Dosage form for intra-articular injection comprising colchicine for use in the treatment of a joint disease such as osteoarthritis

Abstract

The present invention relates to a pharmaceutical composition in the form of a sterile and injectable dosage form comprising a controlled release dosage form comprising colchicine for use in the treatment of arthropathy, such as osteoarthritis, aggressive hand osteoarthritis and any other type of chondropathy, by intraarticular injection of said pharmaceutical composition into the joint, such as osteoarthritis, aggressive hand osteoarthritis, and any other type of chondropathy. The present invention relates to colchicine, in particular colchicine, and / or for the treatment of pain-related arthropathy, and / or for the protection of joints, bones and / or cartilages, in which 80% by weight of colchicine is released for more than one month, and in which colchicine is present in a concentration of 1 to 27.5 mg per mL of sterile and injectable dosage, and / or for the treatment of pain-related arthropathy, and / or for the protection of joints, bones and / or cartilages. The invention also relates to a sterile and injectable pharmaceutical composition comprising a controlled release dosage form containing colchicine, which has a suitable in vitro dissolution characteristic. The invention also relates to a formulation in powder form and to a pharmaceutical composition in sterile and injectable dosage form form suitable for intra-articular injection comprising colchicine, in particulate form comprising a polymer matrix, and to a related kit or article of manufacture.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480021562.6 (22) Application Date 2024.01.23 (30) Priority Data 23305086.3 2023.01.24 EP (85) PCT International Application Entering National Phase Date 2025.09.24 (86) PCT International Application Application Data PCT / EP2024 / 051530 2024.01.23 (87) PCT International Application Publication Data WO2024 / 156699 EN 2024.08.02 (71) Applicant PK Medical Company Address Paris, France (72) Inventors F. Marzouki C. Sanson D. Hayoz G. Pricon (74) Patent Agency Beijing Panhua Weiye Intellectual Property Agency Co., Ltd. 11280 Patent Attorney Guo Guangxun (51) Int.Cl. A61K 9 / 00 (2006.01) A61K 9 / 16 (2006.01) A61K 31 / 165 (2006.01) A61K 45 / 06 (2006.01) A61K 47 / 34 (2017.01) A61P 19 / 02 (2006.01) A61P 29 / 00 (2006.01) (54) Invention Title Intra-articular Injection Formulation Containing Colchicine for Treating Joint Diseases Such as Osteoarthritis (57) Abstract This invention relates to a sterile and injectable dosage form of a pharmaceutical composition comprising a controlled-release formulation containing colchicine. This invention relates to the treatment of arthropathy, such as osteoarthritis, erosive osteoarthritis of the hand, and any other type of chondropathy, and / or the treatment of pain-related arthropathy, and / or the protection of joints, bones, and / or cartilage, by intra-articular injection of the pharmaceutical composition into the joint, wherein the time required to release 80% by weight of colchicine is greater than one month, and wherein colchicine is present at a concentration of 1 to 27.5 mg per mL of sterile and injectable dosage form. The invention also relates to a sterile and injectable dosage form of pharmaceutical composition comprising a controlled-release formulation containing colchicine, having suitable in vitro dissolution properties. The invention further relates to a powder form of formulation and to a sterile and injectable dosage form of pharmaceutical composition containing colchicine suitable for intra-articular injection, which is in particulate form comprising a polymer matrix, and to related kits or articles.Claims (3 pages), Description (37 pages), Drawings (1 page), CN 121013711 A, 2025.11.25, CN 1 21 01 37 11 A. 1. A sterile and injectable dosage form of a pharmaceutical composition comprising a controlled-release formulation containing colchicine, for the treatment of arthropathy, such as osteoarthritis, erosive osteoarthritis of the hand, and any other type of chondropathy, and / or for the treatment of pain-related arthropathy, and / or for the protection of joints, bones, and / or cartilage, wherein the dissolution rate of colchicine is 80% (w / w) over more than one month, as determined according to the following protocol: 20 mg aliquots of the controlled-release formulation containing colchicine are suspended in 50 mL of phosphate buffer (pH 7.4) with stirring at 37°C; then, throughout the duration of release, the sample is periodically injected through a 350 mL aliquot. 1. The supernatant of the sample obtained by UV analysis at nm, and the presence of colchicine at a concentration of 1 to 27,500 μg per mL of sterile, injectable dosage form. 2. The pharmaceutical composition for use according to claim 1, wherein the dissolution rate of colchicine is 80% (w / w) over 1 to 6 months, 2 to 6 months, or 3 to 6 months. 3. The pharmaceutical composition for use according to claim 1 or 2, wherein the controlled-release dosage form containing colchicine is an in-situ formed reservoir or particulate form, particularly particulate or multi-capsule liposome form comprising a polymer matrix. 4. The pharmaceutical composition for use according to any one of the preceding claims, wherein the colchicine-containing controlled-release formulation is in particulate form, particularly in particulate form comprising a polymer matrix, and the colchicine-containing particles have an average particle size equal to or greater than 10 μm as determined by laser diffraction, and particularly have an average particle size of less than 100 μm, more particularly less than 80 μm, and even more particularly less than 50 μm, for example, 10 to 50 μm or 10 to 40 μm. 5. The pharmaceutical composition for use according to claim 4, wherein the particles may be a mixture of particles of different properties, the particles being particles comprising colchicine and a polymer matrix, wherein the polymer matrix comprises: - at least one poly(lactic acid-co-glycolic acid) copolymer, particularly two copolymers exhibiting different molecular weights, - at least one poly(caprolactone), or - at least a mixture comprising at least a poly(lactic acid-co-glycolic acid) copolymer and at least poly(caprolactone).6. The pharmaceutical composition for use according to any one of claims 4 to 5, wherein the polymer matrix further comprises one or more additional polymers or copolymers selected from poly(lactide) copolymers other than poly(lactide-co-glycolic acid), poly(glycolic acid), poly(lactide-co-caprolactone), poly(ethylene glycol), poly(ethylene oxide), PLGA-b-PEO-b-PLGA, PLGA-b-PEO, polyhydroxyalkanoates, poly(hydroxybutyrate), poly(methyl methacrylate), poly(dioxane), poly(valerol), poly(α-hydroxy acid), poly(lactone), poly(amino acid), poly(aminophenol), poly(hydroxybutyrate), poly(hydroxybutyrate), poly(methyl methacrylate), poly(dioxane), poly(valerol), poly(α-hydroxy acid), poly(lactone), poly(aminophenol), poly(hydroxybutyrate ... (Acids), polyanhydrides, poly(orthoesters), poly(acetals), polyurethanes, polysulfides, polyphosphates, poly(ester-co-amides), poly(vinyl alcohol), PVA-g-PLGA, poly(ether ester) multiblock copolymers, polyvinylpyrrolidone, poly(methacrylates), PEO-PPO-PEO, gelatin, heparin, chondroitin sulfate; polysaccharides, such as alginates, starch, chitosan and dextran and any combination thereof, particularly selected from poly(lactide) and poly(caprolactone). 7. The pharmaceutical composition for use according to any one of claims 4 to 6, wherein, relative to the total weight of the polymer matrix, the polymer matrix comprises, by weight, at least one poly(lactic acid-co-glycolic acid) copolymer, at least one polycaprolactone, or a mixture comprising at least said amounts of at least said poly(lactic acid-co-glycolic acid) copolymer and at least polycaprolactone, wherein, in particular, the lactic acid:glycolic acid molar ratio of the poly(lactic acid-co-glycolic acid) copolymer is 50:50 to 90:10, particularly 55:45 to 90:10, more particularly 65:35 to 85:15, for example 75:25, wherein, in particular, the poly(lactic acid-co-glycolic acid) copolymer exhibits the characteristics according to USP <911> The intrinsic viscosity, measured by an Ubbelohde capillary viscometer, is 0.1 to 1.7 dl / g, particularly 0.1 to 1.4 dl / g, and even more particularly 0.1 to 0.9 dl / g. Claims 1 / 3 page 2 CN 121013711 A 8. A pharmaceutical composition for use according to any one of the preceding claims, wherein it is in a sterile and injectable dosage form selected from solutions, suspensions, solid implants, semi-solid implants, powders, and in-situ repositories.9. The pharmaceutical composition for use according to any one of the preceding claims, wherein it further comprises an anesthetic agent selected from lidocaine, ropivacaine, bupivacaine, levobupivacaine, capsaicin, mepivacaine, prilocaine, pharmaceutically acceptable salts thereof, and mixtures thereof, particularly selected from lidocaine, bupivacaine, ropivacaine, and mepivacaine, and more particularly from ropivacaine and bupivacaine, and even more particularly from ropivacaine. 10. The pharmaceutical composition for use according to claim 8 or 9, wherein colchicine is present at a concentration of 1 to 27,500 μg per mL of a sterile and injectable dosage form, particularly a suspension, particularly 3 to 27,500 μg per mL, more particularly 1 to 13,750 µg per mL, for example, 3 to 13,750 µg per mL, and even more particularly, wherein colchicine is present at a concentration of 3 to 3,600 µg per mL, such as 3 to 600 µg per mL when the dissolution rate of colchicine is 80% (wt / wt) over a period of more than 1 month but less than 2 months, such as 9 to 1,800 µg per mL when the dissolution rate of colchicine is 80% (wt / wt) over a period of 2 to 4.5 months, and such as 18 to 3,600 µg per mL when the dissolution rate of colchicine is 80% (wt / wt) over a period of 4.5 to 7 months. µg, and wherein, when an anesthetic is present, the anesthetic is present at a concentration of 1 to 100 mg per mL of sterile and injectable dosage form, particularly a suspension. 11. A pharmaceutical composition for use according to any one of the preceding claims, for treating osteoarthritis, erosive osteoarthritis of the hand, and any other type of chondropathy in patients with inflammatory components, inflammatory pain, or joint effusion. 12. A pharmaceutical composition for use according to any one of the preceding claims, characterized in that it effectively maintains a systemic concentration of colchicine below 5 ng / mL, particularly below 1 ng / mL, more particularly below 0.5 ng / mL, and even more particularly below 0.1 ng / mL, within 24 hours after intra-articular injection, particularly within 1 month, and even more particularly within at least 3 months, and effectively maintains a synovial concentration of colchicine above 0.5 ng / mL, particularly between 0.5 and 100 ng / mL, and even more particularly between 0.5 and 50 ng / mL, within 1 month after intra-articular injection, and even more particularly within 3 months.13. A pharmaceutical composition for use according to any one of the preceding claims, wherein it is used to treat a patient with arthropathy, such as osteoarthritis, erosive osteoarthritis of the hand, and any other type of chondropathy, and / or to treat a patient with pain-related arthropathy, and / or to protect a patient's joints, bones, and / or cartilage, particularly for treating a patient with osteoarthritis and / or pain-related osteoarthritis, said patient having kidney and / or liver damage, said patient being treated simultaneously, separately, or sequentially and non-exclusively with at least one active ingredient selected from the group consisting of. Atazanavir, clarithromycin, darunavir, ritonavir, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, telanavir, ampravir, aprepitant, diltiazem, erythromycin, fluconazole, fosanavir, verapamil, cyclosporine, ranolazine, macrolides and statins, or the patient has chronic comorbidities such as hypertension, chronic kidney disease, diabetes, cardiovascular disease, infection, stroke, depression, peptic ulcer, metabolic syndrome and / or immunosuppression. 14. A sterile and injectable dosage form of a pharmaceutical composition comprising a controlled-release formulation containing colchicine, wherein the pharmaceutical composition exhibits in vitro dissolution characteristics, wherein the dissolution rate of colchicine is less than 25% (w / w) over 24 hours, and more preferably less than 15% (w / w), and greater than 80% (w / w) over more than one month, particularly over three months, and even more particularly over six months, as determined according to the following protocol: 20 mg aliquots of the controlled-release formulation containing colchicine are suspended in 50 mL of phosphate buffer (pH 7.4) with stirring at 37°C; then, throughout the duration of release, the supernatant of the sample taken out is periodically analyzed by UV at 350 nm, and the colchicine is present at a concentration of 1 to 27,500 μg per mL of sterile and injectable dosage form.15. A powder formulation comprising a controlled-release formulation containing colchicine in the form of microparticles, said microparticles having an average particle size equal to or greater than 10 µm as determined by laser diffraction, said microparticles comprising a polymer matrix, wherein, relative to the total weight of the polymer matrix, said polymer matrix comprises, by weight, at least 70%, particularly at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at least a mixture comprising at least said amounts of at least a poly(lactic-co-glycolic acid) copolymer and at least polycaprolactone, wherein, particularly, the lactic acid:glycolic acid molar ratio of the poly(lactic-co-glycolic acid) copolymer is 50:50 to 90:10, particularly 55:45 to 90:10, for example 60:40 to 90:10, more particularly 65:35 to 85:15, for example 75: 25, in particular, poly(lactic acid-co-glycolic acid) copolymers exhibit the characteristics specified in USP <911> The intrinsic viscosity, measured by an Ubbelohde capillary viscometer, is 0.1 to 1.7 dl / g, particularly 0.1 to 1.4 dl / g, and even more particularly 0.1 to 0.9 dl / g. 16. A sterile and injectable dosage form of pharmaceutical composition suitable for intra-articular injection, said pharmaceutical composition being obtained by mixing a powdered formulation according to claim 15 with an aqueous injection solvent, said pharmaceutical composition optionally comprising an excipient selected from tensile enhancers, wetting agents, viscosity enhancers, density enhancers, or mixtures thereof, and said excipient may be present in the aqueous injection solvent or in the powder, and optionally comprising hyaluronic acid.17. A sterile and injectable pharmaceutical composition suitable for intra-articular injection, comprising a controlled-release formulation containing colchicine, said controlled-release formulation being in the form of microparticles comprising a polymer matrix having an average particle size equal to or greater than 10 µm as determined by laser diffraction, wherein, relative to the total weight of the polymer matrix, the polymer matrix comprises, by weight, at least 70%, particularly at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at least a mixture comprising at least said amounts of at least a poly(lactic-co-glycolic acid) copolymer and at least polycaprolactone, wherein, in particular, the lactic acid:glycolic acid molar ratio of the poly(lactic-co-glycolic acid) copolymer is 50:50 to 90:10, particularly 55:45 to 90:10, for example 60:40 to 90:10, more particularly 65:35 to 85:15, for example 75: 25, in particular, poly(lactic acid-co-glycolic acid) copolymers exhibit the characteristics specified in USP <911> The intrinsic viscosity, as determined by an Ubbelohde capillary viscometer, is 0.1 to 1.7 dl / g, particularly 0.1 to 1.4 dl / g, and even more particularly 0.1 to 0.9 dl / g. 18. A sterile and injectable pharmaceutical composition according to claim 16 or 17, wherein the pharmaceutical composition is selected from solutions, suspensions, solid implants, semi-solid implants, powders, and in-situ reservoirs, particularly suspensions, and wherein colchicine is present at a concentration of 1 to 27,500 μg per mL of sterile and injectable dosage form, particularly suspension, particularly 3 to 27,500 μg, and even more particularly 1 to 13,750 µg per mL, for example 3 to 13,750 µg per mL. 19. A cassette or article comprising, in separate compartments: (i) an aqueous injection solvent and (ii) a controlled-release dosage form containing colchicine as defined in any one of claims 3 to 7 or a powder as defined in claim 15, wherein the cassette or article optionally contains an excipient selected from tension enhancers, wetting agents, viscosity enhancers, density enhancers, and mixtures thereof, and optionally contains hyaluronic acid for preparing a pharmaceutical composition suitable for intra-articular injection, wherein (i) and / or (ii) optionally contains an anesthetic in an immediate-release dosage form. 20. The cassette or article of claim 19, wherein the cassette or article is in the form of a vial and a pre-filled syringe, or in the form of a medical device, or in the form of two separate vials.Claims 3 / 3 Page 4 CN 121013711 A Intra-articular injection formulation containing colchicine for treating joint diseases such as osteoarthritis

[0001] The present invention relates to the field of treating joint diseases, such as osteoarthritis, erosive hand osteoarthritis (EHOA), and any other type of cartilage disease and / or pain-related joint diseases by administering colchicine into the joint, and / or protecting joints, bones, and / or cartilage. Colchicine is administered locally via a controlled-release formulation by intra-articular injection.

[0002] Background

[0003] Osteoarthritis (OA) is a multifactorial degenerative joint disease characterized, in particular, by chronic pain, leading to cartilage and tissue destruction, as well as subchondral bone remodeling and mild synovitis. OA is very common and is usually an age- or trauma-related disease, but its phenotypes are diverse (genetic, inflammatory, metabolic, aging, etc.) and often affect the knee, hip, hand, or spinal joints. Synovitis or mild localized inflammation is a common feature of OA and can be a driving factor in disease progression at times, including OA caused by the NLRP3 inflammasome pathway. More specifically, calcium crystals (calcium phosphate and calcium pyrophosphate) often present in OA joints can contribute to joint inflammation. Erosive osteoarthritis of the hand (EHOA) is the most aggressive form of osteoarthritis of the hand, primarily affecting women, characterized by inflammation and erosion of the distal or proximal interphalangeal joints and acute onset of pain, leading to disability and decreased quality of life.

[0004] Treatment for osteoarthritis, EHOA, and any other type of rickets is most commonly symptomatic and aimed at controlling pain, but provides only moderate effectiveness and has safety concerns. Generally, first-line options are primarily oral nonsteroidal anti-inflammatory drugs (NSAIDs), oral or intra-articular corticosteroids.

[0005] Intra-articular administration of corticosteroids has been used extensively in arthropathy for decades, providing slight improvement in pain and mobility, but the effects are not long-lasting (lasting several weeks in the case of immediate-release formulations). However, the toxicological aspects of these administrations are problematic and controversial. In fact, systemic effects have been reported weeks after injection, including Cushing's syndrome, hyperglycemia, decreased bone mineral density, or increased risk of infection. The latter is a direct introduction of infectious agents into the joint or a result of reduced immune response and reactivation of latent tuberculosis infection. This type of treatment is particularly unsuitable for patients at risk, such as those with comorbidities like diabetes or osteoporosis. Additionally, adverse effects on local tissues, such as damage to articular cartilage and tendons, have been described.

[0006] Therefore, the frequency and dosage of intra-articular injections of corticosteroids are limited in medical practice.Therefore, for immediate-release galen formulations, a maximum of three injections per year / per site is recommended, with a minimum interval of three months between injections. The first intra-articular sustained-release corticosteroid formulation (Zilretta® from Flexion Therapeutics) was approved by the FDA in 2017 for osteoarthritis and associated pain, particularly knee osteoarthritis, allowing for continuous treatment for several months. However, this product is not approved for repeated administration.

[0007] Therefore, intra-articular administration of corticosteroids does not appear to be the optimal treatment for long-term osteoarthritis.

[0008] Colchicine is a drug characterized by pleiotropic effects, which are associated with its ability to bind to tubulin and disrupt microtubule polymerization, causing instability of the cytoskeleton and all cellular processes, including cell division, migration, and cell shape. Among these effects, colchicine affects the immune system and downregulates multiple inflammatory pathways, leading to decreased neutrophil function and migration. Therefore, colchicine is used and approved for several inflammatory diseases, such as familial Mediterranean fever, Behçet's disease, and microcrystal disease.

[0009] Colchicine has indeed been used for the nonspecific treatment of crystal-related arthropathy for a long time. Over the past 50 years, short-course, rapidly acting NSAIDs and corticosteroids have been considered as first-line oral medications for the symptomatic treatment of acute gout and pseudogout. The prophylactic and therapeutic efficacy of oral colchicine is reviewed in the article George Nuki, MB, FRCP “Colchicine: its Mechanism of Action and Efficacy in Crystal-Induced Inflammation”, Current Rheumatology Reports, 2008, 10: 218-227. Still in the aforementioned article, the side effects of colchicine, such as strong laxative effects, myelosuppression, neuromyopathy, and rhabdomyolysis, are described extensively, particularly in patients with renal insufficiency, as well as the high mortality associated with overdose. Therefore, the therapeutic index of colchicine is very narrow.

[0010] Colchicine is not currently approved for the treatment of osteoarthritis; however, some clinical studies have shown that oral colchicine may help treat adult patients with knee osteoarthritis, including primary osteoarthritis, which is osteoarthritis not associated with calcium pyrophosphate crystal deposition.However, oral administration of colchicine at test doses may cause side effects, such as gastrointestinal symptoms observed in some patients (Restrepo-Escobar M et al. Revisión sistemática de la literatura sobre el tratamiento con colchicina en pacientes adultos con osteoartritis de rodilla. Rev Colomb Reumatol. 2017; 24: 102–111) and other reviews have not demonstrated such benefits (Singh, A. et al. Efficacy and safety of colchicine for the treatment of osteoarthritis: a systematic review and meta-analysis of intervention trials. Clin Rheumatol (2022)).

[0011] Furthermore, although it is known to treat inflammation or osteoarthritis in the joint by administering the active substance directly, i.e., in situ, it has been found that the active substance escapes relatively easily from the joint, thus reducing the therapeutic effect.

[0012] Encapsulation of colchicine in various carriers, such as polymer microspheres, for sustained release has been reported (Das, GS et al. “Colchicine Encapsulation within Poly(Ethylene Glycol)-Coated Poly(Lactic Acid) / Poly(ε-Caprolactone) Microspheres-Controlled Release Studies” Drug Delivery, 7: 7544, 129–138 (2000)). In this article, colchicine has been investigated for the treatment of other conditions, such as restenosis after angioplasty or vascular injury, in which case attempts were made to encapsulate colchicine in poly(lactic acid) / poly(ε-caprolactone) microspheres for local delivery of colchicine.Another composition comprising biodegradable microcapsules containing colchicine is further described, seeking to treat the same pathological condition, restenosis, via intramural delivery, as described in Gradus-Pizlo Irmina et al: local delivery of biodegradable microcapsules containing colchicine or a colchicine analogue: effects on restenosis and implications of catheter-based drug delivery, Journal of The American College of Cardiology, vol. 26, no. 6, pages Reported in 1549-1557. It is evident that the therapeutic target described is completely different from the therapeutic target of the present invention. Furthermore, the results were not encouraging and indicated a risk of toxicity. In fact, signs of local toxicity were observed in the muscle layer covering and supplied by the artery, which was infused with microparticles containing colchicine or colchicine analogues, but not with control microparticles. It is also noteworthy that in both disclosures, the particle size is smaller than that of the particles implemented in the present invention, as will be apparent in the following description. Furthermore, no long-term treatment, i.e., treatment exceeding one month, is disclosed or suggested.

[0013] In addition, colchicine has previously been reported in US5,747,060 for other effects different from those involved in the framework of this invention, such as the effect of prolonging the duration of anesthetic effects produced by local administration of anesthetics. Therefore, in Example 1 of the aforementioned document, colchicine and bupivacaine were co-administered around the sciatic nerve in an immediate-release formulation, i.e., bupivacaine added directly to an aqueous solution. Intra-articular injection is not described in the aforementioned document, nor is the activity of colchicine in the treatment of intra-articular osteoarthritis described, let alone its sustained-release effect.

[0014] WO2006 / 066419 discloses the same effect of colchicine in prolonging its anesthetic effect, i.e., vanillin is described in the specification, page 2 / 37, 6 CN 121013711 A The combination of a systemic agonist and another molecule—which may be colchicine. One embodiment discloses a composition comprising a mixture of resin toxin and colchicine, which is injected intra-articularly for the treatment of bursitis. However, the injection is specifically intended for immediate release, without seeking to control the local properties and systemic pharmacokinetics of colchicine, nor to prolong its therapeutic exposure.

[0015] The use of colchicine for the treatment of lens-related arthropathy has been well established.However, colchicine is currently commercialized only in immediate-release oral formulations, typically at a daily dose of approximately 1 mg for the treatment of lens-related arthropathy. The FDA-approved dose for acute gout attacks is 1.2 mg colchicine at the first sign of an attack, followed by 0.6 mg one hour later (https: / / www.fda.gov / drugs / postmarket-drug-safety-information-patients-and-providers / colchicine-marketed-colcrys-information). EULAR recommends colchicine as a first-line treatment for acute attacks as a loading dose of 1 mg, followed by 0.5 mg one hour later (Richette, P. et al. 2016 updated EULAR evidence-based recommendations for the management of gout, Ann. Rheum. Dis. 76, 29–42 (2017)). However, as explained above and further elaborated hereafter, local attainment of therapeutically active doses of colchicine is hampered by low tolerability or high toxicity of orally administered colchicine, making drug formulation extremely complex.

[0016] Colchicine in a nanoemulsion system injected into the joints of a Swiss albino mouse model suffering from MSU (sodium urate) crystal-induced gouty arthritis has recently been described: Aboumanei et al. “intra-articular formulation of colchicine loaded nanoemulsion systems for enhanced locoregional drug delivery: In vitro characterization, 99mTc coupling and in vivo biodistribution studies”, DOI: 10.1080 / 03639045.2021.1934865. The biodistribution patterns of 99mTc-ColNE-5 and 99mTc-Col solution (99mTcColS) were investigated. However, the disclosure is limited to observations of radiolabeled colchicine, which are therefore molecules distinct from colchicine itself and within a timeframe of no more than 24 hours.It is well known that labeling with radionuclides such as 99mTc can strongly influence the biodistribution patterns of labeled entities due to changes in their charge, lipophilicity, and stability (Decristoforo et al. “The influence of chelator on the pharmacokinetics of 99mTc-labeled peptides.” QJ NUCL. MED. 46 3 (2002): 195-205). Furthermore, the article does not address the technical issues of a narrow therapeutic index as explained above, and specifically regarding colchicine, i.e., the maximum systemic concentration to be avoided due to toxicity. Therefore, the article also does not mention microparticle systems with larger sizes and higher target doses, which can achieve effective local concentrations to combat osteoarthritis without systemic toxicity. As shown in Figure 3 of the article, ColNE-5, the "colchicine nanoemulsion system," provides 40% colchicine release in less than 3 hours. This contradicts the requirement of this invention to achieve controlled systemic concentrations of colchicine to avoid side effects, and the time required to release 80% of the colchicine by weight is greater than one month. This indicates that achieving such a rapid release, also known as a "burst release," immediately after administration is a non-obvious method that cannot be predicted from the article. As explained below, such rapid release immediately after administration, also known as a "burst release," may be harmful in terms of the level of side effects. In other words, the article does not reveal controlled-release properties of colchicine suitable for human rehabilitation, or even more specifically for the treatment of osteoarthritis.

[0017] Intravenous administration of colchicine is considered effective in the treatment of acute gout attacks, with each single injection dose not exceeding 2–3 mg (Nuki, G. Colchicine: Its mechanism of action and efficacy in crystal-induced inflammation. Curr. Rheumatol. Rep. 10, 218–227 (2008)).However, even though intravenous administration can avoid gastrointestinal side effects, inappropriate administration is associated with serious toxicity (Wallace SL, S. J. Review: systemic toxicity associated with the intravenous colchicine administration - guidelines for use. J Rheumatol. 15, 495–9 (1988), Bonnel, R. A., Villalba, ML, Karwoski, CB & Beitz, J. Deaths associated with inappropriate intravenous colchicine administration. J. Emerg. Med. 22, 385–387 (2002)). This led the regulatory authorities to rule out the use of intravenous colchicine for the treatment of acute gout (Zhang, W. et al. EULAR vidence-based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT), Ann. Rheum. Dis. 65, 1312–1324 (2006)). Furthermore, attempts at intravenous colchicine administration have largely hindered the development of this approach in the field, as reported in E. Niel et al., “Colchicine today”, Joint Bone Spine 73 (2006) 672–678.

[0018] Therefore, there is still a need to develop new formulations, routes of administration and targeted doses of colchicine, both to eliminate side effects, particularly those observed during systemic administration, and to improve efficacy by optimizing the available dose of colchicine, particularly to prolong the duration of its local action at the site of pain, particularly by increasing local concentrations, for the treatment of arthropathy, such as osteoarthritis, erosive osteoarthritis of the hand and any other type of chondropathy, and / or for the treatment of pain-related arthropathy and / or for the protection of joints, bones and / or cartilage, particularly for the treatment of osteoarthritis and / or pain-related osteoarthritis.

[0019] The object of the present invention is to meet the need for further advantages by its effect against pain and / or damage to the articular cartilage of patients suffering from arthropathy, such as osteoarthritis, erosive osteoarthritis of the hand and any other type of chondropathy, and / or pain-related arthropathy, such as osteoarthritis and any other type of chondropathy, and / or pain-related arthropathy, particularly arthritis, and to limit the level of any side effects, including the level of any side effects in patients with osteoarthritis, erosive osteoarthritis of the hand and any other type of chondropathy accompanied by inflammatory components, inflammatory pain or joint effusion. The object of the present invention is also to enhance the protection of joints, bones and / or cartilage in patients suffering from arthropathy and any other type of chondropathy and / or pain-related arthropathy.

[0020] One advantage of the present invention is that it provides a novel means of achieving specific colchicine release characteristics that emphasizes an appropriate ratio between the local concentration and its systemic concentration of colchicine, suitable for providing optimal therapeutic effect locally while avoiding potential systemic toxicity, while providing immediate and reduced pain and inflammation relief throughout the treatment period with only a single intra-articular injection, which can last for more than one month, for example, 1 to 6 months, and is renewable. In embodiments where anesthetics are administered simultaneously, as will be described in more detail below, co-administration of anesthetics can rapidly relieve pain.

[0021] Due to the reduction in side effects obtained by administering the pharmaceutical composition according to the invention, it is also particularly suitable for people suffering from chronic comorbidities (hypertension, chronic kidney disease, diabetes, cardiovascular disease, infection, stroke, depression, peptic ulcer, metabolic syndrome, and / or immunosuppression, etc.) that are quite common in osteoarthritis. In fact, the management of patients with multiple comorbidities remains a challenge for medical practitioners due to the common and major contraindications of nonsteroidal anti-inflammatory drugs or corticosteroids. Compared with existing oral colchicine treatments, the present invention, in addition to avoiding gastrointestinal side effects, also prevents the major toxicity risks in patients with kidney or liver damage or those co-administering with CYP3A4 / PGP drug inhibitors (which are quite common drugs).

[0022] Figure 1 shows the results of ankle joint inflammation scores in rats, used to evaluate the protective effect of the combination according to the invention on bone and cartilage in an in vivo model, as shown in Example 9.

[0023] Summary of the Invention

[0024] This document provides a sterile and injectable dosage form of a pharmaceutical composition comprising a controlled-release dosage form containing colchicine, for the treatment of arthropathy, such as osteoarthritis and any other type of chondropathy and / or pain-related arthropathy, by intra-articular injection of the pharmaceutical composition into the joint, wherein the time required for the release of 80% by weight of colchicine is greater than one month, and wherein colchicine is present in a concentration range of 0.003 to 27.5 mg per mL of sterile and injectable dosage form.

[0025] According to a first aspect, this document provides a sterile and injectable dosage form of a pharmaceutical composition comprising a controlled-release formulation containing colchicine, for the treatment of arthropathy, such as osteoarthritis, erosive osteoarthritis of the hand, and any other type of chondropathy, and / or for the treatment of pain-related arthropathy and / or for the protection of joints, bones, and / or cartilage, by intra-articular injection of the pharmaceutical composition into a joint, wherein the dissolution rate of colchicine is 80% (w / w) over more than one month, as determined according to the following protocol:

[0026] An aliquot of 20 mg of the controlled-release formulation containing colchicine is suspended in 50 mL of phosphate buffer (pH 7.4) with stirring at 37°C; the supernatant of the sample taken out is then periodically analyzed by UV at 350 nm throughout the duration of release, and

[0027] wherein colchicine is present at a concentration ranging from 1 to 27,500 μg per mL of sterile and injectable dosage form.

[0028] This document also provides a sterile and injectable dosage form of a pharmaceutical composition comprising a controlled-release formulation containing colchicine, wherein the pharmaceutical composition exhibits in vitro dissolution characteristics, wherein less than 25% of colchicine, more preferably less than 15% of colchicine is released within 24 hours, and more than 80% of colchicine is released within at least one month, particularly within three months, and even more particularly within six months, and wherein colchicine is present at a concentration range of 0.003 to 27.5 mg per mL of sterile and injectable dosage form.

[0029] According to a second aspect, this document provides a sterile and injectable dosage form of a pharmaceutical composition comprising a controlled-release formulation containing colchicine, wherein the pharmaceutical composition exhibits in vitro dissolution characteristics, wherein the dissolution rate of colchicine is less than 25% (w / w) over 24 hours, and more preferably less than 15% (w / w), and greater than 80% (w / w) over more than one month, particularly over three months, and even more particularly over six months, as determined according to the following protocol:

[0030] An aliquot of 20 mg of the controlled-release formulation containing colchicine is suspended in 50 mL of phosphate buffer (pH 7.4) with stirring at 37°C; the supernatant of the sample taken is then periodically analyzed by UV at 350 nm throughout the release duration, and

[0031] wherein colchicine is present at a concentration of 1 to 27,500 μg per mL of sterile and injectable formulation, and particularly 3 to 27,500 μg per mL of sterile and injectable formulation.

[0032] According to a third aspect, this document provides a powder formulation comprising a controlled-release formulation containing colchicine, said controlled-release formulation being a particulate form comprising a polymer matrix, said particulate having an average particle size equal to or greater than 10 µm as determined by laser diffraction, wherein, relative to the total weight of the polymer matrix, said polymer matrix comprises, by weight, at least 70%, particularly at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at least 90%, of at least one poly(lactic acid-co-glycolic acid) copolymer, at least one polycaprolactone, or at least a mixture comprising said amounts of at least one poly(lactic acid-co-glycolic acid) copolymer and at least one polycaprolactone, wherein, in particular, the lactic acid:glycolic acid molar ratio of the poly(lactic acid-co-glycolic acid) copolymer is 50:50 to 90:10, particularly 55:45 to 90:10, for example 60:40 to 90:10, more particularly 65:35 to 85:15, for example 75: 25, in particular, poly(lactic acid-co-glycolic acid) copolymers exhibit the characteristics specified in USP <911> The intrinsic viscosity, measured by an Ubbelohde capillary viscometer, is 0.1 to 1.7 dl / g, particularly 0.1 to 1.4 dl / g, and even more particularly 0.1 to 0.9 dl / g.

[0033] According to a fourth aspect, this document provides a sterile and injectable dosage form of a pharmaceutical composition suitable for intravenous injection as per section A of CN 121013711, page 5 / 37 of the specification, obtained by mixing a powdered formulation according to the invention with an aqueous injection solvent, wherein the pharmaceutical composition optionally comprises an excipient selected from tensile enhancers, wetting agents, viscosity enhancers, density enhancers, or mixtures thereof, and wherein the excipient may be present in the aqueous injection solvent or in the powder.

[0034] According to a fifth aspect, this document provides a sterile and injectable pharmaceutical composition suitable for intra-articular injection, comprising a controlled-release formulation containing colchicine, said controlled-release formulation being in the form of microparticles comprising a polymer matrix, said microparticles having an average particle size equal to or greater than 10 µm as determined by laser diffraction, wherein, relative to the total weight of the polymer matrix, said polymer matrix comprises, by weight, at least 70%, particularly at weight, at weight, at weight, at weight, or even more particularly at weight, at weight, at least 90% of at least one poly(lactic acid-co-glycolic acid) copolymer, at least one polycaprolactone, or at least a mixture comprising said amounts of at least one poly(lactic acid-co-glycolic acid) copolymer and at least one polycaprolactone, wherein, in particular, the lactic acid:glycolic acid molar ratio of the poly(lactic acid-co-glycolic acid) copolymer is 50:50 to 90:10, particularly 55:45 to 90:10, for example 60:40 to 90:10, more particularly 65:35 to 85: 15, for example 75:25, wherein, in particular, the poly(lactic acid-co-glycolic acid) copolymer exhibits the characteristics specified in the USP. <911> The intrinsic viscosity, measured by an Ubbelohde capillary viscometer, ranges from 0.1 to 1.7 dl / g, particularly from 0.1 to 1.4 dl / g, and even more particularly from 0.1 to 0.9 dl / g.

[0035] According to a sixth aspect, this document provides a kit or article comprising, in separate compartments: (i) an aqueous injection solvent and (ii) a controlled-release formulation containing colchicine as defined herein, or a powder as defined herein, wherein the kit or article optionally contains an excipient selected from tension enhancers, wetting agents, viscosity enhancers, density enhancers, and mixtures thereof, and optionally contains hyaluronic acid, for preparing a pharmaceutical composition suitable for intra-articular injection, wherein (i) and / or (ii) optionally contains an anesthetic in an immediate-release formulation.

[0036] Pharmaceutical compositions suitable for intra-articular injection as described herein effectively treat arthropathy, such as osteoarthritis, erosive osteoarthritis of the hand, and / or any other type of chondropathy and / or pain-related arthropathy, particularly osteoarthritis and / or pain-related osteoarthritis, with minimal long-term side effects. It also effectively protects joints, bones, and / or cartilage, particularly in patients suffering from arthropathy and any other type of chondropathy and / or pain-related arthropathy.

[0037] The pharmaceutical composition suitable for intra-articular injection is suitable for local administration by injection at or near the site of pain.

[0038] Detailed Description of the Invention

[0039] As is evident from the background paragraph above, caution is now exercised in the formulation of colchicine because only oral compositions are available, and high toxicity risks, such as gastrointestinal symptoms and neuromuscular involvement, have been observed. Risks associated with interactions with other active agents have been further reported.Furthermore, although the use of colchicine is sometimes described as promoting the treatment of osteoarthritis, frankly, toxicity limitations have hindered local injection for decades.

[0040] In fact, it has been established in the literature that the recommended effective local dose of colchicine is 0.015 mg / kg to 0.030 mg / kg, with the toxicity limit at 0.1 mg / kg and the lethal dose at 0.8 mg / kg (E. Niel et al., “Colchicine today”, Joint Bone Spine 73 (2006) 672-678). Therefore, it is concluded that the narrow therapeutic window of colchicine is the source of concern for prescribing physicians.

[0041] The inventors have found that intra-articular injection of the pharmaceutical composition according to the invention for controlled release of colchicine has at least comparable and even higher efficacy compared to oral colchicine or intra-articular corticosteroids for the treatment of arthralgia.

[0042] Once colchicine is administered and during the release of colchicine, the present invention provides treatment for arthropathy, particularly osteoarthritis, erosive osteoarthritis of the hand, and any other type of chondropathy and / or pain-related arthropathy, more particularly for the treatment of osteoarthritis, and / or better pain relief and / or protection of joints, bones and / or cartilage. In the present invention, the time required for the release of 80% by weight of colchicine, particularly from controlled-release formulations containing it, and more particularly from microparticles, is greater than one month, and particularly from one to six months, and the colchicine is present at a concentration of 1 to 27,500 μg per mL of sterile and injectable formulation, particularly a suspension, particularly 3 to 27,500 μg per mL.

[0043] Osteoarthritis not only induces cartilage degeneration and associated chronic pain, but can also have very severe, sudden onset. Therefore, having a treatment regimen perfectly suited to achieve the most appropriate dosage is crucial.

[0044] The use or treatment method according to the invention also has the advantage of reducing significant toxicity risks associated with drug interactions with colchicine when administered systemically, particularly in elderly patients or those with renal or hepatic failure, as explained below.

[0045] Compared to intra-articular corticosteroids, this treatment also has the advantage of avoiding systemic effects such as Cushing's syndrome, hyperglycemia, hypertension, decreased bone mineral density, or even the risk of infection. Additionally, it reduces the risk of harmful effects on local tissues such as damage to articular cartilage and tendons.

[0046] Definitions

[0047] As used herein, the term "patient" means an animal that has or is likely to have osteoarthritis, such as a valuable animal used for breeding, companionship, or protection purposes, or preferably means a human or human child.

[0048] In particular, as used herein, the term "patient" means a mammal, including non-human mammals such as rodents, cats, dogs, or primates, or humans; preferably, the subject is human and also extends to birds.

[0049] The identification of patients requiring treatment for joint diseases, such as osteoarthritis, erosive osteoarthritis of the hand, and any other type of rickets and / or pain-related joint diseases, particularly those with osteoarthritis and / or pain-related osteoarthritis, including those with osteoarthritis, erosive osteoarthritis of the hand, or joint effusion, is entirely within the capabilities and knowledge of a person skilled in the art. Veterinarians or physicians skilled in the art can readily identify those patients requiring such treatment by using clinical tests, physical examinations, medical / family history, or biological and diagnostic tests.

[0050] In the context of this invention, as used herein, the term “treating” or “treatment” means reversing, alleviating, or inhibiting the progression of arthropathy, such as osteoarthritis, erosive osteoarthritis of the hand, and any other type of rickets and / or pain-related arthropathy, particularly osteoarthritis and / or pain-related osteoarthritis.

[0051] As used herein, “effective amount” means the amount of the compound of the invention that effectively reduces, eliminates, treats, or controls the symptoms of arthropathy, such as osteoarthritis, erosive osteoarthritis of the hand, and any other type of rickets and / or pain-related arthropathy, particularly osteoarthritis. The term “control” is intended to mean all processes in which the progression of arthropathy, such as osteoarthritis, erosive osteoarthritis of the hand, and any other type of rickets and / or pain-related arthropathy, particularly osteoarthritis and / or pain-related osteoarthritis, may be slowed, interrupted, prevented, or stopped, but does not necessarily indicate the complete elimination of such progression or the related symptoms detailed below.

[0052] The term “therapeutic effective dose” refers to the concentration of a compound that is effective in treating joint diseases, such as osteoarthritis, erosive osteoarthritis of the hand, and any other type of cartilage disease and / or pain-related joint diseases, particularly osteoarthritis and / or pain-related osteoarthritis, for example, when administered after inflammatory pain has already occurred, and which, upon examination, results in a reduction of inflammatory pain.

[0053] As used herein, the term “osteoarthritis” or “OA” includes all disorders and conditions associated with it, such as cartilage loss, associated inflammation and / or pain, and all types, origins, or categories of osteoarthritis.As mentioned above, OA is a degenerative disease, but symptoms can worsen for a period of time and then improve, which is called a sudden onset or abrupt change. Osteoarthritis includes a sudden onset of inflammation, or any progression associated with primary osteoarthritis, i.e., without a known cause, or any progression associated with secondary osteoarthritis, i.e., caused by any disease, such as chondropathy. Symptoms and / or signs associated with OA, especially with a sudden onset of OA, may include, for example, increased joint pain, swelling in the affected area, reduced range of motion in joint position, and / or increased fatigue due to pain.

[0054] As used herein, the term “erosive osteoarthritis of the hand” includes erosive osteoarthritis of the hand (EHOA), which is the most aggressive form of osteoarthritis of the hand, characterized by severe clinical onset and progression leading to joint damage, disability, and decreased quality of life. Clinical signs of inflammation associated with EHOA include acute onset of pain, swelling, and redness. Furthermore, EHOA is characterized by radiographic features such as central erosion, serrated and gull-wing lesions, and rare joint ankylosis.

[0055] As used herein, the term "chondropathy" includes any cause or disease leading to cartilage damage, such as chondromalacia, limb dislocation, chondromatosis, chondromalacia calcification, gout, hemochromatosis, Wilson's disease, acromegaly, oculomotor syndrome, collagen abnormalities, chronic neuropathy of any cause, Kashin-Beck disease, or any inflammatory rheumatic disease.

[0056] According to one embodiment, the use according to the invention is for the treatment of osteoarthritis, erosive hand osteoarthritis, and any other type of chondropathy in patients with inflammatory components, inflammatory pain, or joint effusion.

[0057] As used herein, the term "pharmaceuticalally acceptable" means those compounds, materials, excipients, compositions, or dosage forms that are suitable for contact with human and animal tissues within the limits of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problematic complications, and that are commensurate with a reasonable benefit / risk ratio.

[0058] The term “pharmaceutically acceptable carrier, adjuvant, or solvent” can refer to any pharmaceutically acceptable excipient, such as a non-toxic carrier, adjuvant, or solvent that does not impair the pharmacological activity of the compound formulated therewith.

[0059] Within the framework of this invention, the term “site of pain” or “area of ​​pain” refers to the joint region in which the injectable product causes pain. This can be the knee joint, hip joint, metacarpophalangeal joint, shoulder joint, wrist joint, elbow joint, metatarsophalangeal joint, ankle joint, vertebral joint, and midfoot joint.

[0060] The term “controlled-release composition” or “controlled-release microparticle” refers to a composition or microparticle that allows the release of a specified amount of active ingredient into the body over a specified time period, i.e., a specific pharmacokinetic characteristic. The term “controlled release” encompasses all types of release that differ from immediate release.In other words, the term “controlled release” is equivalent to “modified release” and encompasses delayed release as defined herein, as well as delayed release and pulsed release.

[0061] The terms “delayed release,” “extended release,” and “sustained release” are considered equivalent within the framework of this invention. This type of release means that the release is prolonged over time compared to immediate release; that is, it means that the active ingredient is released slowly over time, allowing the patient to ingest the drug less frequently. In other words, the active ingredient is released gradually over a specific period of time, and is generally also intended to reduce side effects by lowering the maximum concentration.

[0062] The term “drug loading” refers to the mass ratio of the drug in the microparticle to the mass of the microparticle.

[0063] The term “average particle size” or D50 refers to the particle diameter in micrometers that divides the particle volume distribution into half above and half below that diameter.

[0064] Of course, controlled release or modified release can be produced by a combination of immediate release and controlled release.

[0065] The term “D10 = x μm”, which is primarily used in the embodiments, means that 10% of the particles have a size of x μm or smaller.

[0066] The term “D90 = y μm” used primarily in the embodiments refers to 90% of the particles having a size of y μm or smaller. Of course, controlled release or modulated release can be produced by a combination of immediate release and controlled release.

[0067] A “dissolution curve” refers to an in vitro test that reports the cumulative amount of released active ingredient as a function of time. Dissolution data are derived from the conditions under which the measurements were performed and are described in this text. Specification 8 / 37 pages 12 CN 121013711 A

[0068] Colchicine

[0069] Colchicine is an alkaloid extracted from the bulbs of autumn crocus (Colchicum Autumnale). Its IUPAC name is N-[(7S)-1,2,3,10-tetramethoxy-9-oxo-6,7-dihydro-5H-benzo[a]hepten-7-yl]acetamide (CAS 64-86-8).

[0070]

[0071] Colchicine can exist in enantiomeric racemic forms. All of these forms are included within the scope of the invention.

[0072] Furthermore, it can exist in different crystalline forms depending on the solvent used to obtain them. Among the possible solvents, chloroform, dichloromethane, ethyl acetate, benzene, or any other suitable solvent may be mentioned. All such crystalline forms also constitute part of the invention.

[0073] It is primarily known as a gout inhibitor and as an anti-inflammatory agent utilizing its tubulin interaction activity. It is administered orally, although intravenous administration was also attempted but abandoned due to excessive toxicity.

[0074] Therapeutic Use and Methods

[0075] In one embodiment, the pharmaceutical composition suitable for intra-articular injection described herein delivers colchicine in a controlled-release manner at a dose such that the concentration level of colchicine at the treated joint site is higher than the systemic dose usually obtained after oral administration, i.e., higher than 5 nM (2 ng / mL), and the systemic concentration level is maintained below 15 nM (6 ng / mL) (Terkeltaub, RA et al. High versus low dosing of oral colchicine for early acute gout flare: Twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study, Arthritis Rheum. 62, 1060–1068 (2010)).

[0076] According to one embodiment, the pharmaceutical composition as defined above, available for use according to the invention, is used for the protection of joints, bones, and / or cartilage. "Protecting joints, bones, and / or cartilage" means that the occurrence of damage, defects, depressions, or thinning of joints, cartilage, and / or bone can be slowed, interrupted, prevented, or its development stopped. Example 9 below illustrates such an effect.

[0077] According to another embodiment, the pharmaceutical composition of the present invention is further characterized in that it effectively maintains a systemic concentration of colchicine below 5 ng / mL, particularly below 1 ng / mL, more particularly below 0.5 ng / mL, and even more particularly below 0.1 ng / mL, within 24 hours after intra-articular injection, particularly within 1 month, and even more particularly within at least 3 months; and effectively maintains a synovial fluid concentration of colchicine above 0.5 ng / mL, particularly between 0.5 and 100 ng / mL, and even more particularly between 0.5 and 50 ng / mL, within 1 month after intra-articular injection, and even more particularly within at least 3 months.

[0078] The specific release characteristics that achieve both tolerable systemic concentrations of colchicine and suitable local concentrations for appropriate therapeutic effects have never been obtained before, representing the core of this invention. The results show that by employing the pharmaceutical composition according to the invention, a specific ratio between the local or synovial concentration of colchicine and the systemic concentration of colchicine, i.e., with specific in vitro dissolution rates and / or in vivo release rates, the inventors have discovered a surprisingly suitable means for treating patients while avoiding side effects.Instructions for Use, page 9 / 37, 13 CN 121013711 A

[0079] According to a specific embodiment, the ratio between the local or synovial fluid concentration of colchicine obtained after injection of the pharmaceutical composition according to the invention into a joint and the systemic concentration of colchicine can be 100 to 2000 in humans, as described / mentioned in: 1) Petit, A., Redout, EM, van de Lest, CH, de Grauw, JC, Müller, B., Meyboom, R., van Midwoud, P., Vermonden, T., hennink, W. E., & René van Weeren, P. (2015). Sustained intra-articular release of celecoxib from in situ forming gels made of acetyl-capped PCLA-PEG-PCLA triblock copolymers in horses. Biomaterials, 53, 426–436, https: / / doi.org / 10.1016 / j.biomaterials.2015.02.109 and 2) Kraus VB, Conaghan PG, Aazami HA, Mehra P, Kivitz AJ, Lufkin J, Hauben J, Johnson JR, Bodick N. Synovial and systemic pharmacokinetics (PK) of triamcinolone acetonide (TA) following intra-articular (IA) injection of an extended-release microsphere-based.

[0080] To determine the local and systemic concentrations of the colchicine, those skilled in the art may use any known method. For example, LC-MS analysis may be used.

[0081] The description of the specific control of colchicine release implemented within the framework of the present invention can also be illustrated by in vitro dissolution profiles as performed in Examples 1 to 3.

[0082] According to one embodiment, the dissolution medium that can be used to perform such dissolution tests may be phosphate buffer (pH 7.4).

[0083] According to one embodiment, the stirring speed can be 50 to 200, particularly 60 to 100 rpm. This stirring can be achieved by a shaking incubator, particularly a shaking incubator with horizontal movement.

[0084] According to one embodiment, the dissolution of colchicine is measured, for example, by using UV analysis of a UV spectrophotometer, for example at 350 nm, at different time intervals, for example, 24 hours, 1 month, 3 months, and 6 months.

[0085] Thus, the measurement conditions for the colchicine dissolution profile are described below:

[0086] An aliquot of 20 mg of a controlled-release formulation containing colchicine is suspended in 50 mL of phosphate buffer (pH 7.4) with stirring at 37°C; then, the supernatant of the sample is periodically taken out by UV analysis at 350 nm throughout the release duration.

[0087] For example, the dissolution test of colchicine microparticles can be performed according to the method detailed below:

[0088] An aliquot of 20 mg microparticles is suspended in 50 mL of phosphate buffer (pH 7.4) and kept at 37°C in a horizontal shaker at 80 rpm. At different time intervals, 3 mL of the sample is removed and replaced with fresh medium. The removed sample is centrifuged at 4000 rpm for 3 minutes. The supernatant is analyzed by UV at 350 nm.

[0089] As mentioned above, locally administered controlled-release formulations are used to treat patients with arthropathy, such as osteoarthritis, erosive osteoarthritis of the hand, and any other type of chondropathy and / or pain-related arthropathy, particularly osteoarthritis, including osteoarthritis with inflammatory components, inflammatory pain, or joint effusion, erosive osteoarthritis of the hand, and any other type of chondropathy, for pain and inflammation in the joints, and to enhance protection of the joints, bones, and / or cartilage of such patients. Topical administration of the preparation can be performed by injection into the intra-articular or peri-articular space at or near the site of pain in the patient, including the metatarsophalangeal joints, metacarpophalangeal joints, knee joints, shoulder joints, wrist joints, elbow joints, ankle joints, hip joints, vertebral joints, and midfoot joints. The midfoot is the forefoot, located between the posterior and anterior segments of the foot. It is composed of the cuboid, navicular, and three cuneiform bones. The midtarsal and tarsometatarsal joints connect the midfoot to the posterior and anterior segments of the foot, respectively. The midfoot is a complex and multifaceted region where edema and inflammation are typically diffuse.

[0090] In one embodiment, the invention is intended to treat joint pain in patients with osteoarthritis related to osteoarthritis.

[0091] In another embodiment, the invention is intended to treat patients with osteoarthritis, erosive hand osteoarthritis, and any other type of chondropathy accompanied by inflammatory components, inflammatory pain, or joint effusion.

[0092] Administration can be performed by a single injection, provided that the time required to release 80% by weight of colchicine in the microparticles is greater than one month, particularly between one and six months, and the colchicine is present at a concentration of 1 to 27,500 μg per mL of sterile and injectable dosage form, particularly a suspension, at a concentration of 3 to 27,550 μg, and the volume of the pharmaceutical composition is, for example, 0.1 mL to 5 mL. In other words, a single injection locally provides 0.3 to 137,500 μg, particularly 0.3 to 18,000 μg, of colchicine, i.e., the amount of colchicine released during the total release period after injection.

[0093] In one embodiment, multiple injections (two, three, four, or more) are performed annually, depending on the release time of the composition. In this embodiment, each subsequent injection is performed after an appropriate period of time since the previous injection. This appropriate period may be, for example, two weeks or one month.

[0094] According to a specific embodiment, colchicine is present at a concentration of 1 to 27,500 μg per mL of sterile and injectable dosage form, particularly a suspension, at a concentration of 3 to 27,500 μg, more particularly 1 to 13,750 µg, for example 3 to 13,750 µg, and even more particularly wherein colchicine is present at a concentration of 3 to 3,600 µg per mL.

[0095] In a specific embodiment, the same pharmaceutical composition in suspension form can be used for intra-articular injection into any painful joint of a patient suffering from osteoarthritis. However, the amount of pharmaceutical composition to be injected can be adapted to the target joint. This is one of the advantages of the invention, which can provide a suitable amount of colchicine for each application site by adjusting the corresponding desired volume.

[0096] In one embodiment, injections can be performed simultaneously in two or more different painful joints.

[0097] For example, the volume of the pharmaceutical composition according to the invention, particularly in suspension form, injectable into the shoulder, can vary between 2 mL and 5 mL.

[0098] The volume of the pharmaceutical composition according to the invention, particularly in suspension form, which can be injected into the metatarsophalangeal joint, such as the toe, may vary between 0.1 mL and 0.5 mL, typically 0.25 mL.

[0099] The volume of the pharmaceutical composition according to the invention, particularly in suspension form, which can be injected into the metacarpophalangeal joint, such as the finger, may vary between 0.1 mL and 0.5 mL, typically 0.25 mL.

[0100] The volume of the pharmaceutical composition according to the invention, particularly in suspension form, which can be injected into the vertebral joint, may vary between 1 mL and 2 mL.

[0101] The volume of the pharmaceutical composition according to the invention, particularly in suspension form, which can be injected into the midfoot joint, may vary between 0.1 mL and 1 mL.

[0102] The volume of the pharmaceutical composition according to the invention, particularly in suspension form, injectable to the knee, may vary between 2 mL and 5 mL.

[0103] The volume of the pharmaceutical composition according to the invention, particularly in suspension form, injectable to the wrist, may vary between 0.5 mL and 1 mL.

[0104] The volume of the pharmaceutical composition according to the invention, particularly in suspension form, injectable to the elbow, may vary between 2 mL and 5 mL.

[0105] The volume of the pharmaceutical composition according to the invention, particularly in suspension form, injectable to the ankle, may vary between 1 mL and 3 mL.

[0106] The volume of the pharmaceutical composition according to the invention, particularly in suspension form, injectable to the hip, may vary between 2 mL and 5 mL. Instructions for Use, Page 11 / 37, 15 CN 121013711 A

[0107] In one embodiment, the pharmaceutical composition according to the invention, particularly the pharmaceutical composition in suspension form, is characterized by its volume, which can be adapted to joints, i.e., 2 to 5 mL for the shoulder, 1 to 2 mL for the vertebral joints, 0.1 to 1 mL for the midfoot joints, 0.1 to 0.5 mL for the metatarsophalangeal joints, 0.1 to 0.5 mL for the metacarpophalangeal joints, 2 to 5 mL for the knee joint, 0.5 to 1 mL for the wrist joint, 2 to 5 mL for the elbow joint, 1 to 3 mL for the ankle joint, and 2 to 5 mL for the hip.

[0108] It should be understood that the specific dosage and treatment regimen for any particular patient will depend on various factors, including age, weight, overall health condition, sex, diet, time of administration, drug combination, physician's judgment, and the severity of the specific disease being treated.

[0109] In one embodiment, controlled release is suitable to achieve a maximum joint colchicine concentration (Cmax) from 5 nM (2 ng / mL) to 5 μM (2 μg / mL).

[0110] According to a preferred embodiment, injection of the pharmaceutical composition of the invention achieves a systemic concentration of colchicine not exceeding 5 ng / mL, particularly not exceeding 2 ng / mL, more particularly not exceeding 1 ng / mL, more particularly not exceeding 0.5 ng / mL, and even more specifically not exceeding 0.1 ng / mL within 24 hours after intra-articular injection and over the total release period after injection, particularly within 1 month, and even more particularly within at least 3 months.

[0111] In addition, the controlled-release pharmaceutical composition according to the invention can achieve a colchicine synovial concentration greater than 0.5 ng / mL within 24 hours after intra-articular injection, within 1 month, and more particularly within at least 3 months, particularly between 0.5 and 100 ng / mL, and more particularly between 0.5 and 50 ng / mL.

[0112] The dose required to be injected into the painful joint can depend on the type of painful joint, particularly its size. Tables 1a, 1b, and 1c below collect typical doses of colchicine that can be implemented within the framework of the invention. Tables 1a, 1b, and 1c specifically provide more specific doses that can be applied according to the time period of release. Table 1a for 1 month may be valuable for a time period of more than 1 month but less than 2 months, Table 1b for 2 months may be valuable for a time period of 2 to 4.5 months, and Table 1c for 6 months may be valuable for a time period of 4.5 to 7 months.

[0113] According to one embodiment, the volume of the pharmaceutical composition conforming to the invention is 0.1 mL to 5 mL.

[0114] The volume corresponds to the total volume of the composition suitable for injection, i.e., particularly for injection in the form of a suspension. Instructions for Use, Page 12 / 37, 16 CN 121013711 A

[0115]

[0116] Instructions for Use, Page 13 / 37, 17 CN 121013711 A

[0117]

[0118]

[0119] In one embodiment, for small joints selected from metatarsophalangeal joints or metacarpophalangeal joints, the pharmaceutical composition of the present invention, particularly the pharmaceutical composition in suspension form, is administered particularly by a single intra-articular injection and is specifically intended for the treatment of joint diseases such as osteoarthritis, erosive osteoarthritis of the hand, and any other type of chondropathy and / or pain-related joint diseases, particularly osteoarthritis and / or pain-related osteoarthritis, wherein each injection contains 0.3 to 13750 μg, particularly 0.3 to 1800 μg of colchicine, more particularly for a release of about 1 month containing 0.3 to 300 μg of colchicine, and for a release of about 3 months containing 0.9 to 900 μg of colchicine. μg of colchicine, and for a release of approximately 6 months, 1.8 to 1800 μg of colchicine.

[0120] In another embodiment, for the wrist joint, the pharmaceutical composition of the present invention, particularly the pharmaceutical composition in suspension form, is administered particularly by a single intra-articular injection and is specifically intended for the treatment of joint diseases such as osteoarthritis, erosive osteoarthritis of the hand, and any other type of chondropathy and / or pain-related joint diseases, particularly osteoarthritis and / or pain-related osteoarthritis, wherein each injection contains 1.5 to 27,500 μg, particularly 1.5 to 3,600 μg, of colchicine, more particularly 1.5 to 600 μg of colchicine for a release of about 1 month, 4.5 to 1,800 μg of colchicine for a release of about 3 months, and 9 to 3,600 μg of colchicine for a release of about 6 months.

[0121] In another embodiment, for midfoot joints, the pharmaceutical compositions of the present invention, particularly those in suspension form, are administered specifically by a single intra-articular injection and are intended for the treatment of arthropathy, such as osteoarthritis, erosive osteoarthritis of the hand, and any other type of chondropathy and / or pain-related arthropathy, particularly osteoarthritis and / or pain-related osteoarthritis, each injection containing 0.3 to 27,500 μg, particularly 0.3 to 3,600 μg, of colchicine, particularly for a release of about 1 month containing 0.3 to 600 μg of colchicine, for a release of about 3 months containing 0.9 to 1,800 μg of colchicine, and for a release of about 6 months containing 1.8 to 3,600 μg of colchicine.

[0122] In another embodiment, for the ankle joint, the pharmaceutical composition of the present invention, particularly the pharmaceutical composition in suspension form, is administered particularly by a single intra-articular injection and is specifically intended for the treatment of joint diseases such as osteoarthritis, erosive osteoarthritis of the hand and any other type of rickets and / or pain-related joint diseases, particularly osteoarthritis and / or pain-related osteoarthritis, wherein each injection contains 3 to 82,500 μg, particularly 3 to 10,800 μg, of colchicine, particularly 3 to 1,800 μg of colchicine for a release of about 1 month, 9 to 5,400 μg of colchicine for a release of about 3 months, and 18 to 10,800 μg of colchicine for a release of about 6 months.

[0123] In another embodiment, in the vertebral joint, the pharmaceutical composition of the present invention, particularly the pharmaceutical composition in suspension form, is administered particularly by a single intra-articular injection and is specifically intended for the treatment of arthropathy, such as osteoarthritis, erosive osteoarthritis of the hand and any other type of chondropathy and / or pain-related arthropathy, particularly osteoarthritis and / or pain-related osteoarthritis, comprising 3 to 55,000 μg, particularly 3 to 7,200 μg, of colchicine, particularly 3 to 1,200 μg of colchicine for a release of about 1 month, 9 to 3,600 μg of colchicine for a release of about 3 months, and 18 to 7,200 μg of colchicine for a release of about 6 months.

[0124] In another embodiment, for joints selected from the knee, hip, shoulder and elbow joints, the pharmaceutical composition of the present invention, particularly the pharmaceutical composition in suspension form, is administered particularly by a single intra-articular injection and is specifically intended for the treatment of joint diseases such as osteoarthritis, erosive osteoarthritis of the hand and any other type of rickets and / or pain-related joint diseases, particularly osteoarthritis and / or pain-related osteoarthritis, wherein each injection contains 6 to 137,500 μg, particularly 6 to 18,000 μg, of colchicine, particularly 6 to 3,000 μg of colchicine for a release of about 1 month, 18 to 9,000 μg of colchicine for a release of about 3 months, and 36 to 18,000 μg of colchicine for a release of about 6 months.

[0125] According to one embodiment, the pharmaceutical composition of the present invention, particularly the pharmaceutical composition in suspension form, is administered specifically by a single intra-articular injection and is intended for the treatment of arthropathy, such as osteoarthritis, erosive osteoarthritis of the hand, and any other type of chondropathy and / or pain-related arthropathy, particularly osteoarthritis and / or pain-related osteoarthritis, comprising 1 to 27,500 μg of colchicine per mL, particularly 3 to 27,500 μg of colchicine per mL, more particularly 1 to 13,750 μg of colchicine per mL, particularly 3 to 13,750 μg of colchicine per mL.

[0126] In one embodiment, the pharmaceutical composition may be suitable for maintaining a therapeutically acceptable concentration of colchicine in the painful joint for a period of more than 1 month to a maximum of 6 months, more than 2 months to a maximum of 6 months, or more than 3 months to a maximum of 6 months.

[0127] Therefore, this document provides a sterile and injectable pharmaceutical composition for use according to the invention, wherein the time required to release 80% by weight of colchicine is between 1 to a maximum of 6 months, 2 to a maximum of 6 months or 3 to a maximum of 6 months.

[0128] This document also provides pharmaceutical compositions for use according to the invention, wherein the dissolution rate of colchicine is 80% (w / w) between 1 and 6 months, 2 and 6 months, or 3 and 6 months.

[0129] In one embodiment, the pharmaceutical composition of a sterile and injectable dosage form according to the invention is characterized by the fact that the time required to release 80% by weight of colchicine in the microparticles or the time for the dissolution rate of colchicine to be 80% (w / w) exceeds 1 month or is more than 1 month, for example 1.5 months, and can reach 6 months; exceeds 2 months or is more than 2 months, for example 2.5 months, and can reach 6 months; exceeds 3 months or is more than 3 months, for example 3.5 months, and can reach 6 months; exceeds 4 months or is more than 4 months, for example 4.5 months or 5 months, and can reach 6 months.

[0130] According to one embodiment, colchicine is present in the pharmaceutical composition at a concentration of 1 to 27,500 μg per mL of sterile and injectable dosage form, particularly a suspension, particularly 3 to 27,500 μg per mL, more particularly 1 to 13,750 μg per mL, for example 3 to 13,750 μg per mL, and even more particularly wherein colchicine is present at a concentration of 3 to 3,600 μg per mL.

[0131] - For example, when the dissolution rate of colchicine is 80% (w / w) over a period of more than 1 month but less than 2 months, the concentration is 3 to 600 μg per mL;

[0132] - For example, when the dissolution rate of colchicine is 80% (w / w) over a period of 2 to 4.5 months, the concentration is 9 to 1800 μg per mL; and

[0133] - For example, when the dissolution rate of colchicine is 80% (w / w) over a period of 4.5 to 7 months, the concentration is 18 to 3600 μg per mL.

[0134] According to one embodiment, the pharmaceutical composition may be suitable for providing an initial joint colchicine concentration.

[0135] The pharmaceutical composition may or may not exhibit a burst release. In the framework of the invention, "burst release" means the release of an initial large dose of the drug immediately after placement in a release medium, before the release rate reaches a stable curve, i.e., immediately after injection into the joint in the present invention.

[0136] Therefore, when a burst release occurs, the pharmaceutical composition according to the invention can provide an initial release of colchicine at the site of administration, such as in the intra-articular space and / or peri-articular space, after administration. Once the initial release of colchicine decreases, the controlled release of the colchicine microparticle formulation continues to provide therapeutic (e.g., intra-articular and / or peri-articular) concentrations of colchicine to combat inflammation and / or pain during an additional therapeutic period following administration.

[0137] In a specific embodiment, the pharmaceutical composition supplied according to the invention does not exhibit significant burst release. According to the embodiment, less than 25% by weight of colchicine is released 24 hours after administration.

[0138] According to another aspect, the invention relates to a method for treating arthropathy, such as osteoarthritis and any other type of rickets and / or pain-related arthropathy, particularly osteoarthritis and / or pain-related osteoarthritis, comprising at least by injection into the painful joint of a patient in need of the pharmaceutical composition in a sterile and injectable dosage form, the pharmaceutical composition comprising a controlled-release dosage form containing an effective amount of colchicine suitable for intra-articular injection into the joint, wherein the time required for the release of 80% by weight of colchicine in the microparticles is greater than 1 month, particularly between 1 month and 6 months, wherein colchicine is present at a concentration of 0.003 to 27.5 mg per mL of sterile and injectable dosage form, particularly a suspension, particularly 0.003 to 13.75 mg per mL.

[0139] According to another aspect, the present invention relates to a method for treating arthropathy, such as osteoarthritis, erosive osteoarthritis of the hand, and any other type of chondropathy, and / or for treating pain-related arthropathy and / or for protecting joints, bones, and / or cartilage, particularly for treating osteoarthritis and / or pain-related osteoarthritis, comprising at least by injection into the painful joint of a patient in need of the medication a sterile and injectable dosage form of a pharmaceutical composition comprising an effective amount of a controlled-release formulation of colchicine suitable for intra-articular injection into the joint, wherein the dissolution rate of colchicine is 80% (w / w) over more than one month, as measured according to the following protocol:

[0140] 20 mg of an aliquot of a controlled-release formulation containing colchicine is suspended in 50 mL of phosphate buffer (pH 7.4) with stirring at 37°C; then, throughout the duration of release, the supernatant of the sample taken out is periodically analyzed by UV at 350 nm, and

[0141] Colchicine is present at a concentration of 1 to 27,500 μg per mL of sterile and injectable dosage form, particularly a suspension, particularly 3 to 27,500 μg per mL, and even more particularly 1 to 13,750 μg per mL, for example, 3 to 13,750 μg per mL.

[0142] According to another aspect, the present invention relates to a method for treating arthropathy, such as osteoarthritis and any other type of rickets and / or pain-related arthropathy, particularly osteoarthritis and / or pain-related osteoarthritis, comprising administering at least an effective amount of colchicine for controlled release by injection into the joint of a patient in need, particularly wherein the time required for the release of 80% by weight of colchicine is greater than 1 month, particularly between 1 month and 6 months.

[0143] The present invention also provides a method for treating arthropathy, such as osteoarthritis, erosive osteoarthritis of the hand, and any other type of chondropathy, and / or for treating pain-related arthropathy and / or protecting joints, bones, and / or cartilage, particularly for treating osteoarthritis and / or pain-related osteoarthritis, comprising at least the following steps:

[0144] preparing and / or providing a sterile and injectable suspension of a pharmaceutical composition by mixing a powder form of the formulation described herein with an aqueous injection solvent, wherein the pharmaceutical composition optionally comprises an excipient selected from tension enhancers, wetting agents, viscosity enhancers, density enhancers, or mixtures thereof, and wherein the excipient may be present in the aqueous injection solvent or in the powder, and

[0145] injecting the pharmaceutical composition into the painful joint of a patient in need, wherein the volume to be injected is appropriate for the injection site.

[0146] The present invention may be particularly suitable for treating patients with kidney and / or liver damage who are being treated with medication concurrently. In fact, for patients with kidney and / or liver damage, adaptation of the dosing regimen requires adjustment of the recommended oral dose of colchicine. Furthermore, some drugs have been identified in the past as producing undesirable side effects, or even fatal drug interactions, when used in conjunction with oral colchicine treatment, drastically altering the safety profile and necessitating dose adjustments for oral colchicine, which may, for example, require a two- to three-fold reduction in the oral colchicine dose.

[0147] Therefore, in one embodiment, the pharmaceutical composition conforming to the present invention can be given to a patient with renal and / or hepatic impairment. In particular, when intrinsic renal or hepatic impairment reaches a severity level, colchicine plasma levels are considered to rise to a toxicity threshold.

[0148] Patients with renal impairment can be identified and classified using techniques known to physicians, such as via creatinine clearance methods or via glomerular filtration rate (GFR) methods.The method is described in particular detail in Worboys PD, Wong SL, Barriere SL. Pharmacokinetics of intravenous telavancin in healthy subjects with varying degrees of renal impairment. Eur J Clin Pharmacol. 2015 Jun; 71(6): 707-714. For example, the use and method according to the invention can be implemented to treat patients with all grades of renal impairment, such as grades 1 to 5 as defined by the GFR method. The use and method according to the invention can be more particularly suitable for patients with high-grade renal impairment, such as grades 3 to 5 as defined by the GFR method.

[0149] Patients with liver impairment can be identified and classified by techniques known to physicians, such as via the Child-Pugh scoring system or via the MELD scoring system. The method described herein is described in particular in Tsoris A, Marlar CA. Use Of The Child Pugh Score In Liver Disease. 2021 Mar 22. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 31194448 or on the Internet at the following links: https: / / liverfellow.org / post / meld-score-part1 and https: / / liverfellow.org / post / meld-score-part2. For example, the use and method according to the invention can be implemented to treat patients with all scores, ratios, and / or classifications, such as mild, moderate, or severe liver injury as defined by the Child-Pugh method. The use and method according to the invention may be particularly suitable for patients with severe liver injury, such as moderate and severe liver injury, with high scores, ratios, and / or classifications as defined by the Child-Pugh method.

[0150] Therefore, since the systemic plasma level of colchicine is maintained at the threshold that leads to toxicity within the framework of the present invention (page 17 / 37 of specification, 21 CN 121013711 A), no adjustment of the colchicine dose is required, even when used to treat patients with intrinsic factors such as kidney and / or liver damage that would require adjustment of the colchicine dose when currently administered orally.

[0151] Therefore, in one embodiment, the pharmaceutical composition for use according to the invention may also be characterized by the fact that the patient given the pharmaceutical composition has kidney and / or liver damage.

[0152] In another embodiment, a method for treating arthropathy, such as osteoarthritis, erosive hand osteoarthritis, and any other type of chondropathy, and / or for treating pain-related arthropathy and / or for protecting joints, bones, and / or cartilage, particularly for treating osteoarthritis and / or pain-related osteoarthritis, is also provided for patients with kidney and / or liver damage, particularly where the dose of colchicine does not decrease in response to such damage.

[0153] In one embodiment, the pharmaceutical composition conforming to the invention can be co-administered with many of the drugs detailed herein, and in particular, when co-administered with such drugs, it shows improved safety characteristics compared to classic treatment with oral colchicine.

[0154] An example of drug interactions that the invention can avoid is drug interactions that have been clearly identified within the framework of treatment with oral colchicine and are well known to physicians. In cases of potential drug interactions, the classic approach is to adjust the oral colchicine dose according to the severity of the interaction, based on well-known recommendations.

[0155] Such drug-drug interactions (DDIs) can be explained by the fact that some drugs inhibit P-gp and / or CYP3A4, resulting in excessively high peak colchicine plasma concentrations, particularly those exceeding 6 ng / mL, which must be avoided.

[0156] An advantage of the present invention relies on the fact that excessively high plasma concentrations are avoided and co-administration of the drugs is permitted without adjusting the colchicine dose that would have been necessary for oral administration.

[0157] Therefore, in one embodiment, the pharmaceutical composition for use according to the invention is further characterized by the fact that a patient given the pharmaceutical composition may be treated simultaneously, separately or sequentially with the following active ingredients: atazanavir, clarithromycin, darunavir, ritonavir, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, telanavir, ampravir, aprepitant, diltiazem, erythromycin, fluconazole, fosanavir, verapamil, cyclosporine and ranolazine.

[0158] In another embodiment, the pharmaceutical composition for use according to the invention is further characterized by the fact that a patient given the pharmaceutical composition may be treated simultaneously, separately or sequentially with the following active ingredients: atazanavir, clarithromycin, darunavir, ritonavir, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, telanavir, ampravir, aprepitant, diltiazem, erythromycin, fluconazole, fosanavir, verapamil, cyclosporine, ranolazine, macrolides and statins.

[0159] Therefore, this document provides pharmaceutical compositions for use as defined above, wherein they are used to treat arthropathy in patients, such as osteoarthritis, erosive osteoarthritis of the hand, and any other type of chondropathy, and / or to treat pain-related arthropathy in patients, and / or to protect the joints, bones, and / or cartilage of patients, particularly for the treatment of osteoarthritis and / or pain-related osteoarthritis in patients, wherein the patients are treated simultaneously, separately, or sequentially and non-exclusively with at least one active ingredient selected from: atazanavir, clarithromycin, darunavir, ritonavir, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, telanavir, ampravir, aprepitant, diltiazem, erythromycin, fluconazole, fosanavir, verapamil, cyclosporine, ranolazine, macrolides, and statins.

[0160] Therefore, this document provides pharmaceutical compositions for use as defined above, wherein the instructions for use in treating patients are available on page 18 / 37 of CN 121013711 A. Joint diseases, such as osteoarthritis, erosive osteoarthritis of the hand, and any other type of cartilage disease, and / or methods for treating pain-related joint diseases in patients and / or for protecting the joints, bones, and / or cartilage of patients, particularly for treating osteoarthritis and / or pain-related osteoarthritis in patients, wherein the patient is treated simultaneously, separately, or sequentially and non-exclusively with at least one active ingredient selected from: atazanavir, clarithromycin, darunavir, ritonavir, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, telanavir, ampravir, aprepitant, diltiazem, erythromycin, fluconazole, fosanavir, verapamil, cyclosporine, ranolazine, macrolides, and statins, or the patient has chronic comorbidities such as hypertension, chronic kidney disease, diabetes, cardiovascular disease, infection, stroke, depression, peptic ulcer, metabolic syndrome, and / or immunosuppression.

[0161] Therefore, this document further provides a method for treating a patient's arthropathy, such as osteoarthritis, erosive hand osteoarthritis, and any other type of chondropathy, and / or for treating a patient's pain-related arthropathy and / or for protecting a patient's joints, bones, and / or cartilage, particularly for treating a patient's osteoarthritis and / or pain-related osteoarthritis, wherein the patient is treated simultaneously, separately, or sequentially and non-exclusively with at least one active ingredient selected from: atazanavir, clarithromycin, darunavir, ritonavir, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, telanavir, ampravir, aprepitant, diltiazem, erythromycin, fluconazole, Fosanavir, verapamil, cyclosporine, ranolazine, macrolides, and statins, or the patient having chronic comorbidities such as hypertension, chronic kidney disease, diabetes, cardiovascular disease, infection, stroke, depression, peptic ulcer, metabolic syndrome, and / or immunosuppression, particularly where the dose of colchicine does not decrease in response to concomitant administration of such drugs.

[0162] Controlled-release dosage forms containing colchicine

[0163] According to one embodiment, the controlled-release dosage form containing colchicine is in the form of an in-situ formed reservoir or microparticles, particularly in the form of microparticles or multi-capsule liposomes comprising a polymer matrix.

[0164] In one embodiment, the controlled-release dosage form containing colchicine is in the form of an in-situ formed reservoir. In-situ formed reservoirs can be prepared according to techniques known to those skilled in the art, such as pH-induced, heat-induced, or solvent exchange-induced gelation systems containing colchicine, particularly as described in L. Rahnfeld et al. Injectable Lipid-Based Depot Formulations: Where Do We Stand? , Pharmaceutics . 2020 , 12(6): 567, and S . Kempe et al . In-situ forming implants-an attractive formulation principle for parenteral depot formulations Journal of Controlled Release 2012, 161: 668.

[0165] In one embodiment, the controlled-release formulation containing colchicine is in particulate form. The embodiments described herein are described in detail below.

[0166] Controlled-release particulates containing colchicine

[0167] Controlled-release particulates containing colchicine can take the form of various particulates, such as (i) particulates containing a polymer matrix or (ii) multi-capsule liposomes.

[0168] According to one embodiment, the microparticles have an average particle size equal to or greater than 10 μm as determined by laser diffraction measurement.

[0169] According to another embodiment, the microparticles have an average particle size equal to or greater than 10 μm as determined by laser diffraction measurement, particularly less than 100 μm, more particularly less than 80 μm, and even more particularly less than 50 μm, for example, an average particle size of 10 to 50 μm or 10 to 40 μm.

[0170] Within the framework of the present invention, particle size can be measured by laser diffraction measurement.

[0171] The device can typically be a Malvern Mastersizer MS3000 laser diffraction particle size analyzer. A formulation of 0.1 to 1 mg of microparticles per mL of deionized water can be introduced into the device. Measurements can be run three times. Each run can last for 3 seconds, and the suspension can be homogenized before each run.

[0172] The device can also be a multi-wavelength separation analyzer, LUMiReader, which uses a sedimentation method to measure particle size distribution according to ISO 13317. A formulation of 4 mg of microparticles per mL of deionized water can be introduced into the device and analyzed at a wavelength of 470 nm. Each run can last for 50 minutes, and the suspension can be homogenized before each run. The results shown in the examples are the average of four runs.

[0173] Both devices provide similar measurement results and can be used interchangeably. In other words, for simplicity, most of the text only mentions laser diffraction, but other methods as described above can also be used.

[0174] It should be understood that these ranges refer to the average size of all microparticles in a given population. The size of any given individual microparticle can be within the standard deviation above or below the average size.

[0175] In the context of this invention, “microparticles” means particles of any shape and made of any material, particularly suitable for injection into the human body within a pharmaceutical composition, and especially into articulations or joints, having an average particle size greater than 10 μm and less than 100 μm as determined by laser diffraction.

[0176] Microparticles suitable for use in pharmaceutical compositions according to the invention can be selected from various types of microparticles, such as microspheres, microparticle matrices, microsphere matrices, microcapsules, rods, flakes, pills, fibers, and pellets.

[0177] (i) Microparticles comprising a polymer matrix

[0178] The polymer matrix can be selected from various polymers suitable for obtaining controlled-release microparticles. Such polymer matrices are non-toxic to the human body.

[0179] According to one embodiment, the polymer forming the polymer matrix is ​​biodegradable.

[0180] In the context of this invention, a “biodegradable” material refers to a material that is enzymatically or hydrolyzed, and for which there is evidence that its degradation products are incorporated into the biomass and / or eliminated from the organism through metabolism or renal filtration.

[0181] The non-toxic and biodegradable polymer can be natural or synthetic.

[0182] According to one embodiment, the polymer matrix for the microparticles used in the pharmaceutical composition according to the invention comprises at least a poly(lactic acid-co-glycolic acid) copolymer or PLGA.

[0183] According to the embodiment, the polymer matrix may comprise an amount of PLGA greater than 70%, particularly greater than 80%, and even more particularly greater than 90% by weight relative to the total weight of the polymer matrix.

[0184] Suitable polymers are not limited to those that are commercially available and are known as RESOMER (Evonik Industries AG, Germany), LACTEL (Durect, USA), PURASORB (Corbion NV, Netherlands), Viatel (Ashland, USA), and EXPANSORB (Seqens, France).

[0185] According to another embodiment, the polymer matrix of the microparticles for use in the pharmaceutical composition according to the invention comprises at least polycaprolactone (PCL).

[0186] According to the embodiment, the polymer matrix may contain PCL in an amount greater than 70%, particularly greater than 80%, and even more particularly greater than 90% by weight relative to the total weight of the polymer matrix.

[0187] According to another embodiment, the polymer matrix of the microparticles for use in the pharmaceutical composition according to the invention comprises a mixture of at least PCL and at least PLGA.

[0188] In a specific embodiment, the pharmaceutical composition according to the invention is characterized by microparticles, which may be a mixture of microparticles of different properties, said microparticles comprising colchicine and a polymer matrix, wherein the polymer matrix comprises:

[0189] - at least a poly(lactic acid-co-glycolic acid) copolymer,

[0190] - at least poly(caprolactone), or, as per specification page 20 / 37, 24 CN 121013711 A

[0191] - at least a mixture comprising at least a poly(lactic acid-co-glycolic acid) copolymer and at least poly(caprolactone).

[0192] “It may be a mixture of microparticles of different properties” means that the pharmaceutical composition may comprise various types of microparticles, for example, 2, 3 or 4 types of microparticles. “Microparticle type” refers to microparticles of a polymer matrix with different properties, particularly polymer matrices with different properties by exhibiting specific monomer ratios, molecular weights and / or intrinsic viscosity.For example, one type of microparticle may have a polymer matrix comprising at least a poly(lactic acid-co-glycolic acid) copolymer, or even a polymer matrix composed of poly(lactic acid-co-glycolic acid) copolymer; another type of microparticle may have a polymer matrix comprising at least poly(caprolactone), or even a polymer matrix composed of poly(caprolactone); or one type of microparticle may have a polymer matrix comprising at least a poly(lactic acid-co-glycolic acid) copolymer exhibiting a specific monomer ratio, molecular weight and / or intrinsic viscosity, or even a polymer matrix composed of poly(lactic acid-co-glycolic acid) copolymer exhibiting a specific monomer ratio, molecular weight and / or intrinsic viscosity; and another type of microparticle may have a polymer matrix comprising at least a poly(lactic acid-co-glycolic acid) copolymer exhibiting a different specific monomer ratio, molecular weight and / or intrinsic viscosity, or even a polymer matrix composed of poly(lactic acid-co-glycolic acid) copolymer exhibiting a different specific monomer ratio, molecular weight and / or intrinsic viscosity. Therefore, all types of mixtures are covered within the scope of the invention, particularly to facilitate the acquisition of release properties suitable for treating arthropathy, such as osteoarthritis, erosive osteoarthritis of the hand, and any other type of chondropathy, and / or for treating pain-related arthropathy, and / or for protecting joints, bones, and / or cartilage, particularly for treating osteoarthritis and / or pain-related osteoarthritis.

[0193] With regard to poly(lactic acid-co-glycolic acid) copolymers or PLGA, different forms of PLGA can be obtained depending on the molar ratio of lactide to glycolide used for polymerization. Thus, PLGA as used in the present invention can be characterized by its lactic acid:glycolic acid ratio. In the framework of the invention, "lactic acid:glycolic acid ratio" refers to the molar ratio between the monomers lactic acid and glycolic acid used. For example, "PLGA 75:25" or "PLGA with a lactic acid / glycolic acid molar ratio of 75:25" refers to a PLGA whose composition is 75% lactic acid and 25% glycolic acid.

[0194] In one embodiment, the poly(lactic acid-co-glycolic acid) copolymer exhibits the characteristics according to USP <911> The intrinsic viscosity, measured by an Ubbelohde capillary viscometer, ranges from 0.10 to 1.7 dl / g, particularly from 0.10 to 1.4 dl / g, and even more particularly from 0.10 to 0.9 dl / g.

[0195] Within the framework of this invention, "intrinsic viscosity" (IV) is a measure of the increase in flow resistance of a polymer solution relative to a pure solvent. This property is related to molar mass: longer polymer chains result in higher intrinsic viscosity values.

[0196] Intrinsic viscosity can typically be measured using the following method: the intrinsic viscosity of a polymer sample can be determined using an Ubbelohde capillary viscometer. The polymer is dissolved in chloroform. According to USP... <911> Measure the flow time of the solvent and polymer solution and calculate the intrinsic viscosity.

[0197] In one embodiment, the polymer matrix comprises at least one poly(lactic acid-co-glycolic acid) copolymer, at least one polycaprolactone, or a mixture comprising at least said amounts of the poly(lactic acid-co-glycolic acid) copolymer and polycaprolactone in an amount greater than 70%, particularly greater than 80%, and even more particularly greater than 90% by weight relative to the total weight of the polymer matrix, wherein, in particular, the lactic acid:glycolic acid molar ratio of the poly(lactic acid-co-glycolic acid) copolymer is 50:50 to 90:10, particularly 55:45 to 90:10, for example 60:40 to 90:10, and more particularly 65:35 to 85:15, for example 75:25, wherein, in particular, the poly(lactic acid-co-glycolic acid) copolymer exhibits the characteristics according to USP <911> The intrinsic viscosity, measured by an Ubbelohde capillary viscometer, is 0.1 to 1.7 dl / g, particularly 0.1 to 1.4 dl / g, and even more particularly 0.1 to 0.9 dl / g.

[0198] When implementing a poly(lactic acid-co-glycolic acid) copolymer having the lowest lactic acid:glycolic acid molar ratio, for example between 50:50 and 60:40, a suitable copolymer exhibiting intrinsic viscosity is selected based on common knowledge known to those skilled in the art, see page 21 / 37 of the specification, 25 CN 121013711 A, to obtain suitable release characteristics of colchicine for more than one month according to the invention.

[0199] According to one embodiment, more particularly, when the poly(lactic acid-co-glycolic acid) copolymer has a minimum lactic acid:glycolic acid molar ratio, for example between 50:50 and 60:40, the poly(lactic acid-co-glycolic acid) copolymer exhibits an intrinsic viscosity of 0.4 to 1.7 dl / g as determined by an Ubbelohde capillary viscometer according to USP<911>.

[0200] According to the embodiment, the polymer matrix may contain a mixture of PCL and PLGA in an amount greater than 70%, particularly greater than 80%, and even more particularly greater than 90% by weight, relative to the total weight of the polymer matrix.

[0201] The polymer matrix may contain one or more additional polymers, copolymers, or mixtures thereof. These additional polymers, copolymers, or mixtures thereof may be present in the polymer matrix in an amount of 0 to 30%, particularly 0 to 20%, and even more particularly 0 to 10% by weight, relative to the total weight of the polymer matrix.

[0202] Suitable other non-limiting examples of polymers or copolymers include poly(lactide) or PLA other than poly(lactic acid-co-glycolic acid) copolymers, poly(glycolic acid) or PGA other than poly(lactic acid-co-glycolic acid) copolymers, poly(lactide-co-caprolactone), poly(ethylene glycol), poly(ethylene oxide) or PEO, PLGA-b-PEO-b-PLGA, PLGA-b-PEO, polyhydroxyalkanoates, poly(hydroxybutyrate), poly(methyl methacrylate), poly(dioxane), poly(valerol), poly(α-) Hydroxy acids), poly(lactones), poly(amino acids), polyanhydrides, poly(orthoesters), poly(acetals), polyurethanes, polysulfides, polyphosphates, poly(ester-co-amides), poly(vinyl alcohol) or PVA, PVA-g-PLGA, poly(ether ester) multiblock copolymers, polyvinylpyrrolidone, poly(methacrylates), PEO-PPO-PEO (pluronics), gelatin, heparin, chondroitin sulfate; polysaccharides such as alginate, starch, chitosan and dextran and any combination thereof.

[0203] In one embodiment, the controlled-release microparticles according to the invention are PLGA microspheres. In other words, in said embodiment, the polymer matrix does not contain any other polymers or copolymers. In such embodiments, the controlled-release microparticles may comprise different types of PLGA microspheres, that is, they may comprise PLGA microspheres made of poly(lactic acid-co-glycolic acid) copolymers exhibiting different lactic acid:glycolic acid molar ratios and / or intrinsic viscosities.

[0204] According to another embodiment, the particulate matrix may comprise two, three, or more PLGA copolymers, particularly blends of two PLGA copolymers, and may even consist of blends of two, three, or more PLGA copolymers, particularly blends of two PLGA copolymers. In this specification, "polymer matrix comprising at least one poly(lactic acid-co-glycolic acid) copolymer" precisely means that the poly(lactic acid-co-glycolic acid) copolymer can be such a blend.

[0205] The particulates may also comprise pharmaceutically acceptable excipients for modulating drug release properties, such as medium-chain triglycerides, poly(oxyethylene) sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80), sorbitan fatty acid esters, cyclodextrin, lecithin, mannitol, sucrose, inorganic salts, and mixtures thereof.

[0206] The polymer matrix of the particulates may comprise one or more excipients. The excipients may be present in the polymer matrix in an amount not exceeding 15% by weight, particularly not exceeding 10% by weight, and more particularly not exceeding 5% by weight, relative to the total weight of the polymer matrix.

[0207] In one embodiment, the weight percentage of colchicine in the pharmaceutical composition relative to the total weight of the microparticles, or the colchicine loading, is from 0.01% to 40% by weight.

[0208] Method for obtaining microparticles comprising a polymer matrix

[0209] Within the framework of the present invention, any method suitable for manufacturing polymer microparticles having an average particle size of 10 to 100 μm as determined by laser diffraction measurement methods is considered suitable.

[0210] In such manufacturing methods, emulsification-based methods, such as high-pressure homogenization, for example, high-pressure homogenization using a rotor-stator homogenizer in batch or continuous mode, or membrane emulsification, followed by removal of the organic solvent by extraction / evaporation (pages 22 / 37 of specification, CN 121013711 A).

[0211] In general terms of such methods, an emulsion can be prepared and processed on a membrane with pores of a defined size. The obtained microspheres can then be collected, washed, and freeze-dried after extraction and evaporation of the organic solvent.

[0212] According to one specific embodiment, the microparticles can be manufactured by O / W direct emulsion or by W / O / W dual emulsion technology.

[0213] Schoubben, A., Ricci, M. & Giovagnoli, S. Meeting the unmet: from traditional to cutting-edge techniques for poly lactide and poly lactide-co-glycoide microparticle manufacturing. J. Pharm. Investig. 49, 381–404 (2019) reviews various methods for preparing PLGA microparticles that can be used in the framework of the present invention.

[0214] According to one specific embodiment, the microparticles can be manufactured by a water-in-oil-in-solids (S / O / W) dual emulsion technique.

[0215] Giovagnoli, S., et al; Physicochemical characterization and release mechanism of a novel prednisone biodegradable microsphere formulation, J Pharm Sci. 97: 303–317, (2008) describes an example of PLGA microparticles prepared via an S / O / W emulsion technique. Other suitable methods for obtaining the microparticles according to the invention include atomization by a rotating disc, atomization by spray drying, fluidized bed coating, or a combination thereof.

[0216] Alternatively, microparticles may be manufactured using on-demand dripping, drop-by-drop, and jet-breaking methods such as inkjet printing or microfluidic technology.

[0217] Alternatively, microparticles may be manufactured using supercritical fluid technology.

[0218] Alternatively, microfabrication methods, such as template and mold-based techniques, such as soft lithography, can be used to fabricate microparticles.

[0219] All of these fabrication methods are well known to those skilled in the art.

[0220] The fabrication methods cited above are well known to those skilled in the art.

[0221] (ii) Multicystic Liposomes

[0222] Multicystic liposomes (MVLs) are spherical particles with an average diameter of 10–30 μm, consisting of multiple non-concentric lipid bilayers arranged in a honeycomb structure. These lipid layers surround numerous water-filled aqueous compartments, which can be used to encapsulate water-soluble drugs, such as colchicine.

[0223] MVLs typically consist of at least one amphiphilic lipid and one neutral lipid. The amphiphilic lipid is selected from phospholipids, such as phosphatidylcholine or phosphatidylglycerol. Neutral lipids are selected from triglycerides having a monounsaturated fatty acid ester moiety containing 14-18 carbons in the acyl chain (e.g., trioleic acid glyceride, tripalmitoyl glyceride), a saturated fatty acid ester moiety containing 6-8 carbons in the acyl chain (e.g., trihexanoic acid glyceride, tricaprylic acid glyceride), and mixtures thereof. Cholesterol may also be used in the composition.

[0224] MVL is obtained by using a water-in-oil-in-water (W / O / W) double emulsification method. In the first step, a water-in-oil (W / O) emulsion is prepared by mixing phospholipids, trioleic acid glyceride, tricaprylic acid glyceride, and cholesterol dissolved in a volatile and water-immiscible organic solvent with an aqueous solution containing the dissolved drug to be encapsulated. The first emulsion is then emulsified by mixing with a second aqueous solution to produce a water-in-oil-in-water (W / O / W) emulsion. The energy required to form the first and second emulsions can be provided mechanically, by ultrasonic treatment, or a combination thereof. The MVL is finally obtained by removing volatile organic solvents from the complex emulsion using air stripping or rinsing. Finally, unencapsulated material is removed, the MVL is concentrated, and buffer exchange is performed using a percolation or cross-flow filtration system.

[0225] In one embodiment, the neutral lipids used to manufacture the MVL encapsulating colchicine comprise a mixture of trioleic acid glyceride and tricaprylic acid glyceride in a ratio of 50:50 to 0:100. Specification 23 / 37 pages 27 CN 121013711 A

[0226] Pharmaceutical Compositions and Kits

[0227] As described above, pharmaceutical compositions are provided herein in various forms, namely solutions, suspensions, solid implants, semi-solid implants, powders, and in-situ formed reservoirs. Other pharmaceutical compositions are provided in powder form or in kit form.When in powder form, the pharmaceutical composition is primarily intended for storage, while solutions, suspensions, solid implants, semi-solid implants, powders, or in-situ repositories, especially suspensions, are prepared for use with the composition, prepared for injection. The cartridge is capable of separately storing (i) an aqueous injection solvent and (ii) a controlled-release dosage form containing colchicine, particularly for forming a sterile and injectable dosage form, especially a suspension in powder form suitable for injection.

[0228] In one embodiment, the pharmaceutical composition is further characterized in that it is particularly in the form of a sterile and injectable suspension, optionally containing excipients selected from tension enhancers, wetting agents, viscosity enhancers, density enhancers, and mixtures thereof, and wherein it is obtained by mixing a controlled-release dosage form containing colchicine, optionally containing hyaluronic acid, particularly colchicine-containing microparticles, more particularly microparticles as defined above, with an aqueous injection solvent.

[0229] Various embodiments of the alternative forms are described in detail below.

[0230] Solutions, solid implants, semi-solid implants, powders, and in-situ formed reservoirs can be prepared according to methods known to those skilled in the art.

[0231] According to a specific embodiment, the sterile and injectable dosage form is a suspension form, which can be obtained from powders, as detailed below.

[0232] Powders and Suspensions

[0233] In one embodiment, a formulation in powder form is provided comprising a controlled-release dosage form containing colchicine, particularly in a particulate form comprising a polymer matrix, more particularly as defined above, wherein the colchicine loading in the controlled-release dosage form is from 0.01% to 40% by weight.

[0234] In one embodiment, the formulation in powder form comprises a controlled-release dosage form containing colchicine, wherein the controlled-release dosage form containing colchicine is a particulate, particularly a particulate comprising a polymer matrix, more particularly in the form of particulates having an average particle size equal to or greater than 10 μm as determined by laser diffraction, and even more particularly in the form described above.

[0235] The pharmaceutical compositions used in the framework of the present invention can be in the form of sterile and injectable compositions, particularly suspension compositions containing an effective amount of colchicine.

[0236] In the sense of the present invention, "sterile" means an environment that ensures the compounds considered in the compositions according to the present invention meet the safety requirements for routes of administration, particularly for entry into or through joints, as mentioned above. Indeed, for obvious reasons, it is essential that the compositions according to the present invention are free of any contaminants that could trigger undesirable side effects at the host site.

[0237] The pharmaceutical compositions used in the framework of the present invention can be prepared in the form of powders containing the aforementioned microparticles. According to one embodiment, the pharmaceutical composition is a sterile and injectable composition for the controlled release of colchicine, suitable for intra-articular injection.

[0238] Due to their injectable nature, the compositions according to the invention must contain a physiologically acceptable medium, also known as an "aqueous injection solvent".

[0239] "Physiologically acceptable medium" means a medium that is non-toxic and compatible with the injection and / or application of the composition, such as those considered in this invention.

[0240] In another embodiment, a sterile and injectable dosage form of a pharmaceutical composition suitable for intra-articular injection is provided, which is obtained by mixing a powder form of the formulation according to the invention with an aqueous injection solvent, wherein the pharmaceutical composition optionally contains an excipient selected from tension enhancers, wetting agents, viscosity enhancers, density enhancers or mixtures thereof, and wherein the excipient may be present in an aqueous injection carrier or powder, optionally containing hyaluronic acid.

[0241] In another embodiment, a sterile and injectable pharmaceutical composition suitable for intra-articular injection is provided, comprising a controlled-release formulation in the form of colchicine-containing microparticles, said controlled-release formulation comprising a polymer matrix having an average particle size equal to or greater than 10 μm as determined by laser diffraction, wherein said polymer matrix comprises at least one poly(lactic acid-co-glycolic acid) copolymer, at least one poly(caprolactone), or at least a mixture comprising a poly(lactic acid-co-glycolic acid) copolymer and poly(caprolactone), in an amount greater than 70% by weight relative to the total weight of the polymer matrix, particularly greater than 80% by weight, and even more particularly greater than 90% by weight, wherein, in particular, the lactic acid:glycolic acid molar ratio of the poly(lactic acid-co-glycolic acid) copolymer is 50:50 to 90:10, particularly 55:45 to 90:10, for example 60:40 to 90:10, more particularly 65:35 to 85: 15, for example 75:25, wherein, in particular, the poly(lactic acid-co-glycolic acid) copolymer exhibits the characteristics specified in the USP. <911> The intrinsic viscosity, as determined by an Ubbelohde capillary viscometer, is 0.1 to 1.7 dl / g, particularly 0.1 to 1.4 dl / g, and even more particularly 0.1 to 0.9 dl / g.

[0242] In another embodiment, the pharmaceutical composition is provided wherein the colchicine loading in the controlled-release dosage form is 0.01 to 40% by weight.

[0243] In another embodiment, the pharmaceutical composition is selected from solutions, suspensions, solid implants, semi-solid implants, powders, and in-situ reservoirs, particularly suspensions, and is characterized by a concentration of 1 to 27,500 μg per mL of sterile and injectable dosage form, particularly suspensions, particularly 3 to 27,500 μg per mL, even more particularly 1 to 13,750 µg per mL, particularly 3 to 13,750 µg per mL.

[0244] The composition may comprise a solvent or a mixture of physiologically acceptable solvents.

[0245] The composition may comprise a physiologically acceptable aqueous medium.

[0246] As an aqueous medium suitable for the present invention, water may be mentioned, for example.

[0247] As an isotonic agent suitable for preparing the composition according to the present invention, sugar and sodium chloride may be mentioned.

[0248] The aqueous injection solvent may particularly comprise a tension enhancer, a wetting agent, a viscosity enhancer, or a mixture thereof.

[0249] Among tension enhancers, the following may be listed: glucose, mannitol, sorbitol, sucrose, glycerol, sodium chloride, potassium chloride, cyclodextrin, and maltodextrin.

[0250] Among wetting agents, the following may be listed: poly(oxyethylene) sorbitol fatty acid esters, such as those commercially available under the trade name TWEEN; sorbitol fatty acid esters, such as those commercially available under the trade name SPAN; poloxamer and lecithin.

[0251] Among viscosity enhancers, the following can be listed: sodium carboxymethyl cellulose (CMC), glycosaminoglycans such as hyaluronic acid, dextran, collagen, poly(vinylpyrrolidone), poly(ethylene glycol), gelatin, hydroxyethyl cellulose (HEC), methyl cellulose (MC), alginate, gum arabic, and starch.

[0252] According to a specific embodiment, the pharmaceutical composition has a viscosity of 5 to 1000 mPa·s, particularly 5 to 500 mPa·s, particularly 5 to 100 mPa·s, and more particularly 5 to 50 mPa·s at a shear rate of 10 s⁻¹.

[0253] Medicine Box

[0254] This document also provides a medicine box or article comprising (i) an aqueous injection solvent in separate compartments, and (ii) a controlled-release dosage form containing colchicine as defined above or a powder as defined above, wherein the medicine box or article optionally contains an excipient selected from tension enhancers, wetting agents, viscosity enhancers, density enhancers and mixtures thereof, and optionally contains hyaluronic acid for preparing a pharmaceutical composition suitable for intra-articular injection, and wherein (i) and / or (ii) optionally, as per the specification page 25 / 37, 29 CN 121013711 A, contains an anesthetic agent in the form of an immediate-release dosage form.

[0255] The anesthetic agent optionally present will be described in more detail in the “Additional Active Ingredients” paragraph below.

[0256] This document also provides a kit or article comprising (i) an aqueous injection solvent and (ii) a pharmaceutical composition in powder form as defined above, in separate compartments, wherein the pharmaceutical composition optionally comprises an excipient selected from tension enhancers, wetting agents, viscosity enhancers, density enhancers and mixtures thereof, and optionally comprises hyaluronic acid, for preparing a pharmaceutical composition suitable for intra-articular injection, and wherein (i) and / or (ii) optionally comprises an anesthetic in the form of an immediate-release dosage form.

[0257] In another embodiment, the kit or article may be in the form of a vial and a pre-filled syringe, or in the form of a medical device, or in the form of two separate vials. In said embodiment, the two compartments or dual chambers may be obtained by all means known to those skilled in the art of obtaining a mixture of aqueous injectable solvent and powder as described herein. Still in said embodiment, said means may be in the form of a puncturable membrane or a destructible diaphragm, for example, in the form of a puncturable membrane or a destructible diaphragm that can be punctured by pressure applied by the user. In these embodiments, the kit or article may additionally include a label that instructs the user to introduce the obtained pharmaceutical composition into the subject's joint.

[0258] In one embodiment, the kit may be in the form of two separate vials.

[0259] In one embodiment, the first vial contains an aqueous injectable solvent, and the second vial contains a controlled-release formulation containing colchicine, particularly a controlled-release formulation containing colchicine as defined above or a powder as defined above, and an immediate-release formulation of an anesthetic.

[0260] If both (i) and (ii) contain anesthetics, the anesthetics in each (i) and (ii) may be similar or different. As previously stated, throughout the specification, the anesthetic may be a mixture of anesthetics.

[0261] In another embodiment, the kit or article may be in the form of vials and pre-filled syringes, or in the form of a medical device, or in the form of two separate vials. In said embodiment, the two compartments or dual chambers may be obtained by all means known to those skilled in the art of a mixture of aqueous injectable solvent and powder as described herein. Still in said embodiment, said means may be in the form of a puncturable membrane or a destructible diaphragm, for example, in the form of a puncturable membrane or a destructible diaphragm that can be punctured by pressure applied by the user.

[0262] In these embodiments, the kit or article may additionally include a label instructing the user to introduce the obtained pharmaceutical composition into the subject's joint.

[0263] For patient comfort and for safety reasons as explained above, it is advantageous to find a pharmaceutical composition suitable for intra-articular injection into the joint, which requires only a single injection to relieve the patient's pain without requiring multiple injections.

[0264] The present invention also provides a pharmaceutical composition obtained by mixing two compartments of the above-described cassette or article for the treatment of arthropathy, such as osteoarthritis, erosive osteoarthritis of the hand, and any other type of chondropathy and / or for the treatment of pain-related arthropathy and / or for the protection of joints, bones, and / or cartilage, wherein the dissolution rate of colchicine is 80% by weight over more than one month, as measured according to the following protocol:

[0265] An aliquot of 20 mg of a controlled-release formulation containing colchicine is suspended in 50 mL of phosphate buffer (pH 7.4) with stirring at 37°C; then, throughout the duration of release, the supernatant of the sample taken out is periodically analyzed by UV at 350 nm, and wherein colchicine is present at a concentration of 1 to 27,500 μg per mL of sterile and injectable formulation, particularly 3 to 27,500 μg per mL.

[0266] Additional active ingredients

[0267] are typically given to treat arthropathy, such as osteoarthritis, erosive hand osteoarthritis, and any other type of rickets as described in the specification 26 / 37 pages 30 CN 121013711 A, and / or to treat pain-related arthropathy and / or to protect joints, bones, and / or cartilage. Additional therapeutic agents may be administered in combination with colchicine.

[0268] As used herein, the terms “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of the additional active ingredient with colchicine. For example, the combination may be administered simultaneously or sequentially with the additional active ingredient in separate unit dosage forms or together in a single unit dosage form.

[0269] According to one embodiment, an anesthetic may be injected into the painful joint; for example, the anesthetic may be present in the pharmaceutical composition according to the invention.

[0270] According to one embodiment, the pharmaceutical composition for use according to the invention is characterized in that it further comprises an anesthetic agent, which may be selected from lidocaine, ropivacaine, bupivacaine, levobupivacaine, capsaicin, mepivacaine, prilocaine, pharmaceutically acceptable salts thereof, and mixtures thereof, particularly lidocaine, bupivacaine, ropivacaine, and mepivacaine, more particularly ropivacaine and bupivacaine, and even more particularly ropivacaine and ropivacaine hydrochloride. The anesthetic agent is generally an immediate-release formulation, but may also be in the form of a pharmaceutically acceptable salt thereof.

[0271] According to the embodiment, the anesthetic agent may be an immediate-release formulation and may be in the form of a hydrogel.

[0272] The immediate-release anesthetic agent may be directly dissolved in a suspension according to the invention, which is specifically intended for administration to the patient by intra-articular injection. This means that the anesthetic agent is not contained in a controlled-release formulation containing colchicine, such as microparticles.

[0273] In one embodiment, according to the invention, the anesthetic agent may be present directly in a sterile and injectable dosage form, particularly in a suspension, especially in an amount suitable for maintaining below its solubility limit.

[0274] Accordingly, this document further provides a pharmaceutical composition for use according to the invention, wherein the composition is in the form of a sterile and injectable suspension, wherein colchicine is in the form of microparticles comprising a polymer matrix having an average particle size equal to or greater than 10 µm as determined by laser diffraction, and wherein the anesthetic agent is entirely in an immediate-release dosage form and is directly dissolved in the suspension.

[0275] Alternatively, the anesthetic agent may also be in the form of a dehydrated hydrogel.

[0276] In another embodiment, a (iii) dehydrated hydrogel containing an anesthetic agent may be prepared according to techniques known to those skilled in the art. The gel can be formed by dispersing the anesthetic agent, optionally pre-dissolved in water, together with the hydrogel under stirring. Suitable hydrogels include, for example, sodium hyaluronate. When the pharmaceutical composition is in powder form, water should be removed by techniques known to those skilled in the art, such as dehydration or lyophilization. If necessary, they can be reversibly hydrated back.

[0277] In one embodiment, the anesthetic may be present at a concentration of 1 to 100 mg per mL of sterile and injectable dosage form, particularly 1 to 50 mg per mL, and even more particularly 1 to 20 mg per mL. For example, ropivacaine may be present at a concentration of 2 to 20 mg per mL of sterile and injectable dosage form when present.

[0278] According to one embodiment, hyaluronic acid may be injected into painful joints and may be present, for example, in pharmaceutical compositions according to the invention. The use of hyaluronic acid as a viscous supplement in the treatment of arthritis such as osteoarthritis is well known. Therefore, according to one embodiment, the present invention provides a pharmaceutical composition comprising a colchicine-containing controlled-release dosage form according to the invention, said pharmaceutical composition further comprising hyaluronic acid.

[0279] In some embodiments, the present invention provides a pharmaceutical composition comprising a colchicine-containing controlled-release dosage form according to the invention, which further comprises at least one additional therapeutic agent. Suitable alternative active ingredients are described in further detail below.Instructions for Use, pages 27 / 37, 31 CN 121013711 A

[0280] According to one embodiment, the following active ingredients, particularly any anti-inflammatory active ingredient, can be combined:

[0281] - (i) corticosteroids, such as prednisone, prednisolone, methylprednisolone, betamethasone, dexamethasone, triamcinolone, hexamethasone, budesonide, mometasone, ciroxonide, fluticasone, hydrocortisone, and pharmaceutically acceptable salts thereof, especially in low doses,

[0282] - (ii) NSAIDs, such as aspirin, diclofenac, aceclofenac, sulindac, ketoprofen, ibuprofen, ketoprofen, naproxen, oxaprazin, flurbiprofen, indomethacin, promethazine, thiaprofenicol, meloxicam, piroxicam, tenoxicam, etodoxacin, and celecoxib, etoxicam, parecoxib, rofecoxib, vardecoxib, and their pharmaceutically acceptable salts,

[0283] - (iii) Anti-IL-1β drugs, such as anaspirin, canakinumab, lilosip, and their pharmaceutically acceptable salts,

[0284] - (iv) Anti-IL-6 drugs, such as tocilizumab, siltuximab, sarilumab, and their pharmaceutically acceptable salts,

[0285] - (v) Anti-TNFα drugs, such as adalimumab, etanercept, infliximab, cetuzumab, golimumab, and pharmaceutically acceptable salts thereof,

[0286] - (vi) Anti-angiogenic agents, such as bevacizumab and pharmaceutically acceptable salts thereof,

[0287] - (vii) Anti-NGF (nerve growth factor) drugs, such as fasinumab, tanezumab, fulranumab, ABT-110, and pharmaceutically acceptable salts thereof,

[0288] - (viii) Opioids, such as fentanyl, morphine, buprenorphine, hydromorphone, hydrocodone, oxycodone, meperidine, and pharmaceutically acceptable salts thereof,

[0289] - (ix) Inhibitors of class I glucose transporters (e.g., GLUT-1 / GLUT-3), such as cytochalasin B, WZB-117, STF-31, BAY-876,

[0290] - (x) mixtures thereof.

[0291] The additional active ingredients may be formulated as immediate-release and / or controlled-release formulations.

[0292] Administration of the composition

[0293] The pharmaceutical compositions used in the framework of the present invention may be injected using any method known in the art.

[0294] In particular, the pharmaceutical compositions may be administered by means of an injection device suitable for intra-articular injection, such as a syringe equipped with a 19-29G, preferably 22-29G, more preferably 25-29G needle.

[0295] Throughout this specification, including the claims, the expression “comprising a” should be understood to be synonymous with “comprising at least one”, unless otherwise specifically stated.

[0296] It should be understood that the expressions “between… and…” and “from… to…” should be understood to mean that the limit values ​​are included, unless otherwise stated.

[0297] The following examples and figures are presented by way of non-limiting illustration of the invention. Examples

[0298] Analytical Methods

[0299] The particle sizes of Examples 1 and 2 were determined using a Malvern Mastersizer MS3000 laser diffraction particle size analyzer. A suspension of 0.1 to 1 mg of particles per mL of deionized water was introduced into the apparatus using vortex stirring. The measurements were run three times. Each run lasted 3 seconds, and the suspension was homogenized before each run. The results shown in the examples are the average of the three runs.

[0300] The particle size distribution in Examples 5, 6 and the specification, pages 28 / 37, 32 CN 121013711 A 7, was determined using a multi-wavelength separation analyzer, LUMiReader, with sedimentation method. The suspension of 4 mg of particles per mL of deionized water was treated with an ultrasonic bath for 10 seconds. The suspension was then introduced into the apparatus and analyzed at a wavelength of 470 nm. Each run lasted 50 min, and the suspension was homogenized before each run. The results shown in the examples are the average of four runs.

[0301] The particle drug loading was determined by dissolving 30 mg of particles in 2.5 mL of acetonitrile in a 50 mL volumetric flask. After dissolution, 22.5 mL of methanol was added and vortexed. The flask was then filled with water and thoroughly mixed using a vortex. The medium was then centrifuged at 4000 rpm for 30 min, and the supernatant was filtered through a 0.45 µm PTFE filter (Acrodisc wwPTFE), discarding the first 2 mL. The aliquots of the solution were then analyzed by HPLC to determine the drug loading of the microparticles.

[0302] - HPLC analysis was performed using a silica-based reversed-phase C8 column [GL Sciences, Inertsil C8-3, 4.6 × 250 mm (5 μm)] and a mobile phase [55% methanol and 45% 6.8 g / L KH2PO4 solution, adjusted to pH 5.5 with diluted phosphoric acid] at a flow rate of 1 mL / min and with UV detection at 254 nm.

[0303] - For the in vitro release tests of the microparticles in Examples 1, 2 and 3, aliquots of 20 mg of microparticles were suspended in 50 mL of phosphate buffer (50 mM, pH 7.4) and maintained at 37°C in a horizontal shaker set to 80 rpm.At different time intervals, 3 mL of medium was removed and replaced with fresh medium. The removed samples were centrifuged at 4000 rpm for 3 minutes and the supernatant was analyzed by UV at 350 nm.

[0304] - For the in vitro release test of the microparticles in Examples 5, 6 and 7, 20 mg aliquots of microparticles were suspended in 50 mL of phosphate buffer (10 mM, pH 7.4) by ultrasonic bath and kept at 37°C in a horizontal shaker set to 200 rpm. At different time intervals, 3 mL of medium was removed and replaced with fresh medium. The removed samples were centrifuged at 4000 rpm for 3 minutes and the supernatant was analyzed by UV at 350 nm.

[0305] Example 1: Continuously released colchicine microparticles

[0306] A 1% polyvinyl alcohol (PVA, Mowiol 4-88, Sigma-Aldrich) stock solution was prepared by heating 594 g of water to 70°C and dispersing 6 g of PVA therein with magnetic stirring until completely dissolved.

[0307] In a separate container, 0.7 g of colchicine (INDENA, Italy) was dissolved in 2.5 g of dichloromethane (Merck) under vortex stirring. Then, 1.05 g of PLGA 75: 25 Resomer RG 752 S [poly(lactic acid-co-glycolic acid) copolymer 75: 25, having according to USP] <911> The intrinsic viscosity, measured by an Ubbelohde capillary viscometer, was 0.16–0.24 dl / g; (Evonik Industries AG, Essen, Germany) was introduced into the mixture and completely dissolved under vortex stirring to form a polymer-drug solution.

[0308] Then, under high shear (Heidolph homogenizer DIAX 900, 11600 RPM), 5 g of the previously prepared 1% PVA stock solution was added to the drug-polymer solution over 30 seconds.

[0309] The emulsion was then slowly poured into a hardening bath containing 500 mL of the previously prepared 1% PVA stock solution.

[0310] The mixture was stirred continuously for 3 hours using a twin-propeller stirrer at a stirring speed set to 250 rpm until the dichloromethane evaporated.

[0311] The formed microparticles were centrifuged at 4000 rpm for 3 minutes using a shaker centrifuge to remove the main aqueous phase and obtain a concentrated particle slurry before separation through a 12 µm stainless steel sieve (4 cm in diameter).

[0312] The microparticles were then rinsed with 150 mL of water and dried overnight in a desiccator using a 3 Å molecular sieve.

[0313] The collected microparticles were then stored at 5°C.

[0314] Analytical tests, including in vitro properties, were performed as described in the “Analytical Methods” section above and are shown in Table 2 below.Instructions for Use, pages 29 / 37, 33 CN 121013711 A

[0315]

[0316] In this example, PLGA microparticles loaded with colchicine were prepared, with a drug loading content of 3% by weight, an average particle size of 19 µm, and drug release that could be maintained for more than 30 days.

[0317] Example 2: Continuously released colchicine microparticles

[0318] The same polyvinyl alcohol (PVA) storage solution as in Example 1 was prepared.

[0319] In a separate container, 0.7 g of colchicine (INDENA, Italy) was dissolved in 2.5 g of dichloromethane (Merck) under vortex stirring. Then, 1.05 g of PLGA 75: 25 Resomer RG 755 S [poly(lactic acid-co-glycolic acid) copolymer 75: 25, having according to USP <911> The intrinsic viscosity of 0.5–0.7 dl / g, as determined by an Ubbelohde capillary viscometer (Evonik Industries AG, Essen, Germany), was introduced into the mixture and completely dissolved under vortex stirring to form a polymer-drug solution.

[0320] Then, under high shear (Heidolph homogenizer DIAX 900, 11600 RPM), 5 g of the previously prepared 1% PVA stock solution was added to the drug-polymer solution over 30 seconds to form a pre-emulsion.

[0321] The pre-emulsion was then slowly poured into a hardening bath containing 500 mL of the previously prepared 1% PVA stock solution.

[0322] The mixture was stirred continuously for 3 hours using a twin-propeller stirrer at a stirring speed set to 250 RPM until the dichloromethane evaporated.

[0323] The formed microparticles were centrifuged at 4000 rpm for 3 minutes using a shaker centrifuge to remove the main portion of the aqueous phase and obtain a concentrated particle slurry before separation through a 12 µm stainless steel sieve (4 cm in diameter).

[0324] The microparticles were then rinsed with 150 mL of water and dried overnight in a desiccator using a 3 Å molecular sieve.

[0325] The collected microparticles were then stored at 5°C.

[0326] Analytical tests, including in vitro properties, were performed as described in the “Analytical Methods” section above and are shown in Table 3 below. Specification 30 / 37 pages 34 CN 121013711 A

[0327]

[0328] In this embodiment, colchicine-loaded PLGA microparticles were prepared with a drug loading of 6% by weight, an average particle size of 25 µm, and a drug release maintained for at least 100 days.

[0329] Example 3: Continuously released colchicine microparticle composition

[0330] A continuously released colchicine microparticle composition was prepared by blending 0.2 g of particles from Example 1 with 0.2 g of particles from Example 2.

[0331] In vitro properties were performed as described in the “Analytical Methods” section above and are shown in Table 4 below.

[0332]

[0333] Example 4: Pharmaceutical Composition Instructions for Use, Pages 31 / 37, 35 CN 121013711 A

[0334] An aqueous injectable solvent was prepared using pyrogen-free excipients, consisting of 1.4% low-viscosity sodium carboxymethyl cellulose (Aqualon CMC 7LF PH BET, Ashland), 0.1% polysorbate 20 (Acros Organics), 0.13% disodium hydrogen phosphate dihydrate, 0.1% citric acid (Roth), and 0.65% sodium chloride (Roth). The final pH of the solution was adjusted to 7.2 using concentrated sodium hydroxide solution (Roth). The solvent was then autoclaved at 121°C for 15 minutes (MultiControl 2, CertoClav), and aliquots of 5 mL solution were aseptically transferred to 10 mL vials under laminar flow hood.

[0335] The aliquots of particulate matter prepared according to Example 3 were dispersed into each vial using a vortex mixer. This allows for the preparation of sterile and injectable pharmaceutical compositions suitable for intra-articular injection according to the invention.

[0336] These pharmaceutical compositions are suitable for intra-articular injection to treat arthropathy, such as osteoarthritis, erosive osteoarthritis of the hand, and any other type of chondropathy, and / or to treat pain-related arthropathy, and / or to protect joints, bones, and / or cartilage, particularly for treating osteoarthritis and / or pain-related osteoarthritis.

[0337] Example 5: Continuously Released Colchicine Particles

[0338] A 1% by weight polyvinyl alcohol (PVA, Mowiol 4-88, Sigma-Aldrich) stock solution was prepared by heating 2970 g of water to 70°C and dispersing 30 g of PVA therein under magnetic stirring until completely dissolved. The solution was then allowed to cool before further use.

[0339] In a separate container, 1.6 g of colchicine (INDENA, Italy) was dissolved in 13.5 g of dichloromethane (Merck) under vortex stirring until completely dissolved.

[0340] Then, 2.40 g of PLGA 65:35 [poly(lactic acid-co-glycolic acid) copolymer 65:35 with a molecular weight of 40000-75000 from Sigma Aldrich, having according to USP <911> The intrinsic viscosity of 0.55–0.75 dl / g, as determined by an Ubbelohde capillary viscometer, was introduced into the mixture and completely dissolved under magnetic stirring at 300 rpm to form a polymer-drug solution.

[0341] Then, 27.2 g of the previously prepared 1% PVA stock solution was sampled into another 50 mL glass beaker, and the drug-polymer solution was slowly poured into it under high shear (ULTRA TURRAX T25, 9600 rpm) for 10 minutes to form a pre-emulsion.

[0342] The pre-emulsion was then slowly poured into a hardening bath containing 2700 mL of the previously prepared 1% PVA stock solution.

[0343] The mixture was stirred continuously for 3 hours using a twin-propeller stirrer at a stirring speed set to 200 rpm until the dichloromethane evaporated.

[0344] The formed particles were centrifuged at 4000 rpm for 3 minutes using a shaker centrifuge to remove the main portion of the aqueous phase and obtain a concentrated particle slurry before separation using a sintered glass filter with a porosity of 4 (10-16 µm mesh).

[0345] The particles were then rinsed with 150 mL of water and vacuum dried overnight in a desiccator.

[0346] The collected microparticles were then stored at 5°C.

[0347] Analytical tests, including in vitro properties as described in the “Analytical Methods” section above, were performed and are shown in Table 5 below. Specification 32 / 37 pages 36 CN 121013711 A

[0348]

[0349] In this example, colchicine-loaded PLGA microparticles were prepared with a drug loading of 15.5% by weight, an average particle size of 16 µm, and sustained drug release for at least 45 days.

[0350] Example 6: Sustained-release colchicine microparticles

[0351] The same polyvinyl alcohol (PVA) storage solution as in Example 5 was prepared.

[0352] In a separate container, 1.6 g of colchicine (INDENA, Italy) was dissolved in 13.6 g of dichloromethane (Merck) until completely dissolved under vortex stirring.

[0353] Then, 2.40 g of PLGA 75:25 [poly(lactic acid-co-glycolic acid) copolymer 75:25 with a molecular weight of 40,000-75,000 from Sigma Aldrich, having according to USP <911> The intrinsic viscosity of 0.55–0.75 dl / g, as determined by an Ubbelohde capillary viscometer, was introduced into the mixture and completely dissolved under magnetic stirring at 300 rpm to form a polymer-drug solution.

[0354] Then, 27.2 g of the previously prepared 1% PVA stock solution was sampled into another 50 mL glass beaker, and the drug-polymer solution was slowly poured into it under high shear (ULTRA TURRAX T25, 9600 rpm) for 10 minutes to form a pre-emulsion.

[0355] The pre-emulsion was then slowly poured into a hardening bath containing 2700 mL of the previously prepared PVA 1% by weight stock solution.

[0356] The mixture was stirred continuously for 3 hours using a twin-propeller stirrer at a stirring speed set to 200 RPM until the dichloromethane evaporated.

[0357] The resulting microparticles were centrifuged at 4000 rpm for 3 minutes using a shaker centrifuge to remove the main portion of the aqueous phase and to obtain a concentrated particle slurry before separation using a sintered glass filter with a porosity of 4 (10-16 µm mesh).

[0358] The microparticles were then rinsed with 150 mL of water and vacuum dried overnight in a desiccator.

[0359] The collected microparticles were then stored at 5°C.

[0360] Analytical tests, including in vitro properties, were performed as described in the “Analytical Methods” section above and are shown in Table 6 below. Instructions for Use, pages 33 / 37, CN 121013711 A

[0361]

[0362] In this embodiment, colchicine-loaded PLGA microparticles were prepared with a drug loading of 14.2% by weight, an average particle size of 24 µm, and sustained drug release for at least 45 days.

[0363] Example 7: Continuously Released Colchicine Microparticles

[0364] The same polyvinyl alcohol (PVA) storage solution as in Example 5 was prepared.

[0365] In a separate container, 1.0 g of colchicine (INDENA, Italy) was dissolved in 13.5 g of dichloromethane (Sigma Aldrich) until completely dissolved under vortex stirring.

[0366] Then, 1.5 g of PLGA 85:15 [poly(lactic acid-co-glycolic acid) copolymer 85:15] with a molecular weight of 46,000-95,000 from Ashland, having according to USP <911> The intrinsic viscosity of 0.60–0.80 dl / g, as determined by an Ubbelohde capillary viscometer, was introduced into the mixture and completely dissolved under magnetic stirring at 300 rpm to form a polymer-drug solution.

[0367] Then, 27 g of the previously prepared 1% PVA stock solution was sampled into another 50 mL glass beaker, and the drug-polymer solution was slowly poured into it under high shear (ULTRA TURRAX T25, 9600 rpm) for 10 minutes to form a pre-emulsion.

[0368] The pre-emulsion was then slowly poured into a hardening bath containing 2700 mL of the previously prepared 1% PVA stock solution.

[0369] The mixture was stirred continuously for 3 hours using a twin-propeller stirrer at a stirring speed set to 200 RPM until the dichloromethane evaporated.

[0370] The formed microparticles were centrifuged at 4000 rpm for 3 minutes using a shaker centrifuge to remove the main portion of the aqueous phase and obtain a concentrated particle slurry before separation using a sintered glass filter with a porosity of 4 (10-16 µm mesh).

[0371] The microparticles were then rinsed with 150 mL of water and vacuum dried overnight in a desiccator.

[0372] The collected microparticles were then stored at 5°C.

[0373] Analytical tests, including in vitro properties, were performed as described in the “Analytical Methods” section above and are shown in Table 7 below. Specification 34 / 37 pages 38 CN 121013711 A

[0374]

[0375] In this embodiment, colchicine-loaded PLGA microparticles were prepared with a drug loading of 15.1% by weight, an average particle size of 14 µm, and sustained drug release for at least 30 days.

[0376] Example 8: Pharmaceutical Composition

[0377] An aqueous injectable solvent was prepared using pyrogen-free excipients, consisting of 1.4% low-viscosity sodium carboxymethyl cellulose (Aqualon CMC 7LF PH BET, Ashland), 0.1% polysorbate 20 (Emprove Essential Ph Eur. JPE, NF), 0.13% disodium hydrogen phosphate dihydrate, 0.1% citric acid (Roth), and 0.64% sodium chloride (Roth). The final pH of the solution was adjusted to 6.2 using concentrated sodium hydroxide solution (Roth). The solvent was then autoclaved at 121°C for 20 minutes (Tuttnauer 2840EL), and 5 mL aliquots of the solution were aseptically transferred to 10 mL vials under laminar flow hood conditions.

[0378] Using ultrasound, aliquots of colchicine particles with a target concentration of 100 µg / mL and ropivacaine hydrochloride (MOEHS, Spain) with a target concentration of 5 mg / mL, prepared according to Example 5, were dispersed into each vial for 30 seconds. This yielded a sterile and injectable pharmaceutical composition suitable for intra-articular injection according to the invention.

[0379] These pharmaceutical compositions are suitable for intra-articular injection for colchicine release over 3 to 6 months to treat arthropathy, such as osteoarthritis, erosive hand osteoarthritis, and any other type of chondropathy, and / or to treat pain-related arthropathy, and / or to protect joints, bones, and / or cartilage, particularly for treating osteoarthritis and / or pain-related osteoarthritis.

[0380] Example 9: In Vivo-Cartilage Protection

[0381] The pharmaceutical composition as described herein was injected into the ankle joint of inflamed rats, and its effect on cartilage destruction was observed.

[0382] 9.1 Pharmaceutical Composition

[0383] An aqueous injectable solvent was prepared using water for injection and a pyrogen-free excipient under laminar flow.The solvent consisted of 1.4% low-viscosity sodium carboxymethyl cellulose (Aqualon CMC 7LF PH BET, Ashland), 0.1% polysorbate 20 (Emprove Essential, Merck), 0.13% disodium hydrogen phosphate dihydrate (Roth), 0.1% citric acid (Roth), and 0.65% sodium chloride (Roth). The final pH of the solution was adjusted to 7.5 using a concentrated sodium hydroxide solution (Roth).

[0384] The solvent was then autoclaved at 121°C for 20 minutes (Systec 3150EL) and finally stored at 4°C for later use.

[0385] The pharmaceutical composition was prepared by weighing 65 mg of ropivacaine hydrochloride and 10 mg of colchicine microparticles prepared according to section 9.2 of the Examples in a 20 mL autoclaved container.

[0386] Immediately prior to in vivo injection, 12.50 mL of the aqueous injection solvent was introduced into the vial and homogenized using ultrasonic stirring (pages 35 / 37, CN 121013711 A) until the particles were completely and uniformly dispersed. The resulting suspension yielded a colchicine concentration of 40 μg / mL and a ropivacaine hydrochloride concentration of 5 mg / mL. Then, as described in point 9.3 below, 50 μL of this suspension was injected into the inflamed ankle joint of rats.

[0387] 9.2 Preparation of Colchicine Microparticles

[0388] Colchicine microparticles were prepared under laminar flow and in an autoclaved and sterile container as follows:

[0389] A 1% by weight polyvinyl alcohol (PVA, Mowiol 4-88, Sigma-Aldrich) stock solution was prepared by heating 2970 g of sterile water (Gibco 15230-162) to 70°C and dispersing 30 g of PVA therein with magnetic stirring until completely dissolved. The solution was then allowed to cool before further use.

[0390] In a separate autoclaved container, 0.5 g of colchicine (INDENA, Italy) was dissolved in 10.75 mL of dichloromethane (Merck) with magnetic stirring.Then, 2.85 g of PLGA 50: 50 Resomer 503H [poly(lactic acid-co-glycolic acid) copolymer 50: 50, having an intrinsic viscosity of 0.32–0.44 dl / g; (Evonik Industries AG, Essen, Germany)] and 0.15 g of PLGA 50: 50 Resomer 502H [poly(lactic acid-co-glycolic acid) copolymer 50: 50, having an intrinsic viscosity of 0.16–0.24 dl / g; (Evonik Industries AG, Essen, Germany)] were introduced into the mixture and completely dissolved under magnetic stirring to form a polymer-drug solution.

[0391] Then, under high shear (9500 RPM), 28.6 g of the previously prepared 1% by weight stock solution of PVA was added to the drug-polymer solution. Emulsification was performed for 10 minutes using an IKA T25 Ultra-Turrax rotor-stator mixer equipped with an S25N 10G head.

[0392] The emulsion was then slowly poured into a hardening bath containing 2860 g of a previously prepared 1% by weight stock solution of PVA.

[0393] The mixture was stirred continuously for 3 hours at a stirring speed set to 300 rpm using a twin-propeller stirrer until the dichloromethane evaporated.

[0394] The resulting microparticles were centrifuged at 4000 rpm for 3 minutes using a GT2R shaker centrifuge to remove the main portion of the aqueous phase and obtain a concentrated particle slurry. The slurry was then redispersed in approximately 20 mL of water, and the redispersed particles were sieved at 40 µm using a stainless steel Endecotts sieve, followed by 10 µm sieves.

[0395] The collected particles were then vacuum filtered through a 12–25 µm Whatman cellulose filter and washed with 150 mL of sterile water.

[0396] The washed microparticles were then vacuum dried at 2 mBar and 15°C for 17 hours.

[0397] The collected microparticles were then stored at 5°C.

[0398] In this embodiment, colchicine-loaded PLGA microparticles were prepared with a drug loading of 5.1 wt% and an average particle size of 21 µm.

[0399] 9.3 In vivo experiments

[0400] In this embodiment, 16 Sprague Dawley rats were randomly divided into two groups of 8 each.

[0401] • Group 1 (control group) received an intra-articular injection of phosphate-buffered saline (50 μL) into the left ankle, followed by immediate induction of inflammation by injection of λ-carrageenan (1 mg / 30 μL) into the same joint.

[0402] • Group 2 (treatment group) received an intra-articular injection of the drug composition (50 μL) into the left ankle, followed by immediate induction of inflammation by injection of λ-carrageenan (1 mg / 30 μL) into the same joint.

[0403] Three days after injection, all animals were euthanized and the ankle joints were dissected for histological examination. Samples were immersed in 10% formalin overnight. The next day, decalcification was performed in RDO (Eurobio) for 5 hours, followed by decalcification in 0.5 M EDT for 48 hours. The samples were then dehydrated in an automated instrument and embedded in paraffin. 4 μm sections were prepared and stained with hematoxylin and eosin. Observation was performed blinded. Instructions for use 36 / 37 pages 40 CN 121013711 A

[0404]

[0405]

[0406] The results are reported in Figure 1.

[0407] All control animals (Group 1), except one, exhibited cartilage destruction and inflammatory arthritis (moderate to severe, with synovial thickening, presence of inflammatory cells, and invasion of periarticular tissues).

[0408] In contrast, the treated animals (Group 2) showed no inflammatory synovitis (4 / 7 rats), mild inflammatory synovitis (2 / 7 rats), or moderate inflammatory synovitis (1 / 7 rats). Group 2 animals showed no signs of cartilage destruction (5 / 7 rats) or mild signs of cartilage destruction (2 / 7 rats). In summary, these observations demonstrate a clear anti-inflammatory and anti-destructive effect of the treatment in the current rat model of acute arthritis. The inventors anticipate that such chondrogenic protective effects will be observed regardless of the exposure time and release characteristics of colchicine, provided the dose meets an acceptable local concentration window.

[0409] Analysis of ankle cartilage inflammation scores in the treated animals showed a statistically significant difference between Group 2 and Group 1 (p < 0.05, Kruskal-Wallis and Dunnett tests). Furthermore, analysis of the damage scores showed a significant and prominent statistically significant difference between group 2 and group 1 (p < 0.01, Kruskal-Wallis and Dunnett tests). (Instruction manual 37 / 37 pages 41 CN 121013711 A Figure 1; Instruction manual Appendix 1 / 1 page 42 CN 121013711 A)

Claims

1. A sterile and injectable pharmaceutical composition comprising a controlled-release formulation containing colchicine, for the treatment of joint diseases, such as osteoarthritis, erosive osteoarthritis of the hand, and any other type of chondropathy, and / or for the treatment of pain-related joint diseases, and / or for the protection of joints, bones, and / or cartilage, wherein the dissolution rate of colchicine is 80% (w / w) over a period of more than one month, as determined according to the following protocol: A 20 mg aliquot of the controlled-release formulation containing colchicine was suspended in 50 mL of phosphate buffer (pH 7.4) with stirring at 37 °C. The supernatant of the sample was then periodically analyzed by UV scanning at 350 nm throughout the release period. Colchicine is present at concentrations ranging from 1 to 27,500 μg per mL of sterile, injectable formulation.

2. The pharmaceutical composition for use according to claim 1, wherein the dissolution rate of colchicine is 80% (w / w) over 1 to 6 months, 2 to 6 months or 3 to 6 months.

3. The pharmaceutical composition for use according to claim 1 or 2, wherein the controlled-release dosage form containing colchicine is an in-situ formed reservoir or particulate form, particularly a particulate or multi-capsule liposome form comprising a polymer matrix.

4. The pharmaceutical composition for use according to any one of the preceding claims, wherein the colchicine-containing controlled-release dosage form is in particulate form, particularly in particulate form comprising a polymer matrix, and the colchicine-containing particulates have an average particle size equal to or greater than 10 μm as determined by laser diffraction, and particularly have an average particle size of less than 100 μm, more particularly less than 80 μm, and even more particularly less than 50 μm, for example, 10 to 50 μm or 10 to 40 μm.

5. The pharmaceutical composition for use according to claim 4, wherein the microparticles may be a mixture of microparticles of different properties, the microparticles being microparticles comprising colchicine and a polymer matrix, wherein the polymer matrix comprises: - At least one poly(lactic acid-co-glycolic acid) copolymer, particularly two copolymers exhibiting different molecular weights. - At least one poly(caprolactone), or - A mixture containing at least a poly(lactic acid-co-glycolic acid) copolymer and at least a poly(caprolactone).

6. The pharmaceutical composition for use according to any one of claims 4 to 5, wherein the polymer matrix further comprises one or more additional polymers or copolymers selected from poly(lactide) copolymers other than poly(lactide-co-glycolic acid), poly(glycolic acid), poly(lactide-co-caprolactone), poly(ethylene glycol), poly(ethylene oxide), PLGA-b-PEO-b-PLGA, PLGA-b-PEO, polyhydroxyalkanoates, poly(hydroxybutyrate), poly(trimethylammonium carbonate), etc. Methyl ester), poly(dioxane), poly(valerol), poly(α-hydroxy acid), poly(lactone), poly(amino acid), polyanhydride, poly(orthoester), poly(acetal), polyurethane, polysulfide, polyphosphate, poly(ester-co-amide), poly(vinyl alcohol), PVA-g-PLGA, poly(ether ester) multiblock copolymer, polyvinylpyrrolidone, poly(methacrylate), PEO-PPO-PEO, gelatin, heparin, chondroitin sulfate; polysaccharides, such as alginate, starch, chitosan and dextran and any combination thereof, particularly selected from poly(lactide) and poly(caprolactone).

7. The pharmaceutical composition for use according to any one of claims 4 to 6, wherein, relative to the total weight of the polymer matrix, the polymer matrix comprises, by weight, at least one poly(lactic acid-co-glycolic acid) copolymer, at least one polycaprolactone, or a mixture comprising at least said amounts of at least the poly(lactic acid-co-glycolic acid) copolymer and at least polycaprolactone, wherein, in particular, the lactic acid:glycolic acid molar ratio of the poly(lactic acid-co-glycolic acid) copolymer is 50:50 to 90:10, particularly 55:45 to 90:10, more particularly 65:35 to 85:15, for example 75:25, wherein, in particular, the poly(lactic acid-co-glycolic acid) copolymer exhibits the characteristics according to USP <911> The intrinsic viscosity, measured by an Ubbelohde capillary viscometer, ranges from 0.1 to 1.7 dl / g, particularly from 0.1 to 1.4 dl / g, and even more particularly from 0.1 to 0.9 dl / g.

8. The pharmaceutical composition for use according to any one of the preceding claims, wherein it is in a sterile and injectable dosage form selected from solutions, suspensions, solid implants, semi-solid implants, powders, and in-situ repositories.

9. The pharmaceutical composition for use according to any one of the preceding claims, wherein it further comprises an anesthetic agent selected from lidocaine, ropivacaine, bupivacaine, levobupivacaine, capsaicin, mepivacaine, prilocaine, pharmaceutically acceptable salts thereof, and mixtures thereof, particularly selected from lidocaine, bupivacaine, ropivacaine, and mepivacaine, and more particularly from ropivacaine and bupivacaine, and even more particularly from ropivacaine.

10. The pharmaceutical composition for use according to claim 8 or 9, wherein colchicine is present at a concentration of 1 to 27,500 μg per mL of a sterile and injectable dosage form, particularly a suspension, particularly 3 to 27,500 μg per mL, more particularly 1 to 13,750 µg per mL, for example, 3 to 13,750 µg per mL, and even more particularly, wherein colchicine is present at a concentration of 3 to 3,600 µg per mL. - For example, when the dissolution rate of colchicine is 80% (w / w) over a period of more than one month but less than two months, the dosage is 3 to 600 µg per mL. - For example, when the dissolution rate of colchicine is 80% (w / w) over 2 to 4.5 months, 9 to 1800 µg per mL, and - For example, when the dissolution rate of colchicine is 80% (w / w) over 4.5 to 7 months, the concentration is 18 to 3600 µg per mL. And when an anesthetic is present, the anesthetic is present at a concentration of 1 to 100 mg per mL of sterile and injectable dosage form, particularly a suspension.

11. The pharmaceutical composition for use according to any one of the preceding claims, for treating osteoarthritis, erosive hand osteoarthritis, and any other type of rickets in patients with inflammatory components, inflammatory pain, or joint effusion.

12. The pharmaceutical composition for use according to any one of the preceding claims, characterized in that it effectively maintains a systemic concentration of colchicine below 5 ng / mL, particularly below 1 ng / mL, more particularly below 0.5 ng / mL, and even more particularly below 0.1 ng / mL, within 24 hours after intra-articular injection, particularly within 1 month, and even more particularly within at least 3 months, and effectively maintains a synovial fluid concentration of colchicine above 0.5 ng / mL, particularly between 0.5 and 100 ng / mL, and even more particularly between 0.5 and 50 ng / mL, within 1 month after intra-articular injection, and even more particularly within at least 3 months.

13. A pharmaceutical composition for use according to any one of the preceding claims, wherein it is used to treat a patient with arthropathy, such as osteoarthritis, erosive osteoarthritis of the hand, and any other type of chondropathy, and / or to treat a patient with pain-related arthropathy, and / or to protect a patient's joints, bones, and / or cartilage, particularly for treating a patient with osteoarthritis and / or pain-related osteoarthritis, said patient having kidney and / or liver damage, said patient being treated simultaneously, separately, or sequentially and non-exclusively with at least one active ingredient selected from the group consisting of. Atazanavir, clarithromycin, darunavir, ritonavir, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, telanavir, ampravir, aprepitant, diltiazem, erythromycin, fluconazole, fosanavir, verapamil, cyclosporine, ranolazine, macrolides and statins, or the patient has chronic comorbidities such as hypertension, chronic kidney disease, diabetes, cardiovascular disease, infection, stroke, depression, peptic ulcer, metabolic syndrome and / or immunosuppression.

14. A sterile and injectable dosage form of a pharmaceutical composition comprising a controlled-release formulation containing colchicine, wherein the pharmaceutical composition exhibits in vitro dissolution characteristics, wherein the dissolution rate of colchicine is less than 25% (w / w) over 24 hours, and more preferably less than 15% (w / w), and greater than 80% (w / w) over more than one month, particularly more than three months, and even more particularly more than six months, as determined according to the following protocol: A 20 mg aliquot of a controlled-release formulation containing colchicine was suspended in 50 mL of phosphate buffer (pH 7.4) with stirring at 37 °C. The supernatant of the sample was then periodically analyzed by UV at 350 nm throughout the release period, and the colchicine was present at a concentration of 1 to 27,500 μg per mL of sterile injectable formulation.

15. A powder formulation comprising a controlled-release formulation containing colchicine in the form of microparticles, said microparticles having an average particle size equal to or greater than 10 µm as determined by laser diffraction, said microparticles comprising a polymer matrix, wherein, relative to the total weight of the polymer matrix, said polymer matrix comprises, by weight, at least 70%, particularly, at least 80%, and even more particularly, at least 90% of at least one poly(lactic acid-co-glycolic acid) copolymer, at least one polycaprolactone, or at least a mixture comprising said amounts of at least said poly(lactic acid-co-glycolic acid) copolymer and at least polycaprolactone, wherein, particularly, the lactic acid:glycolic acid molar ratio of the poly(lactic acid-co-glycolic acid) copolymer is 50:50 to 90:10, particularly 55:45 to 90:10, for example 60:40 to 90:10, more particularly 65:35 to 85:15, for example 75:25, wherein, particularly, the poly(lactic acid-co-glycolic acid) copolymer exhibits the characteristics according to USP <911> The intrinsic viscosity, measured by an Ubbelohde capillary viscometer, ranges from 0.1 to 1.7 dl / g, particularly from 0.1 to 1.4 dl / g, and even more particularly from 0.1 to 0.9 dl / g.

16. A sterile and injectable dosage form of pharmaceutical composition suitable for intra-articular injection, said pharmaceutical composition being obtained by mixing a powder form of the formulation according to claim 15 with an aqueous injection solvent, said pharmaceutical composition optionally comprising an excipient selected from tension enhancers, wetting agents, viscosity enhancers, density enhancers or mixtures thereof, and said excipient may be present in the aqueous injection solvent or in the powder, and optionally comprising hyaluronic acid.

17. A sterile and injectable pharmaceutical composition suitable for intra-articular injection, comprising a controlled-release formulation containing colchicine, said controlled-release formulation being in the form of microparticles comprising a polymer matrix having an average particle size equal to or greater than 10 µm as determined by laser diffraction, wherein, relative to the total weight of the polymer matrix, the polymer matrix comprises, by weight, at least 70%, particularly at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at weight, at least a mixture comprising at least said amounts of at least a poly(lactic acid-co-glycolic acid) copolymer and at least polycaprolactone, wherein, in particular, the lactic acid:glycolic acid molar ratio of the poly(lactic acid-co-glycolic acid) copolymer is 50:50 to 90:10, particularly 55:45 to 90:10, for example 60:40 to 90:10, more particularly 65:35 to 85:15, for example 75: 25, in particular, poly(lactic acid-co-glycolic acid) copolymers exhibit the characteristics specified in USP <911> The intrinsic viscosity, measured by an Ubbelohde capillary viscometer, ranges from 0.1 to 1.7 dl / g, particularly from 0.1 to 1.4 dl / g, and even more particularly from 0.1 to 0.9 dl / g.

18. The sterile and injectable pharmaceutical composition according to claim 16 or 17, wherein the pharmaceutical composition is selected from solutions, suspensions, solid implants, semi-solid implants, powders and in-situ reservoirs, particularly suspensions, and wherein colchicine is present at a concentration of 1 to 27,500 μg per mL of sterile and injectable dosage form, particularly suspension, particularly 3 to 27,500 μg, more particularly 1 to 13,750 µg per mL, for example 3 to 13,750 µg per mL.

19. A cassette or article comprising, in separate compartments: (i) an aqueous injection solvent and (ii) a controlled-release formulation containing colchicine as defined in any one of claims 3 to 7 or a powder as defined in claim 15, wherein the cassette or article optionally contains an excipient selected from tension enhancers, wetting agents, viscosity enhancers, density enhancers and mixtures thereof, and optionally contains hyaluronic acid for preparing a pharmaceutical composition suitable for intra-articular injection, wherein (i) and / or (ii) optionally contains an anesthetic in an immediate-release formulation.

20. The medicine box or article of claim 19, wherein the medicine box or article is in the form of a vial and a pre-filled syringe or a medical device or two separate vials.

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