Intra-articular injection dosage form containing colchicine for use in the treatment of joint diseases such as osteoarthritis

Abstract

The present invention relates to a pharmaceutical composition in the form of a sterile injectable dosage form, comprising a sustained-release formulation containing colchicine, for use in the treatment of joint diseases such as osteoarthritis, erosive osteoarthritis of the wrist, and any other type of cartilage disease, and / or for use in the treatment of pain-related joint diseases, and / or for use in protecting joints, bones, and / or cartilage, by intra-articular injection of the pharmaceutical composition into a joint, wherein the time required for the release of 80% by weight of colchicine is greater than one month, and the colchicine is present in a concentration ranging from 1 to 27.5 mg per ml of the sterile injectable dosage form. It also relates to a pharmaceutical composition in the form of a sterile injectable dosage form, comprising a sustained-release formulation containing colchicine, having an adapted in vitro dissolution profile. It also relates to a formulation in the form of a powder, a pharmaceutical composition in the form of a sterile injectable dosage form suitable for intra-articular injection containing colchicine, a pharmaceutical composition in the form of microparticles comprising a polymer matrix, and related kits or articles of manufacture.

Description

[Technical Field]

[0001] The present invention relates to the field of treatment of joint diseases such as osteoarthritis, erosive hand osteoarthritis (EHOA) and any other kind of cartilage disease and / or pain-related joint disease and / or protection of joints, bones and / or cartilage by administering colchicine in the joints. Colchicine is administered locally by intra-articular injection via a sustained release dosage form. [Background technology]

[0002] background Osteoarthritis (OA) is a multifactorial degenerative disorder of the joints characterized by chronic pain and resulting in cartilage and tissue destruction, along with subchondral bone modification and low-grade synovial inflammation. OA is highly prevalent and often age-related or traumatic, but has a heterogeneous phenotype (genetic, inflammatory, metabolic, aging, etc.) that commonly affects the knee, hip, hand, or spinal joints. Synovitis or low-grade local inflammation is a common feature of OA and, at some point, may be a driver of disease progression, including OA triggered by the NLRP3 inflammasome pathway. More specifically, calcium crystals (calcium phosphate and calcium pyrophosphate), frequently present in OA joints, may contribute to joint inflammation. Erosive osteoarthritis of the wrist (EHOA), the most aggressive form of osteoarthritis, primarily affects women, is characterized by acute onset of inflammation and erosion of the distal or proximal interphalangeal joints and pain that leads to disability and reduced quality of life.

[0003] Treatments for osteoarthritis and EHOA, as well as any other type of cartilage disease, are mostly symptomatic and aimed at pain control, but provide modest efficacy along with safety concerns. Generally, first-line options are primarily oral nonsteroidal anti-inflammatory drugs (NSAIDs), oral or intra-articular corticosteroids.

[0004] Intra-articular administration of corticosteroids has been commonly used in joint diseases for decades, allowing for slight improvements in pain and mobility, with short-lasting effects (a few weeks in the case of immediate-release forms). However, the toxicological aspects of these administrations are highly problematic and controversial. Indeed, systemic effects, including Cushing's syndrome, hyperglycemia, decreased bone density, and risk of infection, have been reported for several weeks after injection. The latter may be the result of direct introduction of infectious agents into the joint or by weakening the immune response and reactivating latent tuberculosis infection. This type of treatment is not particularly suitable for at-risk patients, i.e., those with comorbidities such as diabetes or osteoporosis. Furthermore, adverse effects have also been described on local tissues, such as damage to articular cartilage and tendons.

[0005] As a result, medical practice limits the frequency and dosage of intra-articular corticosteroid injections. Therefore, for immediate-release galenic preparations, a maximum of three injections per site per year and a minimum interval of three months between two injections is recommended. The first intra-articular sustained-release formulation of corticosteroids (Zilretta® by Flexion Therapeutics) was approved by the FDA in 2017 for osteoarthritis and associated pain, particularly knee osteoarthritis, allowing for continuous treatment over several months. However, this product is not approved for repeated administration.

[0006] Therefore, intra-articular administration of corticosteroids does not appear to be the treatment of choice for the chronic treatment of osteoarthritis.

[0007] Colchicine is a drug characterized by pleiotropic effects related to its ability to bind to tubulin, disrupt microtubule polymerization, and destabilize the cytoskeleton and all cellular processes, including cell division, migration, and cell shape. Among these effects, colchicine affects the immune system, downregulating multiple inflammatory pathways and resulting in decreased neutrophil function and migration. Therefore, colchicine has been approved for use in several inflammatory diseases, such as familial Mediterranean fever, Behçet's disease, and microcrystalline cellulose.

[0008] Colchicine has actually been used for a very long time for the nonspecific treatment of crystal-related arthropathy. Over the past 50 years, the use of short-acting NSAIDs and corticoids has been investigated along with colchicine as the oral medication of choice for the symptomatic treatment of acute gout and pseudogout. George Nuki, MB, FRCP, in his paper "Colchicine: Its Mechanism of Action and Efficacy in Crystal-Induced Inflammation," Current Rheumatology Reports, 2008, 10:218-227, reviews the preventive and therapeutic efficacy of oral colchicine administration. Furthermore, the paper extensively describes colchicine's side effects, such as a potent purging effect, bone marrow suppression, neuromyopathy, and rhabdomyolysis, especially in patients with renal insufficiency, as well as the high mortality rate associated with overdose. Therefore, colchicine has an exceptionally narrow therapeutic index. Although colchicine is not currently an approved treatment for osteoarthritis, several clinical studies have demonstrated that oral colchicine may be useful in treating adult patients with knee osteoarthritis, including primary osteoarthritis, i.e., osteoarthritis not associated with calcium pyrophosphate crystal deposition. However, experimental doses of oral colchicine may cause adverse effects, such as gastrointestinal symptoms, observed in some patients (Restrepo-Escobar M et al. Revision sistematica de la literatura sobre el tratamiento con colchicina en pacientes adultos con osteoarthritis de rodilla. Rev Colomb Reumatol. 2017;24:102-111), and other studies have not explained this benefit (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)).

[0009] Furthermore, it is known to treat inflammation or osteoarthritis of a joint by administering an active substance directly therein, but it has been found that the active substance escapes relatively easily from the joint, thus reducing the effectiveness of the treatment.

[0010] Encapsulation of colchicine for sustained release has been reported in different carriers, such as polymer microspheres (Das, G. Set 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 paper, colchicine was investigated in the treatment of other diseases, such as restenosis after angioplasty or vascular injury. On this occasion, an attempt was made to encapsulate colchicine in poly(lactic acid) / poly(ε-caprolactone) microspheres for local delivery of colchicine. Another composition containing biodegradable microparticles containing colchicine was further described for the treatment of the same lesion, i.e., restenosis, by intramural delivery, as reported by 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 1549-1557. It becomes clear that the therapeutic target is completely different from that of the present invention. Furthermore, the results are not encouraging, pointing to a risk of toxicity. In fact, signs of local toxicity were observed in the muscle layer supplied by the artery infused with microparticles containing colchicine or a colchicine analogue, but not in the control. It is worth noting that in both disclosures, the particle size is smaller than that of the particles embodied in the present invention, as will become clear in the following discussion. Furthermore, long-term treatment, i.e., beyond one month, is neither disclosed nor suggested.

[0011] Furthermore, colchicine has previously been reported in U.S. Patent No. 5,747,060 as acting to prolong the duration of the anesthetic effect produced by local administration of an anesthetic, an effect also outside the scope of the present invention. Thus, colchicine is co-administered in immediate release form, i.e., directly in aqueous solution, with bupivacaine around the sciatic nerve in Example 1 of that document. Intra-articular injection is not described in that document, nor is the activity of colchicine in the treatment of osteoarthritis of the joints, nor is sustained release described.

[0012] WO 2006 / 066419 discloses the same effect of colchicine in combination with a vanilloid receptor agonist and another molecule, possibly colchicine, to extend its anesthetic effect. The examples disclose a composition containing a mixture of resiniferatoxin and colchicine injected intra-articularly for the treatment of capsulitis. Furthermore, however, the injection is dedicated to immediate release, without attempting to control the local profile and systemic pharmacokinetics of colchicine or to extend its therapeutic exposure.

[0013] The use of colchicine for the treatment of crystal-related arthropathy is well established. However, today, colchicine is only available commercially in the classic immediate-release oral dosage form, with a daily dose of approximately 1 mg per day for the treatment of crystal-related arthropathy. The FDA-approved dose for the treatment of acute gout flares is 1.2 mg of colchicine at the first sign of a flare, followed by 0.6 mg one hour later (https: / / www.fda.gov / drugs / postmarket-drug-safety-information-patients-and-providers / colchicine-marketed-colcrys-information). The recommended first-line treatment for acute gout flares according to the EULAR is a 1 mg loading dose 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 shown in more detail later herein, achieving a therapeutically effective dose of colchicine locally is hindered by the poor tolerance or high toxicity of orally administered colchicine, greatly complicating drug formulation.

[0014] Colchicine was recently described in a nanoemulsion system injected into the joints of a Swiss albino mouse model with MSU (monosodium urate) crystal-induced gouty arthritis: Aboumanei et al., “Intra-articular formulation of colchicine-loaded nanoemulsion systems for enhanced locoregional drug delivery: In vitro characterization,” 99m Tc coupling and in vivo biodistribution studies”, DOI:10.1080 / 03639045.2021.1934865. 99m Tc-ColNE-5 and 99mTc-Col solution( 99m studied the biodistribution pattern of radiolabeled colchicine (TcColS), however, the disclosure is limited to observing radiolabeled colchicine, which is therefore a different molecule from colchicine itself, within a period not exceeding 24 hours. 99m It is well known that labeling with radionuclides such as Tc can have a strong effect on the biodistribution pattern of the labeled entity due to alterations in its charge, lipophilicity, and stability (Decristoforo et al., "The influence of chelator on the pharmacokinetics of 99mTc-labeled peptides," QJNUCL.MED.46 3(2002):195-205). Furthermore, the paper does not mention the technical problem of a narrow therapeutic index and being highly specific to colchicine, as explained above, i.e., a maximum systemic concentration that should be avoided for toxicity reasons. Therefore, the paper does not mention a microparticle system with a larger size and targeted dose that can reach an effective local concentration to combat osteoarthritis without systemic toxicity. That is, Figure 3 of the paper clearly shows that ColNE-5, i.e., the "colchicine nanoemulsion system," provides 40% colchicine release in less than 3 hours, which contrasts with the achievement of a controlled systemic concentration of colchicine to avoid side effects required in the present invention, where the time required for 80% colchicine release by weight exceeds 1 month. As explained below in this specification, achieving a release profile that does not have such a rapid release immediately after administration, also called a "burst release," which may be detrimental in terms of side effects to such an extent, represents such an unobvious approach that could not be predicted from the paper. In other words, a colchicine sustained-release profile suitable for human healing, and more specifically for the treatment of osteoarthritis, is not revealed in the paper.

[0015] IV colchicine injections are considered effective in treating acute gout attacks at doses not exceeding 2–3 mg per single injection (Nuki, G. Colchicine: Its mechanism of action and efficacy in crystal-induced inflammation. Curr. Rheumatol. Rep. 10, 218–227 (2008)). However, even when GI side effects can be avoided using intravenous administration, severe toxicity has been associated with inappropriate administration (Wallace SL, SJ Review: Systemic toxicity associated with the intravenous administration of colchicine—guidelines for use. J. Rheumatol. 15, 495–9 (1988); Bonnel, RA, Villalba, ML, Karwoski, CB, & Beitz, J. Deaths associated with inappropriate intravenous colchicine administration. J. Emerg. Med. 22, 385–387 (2002)). This led authorities to rule out the use of intravenous colchicine for the treatment of acute gout (Zhang, W. et al. EULAR evidence-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)). Attempts at intravenous injection of colchicine, as reported by E. Niel et al., "Colchicine today," Joint Bone Spine 73 (2006) 672-678, further discouraged those skilled in the art from considering colchicine injections. Summary of the Invention [Problem to be solved by the invention]

[0016] Therefore, there remains a need to develop new dosage forms, routes of administration and targeted dosages of colchicine, in particular to avoid the side effects observed during systemic administration, and to extend its duration of local action, in particular at the painful site, to improve efficacy by optimizing the available dose of colchicine, in particular by increasing the local concentration, for the treatment of joint diseases such as osteoarthritis, erosive wrist osteoarthritis and any other type of cartilage disease, and / or for use in the treatment of pain-related joint diseases, and / or for use in protecting joints, bones and / or cartilage, in particular for use in the treatment of osteoarthritis and / or pain-related osteoarthritis. [Means for solving the problem]

[0017] The present invention has the object of meeting a need, thereby both obtaining increased benefit from its effect on the pain and / or destruction of articular cartilage in patients suffering from joint diseases, such as osteoarthritis, erosive osteoarthritis of the wrist, and any other type of cartilage disease and / or pain-related joint disease, such as osteoarthritis and any other type of cartilage disease and / or pain-related joint disease, particularly osteoarthritis, and limiting the level of any side effects, including in patients suffering from osteoarthritis, erosive osteoarthritis of the wrist, and any other type of cartilage disease with an inflammatory component, inflammatory pain, or joint effusion. The present invention also aims to enhance the protection of joints, bones, and / or cartilage in patients suffering from joint diseases and any other type of cartilage disease and / or pain-related joint disease.

[0018] One advantage of the present invention is that it provides a new means for achieving a specific colchicine release profile that respects the appropriate ratio between the local colchicine concentration and its systemic concentration, while providing optimal local therapeutic action and simultaneously avoiding potential systemic toxicity, and simultaneously providing immediate pain relief and reduced inflammation throughout a treatment period that can last for more than one month, e.g., 1 to 6 months, with only a single intra-articular injection that can be renewed. In that embodiment, the simultaneous administration of an anesthetic allows for rapid pain relief, as described in more detail later in this specification.

[0019] Due to the reduced side effects achieved by administering the pharmaceutical composition according to the present invention, it is particularly suitable for people suffering from chronic comorbidities that are quite common in osteoarthritis (hypertension, chronic kidney disease, diabetes, cardiovascular disease, infections, stroke, depression, peptic ulcer, metabolic syndrome, and / or immunosuppression). Indeed, the management of osteoarthritis patients with multiple comorbidities remains a challenge for medical professionals due to the frequent and major contraindications for either NSAIDs or corticosteroids. Compared to existing oral colchicine treatments, the present invention not only avoids gastrointestinal side effects but also prevents major toxicity risks for patients suffering from renal or hepatic impairment or those co-administered with CYP3A4 / PGP drug inhibitors (which are quite common). [Brief explanation of the drawings]

[0020] [Figure 1] 1 shows the results of inflammation scores in rat ankle joints to evaluate the effects of the combinations according to the invention in protecting bone and cartilage in an in vivo model, as shown in Example 9. DETAILED DESCRIPTION OF THE INVENTION

[0021] Summary of the Invention Provided herein is a pharmaceutical composition in the form of a sterile injectable dosage form comprising a sustained release dosage form comprising colchicine for use in treating joint diseases such as osteoarthritis and any other type of cartilage disease and / or pain-related joint disease by intra-articular injection of the pharmaceutical composition into a joint, wherein the time required for the release of 80% by weight of colchicine is more than one month, and the colchicine is present in a concentration ranging from 0.003 to 27.5 mg per ml of the sterile injectable dosage form.

[0022] According to a first aspect, there is provided herein a pharmaceutical composition in the form of a sterile injectable dosage form comprising a sustained release dosage form comprising colchicine for use in the treatment of joint diseases such as osteoarthritis, erosive osteoarthritis of the wrist and any other type of cartilage disease, and / or for use in the treatment of pain-related joint diseases, and / or for use in the protection of joints, bones and / or cartilage, by intra-articular injection of said pharmaceutical composition into a joint, wherein the dissolution rate of colchicine is determined according to the following protocol: A 20 mg aliquot of a sustained-release dosage form containing colchicine is suspended in 50 mL of phosphate buffer (pH 7.4) with stirring at 37°C, and then the supernatant of samples withdrawn periodically throughout the release period is analyzed by UV at 350 nm. 80% (w / w) for more than 1 month, as measured according to wherein colchicine is present in a concentration ranging from 1 to 27,500 μg per ml of sterile injectable dosage form.

[0023] Further provided herein is a pharmaceutical composition in the form of a sterile injectable dosage form comprising a sustained release dosage form comprising colchicine, the pharmaceutical composition exhibiting an in vitro dissolution profile wherein less than 25% of the colchicine, more preferentially less than 15% of the colchicine is released within 24 hours and greater than 80% of the colchicine is released within at least 1 month, particularly within 3 months, and even more particularly within 6 months, and wherein the colchicine is present in a concentration ranging from 0.003 to 27.5 mg per ml of the sterile injectable dosage form.

[0024] According to a second aspect, there is provided herein a pharmaceutical composition in the form of a sterile injectable dosage form comprising a sustained release dosage form comprising colchicine, said pharmaceutical composition exhibiting an in vitro dissolution profile, wherein the dissolution rate of colchicine is measured using the following protocol: A 20 mg aliquot of a sustained-release dosage form containing colchicine is suspended in 50 mL of phosphate buffer (pH 7.4) with stirring at 37°C, and then the supernatant of samples withdrawn periodically throughout the release period is analyzed by UV at 350 nm. less than 25% (w / w) within 24 hours, more preferentially less than 15% (w / w), and less than 80% (w / w) after more than 1 month, particularly more than 3 months, and even more particularly more than 6 months, when measured according to Here, colchicine is present in a sterile injectable dosage form in a concentration ranging from 1 to 27500 μg / ml, in particular from 3 to 27500 μg / ml.

[0025] According to a third aspect, there is provided herein a formulation in the form of a powder comprising a sustained release dosage form comprising colchicine in the form of microparticles having an average particle size determined by laser light diffraction measurement of 10 μm or more and comprising a polymer matrix, wherein the polymer matrix is ​​at least one poly(lactic-co-glycolic acid) copolymer, at least one poly(caprolactone), or at least one poly(lactic-co-glycolic acid) copolymer and at least one poly(caprolactone). and at least one mixture of lactic acid and glycolic acid in an amount of more than 70 wt. %, particularly more than 80 wt. %, and more particularly more than 90 wt. %, based on the total weight of the polymer matrix, wherein the poly(lactic-co-glycolic acid) copolymer has a molar ratio of lactic acid to glycolic acid in the range of 50:50 to 90:10, in particular in the range of 55:45 to 90:10, for example, 60:40 to 90:10, more particularly in the range of 65:35 to 85:15, for example, 75:25, and the poly(lactic-co-glycolic acid) copolymer is <911> When measured by an Ubbelohde capillary viscometer according to the method described above, the intrinsic viscosity is in particular 0.1 to 1.7 dl / g, in particular 0.1 to 1.4 dl / g, and even more particularly 0.1 to 0.9 dl / g.

[0026] According to a fourth aspect, there is provided herein a pharmaceutical composition in the form of a sterile injectable dosage form suitable for intra-articular injection, obtainable by mixing a formulation in the form of a powder according to the present invention with an aqueous injection vehicle, the pharmaceutical composition optionally comprising an excipient selected from the group consisting of a tonicity enhancing agent, a wetting agent, a viscosity enhancing agent, a density enhancing agent or mixtures thereof, said excipient may be present in the aqueous injection vehicle or in the powder.

[0027] According to a fifth aspect, there is provided herein a pharmaceutical composition in the form of a sterile injectable dosage form suitable for intra-articular injection, comprising a sustained release dosage form comprising colchicine in the form of microparticles having an average particle size determined by laser light diffraction measurement of 10 μm or more and comprising a polymer matrix, wherein the polymer matrix is ​​selected from the group consisting of at least one poly(lactic-co-glycolic acid) copolymer, at least one poly(caprolactone), or a mixture of at least one poly(lactic-co-glycolic acid) copolymer and at least one poly(caprolactone). and at least one mixture of lactic acid and glycolic acid (lactic acid-co-glycolic acid) copolymers in an amount of more than 70 wt. %, particularly more than 80 wt. %, and more particularly more than 90 wt. %, based on the total weight of the polymer matrix, the poly(lactic acid-co-glycolic acid) copolymer having a molar ratio of lactic acid to glycolic acid in the range of 50:50 to 90:10, in particular in the range of 55:45 to 90:10, for example in the range of 60:40 to 90:10, more particularly in the range of 65:35 to 85:15, for example in the range of 75:25, and the poly(lactic acid-co-glycolic acid) copolymer is <911> When measured by an Ubbelohde capillary viscometer according to the method described above, the intrinsic viscosity is in particular 0.1 to 1.7 dl / g, in particular 0.1 to 1.4 dl / g, and even more particularly 0.1 to 0.9 dl / g.

[0028] According to a sixth aspect, there is provided herein a kit or article of manufacture comprising, in separate compartments, (i) an aqueous injection vehicle and (ii) a sustained release dosage form comprising colchicine as defined below or a powder as defined below, the kit or article of manufacture optionally comprising an excipient selected from the group consisting of a tonicity enhancing agent, a wetting agent, a viscosity enhancing agent, a density enhancing agent or mixtures thereof, optionally comprising hyaluronic acid for preparing a pharmaceutical composition suitable for intra-articular injection, and (i) and / or (ii) optionally comprising an anesthetic agent that is an immediate release agent.

[0029] The pharmaceutical composition suitable for intra-articular injection described herein below is effective for treating joint diseases such as osteoarthritis, erosive wrist osteoarthritis, and any other type of cartilage disease and / or pain-related joint disease, particularly osteoarthritis and / or pain-related osteoarthritis, with minimal long-term side effects. It is further effective for protecting joints, bones, and / or cartilage, particularly in patients suffering from joint diseases and any other type of cartilage disease and / or pain-related joint disease.

[0030] The pharmaceutical composition suitable for intra-articular injection is suitable for local administration by injection at or near the site of pain.

[0031] Detailed Description of the Invention As is evident from the background paragraph above, the formulation of colchicine is delicate today, as only oral compositions are available and a high risk of toxicity, such as gastrointestinal symptoms and neuromuscular disorders, has been observed. Risks associated with interactions with other active agents have also been reported. Furthermore, although the use of colchicine has been described as promising for the treatment of osteoarthritis, toxicity constraints have discouraged local injection for decades.

[0032] In fact, the literature recommends an effective topical dose of colchicine between 0.015 mg / kg and 0.030 mg / kg, with a toxic limit of 0.1 mg / kg and a lethal dose of 0.8 mg / kg established (E. Niel et al., "Colchicine today," Joint Bone Spine 73 (2006) 672-678). Therefore, it can be concluded that colchicine's narrow therapeutic margin is a cause for concern for prescribing physicians.

[0033] The inventors have found that intra-articular injection of a pharmaceutical composition according to the invention for sustained release of colchicine has at least equal, and even higher, efficacy compared to oral colchicine or intra-articular corticosteroid treatment in joint pain disorders.

[0034] It provides treatment of joint diseases, particularly osteoarthritis, erosive osteoarthritis of the wrist, and any other type of cartilage disease and / or pain-related joint disease, more particularly treatment of osteoarthritis and / or better pain relief and / or protection of joints, joints, and / or cartilage immediately after administration and during the release of colchicine.In the present invention, the time required to release 80% by weight of colchicine, particularly from a sustained-release dosage form containing it, more particularly from microparticles, is more than 1 month, particularly 1 to 6 months, and colchicine is present in the sterile injectable dosage form, particularly a suspension, at a concentration ranging from 1 to 27,500 μg / ml, particularly 3 to 27,500 μg / ml.

[0035] Osteoarthritis not only induces cartilage degradation and associated chronic pain, but also relapses that can be very severe. Therefore, it is important to have a perfectly tailored treatment to achieve the most appropriate dosage.

[0036] The use or method of treatment according to the present invention also has the advantage of reducing the risk of significant toxicity associated with drug interactions with colchicine when administered via systemic routes, particularly in elderly patients or patients with renal or hepatic failure as described herein below.

[0037] Compared to intra-articular corticosteroids, this treatment also has the advantage of avoiding systemic effects such as Cushing's syndrome, hyperglycemia, hypertension, decreased bone density, or the risk of infection, and also reduces the risk of adverse local tissue effects such as damage to articular cartilage and tendons.

[0038] definition As used herein, the term "patient" refers to either an animal, such as a valuable animal for breeding, companionship or conservation purposes, or preferably a human or human child, who is suffering from or has the potential to suffer from osteoarthritis.

[0039] In particular, as used in this application, the term "patient" refers to a mammal, including a non-human mammal such as a rodent, cat, dog, or primate, or a human; preferably, the subject is a human, and also extends to avian species.

[0040] Identifying patients in need of treatment for joint diseases such as osteoarthritis, erosive osteoarthritis of the wrist, and any other type of cartilage disease and / or pain-related joint disease, particularly osteoarthritis and / or pain-related osteoarthritis (including patients with osteoarthritis, erosive osteoarthritis of the wrist, and any other type of cartilage disease), who have an inflammatory component, inflammatory pain, or joint effusion, is well within the ability and knowledge of one skilled in the art. A veterinarian or skilled artisan can easily identify patients in need of such treatment by using clinical tests, physical examinations, medical / family history, or biological and diagnostic tests.

[0041] In the context of the present invention, the term "treat" or "treatment" as used herein means to reverse, alleviate or inhibit the progression of a joint disease such as osteoarthritis, erosive wrist osteoarthritis and any other type of cartilage disease and / or pain-related joint disease, in particular osteoarthritis and / or pain-related osteoarthritis.

[0042] As used herein, "effective amount" refers to an amount of the compound of the present invention that is effective in reducing, eliminating, treating or controlling the symptoms of joint diseases such as osteoarthritis, erosive osteoarthritis, and any other type of cartilage disease and / or pain-related joint disease, particularly osteoarthritis. The term "control" is intended to refer to any process that may slow, interrupt, prevent, or stop the progression of joint diseases such as osteoarthritis, erosive osteoarthritis, and any other type of cartilage disease and / or pain-related joint disease, particularly osteoarthritis and / or pain-related osteoarthritis, but does not necessarily indicate the complete elimination of it or related conditions, as detailed herein below.

[0043] The term "therapeutically effective amount" refers to a concentration of a compound effective to treat joint diseases, such as osteoarthritis, erosive wrist osteoarthritis and any other type of cartilage disease and / or pain-related joint disease, particularly osteoarthritis and / or pain-related osteoarthritis, e.g., when administered after the onset of inflammatory pain, results in a reduction of inflammatory pain after testing.

[0044] 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, as well as all types, origins, or groups of osteoarthritis. As mentioned above, OA is a degenerative disease, but symptoms may worsen for a period of time and then improve, known as a relapse or flare-up. Osteoarthritis includes inflammatory relapses or any progression caused by any disease, such as primary osteoarthritis, i.e., without known cause, or secondary osteoarthritis, i.e., cartilage disease. Symptoms and / or conditions associated with OA, and particularly OA relapses, may include, for example, increased joint pain, swelling in the affected area, decreased range of motion at the joint, and / or fatigue due to increased pain.

[0045] As used herein, the term "erosive hand osteoarthritis" includes erosive hand osteoarthritis (EHOA), the most aggressive form of hand osteoarthritis, characterized by severe clinical onset and progression leading to joint damage, disability, and reduced 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 erosive, serrated, and wing-like lesions, and rarely ankylosis.

[0046] As used herein, the term "cartilage disease" includes any cause or disease that results in cartilage damage such as chondromalacia, limb misalignment, chondromatosis, chondrocalcinosis, gout, hemochromatosis, Wilson's disease, acromegaly, ochronosis, collagen abnormalities, chronic neuropathy of any cause, Kasshin-Beck disease or any inflammatory rheumatism.

[0047] According to one embodiment, the use according to the invention is for the treatment of osteoarthritis, erosive osteoarthritis of the wrist and any other type of cartilage disease in patients with an inflammatory component, inflammatory pain or joint effusion.

[0048] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, excipients, compositions or dosage forms that are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problem complications, commensurate with a reasonable benefit / risk ratio.

[0049] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" can refer to any pharmaceutically acceptable excipient, e.g., a non-toxic carrier, adjuvant, or vehicle, that does not destroy the pharmacological activity of the compound with which it is formulated.

[0050] Within the framework of the present invention, the term "painful site" or "pain site" refers to a painful joint area into which the product can be injected, which may be the knee joint, hip joint, metacarpophalangeal joint, shoulder joint, wrist joint, elbow joint, metatarsophalangeal joint, ankle joint, vertebral joint and metatarsal joint.

[0051] The term "sustained release composition" or "sustained release microparticle" refers to a composition or microparticle that allows the release of a specified amount of an active ingredient into the body over a specified period of time, i.e., a specific pharmacokinetic profile. The term "sustained release" encompasses all types of release that are modified compared to immediate release. In other words, the term "sustained release" is equivalent to "modified release" and includes extended release as defined herein, as well as delayed release and pulsed release.

[0052] The terms "extended release", "delayed release" and "sustained release" are considered equivalent in the framework of the present invention. This type of release means that the release is extended over time compared to immediate release, that is, the active ingredient is slowly released over time, which allows patients to take the drug less frequently. In other words, the active ingredient is gradually released over a certain period of time, which generally aims to reduce the maximum concentration and thereby reduce side effects.

[0053] "Drug loading content" means the ratio of the mass of drug in a microparticle to the mass of the microparticle. The term "mean particle size" or D50 means the particle diameter in microns that divides the particle volume distribution between the upper and lower halves of this diameter.

[0054] Sustained or modified release can, of course, result from a combination of immediate and sustained release. "D10=x μm" as used primarily in this example means that 10% of the particles have a size of x μm or less.

[0055] "D90=y μm" as primarily used in this example means that 90% of the particles are y μm or less. Sustained or modified release can, of course, result from a combination of immediate and sustained release.

[0056] "Dissolution profile" refers to an in vitro test that reports a plot of the cumulative amount of active ingredient released as a function of time. The dissolution data arises from the conditions under which the measurements were taken and are described herein.

[0057] Colchicine Colchicine is an alkaloid extracted from the stems of meadow saffron or autumnale (Colchicum autumnale). Its IUPAC name is N-[(7S)-1,2,3,10-tetramethoxy-9-oxo-6,7-dihydro-5H-benzo[a]heptalen-7-yl]acetamide. (CAS 64-86-8)

[0058] [ka]

[0059] Colchicine can exist in its racemic enantiomeric forms, and all such forms are encompassed within the scope of the present invention.

[0060] Furthermore, it can exist in various crystalline forms depending on the solvent used to obtain them. Among the possible solvents, mention may be made of chloroform, dichloromethane, ethyl acetate, benzene or any other suitable solvent. All such crystalline forms also form part of the present invention.

[0061] It is primarily known as an anti-gout agent and, through its tubulin-interacting activity, as an anti-inflammatory agent. It is administered orally, but intravenous administration was also attempted and then discontinued due to excessive toxicity.

[0062] Therapeutic Uses and Methods In one embodiment, the pharmaceutical composition delivers colchicine at a dose and in a sustained-release format suitable for intra-articular injection as described herein, such that the colchicine concentration level at the treated joint exceeds the systemic dose classically achieved after oral administration, i.e., above 5 nM (2 ng / mL), and the systemic concentration level is 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)).

[0063] According to one embodiment, the pharmaceutical composition defined above for use according to the present invention is for protecting joints, bones and / or cartilage. "Protection of joints, bones and / or cartilage" means that the occurrence of destruction, notches, depressions or slimming of joints, cartilage and / or bones can be slowed, interrupted, stopped or the progression thereof can be stopped. The effect is shown in Example 9 below.

[0064] According to another embodiment, the pharmaceutical composition of the invention is further characterized in that it is effective to maintain a systemic colchicine concentration of less than 5 ng / ml, in particular less than 1 ng / ml, more particularly less than 0.5 ng / ml, and even more particularly less than 0.1 ng / ml 24 hours after intra-articular injection, in particular over one month, even more particularly for at least three months, and to maintain a synovial colchicine concentration of more than 0.5 ng / ml, in particular comprised between 0.5 and 100 ng / ml, more particularly comprised between 0.5 and 50 ng / ml, over one month, even more particularly for at least three months after intra-articular injection.

[0065] A specific release profile has not been achieved so far that allows a tolerable systemic concentration of colchicine and at the same time a local concentration of colchicine suitable for having an adequate therapeutic effect, which is the very core of the present invention.With the pharmaceutical composition according to the present invention, i.e., through a specific ratio between the local or synovial concentration of colchicine and the systemic concentration of colchicine, obtained with a specific in vitro dissolution rate and / or in vivo release rate, the inventors have found a surprisingly well-suited means for treating patients while avoiding side effects.

[0066] According to one particular embodiment, the ratio between the local or synovial concentration of colchicine and the systemic concentration of colchicine obtained after intra-articular injection of a pharmaceutical composition according to the invention is: 1) Petit, A., Redout, EM, van de Lest, CH, de Grauw, JC, Muller, B., Meyboom, R., van Midwoud, P., Vermonden, T., Hennink, WE, & Rene 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 As described / referenced in 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 drug, the dose can range from 100 to 2000 in humans.

[0067] To determine the local and systemic concentrations of colchicine, one skilled in the art can use any known method, for example, LC-MS analysis.

[0068] The illustration of the particular control of colchicine release achieved within the framework of the present invention can also be shown via in vitro dissolution profiles as carried out in Examples 1-3.

[0069] According to one embodiment, the dissolution medium that may be used to perform such dissolution tests may be phosphate buffer (pH 7.4).

[0070] According to one embodiment, the stirring speed may be in the range of 50 to 300 rpm, in particular 50 to 200 rpm, more particularly 60 to 100 rpm. This stirring may be obtained by shaking the incubator, in particular with horizontal movement.

[0071] According to one embodiment, the dissolution of colchicine is measured by UV analysis, for example using a UV spectrophotometer, for example at 350 nm, at different intervals, for example at 24 hours, 1 month, 3 months and 6 months.

[0072] Therefore, the conditions for measuring the dissolution profile of colchicine are described later in this specification.

[0073] A 20 mg aliquot of a sustained release dosage form containing colchicine is suspended in 50 mL of phosphate buffer (pH 7.4) with stirring at 37°C, and then the supernatant of samples withdrawn periodically throughout the release period is analyzed by UV at 350 nm.

[0074] By way of example, dissolution testing of colchicine microparticles can be performed according to the method detailed below.

[0075] Aliquots of 20 mg of microparticles are suspended in 50 mL of phosphate buffer (pH 7.4) maintained at 37°C in a horizontal shaker at 80 rpm. At different intervals, 3 mL samples of medium are removed and replaced with fresh medium. The removed samples are centrifuged at 4000 rpm for 3 minutes. The supernatant is analyzed by UV at 350 nm.

[0076] As described above, the sustained-release formulation is locally administered to treat joint pain and inflammation in patients suffering from joint diseases such as osteoarthritis, erosive osteoarthritis of the wrist, and any other type of cartilage disease and / or pain-related joint disease, particularly osteoarthritis (including patients with osteoarthritis, erosive osteoarthritis, and any other type of cartilage disease), and to enhance the protection of joints, bones, and / or cartilage in such patients with inflammatory components, inflammatory pain, or joint effusion.Local administration of the formulation can be carried out by injection into the intra-articular or peri-articular space at or near the patient's painful area, including the metatarsophalangeal joint, metacarpophalangeal joint, knee joint, shoulder joint, wrist joint, elbow joint, ankle joint, hip joint, vertebral joint, and metatarsal joint.The midfoot is the front part of the foot located between the hindfoot and the forefoot.It is composed of the cuboid, navicular, and three cuneiform bones. The transverse tarsal and tarsometatarsal joints connect the midfoot to the hindfoot and forefoot, respectively. The midfoot is a complex and mixed area where the observed edematous inflammation is generally diffuse.

[0077] In one embodiment, the present invention is directed to the treatment of pain associated with osteoarthritis in the joints of patients suffering from osteoarthritis.

[0078] In another embodiment, the present invention is dedicated to the treatment of patients with osteoarthritis, erosive wrist osteoarthritis and any other type of cartilage disease with an inflammatory component, inflammatory pain or joint effusion.

[0079] The administration can be carried out by a single injection, provided that the time required to release 80% by weight of the colchicine in the microparticles is more than one month, particularly one to six months, and the colchicine is present in a sterile injectable dosage form, particularly a suspension, at a concentration ranging from 1 to 27,500 μg / ml, particularly from 3 to 27,500 μg / ml, and the pharmaceutical composition has a volume ranging from, for example, 0.1 ml to 5 ml. In other words, a single injection locally provides a total colchicine weight ranging from 0.3 to 137,500 μg, particularly from 0.3 to 18,000 μg, i.e., the amount of colchicine released within the entire period of release after injection.

[0080] In one embodiment, injection is carried out multiple times a year depending on the release time of the composition (2 times, 3 times, 4 times or more).In this embodiment, each subsequent injection is carried out after an appropriate period of time has elapsed since the previous injection.This appropriate period of time can be, for example, 2 weeks or 1 month.

[0081] According to particular embodiments, colchicine is present in the sterile injectable dosage form, in particular a suspension, at a concentration ranging from 1 to 27500 μg / ml, in particular from 3 to 27500 μg / ml, more particularly from 1 to 13750 μg / ml, for example from 3 to 13750 μg / ml, and even more particularly colchicine is present at a concentration ranging from 3 to 3600 μg / ml.

[0082] In certain embodiments, the same pharmaceutical composition in the form of suspension can be used for intra-articular injection into the painful joints of patients 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 present invention, and by adjusting the corresponding required volume with a single concentration, it can provide the appropriate amount of colchicine for each application site.

[0083] In one embodiment, injections may be given simultaneously in two or more different painful joints. For example, the volume of a pharmaceutical composition according to the invention that can be injected into the shoulder, especially a pharmaceutical composition in the form of a suspension, can vary between 2 and 5 ml.

[0084] The volume of a pharmaceutical composition according to the invention, particularly a pharmaceutical composition in the form of a suspension, that can be injected into a metatarsophalangeal joint, such as a toe, can vary between 0.1 and 0.5 ml, and is typically 0.25 ml.

[0085] The volume of a pharmaceutical composition according to the invention, in particular a pharmaceutical composition in the form of a suspension, that can be injected into a metacarpophalangeal joint, such as a finger, can vary between 0.1 and 0.5 ml, and is typically 0.25 ml.

[0086] The volume of the pharmaceutical composition according to the invention, in particular in the form of a suspension, that can be injected into the vertebral joint can vary between 1 and 2 ml.

[0087] The volume of the pharmaceutical composition according to the invention, in particular in the form of a suspension, that can be injected into the metatarsal joint can vary between 0.1 and 1 ml.

[0088] The volume of the pharmaceutical composition according to the invention that can be injected into the knee, in particular a pharmaceutical composition in the form of a suspension, can vary between 2 and 5 ml.

[0089] The volume of the pharmaceutical composition according to the invention that can be injected into the wrist, in particular a pharmaceutical composition in the form of a suspension, can vary between 0.5 and 1 ml.

[0090] The volume of the pharmaceutical composition in the form of a suspension according to the invention that can be injected, in particular into the elbow, can vary between 2 and 5 ml.

[0091] The volume of the pharmaceutical composition according to the invention that can be injected into the ankle, in particular a pharmaceutical composition in the form of a suspension, can vary between 1 and 3 ml.

[0092] The volume of the pharmaceutical composition in the form of a suspension according to the invention that can be injected, in particular in the renal region, can vary between 2 and 5 ml.

[0093] In one embodiment, the pharmaceutical composition according to the invention, in particular in the form of a suspension, can be characterized by its volume that can be fitted into the joint, i.e. in the range of 2-5 ml for the shoulder, 1-2 ml for the vertebral joint, 0.1-1 ml for the metatarsophalangeal joint, 0.1-0.5 ml for the metatarsophalangeal joint, 0.1-0.5 ml for the metacarpophalangeal joint, 2-5 ml for the knee joint, 0.5-1 ml for the wrist joint, 2-5 ml for the elbow joint, 1-3 ml for the ankle joint, and 2-5 ml for the hip joint.

[0094] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors including age, weight, general health, sex, diet, time of administration, drug combination, as well as the judgment of the treating physician and the severity of the particular disease being treated.

[0095] In one embodiment, the sustained release is suitable to reach a maximum joint colchicine concentration (Cmax) in the range of 5 nM (2 ng / mL) to 5 μM (2 μg / mL).

[0096] According to a preferred embodiment, injection of the pharmaceutical composition of the invention makes it possible to reach a systemic concentration of colchicine 24 hours after intra-articular injection and within the entire period of post-injection release, in particular over one month, even more particularly over at least three months, which does not exceed 5 ng / mL, in particular does not exceed 2 ng / ml, more particularly does not exceed 1 ng / ml, even more particularly does not exceed 0.5 ng / ml, even more particularly does not exceed 0.1 ng / ml.

[0097] Furthermore, injection of the sustained release pharmaceutical composition according to the invention can achieve synovial concentrations of colchicine of more than 0.5 ng / ml, in particular comprised between 0.5 and 100 ng / ml, more particularly comprised between 0.5 and 50 ng / ml, 24 hours after intra-articular injection of colchicine, over a period of one month, even more particularly over a period of at least three months.

[0098] The dose required for injection into a painful joint may depend on the type of painful joint, particularly its size. Tables 1, 1a, 1b, and 1c below summarize typical colchicine dosages that can be implemented within the framework of the present invention. Tables 1a, 1b, and 1c are intended to provide more specific dosages that can be applied depending on the release period. The 1-month dose in Table 1a may correspond to a period of more than 1 month but less than 2 months, the 2-month dose in Table 1b may correspond to a period of 2 to 4.5 months, and the 6-month dose in Table 1c may correspond to a period of 4.5 to 7 months.

[0099] According to one embodiment, the pharmaceutical composition according to the invention has a volume ranging from 0.1 ml to 5 ml.

[0100] The volume corresponds to the total volume of the composition suitable for injection, ie in particular in the form of a suspension.

[0101] [Table 1]

[0102] [Table 2]

[0103] [Table 3]

[0104] [Table 4]

[0105] In one embodiment, the pharmaceutical composition of the present invention, particularly in the form of a suspension, which is administered in a single intra-articular injection and is intended for the treatment of joint diseases such as osteoarthritis, erosive wrist osteoarthritis and any other type of cartilage and / or pain-related joint disease, in particular osteoarthritis and / or pain-related osteoarthritis, comprises 0.3 to 13750 μg, in particular 0.3 to 1800 μg, of colchicine per injection, more particularly 0.3 to 300 μg of colchicine for about 1 month release, 0.9 to 900 μg of colchicine for about 3 months release, and 1.8 to 1800 μg of colchicine for about 6 months release for small joints selected from the metatarsophalangeal joints or metacarpophalangeal joints.

[0106] In another embodiment, the pharmaceutical composition of the present invention, particularly in the form of a suspension, which is particularly intended for the treatment of joint diseases such as osteoarthritis, erosive wrist osteoarthritis and any other type of cartilage and / or pain-related joint disease, particularly osteoarthritis and / or pain-related osteoarthritis, administered in a single intra-articular injection, comprises 1.5 to 27500 μg, particularly 1.5 to 3600 μg, of colchicine per injection, more particularly 1.5 to 600 μg of colchicine for about 1 month release, 4.5 to 1800 μg of colchicine for about 3 months release, and 9 to 3600 μg of colchicine for about 6 months release for the wrist joint.

[0107] In another embodiment, the pharmaceutical composition of the present invention, especially in the form of a suspension, which is especially to be administered by a single intra-articular injection and is dedicated to the treatment of joint diseases such as osteoarthritis, erosive wrist osteoarthritis and any other type of cartilage and / or pain-related joint disease, especially osteoarthritis and / or pain-related osteoarthritis, comprises 0.3 to 27500 μg, especially 0.3 to 3600 μg colchicine per injection, especially 0.3 to 600 μg colchicine for about 1 month release, 0.9 to 1800 μg colchicine for about 3 months release, 1.8 to 3600 μg colchicine for about 6 months release for the metatarsal joint.

[0108] In another embodiment, the pharmaceutical composition of the present invention, especially in the form of a suspension, which is especially to be administered by a single intra-articular injection and is dedicated to the treatment of joint diseases such as osteoarthritis, erosive wrist osteoarthritis and any other kind of cartilage disease and / or pain-related joint disease, especially osteoarthritis and / or pain-related osteoarthritis, comprises 3 to 82500 μg, especially 3 to 10800 μg of colchicine per injection, especially 3 to 1800 μg of colchicine for about 1 month release, 9 to 5400 μg of colchicine for about 3 months release and 18 to 10800 μg of colchicine for about 6 months release for the ankle joint.

[0109] In another embodiment, the pharmaceutical composition of the invention, especially in the form of a suspension, which is especially to be administered by a single intra-articular injection and is dedicated to the treatment of joint diseases such as osteoarthritis, erosive wrist osteoarthritis and any other type of cartilage disease and / or pain-related joint disease, especially osteoarthritis and / or pain-related osteoarthritis, in the facet joints, comprises 3 to 55000 μg of colchicine for about 1 month release, especially 3 to 7200 μg, especially 3 to 1200 μg of colchicine, for about 3 months release 9 to 3600 μg of colchicine and for about 3 months release 18 to 7200 μg of colchicine for about 6 months release.

[0110] In another embodiment, the pharmaceutical composition of the present invention, particularly in the form of a suspension, which is particularly intended for the treatment of joint diseases such as osteoarthritis, erosive wrist osteoarthritis and any other type of cartilage and / or pain-related joint disease, particularly osteoarthritis and / or pain-related osteoarthritis, administered in a single intra-articular injection, comprises 6 to 137,500 μg of colchicine for about 1 month of release, particularly 6 to 18,000 μg of colchicine, in particular 6 to 3,000 μg of colchicine per injection, for about 3 months of release, 18 to 9,000 μg of colchicine for about 3 months of release, and 36 to 18,000 μg of colchicine for about 6 months of release, for a joint selected from the knee, hip, shoulder and elbow.

[0111] According to one embodiment, the pharmaceutical composition of the invention, in particular in the form of a suspension, which is administered in particular by a single intra-articular injection and is intended for the treatment of joint diseases such as osteoarthritis, erosive wrist osteoarthritis and any other type of cartilage disease and / or pain-related joint disease, in particular osteoarthritis and / or pain-related osteoarthritis, comprises 1 to 27500 μg / ml of colchicine, in particular 3 to 27500 μg / ml, more in particular 1 to 13750 μg / ml of colchicine, in particular 3 to 13750 μg / ml of colchicine.

[0112] In one embodiment, the pharmaceutical composition may be suitable for maintaining a therapeutically acceptable concentration of colchicine in a painful joint for a period of more than 1 month and up to 6 months, more than 2 months and up to 6 months, or more than 3 months and up to 6 months.

[0113] Thus, provided herein are pharmaceutical compositions in the form of sterile injectable dosage forms for use in accordance with the present invention, wherein the time required to release 80% by weight of colchicine is from 1 to 6 months, from 2 to 6 months, or from 3 to 6 months.

[0114] There is further provided a pharmaceutical composition for use according to the invention, wherein the dissolution rate of colchicine is 80% (w / w) in 1 to 6 months, 2 to 6 months or 3 to 6 months.

[0115] In one embodiment, the pharmaceutical composition in the form of a sterile injectable dosage form for use according to the present invention is characterized by the fact that the time required to release 80% by weight of colchicine in the microparticles or the dissolution rate of colchicine is 80% (w / w), is 1 month or more than 1 month, such as 1.5 months, may reach 6 months, 2 months or more than 2 months, such as 2.5 months, may reach 6 months, 3 months or more than 3 months, such as 3.5 months, may reach 6 months, for example 4 months or more than 4 months, such as 4.5 or 5 months, may reach 6 months.

[0116] According to one embodiment, colchicine is present in the pharmaceutical composition in a sterile injectable dosage form, in particular a suspension, in the range of 1 to 27500 μg / ml, in particular 3 to 27500 μg / ml, more particularly in the range of 1 to 13750 μg / ml, for example 3 to 13750 μg / ml, and even more particularly colchicine is present in a concentration of 3 to 3600 μg / ml, For example, 3 to 600 μg / ml if the dissolution rate of colchicine is 80% (w / w) for more than 1 month but less than 2 months; -For example, 9 to 1800 μg / ml if the dissolution rate of colchicine is 80% (w / w) at 2 to 4.5 months, and For example, if the dissolution rate of colchicine is 80% (w / w) at 4.5 to 7 months, the dose should be 18 to 3600 μg / ml. It is present in concentrations ranging from

[0117] According to one embodiment, the pharmaceutical composition may be suitable for providing an initial joint colchicine concentration.

[0118] A pharmaceutical composition may or may not exhibit a burst release. In the context of the present invention, "burst release" means that an initial bolus of drug is released immediately upon placement in the release medium, i.e., immediately upon injection into the joint of the present invention, before the release rate reaches a steady profile.

[0119] Thus, when a burst release occurs, upon administration, the pharmaceutical compositions according to the present invention can provide an initial release of colchicine at the site of administration, e.g., the intra-articular and / or peri-articular space. Once the initial release of colchicine subsides, the sustained 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 for an additional treatment period following administration.

[0120] In certain embodiments, pharmaceutical compositions for use according to the present invention do not exhibit a significant burst release, and according to such embodiments, less than 25% by weight of colchicine is released 24 hours after administration.

[0121] In another aspect, the present invention relates to a method for treating joint diseases, such as osteoarthritis and any other type of cartilage disease and / or pain-related joint disease, in particular osteoarthritis and / or pain-related osteoarthritis, which method comprises at least administering by injection into a painful joint of a patient in need thereof a pharmaceutical composition in the form of a sterile injectable dosage form comprising a sustained-release dosage form containing an effective amount of colchicine, which is suitable for intra-articular injection into a joint, wherein the time required to release 80% by weight of the colchicine in the microparticles is more than 1 month, in particular 1 month to 6 months, and the colchicine is present in a concentration ranging from 0.003 to 27.5 mg / ml, in particular 0.003 to 13.75 mg / ml of suspension in the sterile injectable dosage form.

[0122] According to yet another aspect, the present invention relates to a method for the treatment of joint diseases such as osteoarthritis, erosive osteoarthritis of the wrist and any other type of cartilage disease, and / or for the treatment of pain-related joint diseases and / or for the protection of joints, bones and / or cartilage, in particular osteoarthritis and / or pain-related osteoarthritis, which comprises administering by injection into a painful joint of a patient in need thereof a pharmaceutical composition in sterile injectable form comprising at least a sustained release dosage form comprising an effective amount of colchicine, suitable for intra-articular injection into the joint, wherein the dissolution rate of colchicine is determined according to the following protocol: A 20 mg aliquot of the sustained release dosage form containing colchicine is suspended in 50 mL of phosphate buffer (pH 7.4) with stirring at 37°C; then, periodically throughout the release period, the supernatant of the withdrawn samples is analyzed by UV at 350 nm. 80% (w / w) for more than 1 month when measured according to Here, colchicine is present in a sterile injectable dosage form, in particular a suspension, in a concentration ranging from 1 to 27500 μg / ml, in particular from 3 to 27500 μg / ml, more particularly in a concentration of from 1 to 13750 μg / ml, for example from 3 to 13750 μg / ml.

[0123] According to yet another aspect, the present invention relates to a method for the treatment of joint diseases such as osteoarthritis and any other kind of cartilage disease and / or pain-related joint disease, in particular osteoarthritis and / or pain-related osteoarthritis, comprising at least the administration by injection into a joint of a patient in need thereof of at least an effective amount of colchicine for sustained release, in particular the time required for the release of 80% by weight of colchicine is more than 1 month, in particular 1 to 6 months.

[0124] Further provided herein is a method for the treatment of joint diseases such as osteoarthritis, erosive osteoarthritis of the wrist and any other type of cartilage disease, and / or for the treatment of pain-related joint diseases and / or for the protection of joints, bones and / or cartilage, in particular osteoarthritis and / or pain-related osteoarthritis, comprising: - preparing and / or providing a pharmaceutical composition in the form of a sterile injectable suspension by mixing a formulation in the form of a powder as described herein with an aqueous injection vehicle and then with the formulation, optionally comprising an excipient selected from the group consisting of a tonicity enhancing agent, a wetting agent, a viscosity enhancing agent, a density enhancing agent or a mixture thereof, said excipients being optionally present in the aqueous injection vehicle or the powder; - injecting said pharmaceutical composition into a painful joint of a patient in need thereof, the volume injected being adapted to the injection site; The present invention provides a method comprising:

[0125] The present invention may be particularly suitable for treating patients with renal and / or hepatic impairment who are concurrently treated with other drugs. Indeed, in patients with renal and / or hepatic impairment, adjustments to the recommended oral colchicine dosage are necessary due to the appropriate administration scheme. Furthermore, several drugs have been identified in the past as potentially causing undesirable side effects and even fatal drug interactions, significantly altering the safety profile and requiring oral colchicine dosage adjustments, which may require, for example, a two- to three-fold reduction in the oral colchicine dosage.

[0126] Therefore, in one embodiment, pharmaceutical compositions according to the present invention can be administered to patients with renal and / or hepatic impairment, particularly when colchicine plasma levels rise to a toxic threshold when intrinsic renal or hepatic impairment reaches a severe grade.

[0127] Patients with renal impairment can be identified and classified by techniques known to physicians, such as creatinine clearance or glomerular filtration rate (GFR) methods. Such methods are particularly detailed 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. The use and method according to the present invention can be implemented to treat patients with all grades of renal impairment, such as grades 1 to 5 as determined by the GFR method. The use and method according to the present invention may be more particularly suitable for patients with high-grade renal impairment, such as grades 3 to 5 as determined by the GFR method.

[0128] Patients with liver damage can be identified and classified by techniques known to physicians, such as via the Child-Pugh score or MELD score. This method is described in detail 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 online at the following links: https: / / liverfellow.org / post / meld-score-part1 and https: / / liverfellow.org / post / meld-score-part2. The use and method according to the present invention can be implemented, for example, to treat patients with any score, rate, and / or classification according to the Child-Pugh score, such as mild, moderate, or severe liver damage. The uses and methods according to the present invention may be more particularly suitable for patients with high scores, percentages and / or classifications of severe liver damage as set by the Child-Pugh method, such as moderate and severe liver damage.

[0129] Thus, because colchicine systemic plasma levels are maintained below the threshold that results in toxicity within the framework of the present invention, no colchicine dosage adjustment is required, even when treating patients with the effects of intrinsic factors such as renal and / or hepatic impairment that currently require colchicine dosage adjustment when administered orally.

[0130] Thus, in one embodiment, a pharmaceutical composition for use in accordance with the present invention may be further characterized by the fact that the patient to whom the pharmaceutical composition is to be administered has renal impairment and / or hepatic impairment.

[0131] In another embodiment, there is further provided a method for treating joint diseases such as osteoarthritis, erosive wrist osteoarthritis and any other type of cartilage disease, and / or for treating pain-related joint diseases and / or for protecting joints, bones and / or cartilage, particularly osteoarthritis and / or pain-related osteoarthritis, in patients with renal and / or hepatic impairment, particularly wherein the dosage of colchicine is not reduced in response to such impairment.

[0132] In one embodiment, pharmaceutical compositions compatible with the present invention may be co-administered with a wide range of drugs as detailed herein, and in particular exhibit an improved safety profile when co-administered with such drugs compared to classical treatment with oral colchicine.

[0133] An example of a drug interaction that the present invention makes it possible to avoid is an interaction with a drug that has been clearly identified in the context of treatment with oral colchicine and is well known to physicians. In situations of potential drug interactions, the classical approach is to adjust, i.e., reduce, the oral colchicine dosage depending on the severity of the interaction, according to well-known recommendations.

[0134] Such drug-drug interactions (DDIs) can be explained by the fact that some drugs inhibit P-gp and / or CYP3A4, producing excessive colchicine plasma concentration peaks, especially those above 6 ng / mL, which must be avoided.

[0135] One advantage of the present invention resides in the fact that excessive plasma concentrations are avoided, allowing for simultaneous administration of the drugs without adjusting the colchicine dosage, which must be done when administered orally.

[0136] Thus, in one embodiment, the pharmaceutical composition for use according to the present invention may be further characterized by the fact that the patient to whom said pharmaceutical composition is administered may be treated simultaneously, separately or sequentially with the following active ingredients: atazanavir, clarithromycin, darunavir, ritonavir, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, tipranavir, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, cyclosporine and ranolazine.

[0137] In another embodiment, the pharmaceutical composition for use according to the present invention may be further characterized by the fact that the patient to whom said pharmaceutical composition is administered may be treated simultaneously, separately or sequentially with the following active ingredients: atazanavir, clarithromycin, darunavir, ritonavir, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, tipranavir, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, cyclosporine, ranolazine, macrolides and statins.

[0138] Thus, provided herein is a pharmaceutical composition for use as defined above for use in the treatment of joint diseases, such as osteoarthritis, erosive wrist osteoarthritis and any other kind of cartilage disease, and / or for use in the treatment of pain-related joint diseases, and / or for use in the protection of joints, bone and / or cartilage, in particular osteoarthritis and / or pain-related osteoarthritis, in a patient 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, tipranavir, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, cyclosporine, ranolazine, macrolides and statins.

[0139] Thus, herein, in patients 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, tipranavir, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, cyclosporine, ranolazine, macrolides and statins, or There is provided a pharmaceutical composition for use as defined above for use in the treatment of joint diseases, such as osteoarthritis, erosive wrist osteoarthritis and any other kind of cartilage disease, and / or for use in the treatment of pain-related joint diseases, and / or for use in the protection of joints, bones and / or cartilage, in particular osteoarthritis and / or pain-related osteoarthritis, in patients suffering from chronic comorbidities such as hypertension, chronic kidney disease, diabetes, cardiovascular disease, infections, stroke, depression, peptic ulcer, metabolic syndrome and / or immunosuppression.

[0140] Thus, herein, the present invention relates to a method for treating hypertension, chronic kidney disease, or in patients who 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, tipranavir, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, cyclosporine, ranolazine, macrolides, and statins. Further provided are methods for the treatment of joint diseases, such as osteoarthritis, erosive hand osteoarthritis and any other kind of cartilage disease, and / or for use in the treatment of pain-related joint diseases, and / or for use in the protection of joints, bone and / or cartilage, particularly osteoarthritis and / or pain-related osteoarthritis, in patients suffering from chronic co-morbidities such as cancer, diabetes, cardiovascular disease, infection, stroke, depression, peptic ulcer, metabolic syndrome and / or immunosuppression, in particular wherein the dosage of colchicine is not reduced in response to the co-administration of such drugs.

[0141] Colchicine-containing sustained-release dosage forms According to one embodiment, the sustained release dosage form comprising colchicine is in the form of an in-situ forming depot or microparticle, in particular a microparticle comprising a polymer matrix or multivesicular liposomes.

[0142] In one embodiment, the sustained-release dosage form containing colchicine is in the form of an in-situ forming depot. In-situ forming depots, such as pH-induced, heat-induced, or solvent exchange-induced gelling systems containing colchicine, can be prepared according to techniques known to those skilled in the art, as described in particular in L. Rahnfeld et al. "Injectable Lipid-Based Depot Formulations: Where Do We Stand?," Pharmaceuticals. 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.

[0143] In one embodiment, the sustained release dosage form comprising colchicine is in the form of microparticles, an embodiment of which is described in detail below.

[0144] Colchicine-containing sustained-release microparticles The sustained-release microparticles containing colchicine can take the form of a variety of microparticles, such as (i) microparticles containing a polymer matrix or (ii) multivesicular liposomes.

[0145] According to one embodiment, the microparticles have an average particle size, as determined by laser light diffraction measurement, of 10 μm or greater.

[0146] According to another embodiment, the microparticles have an average particle size, determined by laser light diffraction measurement, of 10 μm or more, in particular less than 100 μm, more particularly less than 80 μm, even more particularly less than 50 μm, for example 10-50 μm or 10-40 μm.

[0147] The particle size can be measured in the framework of the present invention by laser light diffraction measurements. The instrument may typically be a Malvern Mastersizer MS3000 laser diffraction particle size analyzer. A preparation of 0.1 to 1 mg of microparticles per ml of deionized water may be introduced into the instrument. Measurements may be taken three times. Each run may last 3 seconds, and the suspension may be homogenized before each run.

[0148] The instrument may also be a LUMiReader multi-wavelength separation analyzer that uses the sedimentation approach to measure particle size distribution according to ISO 13317. A preparation of 4 mg of microparticles per ml of deionized water was introduced into the instrument and analyzed at a wavelength of 470 nm. Each run lasted 50 minutes, and the suspension was homogenized before each run. The results shown in the examples are the average of four runs.

[0149] Both devices provide similar measurements and can be used interchangeably, in other words, for simplicity, only laser diffraction is referred to in most of the text, although other methods, as mentioned above, may also be used.

[0150] It is understood that these ranges refer to the average size of all microparticles in a given population. The size of any given individual microparticle may be within a standard deviation above or below the average size.

[0151] Within the context of the present invention, "microparticles" means particles of any shape, made from any material, suitable for injection into the human body, in particular into an articulation or joint, in particular in a pharmaceutical composition, having an average particle size determined by laser light diffraction measurement of more than 10 μm and less than 100 μm.

[0152] Microparticles suitable for pharmaceutical compositions used in accordance with the present invention may be selected from a variety of types of microparticles, such as microspheres, microparticle matrices, microsphere matrices, microcapsules, rods, wafers, pills, fibers and pellets.

[0153] (i) Microparticles containing a polymer matrix The polymer matrix can be selected from a variety of polymers suitable for obtaining sustained release microparticles, and such polymer matrices are non-toxic to the human body.

[0154] According to one embodiment, the polymers forming the polymer matrix are biodegradable. Within the context of the present invention, a "biodegradable" material refers to a material for which there is evidence that it degrades enzymatically or hydrolytically and the degradation products are incorporated into the biomass and / or removed from the organism by metabolism or renal filtration.

[0155] The non-toxic and biodegradable polymers can be natural or synthetic. According to one embodiment, the polymer matrix of the microparticles used in the pharmaceutical composition used according to the invention comprises at least one poly(lactic-co-glycolic acid) copolymer or PLGA (poly(lactic-co-glycolic acid)).

[0156] According to this embodiment, the polymer matrix may comprise PLGA in an amount of more than 70% by weight, in particular more than 80% by weight, and even more particularly more than 90% by weight, relative to the total weight of the polymer matrix.

[0157] Suitable polymers are commercially available and include, but are not limited to, those known as RESOMER (Evonik Industries AG, Germany), LACTEL (Durect, USA), PURASORB (Corbion NV, The Netherlands), Viatel (Ashland, USA), and EXPANSORB (Seqens, France).

[0158] According to another embodiment, the polymer matrix of the microparticles used in the pharmaceutical composition used according to the invention comprises at least one poly(caprolactone) (PCL).

[0159] According to this embodiment, the polymer matrix may comprise PCL in an amount of more than 70% by weight, in particular more than 80% by weight, and even more particularly more than 90% by weight, relative to the total weight of the polymer matrix.

[0160] According to another embodiment, the polymer matrix of the microparticles used in the pharmaceutical composition according to the invention comprises a mixture of at least one PCL and at least one PLGA.

[0161] In a particular embodiment, the pharmaceutical composition according to the invention features microparticles, which may be a mixture of microparticles of different nature, which are microparticles comprising colchicine and a polymer matrix, wherein the polymer matrix is at least one poly(lactic-co-glycolic acid) copolymer, at least poly(caprolactone), or - at least one mixture of at least one poly(lactic-co-glycolic acid) copolymer and at least one poly(caprolactone); Includes.

[0162] "May be a mixture of microparticles of different properties" means that the pharmaceutical composition may contain various types of microparticles, for example, two, three, or four types of microparticles. "Types of microparticles" refers to microparticles having polymer matrices with different properties, particularly by exhibiting specific ratios of monomers, molecular weights, and / or intrinsic viscosities. For example, one type of microparticle may have a polymer matrix containing at least a poly(lactic-co-glycolic acid) copolymer or consisting of a poly(lactic-co-glycolic acid) copolymer, while another type of microparticle may have a polymer matrix containing at least a poly(caprolactone) copolymer or consisting of a poly(lactic-co-glycolic acid) copolymer exhibiting a specific ratio of monomers, molecular weights, and / or intrinsic viscosities, while another type of microparticle may have a polymer matrix containing at least a poly(lactic-co-glycolic acid) copolymer or consisting of a poly(lactic-co-glycolic acid) copolymer exhibiting a different specific ratio of monomers, molecular weights, and / or intrinsic viscosities. Thus, all kinds of mixtures are included within the scope of the present invention, in particular for obtaining a release profile suitable for the treatment of joint diseases such as osteoarthritis, erosive osteoarthritis of the wrist and any other type of cartilage disease and / or for the treatment of pain-related joint diseases and / or for use in the protection of joints, bones and / or cartilage, in particular osteoarthritis and / or pain-related osteoarthritis.

[0163] As for 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 in polymerization. Therefore, the PLGA used in the present invention can be characterized by its lactic acid:glycolic acid ratio. In the context of the present invention, "lactic acid:glycolic acid ratio" refers to the molar ratio of 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 PLGA whose composition is 75% lactic acid and 25% glycolic acid.

[0164] In one embodiment, the poly(lactic-co-glycolic acid) copolymer is <911> When determined by an Ubbelohde capillary viscometer according to the method of the present invention, the intrinsic viscosity is 0.10 to 1.7 dl / g, in particular 0.10 to 1.4 dl / g, and even more particularly 0.10 to 0.9 dl / g.

[0165] In the framework of the present invention, "intrinsic viscosity" (IV) is a measure of the increased flow resistance of a polymer solution compared to the pure solvent. This property is related to the molar mass; the longer the polymer chain, the higher the value of the intrinsic viscosity.

[0166] Intrinsic viscosity can typically be measured according to the following measurement method: The intrinsic viscosity of a polymer sample can be determined using an Ubbelohde capillary viscometer. The polymer is dissolved in chloroform. The flow time of the solvent and polymer solution is measured according to USP <911> The intrinsic viscosity is calculated by the method described above.

[0167] In one embodiment, the polymer matrix comprises at least one poly(lactic-co-glycolic acid) copolymer, at least one poly(caprolactone), or at least one mixture of poly(lactic-co-glycolic acid) copolymer and poly(caprolactone), in an amount of more than 70 wt.%, particularly more than 80 wt.%, and more particularly more than 90 wt.%, based on the total weight of the polymer matrix, and the poly(lactic-co-glycolic acid) copolymer has a molar ratio of lactic acid:glycolic acid in the range of 50:50 to 90:10, in particular in the range of 55:45 to 90:10, for example, 60:40 to 90:10, more particularly in the range of 65:35 to 85:15, for example, 75:25; and the poly(lactic-co-glycolic acid) copolymer is in the range of 50:50 to 90:10, in particular in the range of 55:45 to 90:10, for example, 60:40 to 90:10, more particularly in the range of 65:35 to 85:15, for example, 75:25. <911> When measured by an Ubbelohde capillary viscometer according to the method described above, the intrinsic viscosity is in particular 0.1 to 1.7 dl / g, in particular 0.1 to 1.4 dl / g, and even more particularly 0.1 to 0.9 dl / g.

[0168] When implementing poly(lactic-co-glycolic acid) copolymers with the lowest lactic acid:glycolic acid molar ratio, for example in the range of 50:50 to 60:40, it is within the general knowledge of a person skilled in the art to select an appropriate copolymer exhibiting an intrinsic viscosity to obtain a suitable release profile of colchicine for more than one month according to the present invention.

[0169] 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, in the range of 50:50 to 60:40, the poly(lactic acid-co-glycolic acid) copolymer is in a range of 100:100 to 150:100, as defined by the U.S.P. <911> When measured by an Ubbelohde capillary viscometer, it exhibits an intrinsic viscosity of 0.4 to 1.7 dl / g.

[0170] According to this embodiment, the polymer matrix may comprise a mixture of PCL and PLGA in an amount of more than 70% by weight, in particular more than 80% by weight, and even more particularly more than 90% by weight, relative to the total weight of the polymer matrix.

[0171] The polymer matrix may comprise one or more additional polymers, copolymers or mixtures thereof, which may be present in the polymer matrix in an amount ranging from 0 to 30% by weight, in particular from 0 to 20% by weight, more particularly from 0 to 10% by weight, relative to the total weight of the polymer matrix.

[0172] Non-limiting examples of suitable additional polymers or copolymers include PLA different from poly(lactide) or poly(lactic-co-glycolic acid) copolymer, PGA different from poly(glycolide) or poly(lactic-co-glycolic acid) copolymer, poly(lactide-co-caprolactone), poly(ethylene glycol), poly(ethylene oxide) or PEO, PLGA-b-PEO-b-PLGA, PLGA-b-PEO, polyhydroxyalkanoates, poly(hydroxybutyrate), poly(trimethylene carbonate), poly(dioxanone), poly(valerolactone), poly(α-hydroxybutyrate), poly( ... Poly(hydroxy acids), poly(lactones), poly(amino acids), polyanhydrides, poly(orthoesters), poly(acetals), polyurethanes, polythioesters, polyphosphoesters, poly(ester-co-amides), poly(vinyl alcohol) or PVA, PVA-g-PLGA, poly(ether ester) multiblock copolymers, polyvinylpyrrolidone, poly(methacrylate), PEO-PPO-PEO (Pluronic®), gelatin, heparin, chondroitin sulfate; polysaccharides such as alginate, starch, chitosan, and dextran, and any combination thereof.

[0173] In one embodiment, the sustained-release microparticles according to the present invention are PLGA microspheres. In other words, in this embodiment, the polymer matrix does not contain any additional polymer or copolymer. In such an embodiment, the sustained-release microparticles may include different types of PLGA microspheres, i.e., PLGA microspheres made using poly(lactic-co-glycolic acid) copolymers exhibiting different lactic acid:glycolic acid molar ratios and / or intrinsic viscosities.

[0174] According to another embodiment, the microparticle matrix can comprise, or even consist of, a blend of two, three or more PLGA copolymers, in particular a blend of two PLGA copolymers. As used herein, "a polymer matrix comprising at least one poly(lactic-co-glycolic acid) copolymer" precisely means that the poly(lactic-co-glycolic acid) copolymer can be such a blend.

[0175] The microparticles may further comprise pharmaceutically acceptable excipients to modify the drug release profile, such as medium chain triglycerides, poly(oxyethylene) sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80), sorbitan fatty acid esters, cyclodextrins, lecithin, mannitol, sucrose, inorganic salts, and mixtures thereof.

[0176] The polymer matrix of the microparticles may contain one or more excipients, which may be present in the polymer matrix in an amount not exceeding 15% by weight, in particular not exceeding 10% by weight, and more particularly not exceeding 5% by weight, relative to the total weight of the polymer matrix.

[0177] In one embodiment, the weight percentage ratio of colchicine in the pharmaceutical composition to the total weight or colchicine loading content of the microparticles ranges from 0.01 to 40% by weight.

[0178] Manufacturing process for obtaining microparticles containing a polymer matrix Any process suitable for producing polymer microparticles having an average particle size, determined by laser light diffraction measurements, in the range of 10 μm to 100 μm is considered suitable within the framework of the present invention.

[0179] Such manufacturing processes include emulsion-based processes such as high pressure homogenization using rotor-stator homogenizers in batch or continuous mode, or membrane emulsification followed by extraction / evaporation to remove the organic solvent.

[0180] As far as the general principle of such a method is concerned, an emulsion can be prepared and processed on a membrane with pores of a determined size, and the resulting microspheres can then be recovered after extraction and evaporation of the organic solvent, washed, and freeze-dried.

[0181] According to one particular embodiment, the microparticles can be produced from an O / W direct emulsion or a W / O / W double emulsion technique.

[0182] Schoubben, A., Ricci, M. & Giovagnoli, S. Meeting the unmet: from traditional to cutting-edge techniques for poly lactide and poly lactide-co-glycolide microparticle manufacturing. J. Pharm. Investig. 49, 381-404 (2019) outlines various methods for producing PLGA microparticles that can be used within the framework of the present invention.

[0183] According to one particular embodiment, the microparticles can be produced from a solid-in-oil-in-water (S / O / W) double emulsion technique.

[0184] 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 by S / O / W emulsion technology. Other manufacturing approaches suitable for obtaining microparticles according to the present invention are atomization by spinning disk, atomization by spray drying, fluidized bed coating, or a combination thereof.

[0185] Alternatively, microparticles can be fabricated using drop-on-demand, drop-by-drop and jet break-up processes such as inkjet printing or microfluidics.

[0186] Alternatively, supercritical fluid technology may be used to produce the microparticles. Alternatively, microparticles can be produced using microfabrication methods such as templating and molding-based techniques such as soft lithography.

[0187] All of these manufacturing processes are well known to those skilled in the art. The above manufacturing processes are well known to those skilled in the art.

[0188] (ii) Multivesicular liposomes Multivesicular liposomes (MVLs) are spherical particles with an average diameter of 10–30 μm, composed of multiple non-concentric lipid bilayers arranged in a honeycomb-like structure. These lipid layers surround numerous water-filled aqueous compartments that can be used to encapsulate water-soluble drugs such as colchicine.

[0189] MVLs are typically composed of at least one amphipathic lipid and one neutral lipid. The amphipathic lipid is selected from phospholipids, such as phosphatidylcholine or phosphatidylglycerol. The neutral lipid is selected from triglycerides containing monounsaturated fatty acid ester moieties with 14-18 carbon atoms in the acyl chain (e.g., triolein, tripalmitolein), saturated fatty acid ester moieties with 6-8 carbon atoms in the acyl chain (e.g., tricaproin, tricaprylin), and mixtures thereof. Cholesterol can also be used in the composition.

[0190] MVLs are obtained using a water-in-oil-in-water (W / O / W) double emulsification process. In the first step, a water-in-oil (W / O) emulsion is prepared by mixing phospholipids, triolein, tricaprylin, and cholesterol solubilized in a volatile, water-immiscible organic solvent with an aqueous solution containing the solubilized drug for encapsulation. This 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 sonication, or a combination thereof. MVLs are finally obtained by removing the volatile organic solvent from the double emulsion using gas stripping or flushing. Finally, removal of non-encapsulated material, concentration of the MVLs, and buffer exchange are performed using either diafiltration or a cross-flow filtration system.

[0191] In one embodiment, the neutral lipid used to prepare the MVLs that encapsulate colchicine comprises a mixture of triolein:tricaprylin in a ratio ranging from 50:50 to 0:100.

[0192] Pharmaceutical Compositions and Kits As mentioned above, the present specification provides pharmaceutical compositions in various forms, namely, solutions, suspensions, solid implants, semi-solid implants, powders, and in-situ forming depots. Further pharmaceutical compositions are provided in powder form or kit form. When in powder form, the pharmaceutical composition is primarily intended for storage, whereas solutions, suspensions, solid implants, semi-solid implants, powders, or in-situ depots, particularly suspensions, are ready-to-use compositions and ready for injection, and kits allow for the separate storage of (i) an aqueous injection vehicle and (ii) a sustained-release dosage form comprising colchicine, particularly a sterile injectable dosage form suitable for injection, particularly in the form of a powder for forming a suspension.

[0193] In one embodiment, the pharmaceutical composition is in the form of a sterile injectable suspension, optionally comprising excipients selected from the group consisting of tonicity-enhancing agents, wetting agents, viscosity-enhancing agents, density-enhancing agents or mixtures thereof, and is further characterized in that it is obtainable by mixing a sustained release dosage form comprising colchicine, optionally comprising hyaluronic acid, in particular colchicine-containing microparticles, more particularly colchicine-containing microparticles as defined above, with an aqueous injection vehicle.

[0194] Various embodiments of this alternative are detailed below. Solutions, solid implants, semi-solid implants, powders and in situ forming depots may be prepared according to methods known to those skilled in the art.

[0195] According to certain embodiments, the sterile injectable dosage form is in the form of a suspension which can be obtained from a powder, as detailed below.

[0196] Powders and suspensions In one embodiment there is provided a powder form comprising a sustained release dosage form comprising colchicine, in particular in the form of microparticles comprising a polymer matrix, more particularly a formulation as defined above, wherein the colchicine loading content in the sustained release dosage form is in the range of 0.01 to 40% by weight.

[0197] In one embodiment, the formulation in the form of a powder comprises a sustained release dosage form comprising colchicine, the sustained release dosage form comprising colchicine being in the form of microparticles, in particular microparticles comprising a polymer matrix, more particularly having an average particle size of 10 μm or more, even more particularly as determined by laser light diffraction measurement as defined above.

[0198] The pharmaceutical compositions used in the framework of the present invention can take the form of sterile injectable compositions, in particular suspension compositions, containing an effective amount of colchicine.

[0199] "Sterile" in the sense of the present invention means an environment that can guarantee the safety requirements for the compounds considered in the composition according to the invention for the administration routes, in particular for the intra- or trans-articular administration routes, as described above. Indeed, for obvious reasons, it is essential that the composition according to the invention is free from contaminants that can initiate undesirable side reactions at the host site.

[0200] The pharmaceutical composition used in the framework of the present invention can be prepared with the formulation in the form of a powder containing the above-mentioned microparticles. According to one embodiment, the pharmaceutical composition is a sterile injectable composition for sustained release of colchicine suitable for intra-articular injection.

[0201] Due to its injectable nature, the composition according to the invention necessarily comprises a physiologically acceptable medium, also called an "aqueous injection vehicle."

[0202] "Physiologically acceptable medium" means a medium that is non-toxic and compatible with the injection and / or application of the compositions as contemplated by the present invention.

[0203] In another embodiment, there is provided a pharmaceutical composition in the form of a sterile injectable dosage form suitable for intra-articular injection, obtainable by mixing the formulation according to the invention in the form of a powder with an aqueous injection vehicle, the pharmaceutical composition optionally comprising an excipient selected from the group consisting of a tonicity enhancing agent, a wetting agent, a viscosity enhancing agent, a density enhancing agent or mixtures thereof, said excipients being optionally present in the aqueous injection vehicle or the powder, optionally including hyaluronic acid.

[0204] In another embodiment, there is provided a pharmaceutical composition in the form of a sterile injectable dosage form suitable for intra-articular injection, comprising a sustained release dosage form comprising colchicine in the form of microparticles having an average particle size determined by laser light diffractometry of 10 μm or more and comprising a polymer matrix, wherein the polymer matrix is ​​at least one poly(lactic-co-glycolic acid) copolymer, at least one poly(caprolactone), or at least one poly(lactic-co-glycolic acid) copolymer and poly(caprolactone). and at least one mixture of at least one of the following in an amount of more than 70 wt. %, particularly more than 80 wt. %, more particularly more than 90 wt. %, based on the total weight of the polymer matrix, wherein the poly(lactic-co-glycolic acid) copolymer has a molar ratio of lactic acid:glycolic acid in the range of 50:50 to 90:10, in particular in the range of 55:45 to 90:10, for example in the range of 60:40 to 90:10, more particularly in the range of 65:35 to 85:15, for example in the range of 75:25; and the poly(lactic-co-glycolic acid) copolymer is <911> When measured by an Ubbelohde capillary viscometer according to the method described above, the intrinsic viscosity is in particular 0.1 to 1.7 dl / g, in particular 0.1 to 1.4 dl / g, and even more particularly 0.1 to 0.9 dl / g.

[0205] In another embodiment, the pharmaceutical composition is provided, wherein the colchicine loading content in the sustained-release dosage form is in the range of 0.01 to 40% by weight.

[0206] In another embodiment, the pharmaceutical composition is selected from solutions, suspensions, solid implants, semi-solid implants, powders and in situ depots, in particular suspensions, characterized by a concentration in a sterile injectable dosage form, in particular suspensions, in the range of 1 to 27500 μg / ml, in particular 3 to 27500 μg / ml, in particular 1 to 13750 μg / ml, in particular 3 to 13750 μg / ml.

[0207] The composition may comprise a solvent or a mixture of physiologically acceptable solvents. The composition may comprise a physiologically acceptable aqueous medium.

[0208] Aqueous media suitable for the present invention may include, for example, water. Suitable isotonic agents for the preparation of compositions according to the invention may include sugars and sodium chloride.

[0209] Aqueous injection vehicles may contain, inter alia, tonicity enhancing agents, wetting agents, viscosity enhancing agents or mixtures thereof.

[0210] Tonicity enhancing agents may include dextrose, mannitol, sorbitol, sucrose, glycerin, sodium chloride, potassium chloride, cyclodextrin, and maltodextrin.

[0211] Among the wetting agents, mention may be made of poly(oxyethylene) sorbitan fatty acid esters such as those sold under the trade name TWEEN®, sorbitan fatty acid esters such as those sold under the trade name SPAN, poloxamers and lecithin.

[0212] Viscosity enhancing agents may include 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.

[0213] According to certain embodiments, the pharmaceutical composition comprises 10s -1 The viscosity at a shear rate of 5 to 1000 mPa·s, particularly 5 to 500 mPa·s, especially 5 to 100 mPa·s, more especially 5 to 50 mPa·s.

[0214] kit Further provided herein is a kit or article of manufacture comprising, in separate compartments, (i) an aqueous injection vehicle and (ii) a sustained release dosage form comprising colchicine as defined above or a powder as defined above, the kit or article of manufacture optionally comprising an excipient selected from the group consisting of a tonicity enhancing agent, a wetting agent, a viscosity enhancing agent, a density enhancing agent or mixtures thereof for preparing a pharmaceutical composition suitable for intra-articular injection, optionally comprising hyaluronic acid, and (i) and / or (ii) optionally comprising an anesthetic in immediate dosage form.

[0215] The optional presence of an anesthetic agent is described in greater detail herein after the section "Additional Active Ingredients."

[0216] Further provided herein is a kit or article of manufacture comprising, in separate compartments, (i) an aqueous injection vehicle and (ii) a pharmaceutical composition in the form of a powder as defined above, optionally comprising an excipient selected from the group consisting of a tonicity enhancing agent, a wetting agent, a viscosity enhancing agent, a density enhancing agent or mixtures thereof, optionally comprising hyaluronic acid to prepare a pharmaceutical composition suitable for intra-articular injection, and (i) and / or (ii) optionally comprising an anesthetic in immediate release dosage form.

[0217] In another embodiment, the kit or article of manufacture may be in the form of a vial and a pre-filled syringe or medical device, or may be in the form of two separate vials. In such embodiments, the two compartments or dual chambers may allow the aqueous injection vehicle described herein and the powder to be mixed by any means known to those skilled in the art. Furthermore, in such embodiments, the means may take the form of a pierceable membrane or a rupturable diaphragm, for example, by pressure that can be applied by the user. In these embodiments, the kit or article of manufacture may further include a label instructing the user to administer the resulting pharmaceutical composition into the target joint.

[0218] In one embodiment, the kit may be in the form of two separate vials. In one embodiment, the first vial contains an aqueous injection vehicle and the second vial contains a sustained release dosage form comprising colchicine, in particular as defined above, or an immediate release dosage form of a powder and anesthetic, as defined above.

[0219] If both (i) and (ii) include an anesthetic, they may be similar or different in each of (i) and (ii). As noted above, the anesthetic may be a mixture of anesthetics throughout the description.

[0220] In another embodiment, the kit or product may be in the form of a vial and a pre-filled syringe or medical device, or may be in the form of two separate vials. In this embodiment, the two compartments or dual chambers may be capable of mixing the aqueous injection vehicle and the powder described herein by any means known to those skilled in the art. In addition, in this embodiment, the means may be in the form of a pierceable membrane or a breakable diaphragm, for example, by the pressure that can be applied by the user.

[0221] In these embodiments, the kit or article of manufacture may further comprise a label instructing the user to introduce the resulting pharmaceutical composition into a joint of a subject.

[0222] For the comfort of the patient and for the safety reasons explained above, it would be advantageous to find a pharmaceutical composition that is suitable for intra-articular injection into the joint, requiring only one injection that would provide relief to the patient without the need for multiple injections.

[0223] Further provided herein is a pharmaceutical composition obtained by mixing the two compartments of the kit or article of manufacture as defined above for use in the treatment of joint diseases such as osteoarthritis, erosive osteoarthritis of the wrist and any other type of cartilage disease, and / or for use in 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 determined according to the following protocol: A 20 mg aliquot of a sustained-release dosage form containing colchicine is suspended in 50 mL of phosphate buffer (pH 7.4) with stirring at 37°C, and then the supernatant of samples withdrawn periodically throughout the release period is analyzed by UV at 350 nm. 80% (w / w) for more than one month as measured according to the formula (I) and colchicine is present in a concentration in the sterile injectable dosage form ranging from 1 to 27500 μg / ml, particularly from 3 to 27500 μg / ml.

[0224] Additional active ingredients Additional therapeutic agents that are normally administered to treat joint diseases such as osteoarthritis, erosive wrist osteoarthritis and any other type of cartilage disease, and / or to treat pain-related joint diseases and / or to protect joints, bones and / or cartilage, particularly osteoarthritis and / or pain-related osteoarthritis, may be administered in combination with colchicine.

[0225] As used herein, the terms "combination," "in combination," and related terms refer to the simultaneous or sequential administration of colchicine with the additional active ingredient. For example, the combination may be administered simultaneously or sequentially in separate unit dosage forms, or with the additional active ingredients together in a single unit dosage form.

[0226] According to one embodiment, an anesthetic may be injected into the painful joint and may, for example, be present in a pharmaceutical composition according to the invention.

[0227] 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, their pharmaceutically acceptable salts and mixtures thereof, in particular lidocaine, bupivacaine, ropivacaine and mepivacaine, more particularly ropivacaine and bupivacaine, and even more particularly ropivacaine and ropivacaine HCl, which is typically in immediate release dosage form and may be in the form of a pharmaceutically acceptable salt thereof.

[0228] According to this embodiment, the anesthetic may be in an immediate release dosage form or may be in the form of a hydrogel.

[0229] Such immediate release dosage forms of an anesthetic agent can be directly solubilized in a suspension according to the invention for administration to a patient by intra-articular injection, which means that the anesthetic agent is not included in a sustained release dosage form containing colchicine, such as microparticles.

[0230] In one embodiment, the anesthetic may be present directly in the sterile injectable dosage form according to the invention, in particular in a suspension, in particular in an amount adapted to remain below its solubility limit.

[0231] Accordingly, there is further provided herein a pharmaceutical composition for use in accordance with the present invention, the composition being in the form of a sterile injectable suspension, the colchicine being in the form of microparticles comprising a polymer matrix having an average particle size determined by laser light diffraction measurement of 10 μm or more, and the anesthetic being entirely in immediate release form and directly solubilized in the suspension.

[0232] The anesthetic may alternatively be in the form of a dehydrated hydrogel. In another embodiment, (iii) a dehydrated hydrogel containing an anesthetic can be prepared according to techniques known to those skilled in the art. The gel can be formed by dispersing an anesthetic, optionally pre-solubilized in water, with stirring with the hydrogel. Among suitable hydrogels, mention may be made of sodium hyaluronate. When the pharmaceutical composition is in the form of a powder, the water is removed by techniques known to those skilled in the art, for example, by dehydration or lyophilization. If necessary, they can be reversibly rehydrated.

[0233] In one embodiment, the anesthetic agent may be present in a concentration ranging from 1 to 100 mg per ml of sterile injectable dosage form, particularly from 1 to 50 mg per ml, and even more particularly from 1 to 20 mg per ml of sterile injectable dosage form. For example, when ropivacaine is present, it may be present in a concentration ranging from 2 to 10 mg per ml of sterile injectable dosage form.

[0234] According to one embodiment, hyaluronic acid can be injected into painful joints, and can be present in the pharmaceutical composition according to the present invention, for example.The use of hyaluronic acid in the treatment of arthritis, such as osteoarthritis, is well known as a thickening agent.Therefore, according to one embodiment, the present invention provides a pharmaceutical composition comprising a sustained-release dosage form comprising colchicine according to the present invention, which further comprises hyaluronic acid.

[0235] In some embodiments, the present invention provides pharmaceutical compositions comprising sustained release dosage forms comprising colchicine according to the present invention, which further comprise at least an additional therapeutic agent. Suitable additional active ingredients are described in more detail below.

[0236] According to one embodiment, the following active ingredients may be combined, in particular any anti-inflammatory active ingredient:

[0237] (i) corticosteroids, especially in low doses, such as prednisone, prednisolone, methylprednisolone, betamethasone, dexamethasone, triamcinolone acetonide, triamcinolone hexacetonide, budenoside, mometasone, ciclesonide, fluticasone, hydrocortisone and pharmaceutically acceptable salts thereof; (ii) NSAIDs such as aspirin, diclofenac, aceclofenac, sulindac, ketorolac, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, indomethacin, proglumetacin, tiaprofenic acid, meloxicam, piroxicam, tenoxicam, etodolac and celecoxib, etoricoxib, parecoxib, rofecoxib, valdecoxib, and pharmaceutically acceptable salts thereof; -(iii) anti-IL-1β agents, such as anakinra, canakinumab, rilonacept and pharmaceutically acceptable salts thereof; -(iv) anti-IL-6 agents such as tocilizumab, siltuximab, sarilumab and pharmaceutically acceptable salts thereof; (v) anti-TNFα agents such as adalimumab, etanercept, infliximab, certolizumab, golimumab, and pharmaceutically acceptable salts thereof; (vi) antiangiogenic agents, such as bevacizumab, and pharmaceutically acceptable salts thereof; -(vii) anti-NGF (nerve growth factor) agents, such as fasinumab, tanezumab, furanumab, ABT-110 and pharmaceutically acceptable salts thereof; (viii) opioids, such as fentanyl, morphine, buprenorphine, hydromorphone, hydrocodone, oxycodone, meperidine and pharmaceutically acceptable salts thereof; (ix) inhibitors of class I glucose transporters (e.g., GLUT-1 / GLUT-3), such as cytochalasin B, WZB-117, STF-31, and BAY-876; -(x) A mixture of them.

[0238] The additional active ingredients may be formulated under immediate and / or sustained release dosage forms. Administration of the Composition The pharmaceutical compositions used in the framework of the present invention can be injected using any of the methods known in the art.

[0239] In particular, the pharmaceutical composition may be administered by means of an injection device suitable for intra-articular injection, such as a syringe equipped with a needle of 19 to 29 G, preferentially 22 to 29 G, more preferentially 25 to 29 G.

[0240] Throughout the description, including the claims, the expression "comprising a" should be understood as synonymous with "comprising at least one," unless otherwise specified.

[0241] The expressions "between" and "in the range of" should be understood to mean that the limits are inclusive unless otherwise specified.

[0242] The following examples and figures are presented as non-limiting illustrations of the present invention. [Example]

[0243] Analysis method The particle sizes in Examples 1 and 2 were determined using a Malvern Mastersizer MS3000 laser diffraction particle size analyzer. A suspension of 0.1-1 mg of microparticles per ml of deionized water was introduced into the instrument using a vortex. Measurements were performed in triplicate. 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.

[0244] The particle sizes of Examples 5, 6, and 7 were determined using a LUMiReader multi-wavelength separation analyzer using a sedimentation method to measure particle size distribution. A suspension of 4 mg of microparticles per ml of deionized water was performed using a bath sonicator for 10 seconds. The suspension was then introduced into the instrument and analyzed at a wavelength of 470 nm. Each run lasted 50 minutes, and the suspension was homogenized before each run. The results shown in the examples are the average of four runs.

[0245] Microparticle 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 mixed under vortexing. The flask was then filled with water and thoroughly mixed using a vortex. The medium was then centrifuged at 4000 rpm for 30 minutes, and the supernatant was filtered through a 0.45 μm PTFE filter (Acrodisc wwPTFE), discarding the first 2 mL. An aliquot of this solution was then analyzed by HPLC to determine the microparticle drug loading.

[0246] - 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, 45% 6.8 g / L KH2PO4 solution, adjusted to pH 5.5 with dilute phosphoric acid] at a flow rate of 1 mL / min with UV detection at 254 nm.

[0247] For in vitro release studies from the microparticles of Examples 1, 2 and 3, aliquots of 20 mg of microparticles were suspended in 50 mL of phosphate buffer (50 mM, pH 7.4) maintained at 37°C in a horizontal shaker set at 80 rpm. At different intervals, 3 mL samples of medium were 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.

[0248] For in vitro release studies from the microparticles of Examples 5, 6 and 7, aliquots of 20 mg of microparticles were suspended in 50 mL of phosphate buffer (10 mM, pH 7.4) maintained at 37°C in a horizontal shaker set at 200 rpm using a sonication bath. At different intervals, 3 mL samples of medium were 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.

[0249] Example 1 Sustained-Release Colchicine Microparticles A 1 wt% 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 in it with magnetic stirring until completely solubilized. The solution was then cooled before further use.

[0250] In a separate container, 0.7 g of colchicine (INDENA, Italy) was solubilized in 2.5 g of methylene chloride (Merck) under vortex stirring until completely solubilized. Then, 1.05 g of PLGA 75:25 Resomer RG 752 S [USP <911> Poly(lactic acid-co-glycolic acid) copolymer 75:25 with an intrinsic viscosity of 0.16–0.24 dl / g as determined by 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.

[0251] 5 g of the previously prepared 1 wt % PVA stock solution was then added to the drug-polymer solution under high shear (Heidolph homogenizer DIAX 900, 11 600 RPM) for 30 seconds to form a pre-emulsion.

[0252] This pre-emulsion was then slowly poured into a hardening bath containing 500 ml of the previously prepared 1 wt % PVA stock solution.

[0253] Stirring was maintained for 3 hours using a double propeller stirrer set at 250 rpm until the methylene chloride had evaporated.

[0254] The formed microparticles were centrifuged using a swinging bucket centrifuge apparatus at 4000 rpm for 3 minutes to remove the major part of the aqueous phase, resulting in a concentrated particle slurry, which was separated through a 12 μm stainless steel sieve (4 cm diameter).

[0255] The microparticles were then rinsed with 150 ml of water and dried overnight in a desiccator over 3 Å molecular sieves.

[0256] The collected microparticles were then stored at 5°C. Analytical testing, including in vitro profiles, was performed as described in the "Analytical Methods" section above and is shown in Table 2 below.

[0257] [Table 5]

[0258] In this example, colchicine-loaded PLGA microparticles were prepared with a colchicine loading content of 3 wt%, a mean particle size of 19 μm, and sustained drug release for more than 30 days.

[0259] Example 2: Sustained-Release Colchicine Microparticles The same polyvinyl alcohol (PVA) stock solution as in Example 1 was prepared.

[0260] In a separate container, 0.7 g of colchicine (INDENA, Italy) was solubilized in 2.5 g of methylene chloride (Merck) under vortex stirring until completely solubilized, followed by 1.05 g of PLGA 75:25 Resomer RG 755 S [USP <911> Poly(lactic acid-co-glycolic acid) copolymer 75:25 with an intrinsic viscosity of 0.5–0.7 dl / g determined by Ubbelohde capillary viscometer according to (Evonik Industries AG, Essen, Germany)] was introduced into the mixture and completely dissolved under vortex stirring to form a polymer-drug solution.

[0261] 5 g of the previously prepared 1 wt % PVA stock solution was then added to the drug-polymer solution under high shear (Heidolph homogenizer DIAX 900, 11 600 rpm) for 30 seconds to form a pre-emulsion.

[0262] This pre-emulsion was then slowly poured into a hardening bath containing 500 ml of the previously prepared 1 wt % PVA stock solution.

[0263] Stirring was maintained for 3 hours using a double propeller stirrer set at 250 RPM until the methylene chloride had evaporated.

[0264] The formed microparticles were centrifuged using a swinging bucket centrifuge apparatus at 4000 rpm for 3 minutes to remove the major part of the aqueous phase, resulting in a concentrated particle slurry, which was separated through a 12 μm stainless steel sieve (4 cm diameter).

[0265] The microparticles were then rinsed with 150 ml of water and dried overnight in a desiccator over 3 Å molecular sieves.

[0266] The collected microparticles were then stored at 5°C. Analytical testing, including in vitro profiles, was performed as described in the "Analytical Methods" section above and is shown in Table 3 below.

[0267] [Table 6]

[0268] In this example, colchicine-loaded PLGA microparticles were prepared with a colchicine loading content of 6% by weight, an average particle size of 25 μm, and sustained drug release over at least 100 days.

[0269] Example 3: Sustained-Release Colchicine Microparticle Composition A sustained-release colchicine microparticle composition was prepared by blending 0.2 g of the particles of Example 1 and 0.2 g of the particles of Example 2.

[0270] In vitro profiles were performed as described in the "Analytical Methods" section above and are shown in Table 4 below.

[0271] [Table 7]

[0272] Example 4: Pharmaceutical Composition An aqueous injection vehicle was prepared using pyrogen-free excipients: 1.4% low-viscosity sodium carboxymethylcellulose (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 vehicle was then autoclaved (MultiControl 2, CertoClav) at 121°C for 15 minutes, and 5 mL aliquots of the solution were aseptically transferred to 10 mL vials under a laminar flow bench.

[0273] An aliquot of the microparticles prepared according to Example 3 was dispersed in each vial using a vortex mixer, thus allowing the preparation of a pharmaceutical composition in the form of a sterile injectable dosage form suitable for intra-articular injection according to the present invention.

[0274] These pharmaceutical compositions are suitable for intra-articular injection to treat joint diseases such as osteoarthritis, erosive osteoarthritis of the wrist and any other type of cartilage disease, and / or to treat pain-related joint diseases and / or to protect joints, bones and / or cartilage, especially osteoarthritis and / or pain-related osteoarthritis.

[0275] Example 5: Sustained-Release Colchicine Microparticles A 1 wt% 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 with magnetic stirring until completely solubilized. The solution was then cooled before further use.

[0276] In a separate container, 1.6 g of colchicine (INDENA, Italy) was solubilized in 13.6 g of methylene chloride (Sigma Aldrich) under vortex stirring until completely solubilized.

[0277] Then, 2.40 g of PLGA 65:35 Mw 40,000-75,000 [USP <911> Poly(lactic-co-glycolic acid) copolymer 65:35 [with an intrinsic viscosity of 0.55-0.75 dl / g as determined by Ubbelohde capillary viscometer according to ] was introduced into the mixture and allowed to completely dissolve under magnetic stirring set at 300 rpm to form a polymer-drug solution.

[0278] 27.2 g of the previously prepared 1 wt % PVA stock solution was sampled into another 50 ml glass beaker, and the polymer-drug solution was slowly poured into it under high shear (ULTRA TURRAX T25,9 600 rpm) for 10 minutes to form a pre-emulsion.

[0279] This pre-emulsion was then slowly poured into a hardening bath containing 2700 ml of the previously prepared 1 wt % PVA stock solution.

[0280] Stirring was maintained for 3 hours using a double propeller stirrer set at 200 RPM until the methylene chloride had evaporated.

[0281] The formed microparticles were centrifuged using a swinging bucket centrifuge device at 4000 rpm for 3 min to remove the main part of the aqueous phase, and a concentrated particle slurry was obtained, which was then separated using a sintered glass filter with a porosity of 4 (10–16 μm mesh).

[0282] The microparticles were then rinsed with 150 ml of water and dried overnight in a desiccator under vacuum. The collected microparticles were then stored at 5°C.

[0283] Analytical testing, including in vitro profiles, was performed as described in the "Analytical Methods" section above and is shown in Table 5 below.

[0284] [Table 8]

[0285] In this example, colchicine-loaded PLGA microparticles were prepared with a colchicine loading content of 15.5 wt%, a mean particle size of 16 μm, and sustained drug release over at least 45 days.

[0286] Example 6: Sustained-Release Colchicine Microparticles The same polyvinyl alcohol (PVA) stock solution was prepared as in Example 5. In a separate container, 1.6 g of colchicine (INDENA, Italy) was solubilized in 13.6 g of methylene chloride (Sigma Aldrich) under vortex stirring until completely solubilized.

[0287] Next, 2.40 g of PLGA 75:25 Mw 66,000-107,000 [USP <911> Poly(lactic-co-glycolic acid) copolymer 75:25 [with an intrinsic viscosity of 0.55-0.75 dl / g as determined by Ubbelohde capillary viscometer according to ] was introduced into the mixture and allowed to dissolve completely under magnetic stirring set at 300 rpm to form a polymer-drug solution.

[0288] 27.2 g of the previously prepared 1 wt % PVA stock solution was sampled into another 50 ml glass beaker, and the polymer-drug solution was slowly poured into it under high shear (ULTRA TURRAX T25,9 600 rpm) for 10 minutes to form a pre-emulsion.

[0289] This pre-emulsion was then slowly poured into a hardening bath containing 2700 ml of the previously prepared 1 wt % PVA stock solution.

[0290] Stirring was maintained for 3 hours using a double propeller stirrer set at 200 RPM until the methylene chloride had evaporated.

[0291] The formed microparticles were centrifuged using a swinging bucket centrifuge device at 4000 rpm for 3 min to remove the main part of the aqueous phase, and a concentrated particle slurry was obtained, which was then separated using a sintered glass filter with a porosity of 4 (10–16 μm mesh).

[0292] The microparticles were then rinsed with 150 ml of water and dried overnight in a desiccator under vacuum. The collected microparticles were then stored at 5°C.

[0293] Analytical testing, including in vitro profiles, was performed as described in the "Analytical Methods" section above and is shown in Table 6 below.

[0294] [Table 9]

[0295] In this example, colchicine-loaded PLGA microparticles were prepared with a colchicine loading content of 14.2 wt %, a mean particle size of 24 μm, and sustained drug release over at least 45 days.

[0296] Example 7: Sustained-Release Colchicine Microparticles The same polyvinyl alcohol (PVA) stock solution was prepared as in Example 5. In a separate container, 1.0 g of colchicine (INDENA, Italy) was solubilized in 13.5 g of methylene chloride (Sigma Aldrich) under vortex stirring until completely solubilized.

[0297] Next, 1.50 g of Ashland PLGA 85:15 VIATEL DLG 8507 Mw 46,000-95,000 [USP <911> Poly(lactic acid-co-glycolic acid) copolymer 85:15 [with an intrinsic viscosity of 0.60-0.80 dl / g as determined by Ubbelohde capillary viscometer according to ] was introduced into the mixture and allowed to completely dissolve under magnetic stirring set at 300 rpm to form a polymer-drug solution.

[0298] 27 g of the previously prepared 1 wt % PVA stock solution was sampled into another 50 ml glass beaker, and the polymer-drug solution was slowly poured into it under high shear (ULTRA TURRAX T25, 9 600 rpm) for 10 min to form a pre-emulsion.

[0299] This pre-emulsion was then slowly poured into a hardening bath containing 2700 ml of the previously prepared 1 wt % PVA stock solution.

[0300] Stirring was maintained for 3 hours using a double propeller stirrer set at 200 RPM until the methylene chloride had evaporated.

[0301] The formed microparticles were centrifuged using a swinging bucket centrifuge device at 4000 rpm for 3 min to remove the main part of the aqueous phase, and a concentrated particle slurry was obtained, which was then separated using a sintered glass filter with a porosity of 4 (10–16 μm mesh).

[0302] The microparticles were then rinsed with 150 ml of water and dried overnight in a desiccator under vacuum. The collected microparticles were then stored at 5°C.

[0303] Analytical testing, including in vitro profiles, was performed as described in the "Analytical Methods" section above and is shown in Table 7 below.

[0304] [Table 10]

[0305] In this example, colchicine-loaded PLGA microparticles were prepared with a colchicine loading content of 15.1 wt %, a mean particle size of 14 μm, and sustained drug release over at least 30 days.

[0306] Example 8: Pharmaceutical Composition An aqueous injection vehicle was prepared using pyrogen-free excipients, consisting of 1.4% low-viscosity sodium carboxymethylcellulose (Aqualon CMC 7LF PH BET, Ashland), 0.1% polysorbate 20 (Emprov 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 vehicle was then autoclaved (Tuttnauer-2840EL) at 121°C for 20 minutes, and 5 mL aliquots of the solution were aseptically transferred to 10 mL vials under a laminar airflow bench.

[0307] An aliquot of the microparticles prepared according to Example 5, targeting a colchicine concentration of 100 μg / ml, and ropivacaine HCl (MOEHS, Spain), targeting a concentration of 5 mg / ml, were dispersed in each vial using ultrasonic treatment for 30 seconds. Thus, a pharmaceutical composition in the form of a sterile injectable dosage form suitable for intra-articular injection according to the present invention can be prepared.

[0308] These pharmaceutical compositions are suitable for intra-articular injection for a 3-6 month colchicine release to treat joint diseases such as osteoarthritis, erosive osteoarthritis of the wrist and any other type of cartilage disease and / or to treat pain-related joint diseases and / or to protect joints, bones and / or cartilage, especially osteoarthritis and / or pain-related osteoarthritis.

[0309] Example 9: In vivo - Chondroprotection The pharmaceutical compositions described herein were injected into inflamed rat ankle joints and their effect on cartilage destruction was observed.

[0310] Pharmaceutical Compositions An aqueous injection vehicle was prepared under laminar flow using water for injection and pyrogen-free excipients. The vehicle consisted of 1.4% low-viscosity sodium carboxymethylcellulose (Aqualon CMC 7LPH 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 concentrated sodium hydroxide solution (Roth).

[0311] The vehicle was then autoclaved (Systec 3150EL) at 121°C for 20 minutes and finally stored at 4°C for later use.

[0312] The pharmaceutical composition was prepared by weighing 65 mg of ropivacaine HCl and 10 mg of colchicine microparticles prepared according to Section 9.2 of the Example Description into a 20 ml autoclave vessel.

[0313] Immediately prior to in vivo injection, 12.50 ml of the aqueous injection vehicle was introduced into the vial and homogenized using ultrasonic agitation until the particles were completely and uniformly dispersed. The suspension thus prepared resulted in a colchicine concentration of 40 μg / ml and a ropivacaine HCl concentration of 5 mg / ml. 50 μL of this suspension was then injected into the inflamed ankle joint of rats, as described later in point 9.3 of this specification.

[0314] 9.2. Preparation of colchicine microparticles Colchicine microparticles were prepared under laminar flow using an autoclave and sterile container as follows: A 1 wt% 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 under magnetic stirring until completely solubilized. The solution was then cooled before further use.

[0315] In a separate autoclave vessel, 0.5 g of colchicine (INDENA, Italy) was solubilized in 10.75 mL of methylene chloride (Merck) under magnetic stirring. Then, 2.85 g of PLGA 50:50 Resomer 503H (50:50 poly(lactic-co-glycolic acid) copolymer with 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 (50:50 poly(lactic-co-glycolic acid) copolymer with an intrinsic viscosity of 0.16–0.24 dL / g; Evonik Industries AG, Essen, Germany) were added to the mixture and completely dissolved under magnetic stirring to form a polymer-drug solution.

[0316] 28.6 g of the previously prepared 1 wt% PVA stock solution was then added to the drug-polymer solution under high shear (9,500 RPM). Emulsification was carried out for 10 minutes using an IKA T25 Ultra-Turrax rotor-stator mixer equipped with a S25N 10G head.

[0317] This emulsion was then slowly poured into a hardening bath containing 2860 g of the previously prepared 1 wt % PVA stock solution.

[0318] Stirring was maintained for 3 hours using a double propeller stirrer set at 300 RPM until the methylene chloride had evaporated.

[0319] The resulting microparticles were centrifuged at 4000 RPM for 3 minutes in a swinging bucket GT2R centrifuge to remove the majority of the aqueous phase, resulting in a concentrated particle slurry. The slurry was then redispersed in approximately 20 ml of water, and the redispersed particles were sieved through a stainless steel Endecotts sieve to 40 μm and then 10 μm.

[0320] The collected particles were then vacuum filtered through a 12-25 μm Whatman cellulose filter and washed with 150 ml of sterile water.

[0321] The washed microparticles were then vacuum dried at 2 mBar and a shelf temperature of 15° C. for 17 hours. The collected microparticles were then stored at 5°C.

[0322] In this example, colchicine-loaded PLGA microparticles were prepared with a drug loading content of 5.1 wt % and an average particle size of 21 μm.

[0323] 9.3. In vivo experiments In this example, 16 Sprague Dawley rats were randomly divided into two groups of 8 rats each.

[0324] • 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.

[0325] Group 2 (treatment group) received an intra-articular injection of the pharmaceutical composition (50 μL) into the left ankle, followed by immediate induction of inflammation by injection of λ-carrageenan into the same joint (1 mg / 30 μL).

[0326] Three days after injection, all animals were euthanized, and the ankle joints were dissected for histological examination. The specimens were immersed in 10% formalin overnight. The following day, decalcification was performed in RDO (Eurobio) for 5 hours, followed by EDT 0.5M for 48 hours. The specimens were then dehydrated in an automat and embedded in paraffin. 4-μm sections were prepared and stained with hematoxylin-eosin. Observations were performed blindly.

[0327] [Table 11]

[0328] [Table 12]

[0329] The results are reported in Figure 1. All but one control animal (Group 1) showed cartilage destruction and inflammatory arthritis (moderate to severe with synovial thickening, presence of inflammatory cells and infiltration of periarticular tissues).

[0330] In contrast, treated animals (Group 2) showed absent (4 / 7 rats), mild (2 / 7 rats), or moderate (1 / 7 rats) inflammatory synovitis. Group 2 animals showed absent (5 / 7 rats) or mild signs (2 / 7) of cartilage destruction. Collectively, these findings demonstrate a clear anti-inflammatory and anti-destructive effect of treatment in this rat model of acute arthritis. We anticipate that such chondroprotective effects will be observed regardless of the exposure time and release profile of colchicine, provided the dosage meets the acceptable local concentration window.

[0331] Analysis of treated ankle cartilage inflammation scores showed a statistical difference between Group 2 and Group 1 (p-value < 0.05, Kruskal-Wallis and Dunnett's test). Furthermore, analysis of destruction scores showed a clear, significant, and statistically significant effect between Group 2 and Group 1 (p-value < 0.01, Kruskal-Wallis and Dunnett's test).

Claims

1. 1. A pharmaceutical composition in the form of a sterile injectable dosage form comprising a sustained release dosage form comprising colchicine for use in the treatment of joint diseases such as osteoarthritis, erosive osteoarthritis of the wrist and any other type of cartilage disease, by intra-articular injection of said pharmaceutical composition into a joint, and / or for use in the treatment of pain-related joint diseases, and / or for use in the protection of joints, bones and / or cartilage, wherein the dissolution rate of colchicine is determined according to the following protocol: A 20 mg aliquot of a sustained-release dosage form containing colchicine is suspended in 50 mL of phosphate buffer (pH 7.4) with stirring at 37°C, and then the supernatant of samples withdrawn periodically throughout the release period is analyzed by UV at 350 nm. 80% (w / w) for more than 1 month, as measured according to The colchicine is present in a concentration ranging from 1 to 27,500 μg per ml of the sterile injectable dosage form. Pharmaceutical compositions.

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

3. 3. A pharmaceutical composition for use according to claim 1 or 2, wherein the sustained release dosage form comprising colchicine is in the form of an in-situ forming depot or microparticle, in particular a microparticle comprising a polymer matrix or multivesicular liposomes.

4. 10. A pharmaceutical composition for use according to any one of the preceding claims, wherein the sustained release dosage form comprising colchicine is in the form of microparticles, in particular microparticles comprising a polymer matrix, and wherein the colchicine-containing microparticles have an average particle size determined by laser light diffraction measurement of 10 μm or more, in particular an average particle size of less than 100 μm, more particularly less than 80 μm, even more particularly less than 50 μm, for example 10 to 50 μm, or 10 to 40 μm.

5. The microparticles, which may be a mixture of microparticles of different properties, are microparticles comprising colchicine and a polymer matrix, wherein the polymer matrix is at least one poly(lactic-co-glycolic acid) copolymer, in particular two copolymers exhibiting different molecular weights; at least one poly(caprolactone), or - at least one mixture of at least one poly(lactic-co-glycolic acid) copolymer and at least one poly(caprolactone); 5. The pharmaceutical composition for use according to claim 4, comprising:

6. The polymer matrix may be selected from the group consisting of poly(lactides) other than poly(lactic acid-co-glycolic acid) copolymers, poly(glycolides) other than poly(lactic acid-co-glycolic acid) copolymers, poly(lactide-co-caprolactone), poly(ethylene glycol), poly(ethylene oxide), PLGA-b-PEO-b-PLGA, PLGA-b-PEO, polyhydroxyalkanoates, poly(hydroxybutyrate), poly(trimethylene carbonate), poly(dioxanone), poly(valerolactone), poly(α-hydroxy acid), poly(lactone), poly(amino acid), polyanhydride, poly(orthoester), poly(acetate), poly(acetate), poly(ethylene oxide), poly(ethylene oxide), poly(ethylene glycol), poly(ethylene oxide ...

6. The pharmaceutical composition for use according to claim 4, further comprising one or more additional polymers or copolymers selected from polyvinyl alcohols, polyurethanes, polythioesters, polyphosphoesters, poly(ester-co-amides), poly(vinyl alcohol), PVA-g-PLGA, poly(ether ester) multiblock copolymers, polyvinylpyrrolidone, poly(methacrylate), PEO-PPO-PEO, gelatin, heparin, chondroitin sulfate; polysaccharides, such as alginate, starch, chitosan and dextran, and any combination thereof, in particular poly(lactide) and poly(caprolactone).

7. The polymer matrix comprises at least one poly(lactic-co-glycolic acid) copolymer, at least one poly(caprolactone), or at least one mixture of at least one poly(lactic-co-glycolic acid) copolymer and at least one poly(caprolactone), in an amount of more than 70 wt.%, in particular more than 80 wt.%, more especially more than 90 wt.%, based on the total weight of the polymer matrix, and the poly(lactic-co-glycolic acid) copolymer is preferably in an amount of more than 50 wt.%, more especially more than 90 wt.%, based on the total weight of the polymer matrix.

7. The pharmaceutical composition for use according to any one of claims 4 to 6, wherein the poly(lactic-co-glycolic acid) copolymer has a molar ratio of lactic acid:glycolic acid in the range of 55:45 to 90:10, in particular in the range of 55:45 to 90:10, more particularly in the range of 65:35 to 85:15, for example 75:25, and wherein the poly(lactic-co-glycolic acid) copolymer exhibits an intrinsic viscosity, measured by Ubbelohde capillary viscosimetry according to USP <911>, of in particular 0.1 to 1.7 dl / g, in particular 0.1 to 1.4 dl / g, even more particularly 0.1 to 0.9 dl / g.

8. 10. A pharmaceutical composition for use according to any one of the preceding claims, in the form of a sterile injectable dosage form selected from a solution, a suspension, a solid implant, a semi-solid implant, a powder and an in situ depot.

9. 10. A pharmaceutical composition for use according to any one of the preceding claims, further comprising an anesthetic agent which may be selected from lidocaine, ropivacaine, bupivacaine, levobupivacaine, capsaicin, mepivacaine, prilocaine, pharmaceutically acceptable salts thereof and mixtures thereof, in particular lidocaine, bupivacaine, ropivacaine and mepivacaine, more particularly ropivacaine and bupivacaine, even more particularly ropivacaine.

10. wherein said colchicine is present in said sterile injectable dosage form, in particular a suspension, in a concentration ranging from 1 to 27500 μg / ml, in particular from 3 to 27500 μg / ml, more particularly from 1 to 13750 μg / ml, for example from 3 to 13750 μg / ml, and even more particularly said colchicine is present in a concentration ranging from 3 to 3600 μg / ml, For example, 3 to 600 μg / ml if the dissolution rate of said colchicine is 80% (w / w) for more than 1 month but less than 2 months, 9 to 1800 μg / ml, for example, if the dissolution rate of the colchicine is 80% (w / w) between 2 and 4.5 months, and For example, 18 to 3600 μg / ml if the dissolution rate of the colchicine is 80% (w / w) between 4.5 and 7 months, and The anesthetic, if present, is present in the sterile injectable dosage form, particularly in a concentration ranging from 1 to 100 mg per ml of suspension. A pharmaceutical composition for use according to claim 8 or 9.

11. 10. A pharmaceutical composition according to any one of the preceding claims for use in the treatment of osteoarthritis, erosive osteoarthritis of the wrist and any other type of cartilage disease in patients with an inflammatory component, inflammatory pain or joint effusion.

12. 10. The pharmaceutical composition for use according to any one of the preceding claims, further characterized in that it is effective to maintain a systemic concentration of colchicine of less than 5 ng / ml, in particular less than 1 ng / ml, more particularly less than 0.5 ng / ml, even more particularly less than 0.1 ng / ml 24 hours after said intra-articular injection, in particular over a period of one month, even more particularly for at least three months, and to maintain a synovial concentration of colchicine of more than 0.5 ng / ml, in particular comprised between 0.5 and 100 ng / ml, more particularly comprised between 0.5 and 50 ng / ml, for a period of one month, even more particularly for at least three months, after said intra-articular injection.

13. Patients who are being 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, tipranavir, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, cyclosporine, ranolazine, macrolides and statins, or who have hypertension, chronic kidney disease, diabetes, cardiovascular disease, 10. A pharmaceutical composition according to any one of the preceding claims for use in the treatment of joint diseases, such as osteoarthritis, erosive hand osteoarthritis and any other kind of cartilage disease, in patients suffering from chronic comorbidities such as infections, stroke, depression, peptic ulcer, metabolic syndrome and / or immunosuppression, and / or for use in the treatment of pain-related joint diseases and / or for use in the protection of joints, bone and / or cartilage, in particular osteoarthritis and / or pain-related osteoarthritis in patients with renal and / or hepatic impairment.

14. 1. A pharmaceutical composition in the form of a sterile injectable dosage form comprising a sustained release dosage form comprising colchicine, said pharmaceutical composition exhibiting an in vitro dissolution profile, wherein the dissolution rate of colchicine is measured according to the following protocol: A 20 mg aliquot of a sustained release dosage form containing colchicine is suspended in 50 mL of phosphate buffer (pH 7.4) with stirring at 37°C, and then the supernatant of samples withdrawn periodically throughout the release period is analyzed by UV at 350 nm. and less than 25% (w / w), more preferentially less than 15% (w / w), within 24 hours, and 80% (w / w) for more than 1 month, in particular for more than 3 months, even more particularly for more than 6 months, when measured according to The colchicine is present in a concentration ranging from 1 to 27,500 μg per ml of sterile injectable dosage form. Pharmaceutical compositions.

15. 1. A formulation in the form of a powder comprising a sustained-release dosage form containing colchicine in the form of microparticles having an average particle size of 10 μm or more as determined by laser light diffraction measurement and comprising a polymer matrix, the polymer matrix comprises at least one poly(lactic-co-glycolic acid) copolymer, at least one poly(caprolactone), or at least one mixture of at least one poly(lactic-co-glycolic acid) copolymer and at least one poly(caprolactone) in an amount of more than 70 wt.%, in particular more than 80 wt.%, and more particularly more than 90 wt.%, based on the total weight of the polymer matrix; and has a molar ratio of lactic acid:glycolic acid in the range of 50:50 to 90:10, in particular in the range of 55:45 to 90:10, for example 60:40 to 90:10, more particularly in the range of 65:35 to 85:15, for example 75:25, and the poly(lactic-co-glycolic acid) copolymer exhibits an intrinsic viscosity, measured by Ubbelohde capillary viscosimetry according to USP <911>, in particular of 0.1 to 1.7 dL / g, in particular of 0.1 to 1.4 dL / g, even more particularly of 0.1 to 0.9 dL / g. formulation.

16. 16. A pharmaceutical composition in the form of a sterile injectable dosage form suitable for intra-articular injection, obtained by mixing the formulation in powder form according to claim 15 with an aqueous injection vehicle, optionally comprising an excipient selected from the group consisting of a tonicity enhancing agent, a wetting agent, a viscosity enhancing agent, a density enhancing agent or a mixture thereof, said excipients may be present in the aqueous injection vehicle or in the powder, and optionally comprising hyaluronic acid.

17. 1. A pharmaceutical composition in the form of a sterile injectable dosage form suitable for intra-articular injection, comprising a sustained release dosage form comprising colchicine in the form of microparticles having an average particle size determined by laser light diffraction measurement of 10 μm or more and comprising a polymer matrix, wherein the polymer matrix comprises at least one poly(lactic-co-glycolic acid) copolymer, at least one poly(caprolactone), or at least one blend of at least one poly(lactic-co-glycolic acid) copolymer and at least one poly(caprolactone) in an amount of more than 70% by weight, in particular 80% by weight, based on the total weight of the polymer matrix. % by weight, more especially more than 90% by weight, wherein the poly(lactic-co-glycolic acid) copolymer has a molar ratio of lactic acid:glycolic acid in the range of 50:50 to 90:10, in particular in the range of 55:45 to 90:10, for example 60:40 to 90:10, more especially in the range of 65:35 to 85:15, for example 75:25, and wherein the poly(lactic-co-glycolic acid) copolymer exhibits an intrinsic viscosity, measured by Ubbelohde capillary viscosimetry according to USP <911>, in particular of 0.1 to 1.7 dl / g, in particular 0.1 to 1.4 dl / g, even more especially 0.1 to 0.9 dl / g.

18. 18. A pharmaceutical composition in the form of a sterile injectable dosage form according to claim 16 or 17, selected from solutions, suspensions, solid implants, semi-solid implants, powders and in situ depots, in particular suspensions, wherein colchicine is present in a concentration ranging from 1 to 27500 μg / ml, in particular from 3 to 27500 μg / ml, more particularly from 1 to 13750 μg / ml of sterile injectable dosage form, in particular suspensions, for example in a concentration ranging from 3 to 13750 μg / ml.

19. 19. A kit or article of manufacture comprising, in separate compartments, (i) an aqueous injection vehicle and (ii) a sustained release dosage form comprising colchicine according to any one of claims 3 to 7 or the powder according to claim 15, said kit or article of manufacture optionally comprising an excipient selected from the group consisting of a tonicity enhancing agent, a wetting agent, a viscosity enhancing agent, a density enhancing agent or a mixture thereof, optionally comprising hyaluronic acid for preparing a pharmaceutical composition suitable for intra-articular injection, and (i) and / or (ii) optionally comprising an anesthetic in immediate release dosage form.

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

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