levels, suppression of the hypothalamus-pituitary-adrenal axis, and adrenal insufficiency. Compared to individuals who received IACS in non-liposome formulations (e.g., those without lipid mixtures), the incidence of adverse reactions in the individuals described herein may be reduced by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0094] The liposome composition provided herein can be used in combination with a variety of additional chemical substances, including but not limited to: analgesics (e.g., bupivacaine, ropivacaine, or lidocaine) or hyaluronic acid preparations (e.g., sine). In some embodiments, the liposome composition of this application may be prepared as a single therapeutic composition with other chemicals, and the liposome composition of this application and the additional chemicals may be administered simultaneously. Alternatively, the liposome composition of this application and the additional chemicals may be prepared independently, for example, as separate therapeutic compositions; and the liposome composition of this application and the additional chemicals may be administered simultaneously, or administered separately at different times during the treatment regimen, through the same or different routes, in a single dose or multiple dose manner.

[0095] This disclosure will be further described with reference to the following specific, non-limiting examples.

[0096] Examples

[0097] The following examples are used to illustrate the preparation and characteristics of specific embodiments of this disclosure.

[0098] Example 1: Preparation of lipid mixture

[0099] Lipids (including DOPC, DOPG and cholesterol) were mixed in a molar percentage of 56.25 to 72.5: 7.5 to 18.75: 10 to 33 (e.g., 67.5: 7.5: 25) and dissolved in 99.9% ethanol at approximately 40°C in a flask to form a lipid solution. The lipids were dissolved using a benchtop ultrasonic cleaner.

[0100] The dissolved lipid solution was added to a 1.0 mM sodium phosphate aqueous solution at a flow rate of 100 mL / min using a peristaltic pump to form a pre-liposome suspension. The pre-liposome suspension was then squeezed through a polycarbonate membrane with a pore size of 0.2 μm 6 to 10 times.A liposome mixture was obtained. The average vesicle size of the liposomes was 120 nm to 140 nm (measured by a Malvern ZetaSizer Nano ZS-90 particle size analyzer, Malvern Instruments Ltd, Worcestershire, UK).

[0101] The liposome mixture was dialyzed and concentrated using a tangential flow filtration system (Millipore Corporation, Billerica, MA, USA) with a Millipore Pellicon 2 Mini Ultrafiltration Module Biomax-100C (filtration area 0.1 m²), followed by sterilization using a 0.2 μm sterile filter.

[0102] The lipid concentration of the filtered liposome mixture was quantified by phosphorous assay. The filtered liposome mixture was then prepared with 2% mannitol and sterilized again using a 0.2 μm sterile filter. Then, the sterilized liposome mixture was freeze-dried to obtain a liposome mixture in cake form.

[0103] Example 2: Preparation of liposome composition

[0104] The liposome composition according to this disclosure was prepared by mixing the liposome mixture described in Example 1 with an aqueous solution of dexamethasone sodium phosphate (DSP; C22H28FNa2O8P; molecular weight: 516.41 g / L). The DSP aqueous solution contained 13.2 mg / mL of DSP and 4 mg / mL of sodium citrate as the DSP composition for subsequent use. Thus, each milliliter of the liposome composition formed (hereinafter also referred to as "liposome DSP") contained approximately 12.0 mg / mL of DSP and approximately 90 μmol to 100 μmol of phospholipids.

[0105] Example 3: A randomized, double-blinded controlled study of the efficacy and safety of liposomal dexamethasone sodium phosphate (DSP) in patients with knee osteoarthritis.

[0106] Liposome DSP was prepared by the methods described above (e.g., Examples 1 and 2). In a phase III randomized, double-blind, placebo-controlled, and activity-controlled clinical trial, liposomal DSP (hereinafter referred to as "TLC599") was intended for local injection.To provide sustained pain relief for knee OA. This study aims to confirm the efficacy of TLC599 in providing pain relief for OA patients over 24 weeks as demonstrated in previous studies, and to investigate the benefits of repeat TLC599 injections within one year.

[0107] The current study aims to evaluate the efficacy and safety of single-dose or repeated-dose TLC599 in patients with K-L scale grade 2 to 3 knee OA. A total of 504 patients (506 enrolled, 2 withdrawn) were randomly assigned to three groups in a 2:1:1 ratio and received an injection of 12 mg TLC599 (TLC599 treatment group), 4 mg DSP (DSP treatment group), and saline placebo (placebo group) on day 1 (baseline or week 0). At week 24, a second injection of TLC599 was given to 203 eligible patients in the TLC599 treatment group who received the first injection. A total of 89 eligible patients in the DSP treatment group who received their first DSP injection received TLC599. A total of 94 eligible patients in the placebo group who received their first placebo injection (page 13 / 20, CN 122349429 A) received a second placebo injection. The study design is shown in Figure 1, and Figure 2 provides an overview of the number of patients who completed the study in both injection phase 1 and injection phase 2. Efficacy and safety were assessed during the first injection phase (defined as a period of up to 24 weeks after the first injection) and the second injection phase (defined as a period of up to 28 weeks after the second injection, or up to 52 weeks after baseline).

[0108] In terms of efficacy parameters, Western University and McMaster University Osteoarthritis Index (WOMAC) pain scores, WOMAC functional scores, and daily average pain (ADP) of the knee were collected and evaluated using statistical methods such as repeated measures mixed model (MMRM) and analysis of covariance (ANCOVA). Meanwhile, the safety analysis was based on all safety information collected throughout the study period, including adverse events (AEs), clinical laboratory data, vital signs, electrocardiograms (ECGs), and knee radiographs.

[0109] The demographic and baseline characteristics of the patients are summarized in Table 1.

[0110] Table 1. Demographics and Baseline Characteristics

[0111] WOMAC = Western University and McMaster University Osteoarthritis Index. Instructions for Use 14 / 20 pages 17 CN 122349429 A

[0112] ADP = Mean Daily Pain.

[0113] For the efficacy endpoints (ANCOVA) used as one of the efficacy endpoints for the change in WOMAC pain from baseline at week 12,The TLC599 treatment group was statistically significantly superior to the placebo group, with a least square mean difference of -0.171 and a p-value of 0.0372 (Table 2). Furthermore, as shown in Figure 3, the TLC599 treatment group was also numerically superior to the placebo group at all time points up to week 24.

[0114] Table 2. Changes in WOMAC pain scores from baseline to week 12

[0115] Table 3 shows the changes in WOMAC function scores of TLC599 versus placebo from baseline during the first injection period. There was a statistically significant treatment difference up to week 12, and at weeks 16, 20, and 24, TLC599 was numerically superior at every subsequent visit until week 24. The changes in WOMAC function scores from baseline for all treatment groups during the first injection period are shown in Figure 4.

[0116] Table 3. Changes in WOMAC functional scores from baseline for TLC599 relative to placebo during the first injection – ANCOVA

[0117] The use of rescue medication (e.g., acetaminophen, opioids, or NSAIDs permitted by the program) is another efficacy assessment of potential clinical benefit. In this study, 500 mg acetaminophen tablets were provided as rescue medication and dispensed upon required screening. Between screening and study endpoint / early termination, patients recorded their acetaminophen rescue medication usage in a diary for the preceding 24 hours daily. Rescue medication was reviewed at each study visit. The permissible daily dose of acetaminophen was a maximum of 3 g / day. Acetaminophen should not be used within 24 hours prior to each study visit. As summarized in Table 4, the cumulative emergency medication consumption analysis by ANCOVA up to week 12 and week 24 showed a statistically significant difference between the TLC599 treatment group and the placebo group, with the TLC599 treatment group consuming less emergency medication overall. This result supports the significant clinical improvement in average pain relief in the TLC599 treatment group. The graph of the cumulative weekly total emergency medication consumption of each treatment group during the first injection period is shown in Figure 5.

[0118] Table 4. Total emergency acetaminophen consumption analysis of TLC599 versus placebo up to week 12 and week 24 – ANCOVA

[0119] For other knee pain-related assessment indicators,The changes from baseline in the weekly mean of average daily pain (ADP) at week 12, and the AUC of the change from baseline in WOMAC pain over the time interval from baseline to week 12, both showed that the TLC599 treatment group was statistically significantly better than the placebo group in improving OA knee pain. Specifically, at all time points during the first injection, the TLC599 treatment group was numerically and statistically superior (p<0.05) to the placebo group, as shown in Figure 6. As summarized in Table 5, statistically significant differences were observed in the weekly mean of ADP from the first injection between TLC599 and placebo at weeks 1, 12, and 24.

[0120] Table 5. Analysis of the weekly mean change in mean daily knee pain from the first injection in TLC599 versus placebo at weeks 1, 12, and 24 – MMRM Instructions for Use, 16 / 20 pages, 19 CN 122349429 A

[0121] In addition, the efficacy of repeated doses of TLC599 in patients with knee OA was further evaluated. Eligible patients in the TLC599 treatment group and the placebo group received a second blinded injection of the same treatment at week 24, while patients in the DSP treatment group received a blinded injection of TLC599 at the same time, see Figures 1 and 2. For eligible patients who received a second injection (N=386), the weekly mean ADP score changes from baseline recorded during the first and second injection periods are graphically shown in Figure 7. The TLC599 treatment group demonstrated numerically better therapeutic efficacy compared to the placebo group in patients receiving a second injection from week 1 to week 52. Similar trends were observed in patients receiving a second TLC599 injection during the second injection period and in patients receiving TLC599 after DSP.

[0122] Regarding safety assessments, clinical laboratory tests, vital signs, ECG, physiological tests, and knee radiographs were all normal and did not raise any safety concerns. No significantly abnormal glucose and HbA1c results were observed throughout the study.

[0123] Chronic use of corticosteroids is known to lead to HPA axis suppression through negative feedback, resulting in adrenal insufficiency. Normal cortisol levels are typically highest in the morning (10 to 20 μg / dL) and lowest around midnight. Therefore,Safety assessment for potential adrenal insufficiency was performed by measuring morning cortisol levels in each group at predetermined time points / visits. Any patient with morning serum cortisol levels less than 10 μg / dL and who also exhibited underlying clinical signs and symptoms suggestive of adrenal insufficiency during the study period (e.g., fever, hypoglycemia, chronic fatigue, anorexia, diarrhea, weight loss, muscle weakness, abdominal pain, nausea, vomiting, hypotension that worsens upon standing, irritability and depression, craving for salty foods, irregular or absent menstruation, loss of interest in sexual activity) underwent ACTH stimulation testing to determine whether they had adrenal insufficiency. Specifically, the ACTH stimulation test used pre-drug serum cortisol samples taken before 9:00 AM as the baseline level (page 17 / 20, CN 122349429 A). Post-stimulation cortisol samples were taken approximately 1 hour after the injection of rehydrated 0.25 mg of synthetic adrenocorticotropic hormone (cosyntropin) to assess post-stimulation serum cortisol levels. Patients who did not pass the ACTH stimulation test (post-stimulation cortisol levels ≤18 μg / dL (or ≤497 nmol / L)) were referred to an endocrinologist for further evaluation and treatment.

[0124] In accordance with this study protocol, patients' cortisol levels were measured at week 20 to qualify for a second injection. Four patients (three in the TLC599 group and one in the placebo group) had morning serum cortisol levels of “0” at week 20 due to sample quality issues. All patients received a second injection after confirming that their retested cortisol levels were above 10 μg / dL. At week 20, nine patients in all three treatment groups had morning serum cortisol concentrations below 5 μg / dL. The incidence of patients with morning serum cortisol concentrations below 5 μg / dL was similar across the three groups: 4 out of 252 patients (1.6%) in the TLC599 group; 3 out of 126 patients (2.4%) in the DSP group; and 2 out of 126 patients (1.6%) in the placebo group. The incidence of morning serum cortisol concentrations below 5 μg / dL in the TLC599 group was numerically lower than in the DSP group and comparable to that in the placebo group, suggesting that this represents a background incidence.

[0125] Furthermore, 113 patients showed morning serum cortisol levels of 5 to 10 μg / dL at week 20. The frequency of these patients in the TLC599 group (52 out of 252 patients; 20.6%) was lower than that in the DSP group (32 out of 126 patients; 25.4%) and the placebo group (29 out of 126 patients; 23.0%). It is noteworthy that...The incidence of morning serum cortisol levels of 5 to 10 μg / dL in the TLC599 group (20.6%) was numerically lower than that in the DSP group (25.4%) and the placebo group (23.0%), indicating that the incidence was comparable across the three treatment groups. Importantly, no patients with cortisol levels below 5 μg / dL or between 5 and 10 μg / dL reported any signs and / or symptoms of adrenal insufficiency at week 20.

[0126] The proportion of patients with low cortisol (morning serum cortisol <5 μg / dL) was presented by treatment group for patients who received at least one injection (Table 6) and for patients who received two injections (Table 7). The results in Tables 6 and 7 show that the incidence of low cortisol values ​​in the placebo group ranged from 1.0% to 7.7% during week 1 to week 52 (end of study). This represents a physiologic sporadic variation of low cortisol levels. In other words, the inherent background incidence of low cortisol levels does not indicate a safety concern.

[0127] Regarding changes in cortisol levels during injection period 1, as shown in Table 6, the TLC599 group (23.6%) showed a greater shift from baseline to low cortisol levels in week 1 compared to the DSP (4 mg) group (0%) or the placebo group (1.7%). However, in week 2, the shifts in low cortisol levels were comparable in the TLC599 group (4.7%) and the DSP group (3.5%), while the incidence in the placebo group was 1.7%. In week 4, the shifts in low cortisol levels were comparable in the TLC599 group (3.4%), the DSP group (3.5%), and the placebo group (4.5%).

[0128] A similar pattern was observed in injection period 2, as shown in Table 7. One week after the TLC599 injection at week 24, 28.6% of patients receiving TLC599 for the first time and 31.6% of patients receiving DSP (4 mg) for the first time had low cortisol levels at week 25, compared to 1.2% of patients receiving a second injection of placebo. At week 26 (two weeks after the second injection), 5.2% of patients in the TLC599 group and 6.6% of patients in the DSP (4 mg) group had low cortisol levels, compared to 1.3% of patients in the placebo group. At week 28, the incidence was similar in the placebo and DSP (4 mg) groups, but lower in the TLC599 group (1.7%).

[0129] Overall, no clinically significant serum cortisol levels outside the normal range were observed throughout the study. The results indicate that there was no cumulative effect on the HPA axis after repeated injections of TLC599, and throughout the entire study period,No patients with low cortisol levels reported any treatment-emergent adverse events (TEAEs) related to adrenal insufficiency. Specifically, no events were documented using the following preferred terms: adrenal insufficiency, adrenal androgen deficiency, adrenal suppression, acute adrenocortical insufficiency, glucocorticoid deficiency, Cushing's syndrome, Cushing's syndrome, hyperadrenalism, or hyperadrenocorticism.

[0130] Table 6. Incidence of low cortisol levels at different time periods – Patients who received at least one injection

[0131] a One patient was not included in this count because morning serum cortisol sampling was performed on day 151 (outside the range of this table).

[0132] Table 7. Incidence of low cortisol levels at different time periods – Patients who received a second injection (Instructions for Use, Page 19 / 20, 22 CN 122349429 A)

[0133] In summary, liposomal DSP (i.e., TLC599) showed a benefit greater than placebo in ADP and WOMAC pain in patients with knee OA after a single injection lasting 24 weeks or longer. A second injection at 24 weeks extended the benefit to week 52. Furthermore, the safety profile showed a reaffirmation of a low incidence of AEs, no treatment-related SAEs, and no symptomatic adrenal insufficiency during the two injection periods. These results demonstrate that TLC599 can provide knee OA prolongation without adverse side effects, and establishes confidence in a good risk-benefit balance with repeated administrations. This disclosure demonstrates the safety and benefit of repeated liposomal DSP injections in knee OA.And to provide alternative treatments that may benefit OA patients in managing knee OA pain over an extended period (e.g., 52 weeks or longer). [Instructions for Use, Page 20 / 20, 23, CN 122349429 A, Figure 1; Instructions for Use, Figure 1 / 6, Page 24, CN 122349429 A, Figure 2; Instructions for Use, Figure 2 / 6, Page 25, CN 122349429 A, Figure 4; Instructions for Use, Figure 3 / 6, Page 26, CN 122349429 A, Figure 5; Instructions for Use, Figure 4 / 6, Page 27, CN 122349429 A, Figure 6; Instructions for Use, Figure 5 / 6, Page 28, CN 122349429 A, Figure 7; Instructions for Use, Figure 6 / 6, Page 29, CN 122349429 A]

Claims

1. A method for treating joint pain in a human individual with chronic osteoarthritis, comprising administering repeated doses of a liposomal composition to the human individual via intra-articular delivery, each dose comprising an effective amount of an intra-articular corticosteroid or a pharmaceutically acceptable salt thereof, and a lipid mixture, wherein the repeated doses of the liposomal composition do not induce signs and / or symptoms of adrenal insufficiency in the human individual.

2. The method of claim 1, wherein repeated doses of the liposome composition are administered at dosing intervals selected from the group consisting of: 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, and 36 weeks.

3. The method of claim 1, wherein the intra-articular corticosteroid or a pharmaceutically acceptable salt thereof is released during a period selected from the group consisting of: 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, and 80 weeks.

4. The method of claim 1, wherein the intra-articular corticosteroid or a pharmaceutically acceptable salt thereof is released at a rate that does not adversely inhibit the hypothalamic-pituitary-adrenal (HPA) axis.

5. The method of claim 1, wherein the intra-articular corticosteroid or a pharmaceutically acceptable salt thereof is released at a rate that does not adversely inhibit the cortisol levels of the human individual.

6. The method of claim 1, wherein the intra-articular corticosteroid or a pharmaceutically acceptable salt thereof is selected from the group consisting of: dexamethasone sodium phosphate, dexamethasone, betamethasone, betamethasone sodium phosphate, betamethasone acetate, betamethasone dipropionate, betamethasone valerate, mometasone furoate, triamcinolone, hexamethasone diacetate, triamcinolone diacetate, methylprednisolone sodium succinate, methylprednisolone acetate, hydrocortisone butyrate, hydrocortisone acetate, aclomethasone dipropionate, halcinonide, fluocinolone, fluocinolone acetonide, and combinations thereof.

7. The method of claim 1, wherein the intra-articular corticosteroid is dexamethasone sodium phosphate (DSP) and has an effective amount of about 6 mg to 18 mg.

8. The method of claim 7, wherein the effective amount of DSP is about 12 mg.

9. The method of claim 1, wherein the lipid mixture comprises dioleoylphosphatidylcholine (DOPC) and dioleoylphosphatidylglycerol (DOPG).

10. The method of claim 9, wherein the lipid mixture further comprises about 10 to 33 molar percentages of cholesterol based on the total amount of the lipid mixture.

11. The method of claim 1, wherein the osteoarthritis is knee osteoarthritis.

12. A dosing regimen for the treatment of long-term joint pain, comprising: repeated doses of a liposomal composition administered intra-articularly to the joints of a patient with osteoarthritis, each dose comprising an effective amount of an intra-articular corticosteroid and a lipid mixture, wherein the dosing regimen does not induce signs and / or symptoms of adrenal insufficiency in the patient with osteoarthritis.

13. The dosing regimen of claim 12, wherein repeated doses of the liposome composition are administered at dosing intervals selected from the group consisting of: 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, and 36 weeks.

14. The dosing regimen of claim 12, wherein the intra-articular corticosteroid or a pharmaceutically acceptable salt thereof is released during a period selected from the group consisting of: weeks 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, and 80.

15. The dosing regimen of claim 12, wherein the intra-articular corticosteroid or a pharmaceutically acceptable salt thereof is released at a rate that does not adversely inhibit the hypothalamic-pituitary-adrenal (HPA) axis.

16. The dosing regimen of claim 12, wherein the intra-articular corticosteroid or a pharmaceutically acceptable salt thereof is released at a rate that does not adversely inhibit the cortisol levels of the human individual.

17. The dosing regimen of claim 12, wherein the intra-articular corticosteroid or a pharmaceutically acceptable salt thereof is selected from the group consisting of: dexamethasone sodium phosphate, dexamethasone, betamethasone, betamethasone sodium phosphate, betamethasone acetate, betamethasone dipropionate, betamethasone valerate, mometasone furoate, triamcinolone, hexamethasone diacetate, triamcinolone diacetate, methylprednisolone sodium succinate, methylprednisolone acetate, hydrocortisone butyrate, hydrocortisone acetate, aclomethasone dipropionate, halcinonide, fluocinolone, fluocinolone acetonide, and combinations thereof.

18. The dosing regimen of claim 12, wherein the intra-articular corticosteroid is dexamethasone sodium phosphate (DSP) and has an effective amount of about 6 mg to 18 mg.

19. The dosing regimen of claim 18, wherein the effective amount of DSP is about 12 mg.

20. The dosing regimen of claim 12, wherein the lipid mixture comprises dioleoylphosphatidylcholine (DOPC) and dioleoylphosphatidylglycerol (DOPG).

21. The dosing regimen of claim 20, wherein the lipid mixture further comprises about 10 to 33 molar percentages of cholesterol, based on the total amount of the lipid mixture.

22. The dosing regimen of claim 12, wherein the osteoarthritis patient is a patient with knee osteoarthritis.

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