Intra-articular injection formulations containing colchicine and anesthetics for the treatment of crystalline and amorphous acute inflammatory arthritis.

Abstract

The present invention relates to a pharmaceutical composition suitable for intra-articular injection, comprising an anesthetic and an immediate-release or controlled-release dosage form containing colchicine. Furthermore, the present invention relates to a pharmaceutical composition in powder form comprising an anesthetic and an immediate-release or controlled-release dosage form containing colchicine, wherein the controlled-release dosage form containing colchicine is in the form of fine particles. Furthermore, the present invention relates to a pharmaceutical composition in powder form comprising an anesthetic and an immediate-release or controlled-release dosage form containing colchicine, wherein the controlled-release dosage form containing colchicine is in the form of fine particles, a kit, and the use of the pharmaceutical composition or kit in the treatment of crystal-associated acute inflammatory arthritis and amorphous acute inflammatory arthritis, particularly crystal-associated arthropathy or erythema or acute type tendinitis and capsulitis, by intra-articular injection of the pharmaceutical composition into the joint, providing immediate and overall treatment-long analgesia.

Description

Technical Field

[0001] The present invention relates to the field of treatment of inflammatory pain of joints with colchicine combined with an anesthetic. The inflammatory pain of joints targeted by the present invention can be acute arthritis associated with crystals and acute arthritis not associated with crystals, particularly the onset or erythema of arthritis, as well as acute forms of tendonitis and synovitis, and simply targets acute diseases. Colchicine and an anesthetic are administered locally by intra-articular injection, and colchicine is administered via an immediate-release dosage form or a controlled-release dosage form.

Background Art

[0002] background Inflammatory arthritis is a group of chronic autoimmune and autoinflammatory diseases characterized by inflammation of joints accompanied by symptoms such as pain, swelling, stiffness, and reduced range of motion. Patients generally experience alternating acute and inactive phases with very strong symptoms in one or several joints. Inflammatory arthritis includes several diseases and conditions such as rheumatoid arthritis, ankylosing spondylitis, juvenile arthritis, psoriatic arthritis, lupus, or microcrystalline diseases.

[0003] In particular, the class of microcrystalline arthropathies corresponds to local tissue inflammation caused by the deposition of microcrystals in joints. These crystals cause an inflammatory reaction and severe joint pain. This disease class includes several conditions that differ particularly in the nature of the crystals: gout (monosodium urate (MSU)), chondrocalcinosis (calcium pyrophosphate (CPP)), calcific tendonitis (calcium phosphate), and Milwaukee shoulder syndrome (calcium phosphate). In this context, crystal-associated arthropathy is characterized by multiple extremely painful acute attacks or erythema, followed by pain, disability, and a decline in quality of life.

[0004] Tendinitis is inflammation of the tendons that can be secondary to several factors, including trauma, degenerative, iatrogenic (i.e., drug-induced), age, and inflammation, causing pain and disability. Tendinitis can occur at any age, but is more common in adults who frequently participate in sports or who experience repeated strong tensile forces on their tendons. Older adults are also susceptible, as tendons tend to lose elasticity and weaken with age. Chronic pain symptoms are also present in calcific tendinitis and acute calcific tendinitis.

[0005] Capsulitis is inflammation of the capsulum, which causes pain and stiffness. Capsulitis most frequently affects the shoulder, in which case it may also be called frozen shoulder.

[0006] In the case of tendinitis and capsulitis, the present invention primarily targets their acute forms, such as calcific tendinitis.

[0007] The recommended treatment for these acute joint diseases is, in most cases, symptomatic, aiming to control pain. Generally, the first-line treatment is primarily oral nonsteroidal anti-inflammatory drugs (NSAIDs), oral or intra-articular corticosteroids, or oral colchicine (legally approved for gout). If possible and the joint is accessible, i.e., in the case of large joints (knees, ankles, wrists, elbows, and shoulders), intra-articular corticosteroid injections may be considered by the physician to avoid systemic administration and thereby avoid the risk of significant side effects.

[0008] Intra-articular administration of corticosteroids, which has been used for decades in the treatment of joint diseases in general, improves pain and mobility with a short-lived effect (several weeks in the case of immediate-release formulations). However, the toxic aspects of these administrations are highly problematic and controversial. In fact, systemic effects, including Cushing's syndrome, hyperglycemia, decreased bone density, or increased risk of infection, have been mentioned in the weeks following injection. The latter may be a result of the direct introduction of infectious agents into the joints or due to a reduced immune response and reactivation of latent tuberculosis infection. This type of treatment is particularly unsuitable for patients at risk, namely those with comorbidities such as diabetes or osteoporosis. In addition, adverse effects on local tissues, such as damage to articular cartilage and tendons, have also been described.

[0009] As a result, the frequency and dosage of intra-articular corticosteroid injections are limited in medical practice. Therefore, for immediate-release herbal formulations, a maximum of three injections per year / per site, with a minimum interval of three months between each injection, is recommended. The first sustained-release intra-articular corticosteroid formulation (Zilretta®, manufactured by Flexion Therapeutics) was approved by the FDA (Food and Drug Administration) in 2017 for osteoarthritis, allowing for continuous treatment over several months. However, this product is not approved for repeated administration.

[0010] Therefore, intra-articular administration of corticosteroids is not considered the optimal treatment for gout attacks or other extremely painful conditions such as chondrocalcinosis.

[0011] Colchicine is a drug characterized by its pleiotropic effects, related to its ability to destabilize the cytoskeleton and all cellular processes (including cell division, migration, and cell morphology) by binding to tubulin and interfering with microtubule polymerization. Among these effects, colchicine affects the immune system, downregulating multiple inflammatory pathways and leading to decreased neutrophil function and migration. Therefore, colchicine is used and approved for several inflammatory diseases, including familial Mediterranean fever, Behçet's disease, and microcrystalline diseases.

[0012] In fact, colchicine has been used for a very long time as a nonspecific treatment for crystal-induced arthropathy. For the past 50 years, colchicine, along with short-term use of rapid-acting NSAIDs and corticoids, has been considered the optimal oral medication for the symptomatic treatment of acute and pseudogout. The preventive and therapeutic effects of oral colchicine are outlined in the paper "Colchicine: its Mechanism of Action and Efficacy in Crystal-Induced Inflammation," Current Rheumatology Reports, 2008, 10:218-227. Furthermore, the same paper extensively describes the side effects of colchicine, including strong laxative effects, myelosuppression, neuromyopathies, and rhabdomyolysis, particularly in patients with renal failure, as well as the high mortality rate associated with overdose.

[0013] Therefore, colchicine has an exceptionally narrow therapeutic index. Consequently, for all these reasons, the use of colchicine remains limited despite its highly proven efficacy.

[0014] Furthermore, while it is known that inflammation in the joints, or other affected areas, can be treated by directly administering active substances, it has been found that the active substances escape from the joints relatively easily, thereby reducing the therapeutic effect.

[0015] Colchicine encapsulation for sustained release has been reported in different carriers, such as high molecular weight microspheres (Das, G. Set 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 is studied in the treatment of other conditions, such as restenosis after angioplasty or vascular injury, and on this occasion, an attempt was made to encapsulate colchicine in poly(lactic acid) / poly(ε-caprolactone) microspheres for local delivery of colchicine. In search of a treatment for the same lesion, namely restenosis, through intramural delivery, another composition containing biodegradable microcapsules containing colchicine has been described, as reported in Gradus-Pizlo Irmina et al: "Local delivery of biodegradable microcapsules containing colchicine or a colchicine analogue: effects on restenosis and implications of catheter-based drug delivery," Journal of The American College of Cardiology, vol. 26, no. 6, pages 1549-1557. Clearly, the therapeutic target is entirely different from that of the present invention. In addition, the results are not promising and point to toxicity risks. Indeed, signs of local toxicity have been observed in the muscular layer supplied by an artery to which uncontrolled microcapsules containing colchicine or a colchicine analogue were injected.

[0016] In addition, colchicine has been previously reported in U.S. Patent No. 5,747,060 for effects other than those indicated within the framework of this invention, specifically for its role in prolonging the duration of the anesthetic effect induced by local administration of anesthetics. Therefore, in Example 1 of the aforementioned document, colchicine is administered simultaneously with bupivacaine around the sciatic nerve in an immediate-release dosage form (i.e., added directly to an aqueous solution). Neither intra-articular injection nor the activity of colchicine in the treatment of inflammatory pain of the joint is described in the aforementioned document.

[0017] International Publication No. 2006 / 066419 discloses the same effects of colchicine as the prolongation of its anesthetic effect, namely the combination of a vanilloid receptor agonist with another molecule, sometimes colchicine. The examples disclose a composition comprising a mixture of resiniferatoxin and colchicine, which is injected intra-articularly for the treatment of capsulitis. The injection is for immediate release only, without attempting to control the local profile and systemic pharmacokinetics of colchicine or to prolong its therapeutic exposure.

[0018] The use of colchicine for the treatment of crystal-associated arthropathy is well established. However, currently, colchicine is only marketed in an immediate-release oral dosage form, and classically, the daily dose for the treatment of crystal-associated arthropathy is approximately 1 mg / day. The FDA-approved dose for the treatment of acute gouty redness is 1.2 mg of colchicine at the time of the first signs of redness, 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 first-line colchicine treatment recommended by EULAR (European Alliance of Associations for Rheumatology) for acute redness is a loading dose of 1 mg, followed by 0.5 mg one hour later (Richette, P. et al. 2016 updated EULAR evidence-based recommendations for the management of gout Ann. Rheum. Dis. 76, 29-42 (2017)). However, as described above, and as illustrated in more detail below, reaching a therapeutically effective topical dose of colchicine is hindered by low tolerance or high toxicity of orally administered colchicine, making drug prescriptions extremely complex.

[0019] Colchicine has recently been injected into the joint of Swiss albino mice 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 This study was published in "Tc coupling and in vivo biodistribution studies," DOI:10.1080 / 03639045.2021.1934865. 99m Tc(technetium)-ColNE(colchicine nanoemulsion)-5 and 99m Tc-Col (colchicine) solution ( 99m The in vivo distribution pattern of TcColS) has been studied. However, the foregoing disclosure is limited to observations of radiolabeled colchicine (which is therefore a different molecule from colchicine itself) and within a period of 24 hours. 99mLabeling with radionuclides such as 99mTc can strongly influence the in vivo distribution 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 aforementioned paper remains silent on the narrow therapeutic index described above, and the technical problem of its high specificity to colchicine, namely the maximum systemic concentration that should be avoided for toxic reasons. Consequently, the paper also remains silent on a microparticle system of targeted doses that can reach an effective local concentration to combat acute lesions without systemic toxicity. Specifically, Figure 3 of the aforementioned paper shows that ColNE-5, i.e., the "colchicine nanoemulsion system," appears to yield a 40% release of colchicine in less than 3 hours, which contradicts the achievement of a controlled systemic concentration of colchicine to avoid side effects, which is essential in the present invention. Achieving a release profile that does not involve such rapid release immediately after administration, also known as "burst release" as described below in this specification, could be harmful in terms of side effects and implies a rather unclear approach that could not be predicted from the aforementioned paper. In other words, neither a controlled-release colchicine profile nor an immediate-release colchicine dose that is harmful in terms of side effects, suitable for treatment in humans, and more specifically, effective in combination with anesthetics, for the treatment of crystal-associated or non-crystal-associated acute inflammatory arthritis, particularly for the treatment of non-crystal-associated acute acute arthritis such as rheumatoid arthritis, ankylosing spondylitis, juvenile arthritis, psoriatic arthritis, and lupus, nor for the treatment of attacks or redness of crystal-associated arthropathy such as gout, chondrocalcinosis, calcific tendinitis, and Milwaukee shoulder syndrome, is disclosed in the aforementioned paper.

[0020] Intravenous injection of colchicine is considered effective in treating acute gout attacks at doses of 2-3 mg or less 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 could be avoided with IV administration, severe toxicity was 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 to the authority to exclude the use of IV 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 IV colchicine injections further disappointed those skilled in the art, as reported in E. Niel et al., "Colchicine today," Joint Bone Spine 73 (2006) 672-678.

[0021] Therefore, it should be noted that none of the prior art documents mentioned above consider the provision of a pharmaceutical composition containing colchicine and an anesthetic suitable for intra-articular injection, which in particular removes the toxicity risk at the systemic and local levels. Summary of the Invention Problems to be Solved by the Invention

[0022] Therefore, there is still a need to develop new dosage forms, administration routes, and targeted dosages of colchicine for the treatment of crystalline-related inflammatory arthritis and non-crystalline-related inflammatory arthritis, both to provide analgesia and reduce inflammation immediately and throughout the duration of erythema, while removing side effects observed particularly during systemic administration, and to improve efficacy by optimizing the available dosage of colchicine, specifically by increasing the local concentration to extend the local duration of action at the painful site, and to protect joints, bones, and / or cartilage, which are particularly critical in a crisis.

[0023] Furthermore, there is still a need to obtain new means and methods for protecting joints, bones, and / or cartilage. Means for Solving the Problems

[0024] The present invention aims to meet these needs, thereby increasing the advantages of its action on reducing inflammation and pain in the treatment of crystalline-related acute inflammatory arthritis and non-crystalline-related acute inflammatory arthritis, limiting the level of any side effects, and protecting joints, bones, and / or cartilage. This means that colchicine targets its action on each component of inflammation and / or pain in crystalline-related acute inflammatory arthritis and non-crystalline-related acute inflammatory arthritis. Colchicine has also been proven to provide a protective effect on bones and cartilage, as exemplified in Examples 9 and 12.

[0025] One of the advantages of the present invention is a novel means of achieving a specific colchicine release profile with immediate or sustained release, which provides the best therapeutic effect locally, while at the same time avoiding potential systemic toxicity while providing analgesia and reducing inflammation over the entire period of immediate and persistent erythema, while complying with an appropriate ratio between the local or synovial concentration of colchicine and its systemic concentration. The co - administration of an anesthetic can actually quickly relieve pain, and the effect can last up to 72 hours.

[0026] Due to the reduction of side effects obtained by the administration of the pharmaceutical composition according to the present invention, it is even more specifically suitable for people suffering from chronic co - morbidities (hypertension, chronic kidney disease, diabetes, heart disease, infections, immunosuppression, etc.), which are quite common conditions in crystalline arthropathies (50% of gout patients have at least 3 co - morbidities). In fact, the management of patients with crystalline arthropathies having multiple co - morbidities still remains a challenge for physicians due to frequent and major contraindications for either colchicine, NSAIDs or corticosteroids. Compared with existing oral colchicine treatments, the present invention, in addition to avoiding gastrointestinal side effects, prevents the major toxicity risks for patients suffering from kidney or liver dysfunction or for patients receiving concomitant medication with CYP3A4 / PGP drug inhibitors, which is a fairly generalized drug therapy.

Brief Description of the Drawings

[0027] [Figure 1] Figure 1 represents the results of the inflammation score of the rat ankle joint for evaluating the effect of colchicine in the protection of bone and cartilage in an in - vivo model, as illustrated in Example 9. [Figure 2] Figure 2 represents the results of the inflammation score of the rat ankle joint for evaluating the effect of the combination according to the present invention in the protection of bone and cartilage in an in - vivo model, as illustrated in Example 12.

Modes for Carrying Out the Invention

[0028] Summary of the Invention According to a first aspect of this specification, a pharmaceutical composition suitable for intra-articular injection is provided, comprising an anesthetic and an immediate-release or controlled-release dosage form containing colchicine, wherein the anesthetic is partially or entirely in an immediate-release dosage form.

[0029] In one embodiment, a pharmaceutical composition suitable for intra-articular injection is provided herein, comprising an anesthetic and a controlled-release dosage form containing colchicine.

[0030] A pharmaceutical composition in powder form is provided, comprising an anesthetic and a colchicine-containing controlled-release dosage form, particularly an immediate-release dosage form having colchicine as defined herein below, and particularly the colchicine-containing controlled-release dosage form, which is in the form of fine particles, particularly fine particles including a polymer matrix, more specifically fine particles having an average particle size of 10 μm or more as determined by laser diffraction, and even more specifically the colchicine-containing controlled-release dosage form, wherein the anesthetic is particularly as defined herein and is in the form of an immediate-release dosage form, either partially or entirely.

[0031] In one embodiment, a pharmaceutical composition is provided in powder form comprising an anesthetic and a controlled-release dosage form containing colchicine, wherein the controlled-release dosage form containing colchicine is in the form of fine particles, particularly fine particles containing a polymer matrix, more specifically fine particles having an average particle size of 10 μm or more as determined by laser diffraction, and even more specifically fine particles as defined herein, and the anesthetic is as defined herein.

[0032] In this specification, within a separate compartment, -(i) an aqueous injection vehicle comprising optionally an immediate-release dosage form of an anesthetic agent identical to or different from the anesthetic agents present in (ii) below as defined herein, -(ii) A controlled-release dosage form or powder comprising colchicine as defined below in this specification, and an anesthetic as defined below in this specification. Further provided are kits or products comprising, optionally, excipients selected from the group consisting of tonicity enhancers, wetting agents, viscosity enhancers, density enhancers, and mixtures thereof, for preparing pharmaceutical compositions suitable for intra-articular injection.

[0033] According to the third main embodiment, in this specification, within a separate compartment, -(i) Aqueous injection vehicle and -(ii) A kit or product comprising a colchicine-containing immediate-release dosage form in a colchicine dose as defined below herein, or a colchicine-containing controlled-release dosage form as defined below herein, or a powder as defined below herein, and optionally an anesthetic, (i) and (ii) include at least one of them an anesthetic, and the anesthetic is in an immediate-release dosage form, A kit or manufactured product is provided that optionally includes excipients selected from the group consisting of tonicity enhancers, wetting agents, viscosity enhancers, density enhancers, and mixtures thereof, for preparing pharmaceutical compositions suitable for intra-articular injection.

[0034] This specification provides a pharmaceutical composition obtained by mixing two compartments of the pharmaceutical composition according to the present invention or the kit defined above, for use in the treatment of crystal-associated acute inflammatory arthritis and non-crystal-associated acute inflammatory arthritis, particularly crystal-associated arthropathy or erythema or acute type tendinitis and capsulitis, for use in the treatment of crystal-associated acute inflammatory arthritis and non-crystal-associated acute inflammatory arthritis, particularly crystal-associated arthropathy or erythema or acute type tendinitis and capsulitis, wherein the dissolution rate of colchicine is 80% (w / w) for more than 1 day, particularly more than 15 days, as measured according to the following protocol.

[0035] A controlled-release formulation containing a fixed amount of 20 mg of colchicine is suspended in 50 mL of phosphate-buffered saline (10 mM, pH 7.4) under stirring at 37°C. The supernatant of the sample collected periodically throughout the entire release period is then analyzed using 350 nm UV light. Here, colchicine is present in a sterile and injectable dosage form, particularly at concentrations ranging from 0.2 to 100 μg per 1 ml of suspension, especially in the range of 2 to 50 μg. The anesthetic is present in a sterile and injectable dosage form, particularly at concentrations ranging from 1 to 120 mg per ml of suspension, especially from 1 to 10 mg, and the dissolution rate of the anesthetic is 80% (w / w) in up to 3 days, as measured according to the following protocol.

[0036] A fixed amount of 20 mg of the anesthetic dosage form is suspended in 20 mL of phosphate-buffered saline (10 mM, pH 7.4) under agitation at 37°C. Then, 1 mL of the medium is periodically taken out throughout the entire release period, filtered through a 0.45 μm PTFE filter, and the filtered sample is analyzed by HPLC. Here, the pharmaceutical composition has a volume ranging from 0.1 ml to 5 ml.

[0037] In one embodiment, the pharmaceutical composition defined above and detailed below herein is for use in the treatment of crystal-associated acute inflammatory arthritis and non-crystal-associated acute inflammatory arthritis, particularly crystal-associated arthropathy or redness or acute type tendinitis and capsulitis, by intra-articular injection of the pharmaceutical composition into the joint, which provides particularly analgesia and inflammation relief, more specifically immediately and over the entire duration of the redness, or the pharmaceutical composition defined above and detailed below herein. A pharmaceutical composition is provided, obtained by mixing two compartments of a kit, wherein the time required to release 80% by weight of colchicine is more than one day, and may reach up to 15 days, the colchicine is present in a sterile and injectable dosage form, particularly at a concentration in the range of 2.5 to 2500 μg per 1 ml of suspension, the anesthetic is present in a sterile and injectable dosage form, particularly at a concentration in the range of 0.05 to 120 mg per 1 ml of suspension, 80% of the anesthetic is released in up to three days, and the pharmaceutical composition has a volume in the range of 0.1 ml to 5 ml.

[0038] Pharmaceutical compositions suitable for intra-articular injection, particularly in the form of suspensions, as described below herein, are effective in treating crystal-associated acute inflammatory arthritis and non-crystal-associated acute inflammatory arthritis with minimal long-term side effects, and are particularly effective in treating non-crystal-associated acute arthritis such as rheumatoid arthritis, ankylosing spondylitis, juvenile arthritis, psoriatic arthritis, and lupus, or in treating attacks or redness of crystal-associated arthropathy such as gout, chondrocalcinosis, calcific tendinitis, and Milwaukee shoulder syndrome.

[0039] The pharmaceutical composition suitable for intra-articular injection is suitable for local administration by injection at or near the site of pain.

[0040] Detailed description of the invention As is evident from the background paragraph above, the prescription of colchicine is delicate, as it is currently only available in oral form and has been observed to have high-risk toxicity, including gastrointestinal symptoms and neuromuscular complications. Furthermore, risks associated with interactions with other active ingredients have been reported. Again, toxicity constraints have prevented local injection for decades.

[0041] In fact, effective topical doses of colchicine are recommended at 0.015 mg / kg to 0.030 mg / kg, with the toxicity limit reached at 0.1 mg / kg and the lethal dose at 0.8 mg / kg (E. Niel et al, "Colchicine Today", Joint Bone Spine 73 (2006) 672-678). Therefore, it can be concluded that the narrow therapeutic margin for colchicine is a source of concern for prescribing physicians.

[0042] The inventors have found that intra-articular injection of the pharmaceutical composition according to the present invention, particularly in the form of a suspension for immediate or controlled release of colchicine, has at least equivalent, and even higher, efficiency compared to oral colchicine or intra-articular corticosteroid treatment in joint pain disorders. It provides better analgesia immediately upon administration. In one embodiment of the present invention, when colchicine is present in a sterile and injectable dosage form, particularly in a concentration ranging from 2.5 to 2500 μg or 0.2 to 100 μg per ml of suspension, more specifically in the range of 2 to 50 μg, the time required to release 80% by weight of colchicine, particularly from a controlled-release dosage form containing it, more specifically from microparticles, is more than 1 day and may reach 15 days, and the time required to release 80% of the anesthetic, particularly ropivacaine, is less than 3 days, which is present in a sterile and injectable dosage form, particularly in a concentration ranging from 0.05 to 120 mg, particularly 1 to 120 mg, more specifically 1 to 10 mg per ml of suspension.

[0043] The diseases for which the aforementioned pharmaceutical composition is specifically intended are very severe. Therefore, it is important to have a perfectly tailored treatment to achieve the most appropriate dosage.

[0044] The therapeutic use or method according to the present invention also has the advantage of reducing the significant toxicity risk associated with drug interactions with colchicine, when administered via systemic routes, and particularly in elderly patients or patients with renal or hepatic failure as described below herein.

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

[0046] definition As used herein, the term “patient” means either an animal, such as a valuable animal for breeding, enterprise or preservation purposes, or preferably a human or a human child, that is suffering from or may suffer from one or more of the diseases and conditions described herein.

[0047] In particular, as used in this application, the term “patient” refers to a non-human mammal such as a rodent, cat, dog, or primate, or a mammal including a human, preferably a human, and also extends to birds.

[0048] Identifying patients requiring treatment for the diseases and conditions described herein is well within the capabilities and knowledge of those skilled in the art. Veterinarians or physicians in the art can readily identify patients requiring such treatment by using clinical trials, physical examinations, medical / family history, or biological and diagnostic tests.

[0049] In the context of the present invention, the terms “to treat” or “to cure” as used herein mean to reverse, alleviate, or inhibit the progression of non-crystalline acute inflammatory arthritis such as rheumatoid arthritis, ankylosing spondylitis, juvenile arthritis, psoriatic arthritis, and lupus, or to treat crystal-related acute inflammatory arthritis, particularly attacks or redness of crystal-related arthropathy such as gout, chondrocalcinosis, calcific tendinitis, and Milwaukee shoulder syndrome, as well as acute forms of tendinitis and capsulitis.

[0050] As used herein, “effective amount” means the amount of the compound of the present invention that is effective in reducing, eliminating, treating, or controlling the symptoms of the diseases and conditions described herein, namely, crystal-associated acute inflammatory arthritis and amorphous acute inflammatory arthritis, particularly amorphous acute arthritis such as rheumatoid arthritis, ankylosing spondylitis, juvenile arthritis, psoriatic arthritis, and lupus, or in treating the attacks or redness of crystal-associated arthropathy such as gout, chondrocalcinosis, calcific tendinitis, and Milwaukee shoulder syndrome, as well as acute forms of tendinitis and capsulitis. The term “control” is intended to refer to all processes that may slow, interrupt, block, or halt the progression of the diseases and conditions described herein, but not necessarily indicate the complete elimination of the symptoms of all diseases and conditions.

[0051] The term "therapeutic dose" refers to the concentration of a compound that is effective in treating crystal-associated acute inflammatory arthritis and non-crystal-associated acute inflammatory arthritis, particularly non-crystal-associated acute arthritis such as rheumatoid arthritis, ankylosing spondylitis, juvenile arthritis, psoriatic arthritis, and lupus, or in treating attacks or redness of crystal-associated arthropathy, for example, if administered after the onset of inflammatory pain, leads to a reduction in inflammatory pain after examination.

[0052] As used herein, the term “pharmaceutically acceptable” means a compound, material, excipient, composition, or dosage form that is within the bounds of lawful medical judgment, suitable for contact with human and animal tissues without complications of excessive toxicity, irritation, allergic reactions, or other problems, in proportion to a reasonable benefit / risk ratio.

[0053] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" may refer to any pharmaceutically acceptable excipient, such as a non-toxic carrier, adjuvant, or vehicle, that does not impair the pharmacological activity of the compound being formulated.

[0054] Within the framework of this invention, the term “painful site” or “pain site” means the joint portion that causes pain and in which the product can be injected. This may be the knee joint, hip joint, metacarpophalangeal joint, shoulder joint, wrist joint, elbow joint, metatarsophalangeal joint, ankle joint, spinal joint, and metatarsophalangeal joint.

[0055] The terms “controlled-release composition” or “controlled-release microparticles” mean a composition or microparticles that release a specified amount of an active ingredient into the body over a specific period of time (i.e., enable a specific pharmacokinetic profile). The term “controlled-release” encompasses all types of release that are modified compared to immediate release. In other words, the term “controlled-release” is equivalent to “release regulation” and includes extended release, delayed release, and pulsed release as defined herein below.

[0056] "Extended release," "prolonged release," and "sustained release" are considered equivalent within the framework of this invention. This type of release means that the release is prolonged over time compared to immediate release; that is, the active ingredient is released slowly over time, reducing the frequency of drug intake for the patient. In other words, the active ingredient is generally released gradually over a specific period, also aiming to reduce side effects by lowering the maximum concentration.

[0057] The term "drug load" refers to the mass ratio of the drug in a microparticle to the mass of the microparticle.

[0058] The term "average particle size" or D50 refers to the particle diameter in microns, which divides the particle volume distribution into an upper and lower half of this diameter.

[0059] The term "D10 = x μm," when used primarily in examples, means that 10% of the particles have a size of x μm or less.

[0060] The term "D90=yμm," when primarily used in examples, means that 90% of the particles have a size of yμm or less. Controlled release, or release regulation, can naturally result from a combination of immediate release and controlled release.

[0061] It should be understood that the aspects and embodiments of the Disclosure described herein include the terms “including,” “having,” and “comprising.” It should be understood that each word “have” and “comprise,” or each variation such as “has,” “having,” “comprises,” or “comprising,” implies the inclusion of a specified element (such as a step of a composition or method), but does not imply the exclusion of any other element. The term “comprising” implies the inclusion of a specified element and the exclusion of any additional element. It should be understood that different embodiments of the Disclosure that use the term “including” or its equivalents cover embodiments in which this term is replaced by “comprising” or “essentially consisting of.”

[0062] A "dissolution profile" refers to an in vitro study that reports a plot of the cumulative amount of the released active ingredient as a function of time. Dissolution data is obtained from the conditions under which the measurement is performed and the conditions described in the text.

[0063] Colchicine Colchicine is an alkaloid extracted from the corm of the meadow saffron (or autumn crocus) (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).

[0064] [ka]

[0065] Colchicine may exist in enantiomerized racemic forms. All of the aforementioned forms are included within the scope of the present invention.

[0066] Furthermore, they can exist in various crystalline forms depending on the solvent used to obtain them. Among the possible solvents are chloroform, dichloromethane, ethyl acetate, benzene, or any other suitable solvent. Moreover, all such crystalline forms form part of the present invention.

[0067] It is primarily known as a gout inhibitor and anti-inflammatory agent, mainly through its tubulin interaction activity. It is administered orally, but intravenous administration has also been attempted and subsequently discontinued due to excessive toxicity.

[0068] Anesthetic The anesthetic agent may be selected from lidocaine, ropivacaine, bupivacaine, levobupivacaine, capsaicin, mepivacaine, prilocaine, pharmaceutically acceptable salts thereof, and mixtures thereof.

[0069] In one embodiment, the anesthetic agent is selected from lidocaine, bupivacaine, ropivacaine, and mepivacaine, pharmaceutically acceptable salts thereof, and mixtures thereof.

[0070] In one embodiment, the anesthetic agent is selected from lidocaine, ropivacaine, bupivacaine, levobupivacaine, capsaicin, mepivacaine, prilocaine, pharmaceutically acceptable salts thereof, and mixtures thereof, particularly from lidocaine, bupivacaine, ropivacaine, and mepivacaine, more specifically from ropivacaine and bupivacaine, and even more specifically from ropivacaine.

[0071] The anesthetic agent may be in a partially or entirely immediate-release dosage form, or in a partially or entirely controlled-release dosage form, which is different from the controlled-release dosage form containing colchicine, or is contained therein, for example, in the form of polymer matrix-containing microparticles, in the form of dehydrated hydrogels, in the form of multivesicular liposomes, or in situ-forming depots, as defined below herein, particularly with respect to colchicine microparticles.

[0072] Therefore, this specification provides a pharmaceutical composition suitable for intra-articular injection, comprising an anesthetic and an immediate-release or controlled-release dosage form containing colchicine, wherein the anesthetic is in a partially or entirely immediate-release dosage form, particularly in a entirely immediate-release dosage form.

[0073] In other words, anesthetics may be formulated to achieve immediate release, sustained release, or a mixture of immediate and sustained release.

[0074] The presence of the anesthetic agent provides immediate pain relief immediately after intra-articular injection of the pharmaceutical composition. This can improve patient comfort. When in a sustained-release formulation, the pain relief can be prolonged. In one embodiment, the anesthetic effect can be prolonged for one, two, or three days, and in particular for one day.

[0075] Various embodiments of the formulation are described in detail in the following paragraph, “Pharmaceutical Compositions and Kits,” in this specification.

[0076] Therapeutic use and methods In one embodiment, a pharmaceutical composition suitable for intra-articular injection as described below herein delivers colchicine in a dose such that the concentration level of colchicine at the treated joint site exceeds the systemic dose classically obtained after oral administration, i.e., more than 5 nM (2 ng / mL), and the systemic concentration level remains below 15 nM (6 ng / mL), and in an immediate-release or controlled-release manner (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)).

[0077] According to one embodiment, the pharmaceutical composition for use is further characterized by the selection of crystalline and amorphous acute inflammatory arthritis from amorphous acute arthritis such as rheumatoid arthritis, ankylosing spondylitis, juvenile arthritis, psoriatic arthritis, lupus, and more specifically from crystalline attacks or redness or acute forms of tendinitis and capsulitis of arthropathy selected from gout, chondrocalcinosis, calcific tendinitis, and Milwaukee shoulder syndrome.

[0078] According to one embodiment, the pharmaceutical composition defined above for use in accordance with the present invention is for the protection of 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, prevented or halted. Examples 9 and 12 below illustrate such effects in particular.

[0079] According to another embodiment, the pharmaceutical composition of the present invention is further characterized by being effective in maintaining a systemic concentration of colchicine after 12 hours of less than 5 ng / ml, particularly less than 1 or 2 ng / ml, more specifically less than 0.5 or 1 ng / ml, and even more specifically less than 0.1 ng / ml, and in maintaining a synovial fluid concentration of colchicine that is greater than 0.5 ng / ml, for example greater than 1 ng / ml, particularly between 0.5 or 1 and 500 ng / ml, more specifically between 0.5 or 1 and 250 ng / ml, more specifically between 0.5 or 1 and 200 ng / ml, for example between 0.5 or 1 and 100 ng / ml, and even more specifically between 0.5 or 1 and 50 ng / ml.

[0080] In another embodiment, the pharmaceutical composition of the present invention is effective in maintaining a synovial fluid concentration of an anesthetic, particularly ropivacaine, between 0.05 and 50 mg / ml, particularly between 0.05 and 25 mg / ml, more specifically between 0.05 and 10 mg / ml, for example between 0.05 and 3 mg / ml, and is further characterized in that the synovial fluid concentration can be maintained for 1 hour, 4 hours, 8 hours, 1 day, 1.5 days, 2 days, or 3 days.

[0081] A specific release profile that enables both an acceptable systemic concentration of colchicine and, simultaneously, a local concentration of colchicine suitable for achieving appropriate therapeutic effects—which represents a very essential part of the present invention—has never been obtained before.

[0082] According to one embodiment, colchicine is in an immediate-release dosage form, and through the maximum dose of colchicine, the inventors have found a means that is remarkably well-suited to treating patients while avoiding side effects.

[0083] In such embodiments, colchicine in powder form can be dissolved in a suitable medium to form a sterile, injectable suspension, and the anesthetic is in an immediate-release dosage form overall, which is also directly solubilized in the suspension. The suspension can be packaged in vials, pre-filled syringes, or medical devices. Alternatively, in one embodiment, in a separate compartment, -(i) Aqueous injection vehicle and -(ii) A kit or product comprising a colchicine immediate-release dosage form in a colchicine dose as defined below herein, (i) and (ii) include at least one of them an anesthetic, and the anesthetic is in an immediate-release dosage form, Further provided are kits or products that optionally include excipients selected from the group consisting of tonicity enhancers, wetting agents, viscosity enhancers, density enhancers, and mixtures thereof, for preparing pharmaceutical compositions suitable for intra-articular injection.

[0084] In one embodiment, the first vial contains an aqueous injection vehicle, and the second vial contains an immediate-release dosage form particularly containing colchicine as defined above, or an immediate-release dosage form of a powder and anesthetic as defined below herein.

[0085] In one embodiment, the specification provides a pharmaceutical composition suitable for intra-articular injection, comprising an anesthetic and an immediate-release dosage form containing colchicine, wherein the anesthetic is partially or entirely in an immediate-release dosage form, and the colchicine concentration is less than 125 μg / ml, particularly in the range of 0.02 to 125 μg / ml, more specifically in the range of 0.02 to 75 μg / ml.

[0086] According to another embodiment, colchicine is in a sustained-release dosage form, and through a specific ratio between the topical or synovial fluid concentration of colchicine and the systemic concentration of colchicine obtained in the pharmaceutical composition according to the above embodiment of the present invention, where colchicine is in a sustained-release dosage form, i.e., has a specific in vitro dissolution rate and / or in vivo release rate, the inventors have found a means that is well suited to treating patients while avoiding side effects.

[0087] Furthermore, the inventors surprisingly found that when colchicine was injected in a sustained-release form, the maximum effective local concentration was considerably lower than that required to achieve an effect with the immediate-release form, sometimes up to 10 times lower.

[0088] According to one particular embodiment, the ratio between the local or synovial fluid concentration of colchicine obtained after injection of the pharmaceutical composition according to the present invention into a joint and the systemic concentration of colchicine may be in the range of 100 to 2000 in humans, as described / referred to below: 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 AJ, Lufkin J, Hauben J, Johnson JR, Bodick N. Synovial and systemic pharmacokinetics(PK) of triamcinolone actonide(TA) following intra-articular(IA) injection of an extended-release microsphere-based. To determine the aforementioned local and systemic concentrations of colchicine, those skilled in the art may use any known method. For example, LC-MS analysis may be used.

[0089] Therefore, in this specification, for use in the treatment of crystal-associated acute inflammatory arthritis and non-crystal-associated acute inflammatory arthritis, particularly crystal-associated arthropathy or redness or acute type tendinitis and capsulitis, by intra-articular injection of the pharmaceutical composition into the joint, which provides particularly analgesia and inflammation relief, more specifically immediately and over the entire period of persistent redness, the pharmaceutical composition according to the present invention, which is further detailed below herein, or a pharmaceutical composition obtained by mixing two compartments of the kit further detailed below in the specification, wherein the dissolution rate of colchicine is as follows A pharmaceutical composition is provided, wherein, as measured according to the protocol described herein, colchicine is present in a sterile and injectable dosage form, particularly in a concentration ranging from 2.5 to 2500 μg or from 0.2 to 100 μg, particularly from 2 to 50 μg per ml of suspension, and the anesthetic is present in a sterile and injectable dosage form, particularly in a concentration ranging from 0.05 to 120 mg, particularly from 1 to 120 mg, more specifically from 1 to 10 mg per ml of suspension, and the dissolution rate of the anesthetic is 80% (w / w) at a maximum of 3 days, as measured according to the protocol described below herein, and the pharmaceutical composition has a volume ranging from 0.1 ml to 5 ml.

[0090] Examples of the specific control of colchicine release achieved within the framework of the present invention can also be illustrated through the in vitro lysis profiles performed in Examples 1-3. Examples of the specific control of anesthetic release, particularly ropivacaine, achieved within the framework of the present invention can also be illustrated through the in vitro lysis profiles performed in Examples 4, 5, 7 and 10.

[0091] According to one embodiment, the dissolution medium that may be used to carry out such a dissolution test may be 10 mM (pH 7.4) phosphate-buffered saline.

[0092] According to one embodiment, the rotational speed may be in the range of 50 to 200, particularly 60 to 100 rpm. This stirring can be achieved by a shaking incubator having horizontal motion in particular.

[0093] According to one embodiment, the dissolution of colchicine is measured at various intervals, for example, 1 day, 2 days, 3 days, 5 days, 7 days, 8 days, 9 days, 10 days, and 13 days, by, for example, UV analysis using a UV spectrophotometer at 350 nm.

[0094] Therefore, the measurement conditions for the colchicine solubility profile are described below in this specification.

[0095] Within the framework of this invention, the protocols used are as follows:

[0096] A fixed amount of 20 mg of colchicine-containing controlled-release formulation is suspended in 50 mL of phosphate-buffered saline (10 mM, pH 7.4) optionally containing 0.02% sodium azide. The suspension is maintained at 37°C using a horizontal shaker or a magnetic stirrer, and the supernatant of collected samples is periodically analyzed at 350 nm by UV light throughout the entire release period.

[0097] The conditions for measuring the solubility profile of anesthetic agents are described below in this specification.

[0098] Within the framework of this invention, the protocols used are as follows:

[0099] A fixed amount of 20 mg of the anesthetic dosage form is suspended in 20 mL of phosphate-buffered saline (10 mM, pH 7.4), with or without the use of an ultrasonic bath, and maintained at 37°C in a horizontal shaker or using a magnetic stirrer. Then, 1 mL of the medium is periodically withdrawn throughout the entire duration of release and filtered through a 0.45 μm PTFE filter (Acrodisc wwPTFE), and the filtered sample is then analyzed by HPLC.

[0100] For example, a dissolution test of colchicine microparticles may be performed according to the method detailed below in this specification.

[0101] A fixed amount of 20 mg of fine particles is suspended in 50 mL of phosphate-buffered saline (10 mM, pH 7.4) containing 0.02% sodium azide, and the mixture is kept in a horizontal shaker at 37°C. At various intervals, 3 mL of the medium is taken out and centrifuged at 4000 rpm for 3 minutes. The supernatant is analyzed by 350 nm UV light. Immediately after UV analysis, the sample is returned to the dissolution flask.

[0102] As described above, immediate-release or controlled-release formulations are administered topically to treat joint pain and inflammation. Topical administration of the formulation can be performed by injection into the intra-articular or peri-articular space near or at the site of pain in the patient, including the metatarsophalangeal, metacarpophalangeal, knee, shoulder, wrist, elbow, ankle, hip, spinal, and metatarsophalangeal joints. The metatarsal is the anterior part of the foot located between the hindfoot and forefoot. It is composed of the cuboid, navicular, and three cuneiform bones. The transverse tarsal and tarsometatarsal joints connect the metatarsal to the hindfoot and forefoot, respectively. The metatarsal is complex and a compound area where observed edema and inflammation are generally diffuse.

[0103] In one embodiment, the present invention is dedicated to the treatment of joint pain, particularly acute inflammatory arthritis associated with crystals and acute inflammatory arthritis associated with non-crystals, more specifically selected from acute inflammatory arthritis associated with non-crystals such as rheumatoid arthritis, ankylosing spondylitis, juvenile arthritis, psoriatic arthritis, and lupus, or dedicated to the treatment of attacks or redness of crystal-associated arthropathy such as gout, chondrocalcinosis, calcific tendinitis, and Milwaukee shoulder syndrome, as well as acute forms of tendinitis and capsulitis.

[0104] In one embodiment, a composition suitable for intra-articular injection is specifically for the treatment of gout attacks.

[0105] In one embodiment, a composition suitable for intra-articular injection is specifically for the treatment of chondrocalcinosis.

[0106] In one embodiment, a composition suitable for intra-articular injection is specifically for the treatment of acute and chronic calcific tendinitis.

[0107] In one embodiment, a composition suitable for intra-articular injection is specifically for the treatment of Milwaukee shoulder syndrome.

[0108] In one embodiment, a composition suitable for intra-articular injection is specifically for the treatment of tendinitis.

[0109] In one embodiment, a composition suitable for intra-articular injection is specifically for the treatment of capsulitis.

[0110] When colchicine is in a sustained-release dosage form, administration may be carried out by a single injection or by a series of injections, provided that the time required to release 80% by weight of colchicine in the microparticles is greater than 1 day and may reach 15 days, particularly between 1.5 and 15 days, and the colchicine is present in a sterile and injectable dosage form, particularly in concentrations ranging from 2.5 to 2500 μg or 0.2 to 100 μg, particularly 2 to 50 μg per ml of suspension, and the anesthetic, particularly ropivacaine, is present in a sterile and injectable dosage form, particularly in concentrations ranging from 0.05 to 120 mg, particularly 1 to 120 mg, particularly 1 to 10 mg per ml of suspension, with 80% of the anesthetic being released over a maximum of 3 days, and the pharmaceutical composition has a volume ranging from 0.1 ml to 5 ml. In other words, a single or sequential injection, preferably a single injection, delivers colchicine topically in doses ranging from 0.02 to 12500 μg, particularly in the ranges of 0.02–1250 μg, 0.02–750 μg, and 0.02–500 μg. As described above, the pharmaceutical composition aims to achieve the targeted therapeutic effect and avoid side effects, particularly reducing the risk of adverse effects on local tissues, such as damage to articular cartilage and tendons, and more specifically, reducing the risk of adverse effects on local tissues at colchicine doses exceeding the aforementioned upper limits.

[0111] In one embodiment, the injection is administered multiple times (two, three, four, or more times). In this embodiment, each injection is administered after a suitable period of time has elapsed since the previous injection. This suitable period may be, for example, two weeks, one month, two months, three months, four months, five months, six months, one year, or longer.

[0112] In one embodiment, colchicine is present in a sterile and injectable dosage form, particularly in concentrations ranging from 2.5 to 2500 μg per 1 ml of suspension, especially 2.5 to 1500 μg, especially 2.5 to 1000 μg, more specifically 2.5 to 500 μg, even more specifically 2.5 to 250 μg, or 0.2 to 100 μg, particularly 2 to 50 μg.

[0113] In one embodiment, the anesthetic agent is present in a sterile and injectable dosage form, particularly in concentrations ranging from 0.05 to 120 mg, especially 0.05 to 60 mg, more specifically 0.05 to 20 mg, for example 1 to 120 mg, and especially 1 to 10 mg per ml of suspension.

[0114] In certain embodiments, the same pharmaceutical composition, particularly in the form of a suspension, can be used for intra-articular injection into any painful joint. However, the amount of the pharmaceutical composition injected can be adapted to the target joint. This is one of the advantages of the present invention, as a single concentration can be used to provide adapted amounts of colchicine and anesthetic for each application site by adapting the corresponding required amount.

[0115] In one embodiment, the injection may be administered simultaneously to two or more different painful joints.

[0116] For example, the volume of the pharmaceutical composition according to the present invention, particularly in the form of a suspension, which can be injected into the shoulder, may vary between 2 and 5 ml.

[0117] The volume of the pharmaceutical composition according to the present invention, which can be injected into the metatarsophalangeal joints, for example, the toes, and is particularly in the form of a suspension, may vary between 0.1 and 0.5 ml, and is typically 0.25 ml.

[0118] The volume of the pharmaceutical composition according to the present invention, which can be injected into the metacarpophalangeal joints, for example, the fingers, and is particularly in the form of a suspension, may vary between 0.1 and 0.5 ml, and is typically 0.25 ml.

[0119] The volume of the pharmaceutical composition according to the present invention, which can be injected into the spinal joints and is particularly in the form of a suspension, may vary between 1 and 2 ml.

[0120] The volume of the pharmaceutical composition according to the present invention, particularly in the form of a suspension, which can be injected into the metatarsophalangeal joint, may vary between 0.1 and 1 ml.

[0121] The volume of the pharmaceutical composition according to the present invention, which can be injected into the knee and is particularly in the form of a suspension, may vary between 2 and 5 ml.

[0122] The volume of the pharmaceutical composition according to the present invention, which can be injected into the wrist and is particularly in the form of a suspension, may vary between 0.5 and 1 ml.

[0123] The volume of the pharmaceutical composition according to the present invention, which can be injected into the elbow and is particularly in the form of a suspension, may vary between 2 and 5 ml.

[0124] The volume of the pharmaceutical composition according to the present invention, which can be injected into the ankle and is particularly in the form of a suspension, may vary between 1 and 3 ml.

[0125] The volume of the pharmaceutical composition according to the present invention, which can be injected into the groin and is particularly in the form of a suspension, may vary between 2 and 5 ml.

[0126] In one embodiment, the pharmaceutical composition according to the present invention, particularly in the form of a suspension, may be characterized by its volume, which may be adapted to a joint, namely, in the range of 2-5 ml for the shoulder, 1-2 ml for the spinal 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.

[0127] Furthermore, it should be understood that the specific dosage and treatment regimen for any particular patient depends on a variety of factors, including age, weight, overall health, sex, diet, timing of administration, drug combinations, and the judgment of the treating physician and the severity of the specific disease being treated.

[0128] In one embodiment, controlled release is suitable for delivering a colchicine maximal concentration (Cmax) in the range of 5 nM (2 ng / mL) to 5 μM (2 μg / mL) to the joint.

[0129] According to a preferred embodiment, when colchicine is in a sustained-release dosage form, injection of the pharmaceutical composition of the present invention allows for a systemic concentration of colchicine 12 hours after intra-articular injection to reach 5 ng / mL or less, particularly less than 1 or 2 ng / mL, more specifically less than 0.5 or 1 ng / mL, and even more specifically less than 0.1 ng / mL.

[0130] In addition, injection of the controlled-release pharmaceutical composition according to the present invention can achieve a synovial fluid concentration of colchicine 12 hours after intra-articular injection of greater than 0.5 ng / mL, for example greater than 1 ng / mL, particularly 0.5 or 1 to 500 ng / mL, more specifically 0.5 or 1 to 250 ng / mL, more specifically 0.5 or 1 to 200 ng / mL, for example 0.5 or 1 to 100 ng / mL, and even more specifically 0.5 or 1 to 50 ng / mL.

[0131] The dose required for injection into a painful joint may depend on the type of painful joint, particularly its size. Table 1a below summarizes typical doses of colchicine that may be incorporated within the framework of this invention.

[0132] The volume corresponds to the total volume of the composition suitable for injection, i.e., particularly in the form of a suspension.

[0133] [Table 1]

[0134] Therefore, according to one embodiment, for joints with a volume in the range of 0.1 to 0.5 ml, the dose of colchicine may be in the range of 0.2 to 25 μg; for joints with a volume in the range of 0.5 to 1 ml or 0.1 to 1 ml, the dose of colchicine may be in the range of 0.2 to 50 μg; for joints with a volume in the range of 1 to 2 ml or 1 to 3 ml, the dose of colchicine may be in the range of 2 to 150 μg; and for joints with a volume in the range of 2 to 5 ml, the dose of colchicine may be in the range of 4 to 250 μg.

[0135] As far as the anesthetic is concerned, it may be preferable that the local concentration of the anesthetic, particularly ropivacaine, be reached immediately after injection at a concentration of 0.05–50 mg / ml, especially 0.05–25 mg / ml, and more preferably 0.05–10 mg / ml, for example, 0.05–3 mg / ml, and that local concentration may last for 4 hours, 8 hours, 1 day, 1.5 days, 2 days, or 3 days.

[0136] The dose required for injection into a painful joint may depend on the type of painful joint, particularly its size. Table 1b below summarizes typical doses of anesthetics, especially ropivacaine, that may be incorporated within the framework of this invention.

[0137] [Table 2]

[0138] Therefore, according to one embodiment, for a joint with a volume in the range of 0.1 to 0.5 ml, the dose of the anesthetic may be in the range of 0.1 to 5 mg; for a joint with a volume in the range of 0.5 to 1 ml or 0.1 to 1 ml, the dose of the anesthetic may be in the range of 0.1 to 10 mg; for a joint with a volume in the range of 1 to 2 ml or 1 to 3 ml, the dose of the anesthetic may be in the range of 1 to 30 mg; and for a joint with a volume in the range of 2 to 5 ml, the dose of the anesthetic may be in the range of 2 to 50 mg.

[0139] In one embodiment, a pharmaceutical composition according to the present invention, particularly in the form of a suspension, administered by a single intra-articular injection, and specifically for the treatment of acute crystalline or non-crystalline inflammatory arthritis or acute tendinitis and capsulitis, comprises, per single injection, 0.25 to 1250 μg or 0.02 to 50 μg, for example 0.2 to 25 μg of colchicine and 0.005 to 60 mg or 0.1 to 60 mg, particularly 0.1 to 5 mg of an anesthetic, particularly ropivacaine, for a small joint selected from the metatarsophalangeal or metacarpophalangeal joints.

[0140] In another embodiment, a pharmaceutical composition according to the present invention, particularly in the form of a suspension, administered in a single intra-articular injection, and specifically for the treatment of acute crystalline or non-crystalline inflammatory arthritis or acute tendinitis and capsulitis, comprises, for the wrist joint, 1.25 to 2500 μg or 0.1 to 100 μg, particularly 1 to 50 μg of colchicine per single injection and 0.025 to 120 mg or 0.5 to 120 mg, particularly 0.5 to 10 mg of an anesthetic, particularly ropivacaine.

[0141] In another embodiment, a pharmaceutical composition according to the present invention, particularly in the form of a suspension, administered in a single intra-articular injection, and specifically for the treatment of acute crystalline or non-crystalline inflammatory arthritis or acute tendinitis and capsulitis, comprises, for the metatarsophalangeal joint, 0.25 to 2500 μg or 0.02 μg to 100 μg, particularly 0.2 μg to 50 μg of colchicine per single injection and 0.005 to 120 mg or 0.1 to 120 mg, particularly 0.1 to 10 mg of an anesthetic, particularly ropivacaine.

[0142] In another embodiment, a pharmaceutical composition according to the present invention, particularly in the form of a suspension, administered in a single intra-articular injection, and specifically for the treatment of acute crystalline or non-crystalline inflammatory arthritis or acute tendinitis and capsulitis, comprises, for the ankle joint, 2.5 to 7500 μg or 0.2 to 300 μg, particularly 2 to 150 μg of colchicine and 0.05 to 360 mg or 1 to 360 mg, particularly 1 to 30 mg of an anesthetic, particularly ropivacaine, per single injection, or for the spinal joint, 2.5 to 5000 μg or 0.2 to 200 μg, particularly 2 to 100 μg of colchicine and 0.05 to 240 mg or 1 to 240 mg, particularly 1 to 20 mg of an anesthetic, particularly ropivacaine, per single injection.

[0143] In another embodiment, a pharmaceutical composition according to the present invention, particularly in the form of a suspension, administered in a single intra-articular injection, and specifically for the treatment of acute crystalline or non-crystalline inflammatory arthritis or acute tendinitis and capsulitis, comprises, per single injection, 5 to 12,500 μg or 0.4 to 500 μg, particularly 4 to 250 μg of colchicine and 0.1 to 600 mg or 2 to 600 mg, particularly 2 to 50 mg of an anesthetic, particularly ropivacaine, for a joint selected from the knee, hip, shoulder, and elbow joints.

[0144] According to one embodiment, a pharmaceutical composition according to the present invention, particularly in the form of a suspension, administered in a single intra-articular injection, and specifically for the treatment of acute crystalline or amorphous inflammatory arthritis or acute tendinitis and capsulitis, comprises 2.5 to 2500 μg / ml, particularly 2.5 to 250 μg / ml of colchicine and 0.05 to 120 mg / ml, particularly 0.05 to 60 mg / ml of an anesthetic, particularly ropivacaine. In one embodiment, a pharmaceutical composition according to the present invention, particularly in the form of a suspension, may, for example, comprise 2.5 to 1000 μg / ml, particularly 2.5 to 500 μg / ml, more specifically 2.5 to 250 μg / ml of colchicine and 0.05 to 120 mg / ml, particularly 0.05 to 60 mg / ml of an anesthetic, particularly ropivacaine. In one embodiment, the pharmaceutical composition in the present invention, particularly in the form of a suspension, may include, for example, 2.5 to 500 μg / ml, particularly 2.5 to 250 μg / ml of colchicine and 0.05 to 60 mg / ml, particularly 0.05 to 20 mg / ml of an anesthetic, particularly ropivacaine.

[0145] In one embodiment, the pharmaceutical composition in the present invention, particularly in the form of a suspension, may include, for example, 0.2 to 100 μg / ml, particularly 2 to 50 μg / ml of colchicine and 1 to 120 mg / ml, particularly 1 to 10 mg / ml of an anesthetic, particularly ropivacaine.

[0146] 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 time between 1 and 9 days, 1 and 8 days, 1 and 7 days, or 1 and 6 days, depending on the nature of the lesion being treated, for example, 5, 6, 7, 8, 9, or 10 days, more specifically 5 or 10 days.

[0147] In one embodiment, the pharmaceutical composition may be suitable for maintaining a therapeutically acceptable concentration of an anesthetic, particularly ropivacaine, in a painful joint for three days, two days, or especially from immediately after administration to one day after administration.

[0148] In one embodiment, a pharmaceutical composition for use according to the present invention is characterized by the fact that the time required to release 80% by weight colchicine in the microparticles is more than 1 day, for example 1.5 days and may reach 10 days, more than 1 day, for example 1.5 days and may reach 7 days, more than 1 day, for example 1.5 days and may reach 5 days, for example 1 day, for example 1.5 days, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days or 10 days, more specifically more than 1 day, for example 1.5 days and may reach 7 days, or occupying 2 to 15 days, 2 to 10 days and 2 to 7 days, and the time required to release 80% by weight anesthetic is up to 3 days, for example up to 2 days, in particular up to 1 day.

[0149] In one embodiment, a pharmaceutical composition for use according to the present invention is characterized by the fact that the dissolution rate of colchicine is 80% (w / w) in more than 1 day, for example 1.5 days, which may be 10 days, more than 1 day, for example 1.5 days, which may be 7 days, more than 1 day, for example 1.5 days, which may be 5 days, for example 1 day, for example 1.5 days, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days, more specifically more than 1 day, for example 1.5 days, which may be 7 days, or a period of 2 to 15 days, 2 to 10 days and 2 to 7 days, and the dissolution rate of the anesthetic is 80% (w / w) in up to 3 days, for example up to 2 days, in particular up to 1 day.

[0150] In one embodiment, a pharmaceutical composition in the present invention, particularly in the form of a suspension, can release colchicine for 5 to 10 days and comprises 2.5 to 2500 μg / ml of colchicine and 0.05 to 120 mg / ml of an anesthetic, particularly ropivacaine, 2.5 to 1500 μg / ml of colchicine and 0.05 to 60 mg / ml of an anesthetic, particularly ropivacaine, or 2.5 to 250 μg / ml of colchicine and 0.05 to 20 mg / ml of an anesthetic, particularly ropivacaine.

[0151] In one embodiment, the pharmaceutical composition of the present invention, particularly in the form of a suspension, can release colchicine for 6 to 9 days and contains 2.5 to 2500 μg / ml of colchicine and 0.05 to 120 mg / ml of an anesthetic, particularly ropivacaine, particularly 2.5 to 250 μg / ml of colchicine and 0.05 to 120 mg / ml of an anesthetic, particularly ropivacaine.

[0152] According to one particular embodiment, when another acute redness occurs under the same conditions and pharmacologic, the treatment may be updated.

[0153] According to one embodiment, more specifically for the treatment of acute arthritis associated with the presence of microcrystals or inflammatory arthritis associated with non-crystalline materials, more specifically for gout attacks, chondrocalcinosis and acute calcific tendinitis, the pharmaceutical composition may be suitable for inducing colchicine concentration in the joints in the early stages.

[0154] The pharmaceutical composition may or may not exhibit burst release. Within the scope of this invention, “burst release” means that the initial bolus of the drug is released immediately in the release medium, i.e., immediately after injection into the node, before the release rate reaches a stable profile.

[0155] In any case, the duration of the colchicine burst release may be 0 to 1 day, for example, from the beginning to the end of day 1, particularly 0 to 6 hours, 0 to 3 hours, or more specifically 0 to 2 hours.

[0156] Therefore, when a burst release of colchicine occurs during administration, the pharmaceutical composition according to the present invention can induce an initial release of colchicine at the administration site, e.g., in the intra-articular and / or peri-articular space. Once the initial release of colchicine subsides, controlled release of the colchicine microparticle formulation continues to bring about colchicine concentration at the treatment site (e.g., intra-articular and / or peri-articular), combating inflammation and / or pain during the additional treatment period after administration.

[0157] In certain embodiments, the pharmaceutical composition according to the present invention does not exhibit a significant burst release of colchicine. According to the embodiments, less than 50% by weight of colchicine is released 12 hours after administration. This is one of the notable features of Aboumanei et al., discussed in the preamble.

[0158] In another embodiment, a pharmaceutical composition for use according to the present invention may be further characterized in that less than 50% by weight of colchicine is released 12 hours after administration.

[0159] In another embodiment, a pharmaceutical composition for use according to the present invention may be further characterized in that the pharmaceutical composition exhibits an in vitro solubility profile, releasing less than 25% colchicine within 60 minutes, less than 50% colchicine within 12 hours, and at least 80% of the anesthetic within 3 days, 2 days, or 1 day.

[0160] In another aspect, the present invention relates to a method for treating acute inflammatory arthritis associated with crystals and acute inflammatory arthritis associated with non-crystals, particularly rheumatoid arthritis, ankylosing spondylitis, juvenile arthritis, psoriatic arthritis, lupus, and other non-crystals associated with arthropathy, or attacks or redness of crystals associated with arthropathy, or acute tendinitis and capsulitis, by injecting a pharmaceutical composition comprising a controlled-release dosage form containing an anesthetic and an effective amount of colchicine, suitable for intra-articular injection into the joint, into the painful joint of a patient in need. The present invention relates to a method comprising administering a drug such that the time required to release 80% by weight of colchicine is more than one day, may reach 15 days, and particularly accounts for 1.5 to 15 days, wherein the colchicine is present in a sterile and injectable dosage form, particularly at a concentration in the range of 2.5 to 2500 μg per ml of suspension, and an anesthetic, particularly ropivacaine, is present in a sterile and injectable dosage form, particularly at a concentration in the range of 0.05 to 120 mg per ml of suspension, with 80% of the anesthetic being released over a maximum of three days, and the pharmaceutical composition having a volume in the range of 0.1 ml to 5 ml.

[0161] This specification provides a method for treating acute inflammatory arthritis associated with crystals and acute inflammatory arthritis associated with non-crystals, particularly acute arthritis associated with non-crystals (such as rheumatoid arthritis, ankylosing spondylitis, juvenile arthritis, psoriatic arthritis, lupus, etc.) or attacks or redness of crystal-associated arthropathy or acute tendinitis and capsulitis, comprising at least administering by injection to the painful joint of a patient in need of the pharmaceutical composition comprising a controlled-release dosage form containing an anesthetic and an effective amount of colchicine, suitable for intra-articular injection into the joint, wherein the dissolution rate of colchicine is 80% (w / w) after more than 1 day, particularly more than 15 days, as measured according to the following protocol.

[0162] A controlled-release formulation containing a fixed amount of 20 mg of colchicine is suspended in 50 mL of phosphate-buffered saline (10 mM, pH 7.4) under stirring at 37°C. The supernatant of the sample collected periodically throughout the entire release period is then analyzed using 350 nm UV light. Here, colchicine is present in a sterile and injectable dosage form, particularly at concentrations ranging from 0.2 to 100 μg per 1 ml of suspension, especially in the range of 2 to 50 μg. The anesthetic is present in a sterile and injectable dosage form, particularly at concentrations ranging from 1 to 120 mg per ml of suspension, especially from 1 to 10 mg, and the dissolution rate of the anesthetic is 80% (w / w) in up to 3 days, as measured according to the following protocol.

[0163] A fixed amount of 20 mg of the anesthetic dosage form is suspended in 20 mL of phosphate-buffered saline (10 mM, pH 7.4) under agitation at 37°C. Then, 1 mL of the medium is periodically taken out throughout the entire release period, filtered through a 0.45 μm PTFE filter, and the filtered sample is analyzed by HPLC. Here, the pharmaceutical composition has a volume ranging from 0.1 ml to 5 ml.

[0164] Furthermore, in another aspect, the present invention relates to a method for treating acute inflammatory arthritis associated with crystals and acute inflammatory arthritis associated with non-crystals, particularly acute arthritis associated with non-crystals (such as rheumatoid arthritis, ankylosing spondylitis, juvenile arthritis, psoriatic arthritis, lupus, etc.) or attacks or redness of crystal-associated arthropathy or acute tendinitis and capsulitis, comprising administering at least an effective amount of an anesthetic and at least an effective amount of colchicine, for immediate release or controlled release, by intra-articular injection to a patient in need.

[0165] In this specification, a method for treating crystal-associated acute inflammatory arthritis and non-crystal-associated acute inflammatory arthritis, particularly a crystal-associated attack or redness of arthropathy or acute type tendinitis and capsulitis, comprising at least: - A step of preparing and / or providing a sterile and injectable pharmaceutical composition, particularly in the form of a suspension, by mixing a formulation in the form of an immediate-release formulation of colchicine, a controlled-release formulation containing colchicine as detailed below herein, or a powder as described below herein, with an aqueous injection vehicle, wherein the pharmaceutical composition optionally contains excipients selected from the group consisting of tonicity enhancers, wetting agents, viscosity enhancers, density enhancers, and mixtures thereof, and the excipients may be present in the aqueous injection vehicle or in the controlled-release formulation or powder containing colchicine. A method is further provided which includes the step of injecting the pharmaceutical composition into a painful joint of a patient in need thereof, wherein the volume to be injected is adapted to the injection site.

[0166] The present invention may be particularly suitable for treating patients with renal and / or hepatic impairment who are being treated simultaneously with multiple drugs. In fact, in patients with renal and / or hepatic impairment, particularly in the treatment of gouty redness, adjustment of the recommended oral dose of colchicine is essential for the suitability of the administration scheme. Moreover, in the past, several drugs have been identified as causing undesirable side effects in oral colchicine therapy, and even causing fatal drug interactions, drastically altering the safety profile, and requiring adjustment of the oral colchicine dose, for example, requiring a 2-3 times reduction in the oral colchicine dose.

[0167] Therefore, in one embodiment, a pharmaceutical composition according to the present invention may be administered to a patient with renal and / or hepatic impairment. In particular, colchicine plasma levels are considered to rise to the toxicity threshold when the renal or hepatic impairment reaches a severe intrinsic grade.

[0168] Patients with renal impairment can be identified and classified by techniques known to physicians, such as via creatinine clearance or glomerular filtration rate (GFR) measurements. These methods are described in detail, in particular, 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 uses and methods according to the present invention can be incorporated, for example, to treat patients with all grades of renal impairment, such as grades 1-5 as defined by the GFR method. The uses and methods according to the present invention may be more specifically suited to patients with higher grades of renal impairment, such as grades 3-5 as defined by the GFR method.

[0169] Patients with liver dysfunction may be identified and classified by techniques known to physicians, such as via the Child-Pugh classification system or via the MELD score. These methods are described in particular in Tsoris A, Marlar CA. Use Of The Child Pugh Score In Liver Disease. 2021 Mar 22. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. PMID:31194448 or on the internet at the following links: https: / / liverfellow.org / post / meld-score-part1 and https: / / liverfellow.org / post / meld-score-part2. The uses and methods according to the present invention may be incorporated, for example, to treat patients with all scores, percentages and / or classifications set forth by the Child-Pugh classification system, e.g., mild, moderate, or severe liver dysfunction. The uses and methods according to the present invention may be more specifically suited to patients with severe hepatic impairment, such as moderate and severe hepatic impairment, with high scores, percentages, and / or classifications as defined by the Childe-Pugh classification system.

[0170] Therefore, since systemic plasma levels of colchicine are maintained below the toxicity threshold within the framework of the present invention, adjustment of the colchicine dosage is not required, even when treating patients affected by intrinsic factor, such as patients with renal and / or hepatic impairment, for example, patients who currently require adjustment of colchicine dosage when administered orally.

[0171] Therefore, in one embodiment, a pharmaceutical composition for use according to the present invention may be further characterized by the fact that the patient to whom the pharmaceutical composition is administered has renal and / or hepatic dysfunction.

[0172] In one other embodiment, a method is provided for the treatment of acute inflammatory arthritis associated with crystals and acute inflammatory arthritis associated with non-crystals, particularly rheumatoid arthritis, ankylosing spondylitis, juvenile arthritis, psoriatic arthritis, lupus, or other non-crystal-associated acute arthritis, or acute type tendinitis and capsulitis of arthropathy, as defined above herein, in patients with renal and / or hepatic impairment, wherein the dose of colchicine is not reduced in response to such impairment.

[0173] In one embodiment, a pharmaceutical composition according to the present invention can be administered co-administered with a wide range of drugs detailed below herein, and in particular, when administered co-administered with such drugs, it exhibits an improved safety profile compared to classical oral colchicine treatment.

[0174] Examples of drug interactions that this invention makes avoidable include interactions with drugs that are clearly identified within the context of oral colchicine therapy and are well known to physicians. In situations of potential drug interactions, the classic approach is to adjust, i.e., reduce, the dosage of oral colchicine according to the severity of the interaction, as is well recommended.

[0175] Such drug-drug interactions (DDIs) can be explained by the fact that some drugs inhibit P-gp and / or CYP3A4, producing peaks of colchicine at excessive plasma concentrations, particularly above 6 ng / mL, which must be avoided.

[0176] One advantage of the present invention lies in the fact that excessive plasma concentrations are avoided, and it is possible to administer drugs simultaneously without adjusting the colchicine dosage, which is essential when administering orally.

[0177] Therefore, in one embodiment, a pharmaceutical composition for use according to the present invention may be further characterized by the fact that a patient to whom the pharmaceutical composition is administered can be treated simultaneously, separately, or sequentially with the following active ingredients: atazanavir, clarithromycin, darunavir, ritonavir, indinavir, itraconazole, ketoconazole, lopinavir, ritonavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, tipranavir, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, cyclosporine, and lanolazine.

[0178] Therefore, this specification provides pharmaceutical compositions for use as defined above, for use in the treatment of crystal-associated acute inflammatory arthritis and non-crystal-associated acute inflammatory arthritis, particularly crystal-associated arthropathy or erythrosis or acute type tendinitis and capsulitis, in patients who are simultaneously, separately, sequentially and non-exclusively treated 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, lanolazine, macrolides and statins, or in patients suffering from chronic comorbidities such as hypertension, chronic kidney disease, diabetes, heart disease, infection and / or immunosuppression.

[0179] Therefore, in this specification, at least one active ingredient selected from atazanavir, clarithromycin, darunavir, ritonavir, indinavir, itraconazole, ketoconazole, lopinavir, ritonavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, tipranavir, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, cyclosporine, and lanolazine may be used simultaneously or separately. Further provided are methods for the treatment of patients receiving continuous treatment for crystal-associated acute inflammatory arthritis and non-crystal-associated acute inflammatory arthritis, particularly non-crystal-associated acute arthritis such as rheumatoid arthritis, ankylosing spondylitis, juvenile arthritis, psoriatic arthritis, lupus, or crystal-associated arthropathy, including attacks or redness or acute forms of tendinitis and capsulitis, wherein the dose of colchicine is not reduced in response to the co-administration of such drugs.

[0180] Controlled-release formulations containing colchicine According to one embodiment, the controlled-release dosage form containing colchicine is in the form of an in-situ-forming depot, a hydrogel, or microparticles, particularly microparticles or multivesicular liposomes containing a polymer matrix.

[0181] In one embodiment, the controlled-release dosage form containing colchicine is in the form of an in-situ forming depot. In-situ forming depots containing colchicine, such as pH-induced, heat-induced, or solvent-exchange-induced gelation systems, can be prepared according to techniques known to those skilled in the art, particularly as described in L. Rahnfeld et al. *Injectable Lipid-Based Depot Formulations: Where Do We Stand? Pharmaceutics. 2020, 12(6):567* and S. Kempe et al. *In-situ forming implants - an attractive formulation principle for parenteral depot formulations* *Journal of Controlled Release 2012, 161:668*.

[0182] In another embodiment, the controlled-release dosage form containing colchicine is in the form of a hydrogel. The hydrogel can be prepared according to techniques known to those skilled in the art. In particular, the hydrogel can be formed by dispersing colchicine, optionally pre-solubilized in water, with the hydrogel under stirring. Among suitable hydrogels, sodium hyaluronate is a good example. When the pharmaceutical composition is in powder form, water is removed by techniques known to those skilled in the art, for example, by dehydration or freeze-drying. If necessary, they may be reversibly hydrated back.

[0183] In one embodiment, the controlled-release dosage form containing colchicine is in the form of microparticles. This embodiment is described in detail below in this specification.

[0184] In the following description, "molecular weight" is expressed as polystyrene equivalent molecular weight (Mw) and is determined by gel permeation chromatography (GPC; also known as size exclusion chromatography (SEC)) on a set of SDV columns of the relevant dimensions. Detection is performed using tetrahydrofuran (THF) as the eluent, with a refractive index detector and a temperature-controlled column compartment. The sample is dissolved in THF or chloroform. Polystyrene standards (a set of three vials containing 12 standards) are dissolved in THF. The entire sequence is calibrated with polystyrene standards. The Mw (weight-average molecular weight) result is calculated as the average value of the triple injection.

[0185] Throughout this document, we assume that "kg / mol" and "kDa" are equivalent units and can be used interchangeably.

[0186] Colchicine-containing controlled-release particles Colchicine-containing controlled-release microparticles can take the form of (i) microparticles containing a polymer matrix or (ii) various microparticles such as multivesicular liposomes.

[0187] According to one embodiment, the fine particles have an average particle size of 10 μm or larger, as determined by laser diffraction measurement.

[0188] According to another embodiment, the fine particles have an average particle size determined by laser diffraction, which is 10 μm or larger, particularly less than 100 μm, more specifically less than 80 μm, and even more specifically less than 50 μm, for example, 10 to 50 μm or 10 to 40 μm.

[0189] The particle size can be measured within the scope of this invention by laser diffraction measurement.

[0190] The apparatus may typically be a Malvern Mastersizer MS3000 laser diffraction particle size analyzer. A preparation of 0.1 to 1 mg of fine particles per 1 ml of deionized water may be introduced into the apparatus. The measurement can be performed three times. Each run may last 3 seconds, and the suspension may be homogenized before each run.

[0191] The apparatus may also be a multi-wavelength Separation Analyser LUMiReader that uses a sedimentation technique to measure particle size distribution in accordance with ISO 13317.

[0192] Both devices provide similar measurement results.

[0193] It should be understood that these ranges refer to the average size of all particles in a given population. The size of any given individual particle can be within a standard deviation above or below the average size.

[0194] Within the context of the present invention, “fine particles” means particles in a pharmaceutical composition that are of any shape and made of any material, particularly suitable for injection into the human body, especially into joints or arteries, and having an average particle size greater than 10 μm and less than 100 μm, as determined by laser diffraction.

[0195] Suitable microparticles for use in pharmaceutical compositions according to the present invention can be selected from various types of microparticles, such as microspheres, microparticle matrices, microsphere matrices, microcapsules, rods, wafers, pills, fibers, and pellets.

[0196] (i) Microparticles containing a polymer matrix The polymer matrix can be selected from a variety of polymers suitable for obtaining controlled-release particles. Such polymer matrices are non-toxic to the human body.

[0197] According to one embodiment, the polymer forming the polymer matrix is ​​biodegradable.

[0198] Within the context of this invention, "biodegradable" materials refer to materials that are broken down by enzymes or hydrolysis, and for this purpose, it has been proven that the degradation products are incorporated into the biomass and / or eliminated from the organism by metabolism or renal filtration.

[0199] Non-toxic and biodegradable polymers may be natural or synthetic.

[0200] According to one embodiment, the polymer matrix of fine particles used in a pharmaceutical composition used according to the present invention comprises at least one poly(lactic-coglycolic acid) copolymer or PLGA (poly(lactic-coglycolic acid) copolymer).

[0201] According to the above embodiment, the polymer matrix may contain PLGA in an amount of more than 70% by weight, particularly more than 80% by weight, and more specifically more than 90% by weight, relative to the total weight of the polymer matrix.

[0202] Suitable polymers are not limited to those commercially available and known as RESOMER (Evonik Industries AG, Germany), LACTEL (Durect, USA), PURASORB (Corbion NV, Netherlands), Viatel (Ashland, USA), and EXPANSORB (Seqens, France).

[0203] Examples of suitable polymers are listed in Table 2. This list is not limiting.

[0204] [Table 3]

[0205] According to another embodiment, the polymer matrix of the fine particles used in the pharmaceutical composition used in accordance with the present invention comprises at least poly(caprolactone) (PCL).

[0206] According to the above embodiment, the polymer matrix may contain PCL in an amount of more than 70% by weight, particularly more than 80% by weight, and more specifically more than 90% by weight, relative to the total weight of the polymer matrix.

[0207] According to another embodiment, the polymer matrix of the fine particles used in the pharmaceutical composition according to the present invention comprises a mixture of at least PCL and at least PLGA.

[0208] In certain embodiments, the pharmaceutical composition according to the present invention may be a mixture of fine particles of different properties, comprising colchicine and a polymer matrix, characterized by fine particles comprising at least one poly(lactic acid-coglycolic acid) copolymer, particularly two copolymers exhibiting different molecular weights, at least one poly(caprolactone), or at least a mixture of at least one poly(lactic acid-coglycolic acid) copolymer and at least one poly(caprolactone).

[0209] "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. "Type of microparticle" means microparticles having polymer matrices of different properties, particularly exhibiting specific ratios of monomers and / or molecular weights. For example, one type of microparticle may have a polymer matrix comprising, or even comprising, at least one poly(lactic acid-coglycolic acid) copolymer, another type of microparticle may have a polymer matrix comprising, or even comprising, at least poly(caprolactone), or one type of microparticle may have a polymer matrix comprising, or even comprising, at least one poly(lactic acid-coglycolic acid) copolymer exhibiting a specific ratio of monomers and / or molecular weight, another type of microparticle may have a polymer matrix comprising, or even comprising, at least one poly(lactic acid-coglycolic acid) copolymer exhibiting different specific ratios of monomers and / or molecular weights. Thus, all types of mixtures are included within the scope of the invention for the benefit of obtaining a release profile suitable for the treatment of lesions particularly considered herein.

[0210] The polymer matrix may contain one or more additional polymers, copolymers, or mixtures thereof. The additional polymers, copolymers, or mixtures thereof may be present in the polymer matrix in an amount ranging from 0 to 30% by weight, particularly 0 to 20% by weight, and more specifically 0 to 10% by weight, relative to the total weight of the polymer matrix.

[0211] Suitable additional polymers or copolymers, non-limiting examples, include poly(lactide) or PLA (poly(lactide)) different from poly(lactic acid-coglycolic acid) copolymer, poly(glycolide) or PGA (poly(glycolide)) different from poly(lactic acid-coglycolic acid) copolymer, poly(lactide-cocaprolactone), poly(ethylene glycol), poly(ethylene oxide), or PEO (poly(ethylene Examples include oxides, PLGA-b-PEO-b-PLGA, PLGA-b-PEO, polyhydroxyalkanoates, poly(hydroxybutyrate), poly(trimethylenecarbonate), poly(dioxanone), poly(valerolactone), poly(alpha-hydroxy acid), poly(lactone), poly(amino acid), polyanhydride, poly(orthoester), poly(acetal), polyurethane, polythioester, polyphosphoester, poly(ester-co-amide), poly(vinyl alcohol) or PVA (poly(vinyl alcohol)), PVA-g-PLGA, poly(etherester) multiblock copolymer, polyvinylpyrrolidone, poly(methacrylate), PEO-PPO-PEO (Pluronic®), gelatin, heparin, chondroitin sulfate; polysaccharides such as arginate, starch, chitosan and dextran, and any combination thereof.

[0212] As far as poly(lactic acid-coglycolic acid) copolymers or PLGAs are concerned, 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. Within the framework of the present invention, "lactic acid / glycolic acid ratio" or "lactide:glycolide molar ratio" means the molar ratio between the monomer lactic acid and glycolic acid used. For example, "PLGA 50:50" or "PLGA having a 50:50 lactic acid / glycolic acid molar ratio" means a PLGA whose composition is 50% lactic acid and 50% glycolic acid.

[0213] In one embodiment, the polymer matrix is ​​(i) a poly(lactic acid-coglycolic acid) copolymer or a mixture of poly(lactic acid-coglycolic acid) copolymers having a molar ratio of lactic acid:glycolic acid of 50:50, particularly in the range of 40:60 to 75:25, more specifically in the range of 40:60 to 65:35, and even more specifically in the range of 40:60 to 60:40, for example, (ii) poly(caprolactone), and (iii) a poly(lactic acid-coglycolic acid) copolymer having a molar ratio of lactic acid:glycolic acid of 50:50, particularly in the range of 40:60 to 75:25, more specifically in the range of 40:60 to 65:35, and further More specifically, the material comprises at least one polymer selected from a poly(lactic acid-coglycolic acid) copolymer or a mixture of poly(lactic acid-coglycolic acid) copolymers and at least one poly(caprolactone), having a lactic acid:glycolic acid molar ratio in the range of 40:60 to 60:40, for example, 50:50, wherein the amount of the polymer selected from (i), (ii), and (iii) is greater than 70% by weight, particularly greater than 80% by weight, and more specifically greater than 90% by weight, relative to the total weight of the polymer matrix.

[0214] In one embodiment, the polymer matrix contains, in an amount of more than 70% by weight, particularly more than 80% by weight, and more specifically more than 90% by weight, of the total weight of the polymer matrix, at least one poly(lactic acid-coglycolic acid) copolymer having a molar ratio of lactic acid:glycolic acid of at least one poly(lactic acid-coglycolic acid) copolymer and at least one poly(caprolactone), or a mixture of at least one poly(lactic acid-coglycolic acid) copolymer and at least one poly(caprolactone), having a molar ratio of lactic acid:glycolic acid of at least one poly(lactic acid-coglycolic acid) copolymer having a molar ratio of lactic acid:glycolic acid of at least one poly(lactic acid-coglycolic acid) of at least one poly(caprolactone), particularly in the range of 40:60 to 75:25, more specifically in the range of 40:60 to 65:35, and more specifically in the range of 40:60 to 60:40, for example, a molar ratio of lactic acid:glycolic acid of 50:50.

[0215] According to the above embodiment, the polymer matrix may contain a mixture of PCL and PLGA in an amount of more than 70% by weight, particularly more than 80% by weight, and more specifically more than 90% by weight, based on the total weight of the polymer matrix.

[0216] According to a more specific embodiment of the above-described embodiment, the polymer matrix does not contain any additional polymers or copolymers.

[0217] When PLGA copolymers are incorporated as polymer matrices, they can have a wide range of molecular weights and monomer ratios of lactic acid to glycolic acid, particularly in the range of 75:25 to 50:50, more specifically in the range of 40:60 to 75:25, even more specifically in the range of 40:60 to 65:35, for example, in the range of 40:60 to 60:40, for example, 50:50.

[0218] In one embodiment, the colchicine-containing controlled-release microparticles according to the present invention are PLGA microspheres having a lactic acid / glycolic acid molar ratio in the range of 40:60 to 75:25, more specifically in the range of 40:60 to 65:35, even more specifically in the range of 40:60 to 60:40, for example, 50:50, and even further, PLGA microspheres as a mixture of microparticles of particularly different properties or types. In one embodiment, the colchicine-containing microparticles may be selected from particles having one, two, three, or four types, particularly two types of PLGA polymer matrices. The properties of the microparticles may vary, for example, with respect to molecular weight.

[0219] In one embodiment, the polymer matrix of colchicine-containing microparticles may contain, or even consist of, one PLGA having a lactic acid:glycolic acid molar ratio in the range of 40:60 to 75:25, more specifically in the range of 40:60 to 65:35, and even more specifically in the range of 40:60 to 60:40, for example 50:50, and a molecular weight of 5 to 100 kg / mol, more preferably 5 to 75 kg / mol.

[0220] In one embodiment, the polymer matrix of colchicine-containing microparticles may contain, or even consist of, two, three, or four PLGAs, preferably a mixture of two PLGAs, having different molecular weights, with a lactic acid:glycolic acid molar ratio in the range of 40:60 to 75:25, more specifically in the range of 40:60 to 65:35, and even more specifically in the range of 40:60 to 60:40, for example, 50:50.

[0221] In one more specific embodiment, the polymer matrix of colchicine-containing microparticles is - A single PLGA(1) having a lactic acid:glycolic acid molar ratio in the range of 40:60 to 75:25, more specifically in the range of 40:60 to 65:35, even more specifically in the range of 40:60 to 60:40, for example 50:50, and a molecular weight of 20 to 100 kg / mol, more preferably 20 to 75 kg / mol, -A lactic acid:glycolic acid molar ratio in the range of 40:60 to 75:25, more specifically in the range of 40:60 to 65:35, and even more specifically in the range of 40:60 to 60:40, for example 50:50, and a molecular weight of 5 to 40 kg / mol, one PLGA(2) It may contain a mixture of the above, or may even consist of the above. The weight ratio P2 / (P1+P2) is less than 30% by weight, and especially less than 20% by weight, where "P1" is the weight of PLGA(1) and "P2" is the weight of PLGA(2).

[0222] Therefore, in this specification, the polymer matrix comprises, or even comprises, one first poly(lactic acid-coglycolic acid) copolymer and one second poly(lactic acid-coglycolic acid) copolymer, both poly(lactic acid-coglycolic acid) copolymers having a lactic acid:glycolic acid molar ratio in the range of 40:60 to 75:25, more specifically in the range of 40:60 to 65:35, and even more specifically in the range of 40:60 to 60:40, for example, 50:50. The present invention provides a pharmaceutical composition comprising a first poly(lactic acid-coglycolic acid) copolymer having a molecular weight of 20 to 100 kg / mol, more preferably 20 to 75 kg / mol, a second poly(lactic acid-coglycolic acid) copolymer having a molecular weight of 5 to 40 kg / mol, and a weight ratio P2 / (P1+P2) of less than 30% by weight, particularly less than 20% by weight, where P1 is the weight of the first poly(lactic acid-coglycolic acid) copolymer and P2 is the weight of the second poly(lactic acid-coglycolic acid) copolymer.

[0223] Any suitable method for producing polymers known in the art may be used, and the molecular weight may typically be in the range of 5 to 150 kDa, particularly 5 to 100 kDa, 5 to 80 kDa, more specifically 5 to 75 kDa, even more specifically 5 to 55 kDa or 5 to 50 kDa, for example, 5 to 40 kDa.

[0224] As mentioned above, "kg / mol" and "kDa" are equivalent units and can be used interchangeably.

[0225] According to further specific embodiments, the polymer forming the polymer matrix contains PLGA in an amount of, for example, 100% by weight relative to the total weight of the polymer matrix, and the PLGA is as follows: Molecular weights of -5 to 80 kDa, and -75:25 to 50:50 molar ratio of lactide:glycolide Defined by:

[0226] According to a more specific embodiment, the polymer forming the polymer matrix contains PLGA in an amount of, for example, 100% by weight relative to the total weight of the polymer matrix, and the PLGA is as follows: Molecular weights of -5 to 55 kDa or 5 to 50 kDa, and -50:50 molar ratio of lactide:glycolide Defined by:

[0227] According to one embodiment, PLGA is a terminally capped carboxylic acid, ester, or PEG, and is particularly a terminally capped carboxylic acid.

[0228] According to another embodiment, the particulate matrix may comprise, or even consist of, two, three or more PLGA copolymers, particularly a blend of two PLGA copolymers, more specifically one low molecular weight and one high molecular weight. In this specification, “polymer matrix comprising at least one poly(lactic acid-coglycolic acid) copolymer” means, more precisely, that the poly(lactic acid-coglycolic acid) copolymers may be such a blend.

[0229] The microparticles may further contain pharmaceutically acceptable excipients for modulating 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, cyclodextrin, lecithin, mannitol, sucrose, inorganic salts, and mixtures thereof.

[0230] The polymer matrix of fine particles may contain one or more excipients. The excipients may be present in the polymer matrix in an amount of 15% by weight or less, particularly 10% by weight or less, and more specifically 5% by weight or less, relative to the total weight of the polymer matrix.

[0231] In one embodiment, the weight percentage ratio between colchicine and the total weight of the microparticles, or the drug load in the pharmaceutical composition, is in the range of 0.1 to 35% by weight, particularly 0.5 to 30% by weight, more specifically 1 to 25% by weight, and even more specifically 1 to 10% by weight.

[0232] Manufacturing process for obtaining microparticles containing a polymer matrix Any process suitable for producing polymer microparticles having an average particle size in the range of 10 μm to 100 μm, as determined by laser diffraction measurement, is considered appropriate within the framework of the present invention.

[0233] Examples of such manufacturing processes include high-pressure homogenization using a rotor-stator homogenizer in batch or continuous mode, or emulsion-based processes such as membrane emulsification, followed by removal of organic solvents by extraction / evaporation.

[0234] As long as the general principles of such methods are taken into consideration, emulsions can be prepared and treated on a membrane having pores of a predetermined size. The resulting microspheres can then be recovered after extraction and evaporation of the organic solvent, washing, and freeze-drying.

[0235] According to one particular embodiment, the fine particles can be manufactured from O / W positive emulsion or W / O / W double emulsion technology.

[0236] 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.

[0237] According to one particular embodiment, the particulate matter can be produced from solid-in-oil-water (S / O / W) double emulsion technology.

[0238] Giovagnoli, S., et al.; Physicochemical characterization and release mechanism of a novel prednisone biodegradable microsphere formulation, J Pharm Sci. 97:303-317, (2008) describes an example of PLGA microparticles prepared via S / O / W emulsion technology. Other suitable manufacturing methods for obtaining microparticles according to the present invention include atomization by rotating disc, atomization by spray drying, fluidized bed coating, or a combination thereof.

[0239] Alternatively, the microparticles can be manufactured using drop-on-demand, drop-by-drop, and jet breakup methods, such as inkjet printing or microfluidics.

[0240] Alternatively, the microparticles can be manufactured using supercritical fluid technology.

[0241] Alternatively, microparticles can be manufactured using microfabrication methods such as soft lithography, which is based on templates and molds.

[0242] All of these manufacturing processes are well known to those skilled in the art.

[0243] The manufacturing processes described above are well known to those skilled in the art.

[0244] (ii) Multivesicular liposomes Multivesicular liposomes (MVLs) are spherical particles with an average diameter of 10–30 μm, composed of multiple non-concentrically arranged lipid bilayers within a honeycomb-like structure. These lipid layers surround numerous water-filled aqueous compartments, which can be used to encapsulate water-soluble drugs such as colchicine.

[0245] A MVL is classically composed of at least one amphiphilic lipid and one neutral lipid. The amphiphilic lipid is selected from phospholipids, for example, phosphatidylcholine or phosphatidylglycerol. The neutral lipid is selected from triglycerides having a monounsaturated fatty acid ester moiety containing 14 to 18 carbon atoms in the acyl chain (e.g., triolein, tripalmitorein), saturated fatty acid ester moieties containing 6 to 8 carbon atoms in the acyl chain (e.g., tricaproine, tricaprylin), and mixtures thereof. Cholesterol may also be used in the composition.

[0246] MVL is obtained by using a water-in-oil double emulsification method. In the first step, a water-in-oil emulsion is prepared by mixing phospholipids, triolein, tricaprylin, and cholesterol solubilized in a volatile, water-miscible organic solvent with an aqueous solution containing the solubilizing agent to be encapsulated. The first emulsion is then emulsified by mixing with a second aqueous solution to produce a water-in-oil emulsion. The energy required to form the first and second emulsions can be supplied mechanically, by sonication, or a combination thereof. The MVL is finally obtained by removing the volatile organic solvent from the double emulsion using gas stripping or flushing. Finally, removal of unencapsulated material, concentration of the MVL, and buffer exchange are performed using either a dialysis filtration or cross-flow filtration system.

[0247] In one embodiment, the neutral lipids used to produce MVLs encapsulating colchicine include a mixture of triolein:tricaprylin in a ratio ranging from 50:50 to 0:100.

[0248] Controlled-release dosage form containing anesthetic agents In one embodiment, the pharmaceutical composition is characterized in that the anesthetic is in a partially or entirely immediate-release dosage form, particularly in a whole immediate-release dosage form, or in a partially or entirely controlled-release dosage form, wherein the controlled-release dosage form is different from the controlled-release dosage form containing colchicine, or is contained therein, for example, in the form of microparticles containing a polymer matrix, in the form of a hydrogel, in the form of a multivesicular liposome, or in the form of an in-situ forming depot, particularly as defined above with respect to colchicine.

[0249] In other words, within the framework of the present invention, if the anesthetic agent represents a portion of it in the form of a controlled-release dosage form, the portion may be different from the controlled-release dosage form or the dosage form portion containing colchicine, i.e., the portion of the anesthetic agent may be present in a controlled-release dosage form containing colchicine, for example, in colchicine-containing microparticles.

[0250] The anesthetic agent may be in the form of controlled-release microparticles, for example, (i) microparticles containing a polymer matrix obtained via an oil-in-water emulsion (O / W), a water-in-oil-in-water emulsion (W / O / W), or a solid-in-oil-in-water emulsion (S / O / W); (ii) multivesicular liposomes; (iii) dehydrated hydrogels; or (iv) in situ-forming depots obtained particularly from pH-induced, heat-induced, or solvent-exchange-induced gelation systems.

[0251] In one embodiment, (i) controlled-release microparticles containing an anesthetic agent may be prepared according to the same properties and methods as described above for the preparation of controlled-release microparticles containing colchicine. In particular, the same size and polymer matrix properties may be used.

[0252] In particular, the fine particles containing the anesthetic agent may have a polymer matrix, the polymer matrix comprising at least one poly(lactic acid-coglycolic acid) copolymer, at least one poly(caprolactone), or at least a mixture of at least one poly(lactic acid-coglycolic acid) copolymer and at least one poly(caprolactone).

[0253] In addition, the fine particles containing the anesthetic agent may have an average particle size of 5 μm or larger, as determined by laser diffraction measurement. The fine particles may have an average particle size of less than 100 μm, particularly less than 80 μm, more specifically less than 50 μm, for example, 5 to 70 μm or 5 to 40 μm.

[0254] In one embodiment, the polymer matrix of microparticles containing an anesthetic used in a pharmaceutical composition used according to the present invention comprises at least one poly(lactic acid-coglycolic acid) copolymer or PLGA.

[0255] According to the above embodiment, the polymer matrix of microparticles containing an anesthetic agent may contain PLGA in an amount of more than 70% by weight, particularly more than 80% by weight, and more specifically more than 90% by weight, relative to the total weight of the polymer matrix.

[0256] In one embodiment, the controlled-release microparticles containing the anesthetic agent according to the present invention are PLGA microspheres having a molar ratio of lactic acid / glycolic acid in the range of 40:60 to 75:25, more specifically in the range of 40:60 to 65:35, even more specifically in the range of 40:60 to 60:40, for example, 50:50, and even more specifically, PLGA microspheres as a mixture of microparticles of different properties or types. The properties of the microparticles may vary, for example, with respect to molecular weight.

[0257] According to one embodiment of such a configuration, the molecular weight of the PLGA incorporated can vary from 5 to 40 kg / mol, particularly from 5 to 20 kg / mol.

[0258] In one embodiment, the polymer matrix of the anesthetic-containing microparticles may contain, or even consist of, one PLGA having a lactic acid:glycolic acid molar ratio in the range of 40:60 to 75:25, more specifically in the range of 40:60 to 65:35, even more specifically in the range of 40:60 to 60:40, for example 50:50, and a molecular weight of 5 to 40 kg / mol, more preferably 5 to 20 kg / mol.

[0259] In one embodiment, the polymer matrix of the anesthetic-containing microparticles may contain, or even consist of, two, three, or four PLGAs, preferably a mixture of two PLGAs, having different molecular weights, with a lactic acid:glycolic acid molar ratio in the range of 40:60 to 75:25, more specifically in the range of 40:60 to 65:35, and even more specifically in the range of 40:60 to 60:40, for example, 50:50.

[0260] This specification provides a pharmaceutical composition according to the present invention, wherein at least a portion of an anesthetic is contained in microparticles comprising a polymer matrix, the polymer matrix comprising, or further comprising, at least one poly(lactic acid-coglycolic acid) copolymer having a lactic acid:glycolic acid molar ratio in the range of 40:60 to 75:25, more specifically in the range of 40:60 to 65:35, and even more specifically in the range of 40:60 to 60:40, for example, 50:50.

[0261] According to another embodiment, the polymer matrix of the microparticles containing an anesthetic agent used in the pharmaceutical composition according to the present invention comprises at least poly(caprolactone) (PCL). All other polymers listed in Table 2 above may also be used to prepare the microparticles containing the anesthetic agent.

[0262] According to the above embodiment, the polymer matrix may contain PCL in an amount of more than 70% by weight, particularly more than 80% by weight, and more specifically more than 90% by weight, relative to the total weight of the polymer matrix.

[0263] According to another embodiment, the polymer matrix of microparticles containing an anesthetic agent used in a pharmaceutical composition according to the present invention comprises a mixture of at least PCL and at least PLGA.

[0264] In certain embodiments, the pharmaceutical composition according to the present invention is characterized by the fact that the pharmaceutical composition comprises microparticles containing an anesthetic agent, which are microparticles containing an anesthetic agent and a polymer matrix, the polymer matrix comprising at least one poly(lactic acid-coglycolic acid) copolymer, at least one poly(caprolactone), or at least a mixture of at least one poly(lactic acid-coglycolic acid) copolymer and at least one poly(caprolactone).

[0265] In one embodiment, the polymer matrix contains, in an amount of more than 70% by weight, particularly more than 80% by weight, and more specifically more than 90% by weight, of the total weight of the polymer matrix, at least one poly(lactic acid-coglycolic acid) copolymer having a molar ratio of lactic acid:glycolic acid of 50:50, for example, at least one poly(caprolactone), or a mixture of at least one poly(lactic acid-coglycolic acid) copolymer and at least one poly(caprolactone) having a molar ratio of lactic acid:glycolic acid of 50:50, particularly in the range of 40:60 to 75:25, more specifically in the range of 40:60 to 65:35, and more specifically in the range of 40:60 to 60:40, for example, at least one poly(lactic acid-coglycolic acid) copolymer and at least one poly(caprolactone).

[0266] According to the above embodiment, the polymer matrix may contain a mixture of PCL and PLGA in an amount of more than 70% by weight, particularly more than 80% by weight, and more specifically more than 90% by weight, based on the total weight of the polymer matrix.

[0267] The microparticles containing the anesthetic agent may also include any additional suitable polymers and / or acceptable excipients, as described above, for the preparation of the microparticles containing colchicine.

[0268] According to one embodiment, the weight percentage ratio between the drug loading amount or the total weight of the anesthetic and the microparticles is in the range of 1% to 40%, particularly 5 to 40%, even more specifically 5 to 30%, for example 10 to 30%.

[0269] In one embodiment, the controlled-release microparticles containing an anesthetic according to the present invention are PLGA microspheres. In other words, in the said embodiment, the polymer matrix does not contain any additional polymer or copolymer.

[0270] When PLGA copolymers are incorporated as the polymer matrix, they can have a wide range of molecular weights and monomer ratios of lactic acid to glycolic acid, particularly 75:25 to 50:50, even more specifically 50:50. Any suitable method known in the art for making polymers can be used, and the molecular weight can typically be in the range of 5 to 150 kDa, particularly 5 to 80 kDa, more specifically 5 to 55 kDa or 5 to 50 kDa.

[0271] As described above, "kg / mol" and "kDa" are equivalent units and can be used interchangeably.

[0272] According to a further specific embodiment, the polymer forming the polymer matrix contains PLGA, for example, in an amount of 100% by weight based on the total weight of the polymer matrix, and PLGA is as follows: - a molecular weight of 5 to 80 kDa, and - a molar ratio of lactide:glycolide of 75:25 to 50:50 is defined by.

[0273] According to a more specific embodiment, the polymer forming the polymer matrix contains PLGA, for example, in an amount of 100% by weight based on the total weight of the polymer matrix, and PLGA is as follows: - a molecular weight of 5 to 55 kDa or 5 to 50 kDa, and - a molar ratio of lactide:glycolide of 50:50 Defined by:

[0274] According to one embodiment, PLGA is either a terminally capped carboxylic acid or an ester, and is particularly a terminally capped carboxylic acid.

[0275] According to another embodiment, the particulate matrix containing the anesthetic agent may comprise, or even consist of, a blend of two PLGA copolymers, particularly one low molecular weight and one high molecular weight.

[0276] In another embodiment, (ii) multivesicular liposomes containing an anesthetic agent may be prepared according to the same properties and methods as described above for the preparation of multivesicular liposomes containing colchicine.

[0277] In another embodiment, (iii) a dehydrated hydrogel containing an anesthetic agent may be prepared according to techniques known to those skilled in the art. For example, the hydrogel may be achieved according to the method described in Example 5. The gel may be formed by dispersing an anesthetic agent, optionally pre-solubilized in water, with the hydrogel under stirring. Among suitable hydrogels, sodium hyaluronate is a good example. When the pharmaceutical composition is in powder form, water may be removed by techniques known to those skilled in the art, for example, by dehydration or freeze-drying. If necessary, they may be reversibly hydrated back.

[0278] In another embodiment, (iv) an in-situ forming depot containing an anesthetic, for example, a pH-induced, heat-induced, or solvent-exchange-induced gelation system, may be prepared according to techniques known to those skilled in the art, as described in particular L. Rahnfeld et al. Injectable Lipid-Based Depot Formulations: Where Do We Stand? Pharmaceutics. 2020, 12(6):567, S. Kempe et al. In-situ forming implants - an attractive formulation principle for parenteral depot formulations Journal of Controlled Release 2012, 161:668, and KSOh et al. Preclinical studies of ropivacaine extended-release from a temperature-responsive hydrogel for prolonged relief of pain at the surgical wound. Int. J. of. Pharmaceutics. 2019, 558(225-230).

[0279] Pharmaceutical compositions and kits As described above, pharmaceutical compositions are provided herein in various forms, namely, solutions, suspensions, solid implants, semi-solid implants, powders, and in-situ forming depots. Furthermore, pharmaceutical compositions are provided in powder form or kit form. When in powder form, pharmaceutical compositions are primarily intended for storage, while solutions, suspensions, solid implants, semi-solid implants, powders, or in-situ forming depots, particularly suspensions, are kits that allow for the separate storage of immediately usable compositions, immediately injectable ones, and controlled-release dosage forms containing colchicine, particularly in powder form for forming (i) aqueous injection vehicles and (ii) sterile and injectable dosage forms, especially suspensions, which are suitable for injection.

[0280] In one embodiment, the pharmaceutical composition is further characterized in that it is in the form of a sterile and injectable suspension, in particular, which optionally contains excipients selected from the group consisting of tonicity enhancers, wetting agents, viscosity enhancers, density enhancers and mixtures thereof, and is obtained by mixing a controlled-release dosage form containing colchicine, in particular colchicine-containing microparticles, more specifically as defined above, with an aqueous injection vehicle and an anesthetic, in particular as defined above.

[0281] Various embodiments of the aforementioned alternative configurations are described in detail below.

[0282] Solutions, solid implants, semi-solid implants, powders, and in-situ type forming depots can be prepared according to methods known to those skilled in the art.

[0283] According to certain embodiments, the sterile and injectable dosage form is in the form of a suspension that can be obtained from the powders detailed below.

[0284] Powder and suspension In one embodiment, a pharmaceutical composition is provided in powder form comprising an anesthetic and an immediate-release or controlled-release dosage form containing colchicine, wherein the controlled-release dosage form containing colchicine is in the form of fine particles, particularly fine particles containing a polymer matrix, more specifically fine particles having an average particle size of 10 μm or more as determined by laser diffraction, and even more specifically in the form of the fine particles defined above, and the anesthetic is as defined above.

[0285] In one embodiment, a pharmaceutical composition is provided in powder form, comprising an anesthetic and controlled-release microparticles containing colchicine, wherein the microparticles are microparticles comprising a polymer matrix or multivesicular liposomes, and the colchicine-containing microparticles have an average particle size of 10 μm or more as determined by laser diffraction measurement.

[0286] In one embodiment, a pharmaceutical composition is provided in the form of a powder or in the form of a sterile and injectable dosage form, comprising microparticles comprising colchicine and a polymer matrix (the polymer matrix comprises at least one poly(lactic-co-glycolic acid) copolymer, particularly showing different molecular weights, particularly in the range of 40:60 to 75:25, more specifically in the range of 40:60 to 65:35, even more specifically in the range of 40:60 to 60:40, for example two copolymers having a molar ratio of lactic acid / glycolic acid of 50:50), as well as microparticles comprising an anesthetic and a polymer matrix (the polymer matrix comprises or even consists of at least one poly(lactic-co-glycolic acid) copolymer having a molar ratio of lactic acid:glycolic acid in the range of 40:60 to 75:25, more specifically in the range of 40:60 to 65:35, even more specifically in the range of 40:60 to 60:40, for example 50:50).

[0287] In another embodiment, a pharmaceutical composition in the form of a sterile and injectable suspension suitable for intra-articular injection, obtained by mixing a composition according to the invention in powder form with an aqueous injectable vehicle, optionally comprises an excipient selected from the group consisting of a tonicity enhancer, a wetting agent, a viscosity enhancer, a density enhancer and mixtures thereof, wherein the excipient may be present in the aqueous injectable vehicle or in the powder.

[0288] According to one embodiment, the powder further comprises an immediate-release dosage form containing colchicine, and the maximum weight ratio of the immediate-release colchicine to the total amount of colchicine is 25%.

[0289] When the pharmaceutical composition according to the invention is in powder form, an immediate-release dosage form of the above-mentioned anesthetic may be mixed with the powder containing colchicine prepared as described above.

[0290] Furthermore, if the pharmaceutical composition is in powder form, in order to achieve sustained release, the anesthetic may be present in the form of (i) microparticles containing a polymer matrix obtained via an oil-in-water emulsion (O / W), a water-in-oil-in-water emulsion (W / O / W), or a solid-in-oil-in-water emulsion (S / O / W), (ii) multivesicular liposomes, (iii) dehydrated hydrogels, or (iv) in situ-type forming depots obtained particularly from pH-induced, heat-induced, or solvent-exchange-induced gelation systems.

[0291] In one embodiment, the anesthetic exists in the form of controlled-release microparticles as detailed above. In such embodiments, the controlled-release dosage form containing colchicine, which is in the form of an in-situ forming depot, a hydrogel, or microparticles, particularly microparticles comprising a polymer matrix and multivesicular liposomes, and the controlled-release dosage form containing the anesthetic, particularly microparticles containing the anesthetic, are distinct and are formulated together in a unique sterile and injectable dosage form, particularly a suspension, or in a pharmaceutical composition according to the present invention.

[0292] The immediate-release dosage form of the anesthetic described above can be directly solubilized in the suspension according to the present invention and is intended for administration to the patient by intra-articular injection. This means that the anesthetic is not contained within the colchicine microparticles.

[0293] In one embodiment, the anesthetic agent may be present directly in a sterile and injectable dosage form, particularly a suspension, according to the present invention, in an amount adapted to remain below its solubility limit.

[0294] Therefore, the Specified herein further provides a pharmaceutical composition in the form of a sterile and injectable suspension, wherein colchicine is in the form of fine particles comprising a polymer matrix with an average particle size of 10 μm or more, as determined by laser diffraction, and the anesthetic is in an overall immediate-release dosage form and is directly solubilized in the suspension.

[0295] The present invention further relates to a pharmaceutical composition in the form of a sterile and injectable suspension suitable for intra-articular injection, obtained by mixing a formulation in the form of powder described above with an aqueous injection vehicle, wherein the composition optionally contains an excipient selected from the group consisting of tonicity enhancers, wetting agents, viscosity enhancers, density enhancers, and mixtures thereof, wherein the excipient may be present in the aqueous injection vehicle or in the powder.

[0296] In one embodiment, the pharmaceutical composition is characterized by a colchicine concentration in the range of 2.5 to 2500 μg per ml of suspension, particularly in the range of 2.5 to 1500 μg per ml of suspension, particularly in the range of 2.5 to 1000 μg per ml of suspension, more specifically in the range of 2.5 to 500 μg per ml of suspension, even more specifically in the range of 2.5 to 250 μg, or 0.2 to 100 μg, particularly in the range of 2 to 50 μg, and an anesthetic, particularly ropivacaine, present in a concentration in the range of 0.05 to 120 mg per ml of suspension, particularly in the range of 0.05 to 60 mg per ml of suspension, more specifically in the range of 0.05 to 20 mg per ml of suspension, for example, 1 to 120 mg, particularly in the range of 1 to 10 mg.

[0297] The pharmaceutical compositions used within the framework of this invention may take the form of sterile, injectable compositions, particularly suspension compositions, that contain an effective amount of colchicine.

[0298] "Sterile," in the sense of the present invention, means an environment that can guarantee the safety requirements described above, particularly regarding the administration route into or through the joint, for the compounds considered in the compositions according to the present invention. In fact, for obvious reasons, it is essential that the compositions according to the present invention do not contain any contaminants that could initiate undesirable side reactions at the host site.

[0299] The pharmaceutical compositions used within the framework of the present invention may be prepared using formulations in the form of a powder containing the above-described fine particles. According to one embodiment, the pharmaceutical composition is a sterile and injectable composition suitable for intra-articular injection for the controlled release of colchicine and the immediate and / or controlled release of an anesthetic.

[0300] Due to their injectable properties, the compositions according to the present invention always contain a physiologically acceptable medium, also known as an "aqueous injection vehicle."

[0301] "Physiologically acceptable medium" means a non-toxic medium suitable for injection and / or application of compositions such as those considered in the present invention.

[0302] More specifically, the present invention relates to a pharmaceutical composition as defined above, obtained by mixing a formulation in the form of powder described above with an aqueous injection vehicle, wherein the pharmaceutical composition optionally contains an excipient selected from the group consisting of a tonicity enhancer, a wetting agent, a viscosity enhancer, a density enhancer, and mixtures thereof, wherein the excipient may be present in the aqueous injection vehicle or in the powder.

[0303] The composition may contain a solvent or a mixture of physiologically acceptable solvents.

[0304] The composition may contain a physiologically acceptable aqueous medium.

[0305] Water can be cited as a suitable aqueous medium for the present invention.

[0306] Suitable isotonic agents for preparing the composition according to the present invention include sugars and sodium chloride.

[0307] Aqueous injection vehicles may particularly contain tonicity enhancers, wetting agents, viscosity enhancers, or mixtures thereof.

[0308] Among tonicity enhancers, the following can be mentioned: dextrose, mannitol, sorbitol, sucrose, glycerin, sodium chloride, potassium chloride, cyclodextrin, and maltodextrin.

[0309] Among humectants, the following can be mentioned: poly(oxyethylene)sorbitan fatty acid esters, for example, those commercially available under the trade name TWEEN®; sorbitan fatty acid esters, for example, those commercially available under the trade name SPAN; poloxamers; and lecithin.

[0310] Among viscosity enhancers, the following can be mentioned: sodium carboxymethylcellulose (CMC), glycosaminoglycans such as hyaluronic acid, dextran, collagen, poly(vinylpyrrolidone), poly(ethylene glycol), gelatin, hydroxyethylcellulose (HEC), methylcellulose (MC), arginate, acacia gum, and starch.

[0311] According to a particular embodiment, the pharmaceutical composition is 10s -1 It has a viscosity of 5–1000 mPa.s, particularly 5–500 mPa.s, particularly 5–100 mPa.s, and more specifically 5–50 mPa.s at a shear rate.

[0312] kit Further provided herein are kits or products comprising, in a separate compartment, (i) an aqueous injection vehicle containing an immediate-release dosage form of an anesthetic as defined herein, and (ii) an immediate-release or controlled-release dosage form or a defined powder containing colchicine as defined above, wherein at least one of (i) and (ii) contains an anesthetic, the anesthetic is in a partially or entirely immediate-release dosage form, and optionally includes excipients selected from the group consisting of tonicity enhancers, wetting agents, viscosity enhancers, density enhancers and mixtures thereof, for preparing a pharmaceutical composition suitable for intra-articular injection.

[0313] In one embodiment, the kit may be in the form of two separate vials.

[0314] In one embodiment, the first vial contains an aqueous injection vehicle, and the second vial contains, in particular, an immediate-release or controlled-release dosage form containing colchicine as defined above, or the powder as defined above, and an immediate-release dosage form of an anesthetic.

[0315] If both (i) and (ii) contain an anesthetic, it may be similar or different in each of (i) and (ii). As previously stated, throughout this description, the anesthetic may be a mixture of anesthetics.

[0316] In another embodiment, the kit and product may be in the form of vials and pre-filled syringes or medical devices, or in the form of two separate vials. In the embodiment, two compartments or dual chambers can enable mixing of the aqueous injection vehicle and the powder described herein by all means known to those skilled in the art. Furthermore, in the embodiment, the means may take the form of a punctureable membrane or a breakable diaphragm, for example, through pressure that can be applied by the user.

[0317] In these embodiments, the kit or product may additionally include a label instructing the user to introduce the resulting pharmaceutical composition into the joint of the subject.

[0318] According to one embodiment, the pharmaceutical composition may further comprise an immediate-release dosage form containing colchicine. The presence of such an immediate-release dosage form aims to achieve rapid colchicine concentration in the joint to rapidly relieve pain. In one embodiment, the maximum weight ratio of immediate-release colchicine to the total amount of colchicine is 25%.

[0319] In certain embodiments of the present invention, the weight ratio of immediate-release colchicine to the total amount of colchicine may be 0-5%, 0-10%, 0-15%, or 0-20%.

[0320] In some embodiments, the release time of the immediate-release dosage form is 0 to 6 hours. In some embodiments, the release time of the immediate-release dosage form is 0 to 2 hours.

[0321] The immediate-release dosage form may take the form of a controlled-release dosage form, particularly an immediate fraction mixed with the above-mentioned microparticles, or it may be present in the continuous phase to which the dosage form, particularly the microparticles, is mixed when preparing the pharmaceutical composition according to the present invention. The continuous phase may, of course, contain any further preferred, pharmaceutically acceptable excipients other than those already present in the microparticles.

[0322] For reasons of patient comfort and safety as described above, it is advantageous to find a pharmaceutical composition that is suitable for intra-articular injection into the joint, requires only one injection rather than multiple injections, and can alleviate the patient's symptoms with this injection.

[0323] Kits incorporating any form of colchicine, i.e., immediate-release or sustained-release, may be used in the treatment of crystal-associated acute inflammatory arthritis and non-crystal-associated acute inflammatory arthritis, particularly crystal-associated arthropathy or erythema or acute-type tendinitis and capsulitis, by intra-articular injection of the kit into the joint, wherein crystal-associated acute inflammatory arthritis and non-crystal-associated acute inflammatory arthritis are selected from non-crystal-associated acute arthritis such as rheumatoid arthritis, ankylosing spondylitis, juvenile arthritis, psoriatic arthritis, lupus, and more specifically from crystal-associated arthropathy attacks or erythema or acute-type tendinitis and capsulitis, selected from gout, chondrocalcinosis, calcific tendinitis, and Milwaukee shoulder syndrome.

[0324] Kits incorporating any form of colchicine, i.e., immediate-release or sustained-release, may be used in the treatment of crystal-associated acute inflammatory arthritis and non-crystal-associated acute inflammatory arthritis, particularly crystal-associated arthropathy or erythema or acute-type tendinitis and capsulitis, in patients with renal and / or hepatic impairment, along with atazanavir, clarithromycin, darunavir, ritonavir, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir, saquinavir, It may be used for the protection of joints, bones and / or cartilage in patients treated simultaneously, separately, sequentially and non-exclusively with at least one active ingredient selected from telithromycin, tipranavir, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, cyclosporine, lanolazine, macrolides and statins, or in patients with chronic comorbidities such as hypertension, chronic kidney disease, diabetes, heart disease, infections and / or immunosuppression.

[0325] Additional active ingredients Depending on the specific condition or disease being treated, additional therapeutic agents that are normally administered to treat that condition may be given in combination with colchicine and an anesthetic.

[0326] As used herein, the terms “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of the additional active ingredient with colchicine and the anesthetic. For example, a combination may be administered with the additional active ingredient simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form.

[0327] According to one embodiment, hyaluronic acid may be injected into a painful joint, or it may be present, for example, in a pharmaceutical composition according to the present invention. The use of hyaluronic acid in the treatment of arthritis such as osteoarthritis is well known as intra-articular replacement therapy. Accordingly, according to one embodiment, the present invention provides a pharmaceutical composition according to the present invention comprising colchicine and an anesthetic, further comprising hyaluronic acid.

[0328] In some embodiments, the present invention provides pharmaceutical compositions comprising colchicine and an anesthetic according to the present invention, further comprising at least an additional therapeutic agent. Preferred additional active ingredients are described in further detail below.

[0329] According to one embodiment, the following active ingredients, in particular any anti-inflammatory active ingredients, may be combined: -(i) Corticosteroids, such as prednisone, prednisolone, methylprednisolone, betamethasone, dexamethasone, triamcinolone acetonide, triamcinolone hexaacetonide, budenoside, mometasone, ciclesonide, fluticasone, hydrocortisone, and pharmaceutically acceptable salts thereof (especially in low doses), -(ii) NSAIDs, e.g., aspirin, diclofenac, aceclofenac, sulindac, ketrolac, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, indomethacin, proglummetacin, tiaprofenic acid, meloxicam, piroxicam, tenoxicam, etodolac and celecoxib, etoricoxib, parecoxib, rofecoxib, valdecoxib, and pharmaceutically acceptable salts thereof. -(iii) Anti-IL-1β agents, e.g., anakinra, canakinumab, lilonacept, and pharmaceutically acceptable salts thereof. -(iv) Anti-IL-6 agents, e.g., tocilizumab, siltuximab, sarilumab, and pharmaceutically acceptable salts thereof. -(v) Anti-TNFα agents, e.g., adalimumab, etanercept, infliximab, certolizumab, golimumab, and pharmaceutically acceptable salts thereof. -(vi) Antiangiogenic agents, e.g., bevacizumab, and pharmaceutically acceptable salts thereof, -(vii) Anti-NGF (Nerve Growth Factor) agents, e.g., facinumab, tanezumab, fluranumab, 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), e.g., cytochalasin B, WZB-117, STF-31, BAY-876, -(x) A mixture of these.

[0330] The additional active ingredients may be formulated in immediate-release and / or controlled-release dosage forms.

[0331] Administration of composition Pharmaceutical compositions used within the framework of this invention can be injected using any method known in the art.

[0332] In particular, the pharmaceutical composition may be administered by a syringe suitable for intra-articular injection, such as a syringe equipped with a needle of 19-29G, preferably 22-29G, and more preferably 25-29G.

[0333] Throughout this description, including the claims, the expression “includes” should be understood to mean “includes at least one” unless otherwise specified.

[0334] The expressions "between... and..." and "within the range of..." should be understood to include a limit unless otherwise specified. [Examples]

[0335] The following embodiments and figures are presented as non-limiting examples of the present invention.

[0336] Analysis method -Particle size was determined using a Malvern Mastersizer MS3000 laser diffraction particle size analyzer. Preparations of 0.1–1 mg of fine particles per 1 ml of deionized water were prepared with or without an ultrasonic bath and then introduced into the instrument. Three measurements were performed. 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.

[0337] -The drug load of colchicine microparticles in Examples 1, 2, and 3 was determined by dissolving 15 mg of particles in 1.25 mL of acetonitrile. After dissolution was complete, 11.25 mL of methanol was added. Then, 12.5 mL of deionized water was introduced, and the mixture was thoroughly mixed using vortex stirring. 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). A fixed volume of 2 mL of the filtered supernatant was then analyzed by HPLC to determine the drug load of the microparticles. HPLC was performed on an Agilent HP1200 system using a silica-based reversed-phase C8 column [GL Science, Inertsil C8-3, 4.6 × 250 mm (5 μm)] set to 25 °C. The mobile phase consisted of 55% methanol and a 45% 6.8 g / L KH2PO4 solution pre-adjusted to pH 5.5 with diluted phosphoric acid. The flow rate was set to 1 mL / min, the injection volume to 20 μL, and UV detection was set to 254 nm.

[0338] -The drug load of ropivacaine microparticles in Examples 4, 7, and 10 was determined by dissolving 15 mg of particles in 1.25 mL of acetonitrile. After dissolution was complete, 11.25 mL of methanol was added. Then, 12.5 mL of deionized water was introduced, and the mixture was thoroughly mixed using a vortex mixer. Next, the medium was centrifuged at 4000 rpm for 30 minutes, and the supernatant was filtered through a 0.45 μm PTFE filter (Acrodisc wwPTFE). Then, a fixed volume of 2 ml of the filtered supernatant was analyzed by HPLC to determine the drug load of the microparticles. HPLC was performed on an Agilent HP1200 system using a silica-based reversed-phase C8 column [GL Science, Inertsil C8-3, 4.6 × 250 mm (5 μm)] set to 25°C. The mobile phase consisted of 40% acetonitrile and 60% 6.8 g / L KH2PO4 solution pre-adjusted to pH 5.5 with diluted phosphoric acid. The flow rate was set to 1 mL / min, the injection volume to 20 μL, and UV detection to 215 nm.

[0339] -To perform in vitro release tests from colchicine microparticles in Examples 1, 2, and 3, a fixed amount of 20 mg of microparticles was suspended in 50 mL of phosphate-buffered saline (10 mM, pH 7.4) and maintained at 37°C using a horizontal shaker (GFL's commercially available incubator model 3033) or a magnetic stirrer. At various intervals, 3 mL of the medium was taken and centrifuged at 4000 rpm for 3 minutes. The supernatant was analyzed by 350 nm UV (FastTrack-Mettler Toledo). Immediately after UV analysis, the sample was returned to the dissolution flask.

[0340] -To perform in vitro release tests from ropivacaine microparticles in Examples 4, 7, and 10, a fixed amount of 20 mg of microparticles was suspended in 20 mL of phosphate-buffered saline (10 mM, pH 7.4), with or without the use of an ultrasonic bath, and maintained at 37°C in a horizontal shaker (GFL's commercially available incubator model 3033) or using a magnetic stirrer. At various intervals, 1 mL of the medium was taken and filtered through a 0.45 μm PTFE filter (Acrodisc wwPTFE), while the volume taken from the container was replaced with fresh medium. The filtered samples were then analyzed by HPLC as described above.

[0341] Example 1: Sustained-release colchicine microparticles and pharmaceutical composition containing the same Colchicine microparticles were prepared under laminar flow using an autoclave and sterilized container as follows: A 1% by weight polyvinyl alcohol (PVA, Mowiol 4-88, Sigma-Aldrich) stock solution was prepared by heating 2970 g of sterile water (Gibco 15230-162) to 70°C and dispersing 30 g of PVA in it under magnetic stirring until completely solubilized. The solution was then cooled before use.

[0342] In a separate autoclaved container, 4.03 g of colchicine (INDENA, Italy) was solubilized in 10.75 mL of methylene chloride (Merck) under magnetic stirring. Then, 6.02 g of PLGA 50:50 Resomer 503H [poly(lactic acid-coglycolic acid) copolymer 50:50, Mw=24~38 kg / mol, (Evonik Industries AG, Essen, Germany)] was introduced into the mixture and completely dissolved under magnetic stirring to form a polymer-drug solution.

[0343] Next, 28.6 g of the previously prepared PVA (1 wt%) stock solution was added to the drug-polymer solution using an IKA T25 Ultra-Turrax rotor-stator mixer equipped with an S25N 10G head, under high shear (11000 RPM) for a duration of 60 seconds.

[0344] Next, this emulsion was slowly poured into a curing bath containing 2860g of the previously prepared PVA (1% by weight) stock solution.

[0345] Stirring was maintained for 3 hours using a double-propeller stirrer at a stirring speed of 300 RPM until the methylene chloride evaporated.

[0346] The formed fine particles were centrifuged at 4000 RPM for 3 minutes using a swing bucket GT2R centrifuge to remove the main part of the aqueous phase and obtain a concentrated particle slurry, which was then vacuum filtered through a 12-25 μm Whatman cellulose filter and washed with 150 ml of water.

[0347] The washed particles were then vacuum-dried at 0.08 mBar and a shelf temperature of 15°C for 17 hours.

[0348] Next, the collected particles were stored at 5°C.

[0349] The analytical tests, including the in vitro profile, were carried out as described in the "Analytical Methods" section above, and are shown in Table 3 below.

[0350] [Table 4]

[0351] In this example, colchicine-loaded PLGA microparticles with a drug load of 22% by weight were prepared.

[0352] An aqueous injection vehicle was prepared under laminar flow using pyrogen-free excipients, consisting of 1.4% low-viscosity sodium carboxymethylcellulose (Aqualon CMC 7LF PH BET, Ashland), 0.1% polysorbate 20 (Merck Emprove Essential), 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 6.9 using concentrated sodium hydroxide solution (Roth). The vehicle was then autoclaved at 121°C for 20 minutes (Systec 3150EL), and a constant volume of 55 mL of the solution was aseptically transferred under laminar flow into a 100 mL vial.

[0353] Fifteen minutes before the in vivo injection described in Example 10 below, a fixed amount of 10 mg of microparticles prepared according to this example was dispersed in 55 mL of an injection vehicle using ultrasound for 30 seconds until a homogeneous dispersion was obtained. From the suspension of colchicine-loaded PLGA microparticles thus prepared, colchicine concentrations of 0.04 mg / ml or 40 μg / ml were obtained.

[0354] Example 2: Sustained-release colchicine microparticles Colchicine microparticles were prepared as follows: 8712 g of deionized water was heated to 70°C, and 88 g of PVA was dispersed in it under magnetic stirring until completely solubilized, thereby preparing a 1 wt% polyvinyl alcohol (PVA, Mowiol 4-88, Sigma-Aldrich) stock solution. The solution was then cooled before use.

[0355] In a separate container, 1.5 g of colchicine (INDENA, Italy) was solubilized in 32.25 mL of methylene chloride (Merck) under magnetic stirring. Then, 8.55 g of PLGA 50:50 Resomer 503H [poly(lactic acid-coglycolic acid) copolymer 50:50, Mw=24~38 kg / mol, (Evonik Industries AG, Essen, Germany)] and 0.45 g of PLGA 50:50 Resomer 502H [poly(lactic acid-coglycolic acid) copolymer 50:50, Mw=7~17 kg / mol, (Evonik Industries AG, Essen, Germany)] were introduced into the mixture and completely dissolved under magnetic stirring to form a polymer-drug solution.

[0356] Next, 85.8 g of the previously prepared PVA (1 wt%) stock solution was added to the drug-polymer solution under high shear (9500 RPM). Emulsification was performed for a continuous period of 10 minutes using an IKA T25 Ultra-Turrax rotor-stator mixer equipped with an S25N 10G head.

[0357] Next, this emulsion was slowly poured into a curing bath containing 7000g of the previously prepared PVA (1% by weight) stock solution.

[0358] Stirring was maintained for 3 hours using a double-propeller stirrer at a stirring speed of 300 RPM until the methylene chloride evaporated.

[0359] The formed fine particles were centrifuged at 4000 RPM for 3 minutes using a swing bucket GT2R centrifuge to remove the main part of the aqueous phase and obtain a concentrated particle slurry. The slurry was then redispersed in approximately 20 ml of water, and the redispersed particles were sieved using a stainless steel Endecotts sieve to 40 μm and then 10 μm.

[0360] Next, the collected particles were vacuum filtered through a 12-25 μm Whatman cellulose filter and washed with 150 ml of water.

[0361] The washed particles were then vacuum-dried at 2 mBar and a shelf temperature of 15°C for 17 hours.

[0362] Next, the collected particles were stored at 5°C.

[0363] The analytical tests, including the in vitro profile, were performed as described in the "Analytical Methods" section above, and are shown in Table 4 below.

[0364] [Table 5]

[0365] In this example, colchicine-loaded PLGA microparticles were prepared with a drug load of 4.3% by weight and an average particle size of 24 μm.

[0366] Example 3: Sustained-release colchicine microparticles Colchicine microparticles were prepared under laminar flow using an autoclave and sterilized container as follows: A 1% by weight polyvinyl alcohol (PVA, Mowiol 4-88, Sigma-Aldrich) stock solution was prepared by heating 2970 g of sterile water (Gibco 15230-162) to 70°C and dispersing 30 g of PVA in it under magnetic stirring until completely solubilized. The solution was then cooled before use.

[0367] In a separate autoclaved container, 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 [poly(lactic acid-coglycolic acid) copolymer 50:50, Mw=24~38 kg / mol, (Evonik Industries AG, Essen, Germany)] and 0.15 g of PLGA 50:50 Resomer 502H [poly(lactic acid-coglycolic acid) copolymer 50:50, Mw=7~17 kg / mol, (Evonik Industries AG, Essen, Germany)] were introduced into the mixture and completely dissolved under magnetic stirring to form a polymer-drug solution.

[0368] Next, 28.6 g of the previously prepared PVA (1 wt%) stock solution was added to the drug-polymer solution under high shear (9500 RPM). Emulsification was performed for a continuous period of 10 minutes using an IKA T25 Ultra-Turrax rotor-stator mixer equipped with an S25N 10G head.

[0369] Next, this emulsion was slowly poured into a curing bath containing 2860g of the previously prepared PVA (1% by weight) stock solution.

[0370] Stirring was maintained for 3 hours using a double-propeller stirrer at a stirring speed of 300 RPM until the methylene chloride evaporated.

[0371] The formed fine particles were centrifuged at 4000 RPM for 3 minutes using a swing bucket GT2R centrifuge to remove the main part of the aqueous phase and obtain a concentrated particle slurry. The slurry was then redispersed in approximately 20 ml of water, and the redispersed particles were sieved using a stainless steel Endecotts sieve to 40 μm and then 10 μm.

[0372] Next, the collected particles were vacuum filtered through a 12-25 μm Whatman cellulose filter and washed with 150 ml of sterile water.

[0373] The washed particles were then vacuum-dried at 2 mBar and a shelf temperature of 15°C for 17 hours.

[0374] Next, the collected particles were stored at 5°C.

[0375] The analytical tests, including the in vitro profile, were carried out as described in the "Analytical Methods" section above, and are shown in Table 5 below.

[0376] [Table 6]

[0377] In this example, colchicine-loaded PLGA microparticles were prepared with a drug load of 5.1% by weight and an average particle size of 21 μm.

[0378] Example 4: Sustained-release ropivacaine microparticles Ropivacaine microparticles were prepared as follows: 4.01 g of ropivacaine HCl (Benechim, Belgium) was dispersed in 100 ml of deionized water until completely solubilized. The pH was then adjusted to 9.9, thus obtaining ropivacaine base in the form of a precipitate. The solid was filtered (Buchner, 11 μm) and vacuum-dried at room temperature for 17 hours. Approximately 2.6 g of ropivacaine base was recovered.

[0379] Separately, 3069 g of deionized water was heated to 70°C, and 31 g of PVA was dispersed in it under magnetic stirring until completely solubilized, thereby preparing a 1 wt% polyvinyl alcohol (PVA, Mowiol 4-88, Sigma-Aldrich) stock solution. The solution was then cooled before use.

[0380] In a separate container, 0.5 g of the previously recovered ropivacaine base was solubilized in 10.75 mL of methylene chloride (Merck) under magnetic stirring. Then, 3 g of PLGA 50:50 Resomer 502H [poly(lactic acid-coglycolic acid) copolymer 50:50, Mw=7~17 kg / mol, (Evonik Industries AG, Essen, Germany)] was introduced into the mixture and completely dissolved under magnetic stirring to form a polymer-drug solution.

[0381] Next, 26.3 g of the previously prepared PVA (1 wt%) stock solution was slowly added to the drug-polymer solution under high shear (9500 RPM). Emulsification was carried out over a continuous period of 10 minutes using an IKA T25 Ultra-Turrax rotor-stator mixer equipped with an S25N 10G head.

[0382] Next, this emulsion was slowly poured into a curing bath containing 2989 g of the previously prepared PVA (1 wt%) stock solution.

[0383] Stirring was maintained for 3 hours using a double-propeller stirrer at a stirring speed of 300 RPM until the methylene chloride evaporated.

[0384] The formed fine particles were centrifuged at 4000 RPM for 3 minutes using a swing bucket GT2R centrifuge to remove the main part of the aqueous phase and obtain a concentrated particle slurry. The slurry was then redispersed in approximately 20 ml of water, and the redispersed particles were sieved through a 40 μm stainless steel Endecotts sieve.

[0385] Next, the collected particles were vacuum filtered through a 12-25 μm Whatman cellulose filter and washed with 150 ml of water.

[0386] The washed particles were then vacuum-dried at 2 mBar and a shelf temperature of 15°C for 17 hours.

[0387] Next, the collected particles were stored at 5°C.

[0388] The analytical tests, including the in vitro profile, were performed as described in the "Analytical Methods" section above, and are shown in Table 6 below.

[0389] [Table 7]

[0390] In this example, ropivacaine-loaded PLGA microparticles were prepared with a drug load of 5.7% by weight and an average particle size of 13 μm.

[0391] Example 5: Ropivacaine Hydrogel A 20 mg / ml stock solution of ropivacaine was prepared by solubilizing 201 mg of ropivacaine HCl (Benechim, Belgium) in 10 ml of deionized water. Once completely solubilized, 150 mg of sodium hyaluronate 1500 kDa (Tebubio H-1500) was dispersed in the stock solution under magnetic stirring for approximately 4 hours until completely solubilized. The mixture was then covered and left at room temperature overnight.

[0392] The following day, a fixed amount (1 ml) of prepared ropivacaine hydrogel was placed in a dialysis bag (12-14 kDa) and immersed in a 50 ml Schott flask filled with 25 ml of phosphate-buffered saline (10 mM). The container was sealed and left to stand under magnetic agitation.

[0393] At predetermined intervals, 500 μL of the medium was withdrawn and replaced with fresh PBS (10 mM) medium. The released ropivacaine was quantified by HPLC as described in the "Analytical Method" section above, and the results are shown in Table 7 below.

[0394] [Table 8]

[0395] Example 6: Pharmaceutical composition An aqueous injection vehicle was prepared under laminar flow using injection-grade water and excipients free of pyrogens. The vehicle consisted of 1.4% low-viscosity sodium carboxymethylcellulose (Aqualon CMC 7LF PH BET, Ashland), 0.1% polysorbate 20 (Merck's Emprove Essential), 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 using concentrated sodium hydroxide solution (Roth).

[0396] Next, the vehicle was autoclaved at 121°C for 20 minutes (Systec 3150EL) and finally stored at 4°C for later use.

[0397] The pharmaceutical composition was prepared by weighing 10 mg of colchicine microparticles prepared according to Example 3, 860 mg of ropivacaine microparticles prepared according to Example 4, and 51 mg of ropivacaine HCl into a 20 ml pre-autoclaved container.

[0398] 12.85 ml of aqueous injection vehicle was introduced into a vial and homogenized until the particles were completely dispersed. From the resulting suspension, colchicine concentrations of 40 μg / ml, ropivacaine delivered in the form of 3.8 mg / ml fine particles, and ropivacaine delivered in the form of immediate release were obtained. 50 μL of this suspension was then injected into the ankle joint of inflamed rats.

[0399] Example 7: Sustained-release ropivacaine microparticles A 1% by weight polyvinyl alcohol (PVA, Mowiol 4-88, Sigma-Aldrich) stock solution was prepared by heating 3069 g of deionized water to 70°C and dispersing 31 g of PVA in it under magnetic stirring until completely solubilized. The solution was then cooled before use.

[0400] In a separate container, 0.508 g of ropivacaine base, prepared earlier as described in Example 4, was solubilized in 10.75 mL of methylene chloride (Merck) under magnetic stirring. Then, 3,003 g of PLGA 50:50 Resomer 502H [poly(lactic acid-coglycolic acid) copolymer 50:50, Mw=7~17 kg / mol, (Evonik Industries AG, Essen, Germany)] was introduced into the mixture and completely dissolved under magnetic stirring to form a polymer-drug solution.

[0401] Next, 26.30 g of the previously prepared PVA (1 wt%) stock solution was slowly added to the drug-polymer solution under high shear (9500 RPM). Emulsification was performed for a continuous period of 10 minutes using an IKA T25 Ultra-Turrax rotor-stator mixer equipped with an S25N 10G head.

[0402] Next, this emulsion was slowly poured into a curing bath containing 2974 g of the previously prepared PVA (1 wt%) stock solution.

[0403] Stirring was maintained for 3 hours using a double-propeller stirrer at a stirring speed of 300 RPM until the methylene chloride evaporated.

[0404] The formed fine particles were centrifuged at 4000 RPM for 3 minutes using a swing bucket GT2R centrifuge to remove the main part of the aqueous phase and obtain a concentrated particle slurry. The slurry was then redispersed in approximately 20 ml of water, and the redispersed particles were sieved through a 40 μm stainless steel sieve.

[0405] Next, the collected particles were vacuum filtered through a cellulose filter with a diameter of 12-25 μm and washed with 150 ml of water.

[0406] The washed particles were then vacuum-dried at 2 mBar and a shelf temperature of 15°C for 17 hours.

[0407] Next, the collected particles were stored at 5°C.

[0408] The analytical tests, including the in vitro profile, were performed as described in the "Analytical Methods" section above, and are shown in Table 8 below.

[0409] [Table 9]

[0410] In this example, ropivacaine-loaded PLGA microparticles were prepared with a drug load of 3.6% by weight and an average particle size of 14 μm.

[0411] Example 8: Pharmaceutical composition An aqueous injection vehicle was prepared under laminar flow using injection-grade water and excipients free of pyrogens. The vehicle consisted of 1.4% low-viscosity sodium carboxymethylcellulose (Aqualon CMC 7LF PH BET, Ashland), 0.1% polysorbate 20 (Merck's Emprove Essential), 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 6.9 using concentrated sodium hydroxide solution (Roth).

[0412] Next, the vehicle was autoclaved at 121°C for 20 minutes (Systec 3150EL) and finally stored at 4°C for later use.

[0413] The pharmaceutical composition was prepared by weighing 10 mg of colchicine microparticles prepared according to Example 3, 1,600 g of ropivacaine microparticles prepared according to Example 7, and 51 mg of ropivacaine HCl in a 20 ml autoclaved container.

[0414] Immediately before in vivo injection, 12.85 ml of aqueous injection vehicle was introduced into a vial and homogenized using ultrasonic stirring until the particles were completely and uniformly dispersed. From the suspension thus prepared, a colchicine concentration of 40 μg / ml, a ropivacaine concentration delivered in the form of 4.5 mg / ml fine particles, and a ropivacaine concentration delivered in the form of immediate release of 4 mg / ml were obtained. Next, 50 μL of this suspension was injected into the ankle joint of an inflamed rat described in Example 9.

[0415] Example 9: In vivo protection of cartilage The pharmaceutical composition described in Example 8 was injected into the ankle joint of an inflamed rat, and its effect on cartilage destruction was observed.

[0416] In this example, 16 Sprague Dawley rats were randomly divided into two groups, with 8 rats in each group.

[0417] • In the first group (control group), inflammation was immediately induced by intra-articular injection of phosphate-buffered saline (50 μL) into the left ankle, followed by injection of λ-carrageenan (1 mg / 30 μL) into the same joint.

[0418] • In the second group (treatment group), inflammation was immediately induced by intra-articular injection of the pharmaceutical composition (50 μL) into the left ankle, followed by injection of λ-carrageenan (1 mg / 30 μL) into the same joint.

[0419] Three days after injection, all animals were euthanized, and the ankle joints were dissected for histological examination. The samples were immersed overnight in 10% formalin. The following day, decalcification was performed in RDO (Eurobio) for 5 hours, followed by EDTA (0.5M) for 48 hours. The samples were then dehydrated in an automat and embedded in paraffin. 4 μm sections were prepared and stained with hematoxylin-eosin. Observation was blinded.

[0420] Inflammation and synovial invasion were scored using a Likert scale ranging from 0 to 3.

[0421] [Table 10]

[0422] Cartilage destruction was also scored based on a Likert scale ranging from 0 to 3.

[0423] [Table 11]

[0424] The results are reported in Figure 1.

[0425] All control animals (Group 1) exhibited varying degrees of arthritis in all cases, showing traces of local inflammation (moderate to severe) with variable synovial thickening, influx of inflammatory cells, and periarticular tissue infiltration due to marked inflammation, often in the subsynovial and perisynovial fat. The latter findings were observed particularly in the posterior region (Kager triangle), attributable to direct contact with the injected inflammatory substance (i.e., carrageenan). Bone and cartilage destruction was observed in 5 of the 8 rats in Group 1, with niches forming in the bone structure.

[0426] Animals treated with the pharmaceutical composition (Group 2) showed a clear improvement in these signs. With treatment, inflammation was generally mild, and no bone or cartilage destruction was observed. These differences were statistically significant (non-parametric Mann-Whitney test, p<0.01).

[0427] Example 10: Sustained-release ropivacaine microparticles Ropivacaine microparticles were prepared as follows: 4.08 g of ropivacaine HCl (Benechim, Belgium) was dispersed in 100 ml of deionized water for approximately 24 hours until completely solubilized. The pH was then adjusted to 9.9, thus obtaining ropivacaine base in the form of a precipitate. The solid was filtered (Buchner, 11 μm) and vacuum-dried at room temperature for 17 hours. Approximately 3.08 g of ropivacaine base was recovered.

[0428] Separately, 3071 g of deionized water was heated to 70°C, and 30 g of PVA was dispersed in it under magnetic stirring until completely solubilized to prepare a 1 wt% polyvinyl alcohol (PVA, Mowiol 4-88, Sigma-Aldrich) stock solution. The solution was then cooled before use.

[0429] In a separate container, 1.0 g of the previously recovered ropivacaine base was solubilized in 10.75 mL of methylene chloride (Merck) under magnetic stirring. Then, 1.50 g of PLGA 50:50 Resomer 502H [poly(lactic acid-coglycolic acid) copolymer 50:50, Mw=7~17 kg / mol, (Evonik Industries AG, Essen, Germany)] was introduced into the mixture and completely dissolved under magnetic stirring to form a polymer-drug solution.

[0430] Next, 26.30 g of the previously prepared PVA (1 wt%) stock solution was slowly added to the drug-polymer solution under high shear (9500 RPM). Emulsification was performed for a continuous period of 10 minutes using an IKA T25 Ultra-Turrax rotor-stator mixer equipped with an S25N 10G head.

[0431] Next, this emulsion was slowly poured into a curing bath containing 2989.25 g of the previously prepared PVA (1 wt%) stock solution.

[0432] Stirring was maintained for 3 hours using a double-propeller stirrer at a stirring speed of 300 RPM until the methylene chloride evaporated.

[0433] The formed fine particles were centrifuged at 4000 RPM for 3 minutes using a swing bucket GT2R centrifuge to remove the main part of the aqueous phase and obtain a concentrated particle slurry. The slurry was then redispersed in approximately 20 ml of water, and the redispersed particles were sieved through a 40 μm stainless steel Endecotts sieve.

[0434] Next, the collected particles were vacuum filtered through a 12-25 μm Whatman cellulose filter and washed with 150 ml of water.

[0435] Next, the washed particles were vacuum-dried at 2 mBar and a shelf temperature of 5°C for 17 hours.

[0436] Next, the collected particles were stored at 5°C.

[0437] The analytical tests, including the in vitro profile, were carried out as described in the "Analytical Methods" section above, and are shown in Table 9 below.

[0438] [Table 12]

[0439] In this example, ropivacaine-loaded PLGA microparticles were prepared with a drug load of 26.6% by weight and an average particle size of 8 μm.

[0440] Example 11: Composition comprising a controlled-release form of colchicine and an immediate-release form of ropivacaine An aqueous injection vehicle was prepared under laminar flow using injection-grade water and excipients free of pyrogens. The vehicle consisted of 1.4% low-viscosity sodium carboxymethylcellulose (Aqualon CMC 7LPH BET, Ashland), 0.1% polysorbate 20 (Merck's Emprove Essential), 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).

[0441] Next, the vehicle was autoclaved at 121°C for 20 minutes (Systec 3150EL) and finally stored at 4°C for later use.

[0442] The pharmaceutical composition was prepared by weighing 65 mg of ropivacaine HCl and 10 mg of colchicine microparticles prepared according to Example 3 into a 20 ml autoclaved container.

[0443] Immediately before in vivo injection, 12.50 ml of aqueous injection vehicle was introduced into a vial and homogenized using ultrasonic stirring until the particles were completely and uniformly dispersed. From the suspension thus prepared, a colchicine concentration of 40 μg / ml and a ropivacaine HCl concentration of 5 mg / ml were obtained. Next, 50 μL of this suspension was injected into the ankle joint of an inflamed rat described in Example 12.

[0444] Example 12: In vitro cartilage protection using a combination of colchicine and ropivacaine The pharmaceutical composition described in Example 11 was injected into the ankle joint of an inflamed rat, and its effect on cartilage destruction was observed.

[0445] In this example, 16 Sprague Dawley rats were randomly divided into two groups, with 8 rats in each group.

[0446] • In the first group (control group), inflammation was immediately induced by intra-articular injection of phosphate-buffered saline (50 μL) into the left ankle, followed by injection of λ-carrageenan (1 mg / 30 μL) into the same joint.

[0447] • In the second group (treatment group), inflammation was immediately induced by intra-articular injection of the pharmaceutical composition (50 μL) into the left ankle, followed by injection of λ-carrageenan (1 mg / 30 μL) into the same joint.

[0448] Three days after injection, all animals were euthanized, and the ankle joints were dissected for histological examination. The specimens were immersed overnight in 10% formalin. 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. Observation was blinded.

[0449] Inflammation and synovial invasion were scored using a Likert scale ranging from 0 to 3.

[0450] [Table 13]

[0451] Cartilage destruction was also scored based on a Likert scale ranging from 0 to 3.

[0452] [Table 14]

[0453] The results are reported in Figure 2.

[0454] All but one control animal (Group 1) showed cartilage destruction and inflammatory arthritis (moderate to severe, with synovial thickening, presence of inflammatory cells, and periarticular tissue infiltration).

[0455] In contrast, treated animals (Group 2) showed absent (4 / 7 rats), mild (2 / 7 rats), or moderate (1 / 7 rats) inflammatory synovitis. Animals in Group 2 showed absent (5 / 7 rats) or mild signs (2 / 7) cartilage destruction. In summary, these findings demonstrate the clear anti-inflammatory and anti-destructive effects of the treatment in this rat model of acute arthritis.

[0456] Analysis of inflammation scores in treated ankle cartilage showed a statistically significant difference between Group 2 and Group 1 (p < 0.05, Kruskal-Wallis test and Dunnett test). Furthermore, analysis of destruction scores showed a clear and significant statistically important effect of Group 2 compared to Group 1 (p < 0.01, Kruskal-Wallis test and Dunnett test).

Claims

1. A pharmaceutical composition suitable for intra-articular injection, comprising an anesthetic and an immediate-release or controlled-release dosage form containing colchicine, wherein the anesthetic is partially or entirely in an immediate-release dosage form.

2. The pharmaceutical composition according to claim 1, wherein the dosage form containing colchicine is an immediate-release dosage form, and the colchicine concentration is less than 125 μg per 1 ml of sterile and injectable dosage form, particularly in the range of 0.02 to 125 μg / ml, and more specifically in the range of 0.02 to 75 μg / ml.

3. The pharmaceutical composition according to claim 1, wherein the dosage form containing colchicine is a controlled-release dosage form containing colchicine, and is in the form of an in-situ type forming depot, a hydrogel, or microparticles, particularly microparticles containing a polymer matrix and multivesicular liposomes.

4. The pharmaceutical composition according to claim 3, wherein the controlled-release dosage form containing colchicine is in the form of fine particles, particularly fine particles containing a polymer matrix, and the colchicine-containing fine particles have an average particle size of 10 μm or more as determined by laser diffraction measurement, particularly less than 100 μm, more specifically less than 80 μm, and even more specifically less than 50 μm, for example, having an average particle size of 10 to 50 μm or 10 to 40 μm.

5. The pharmaceutical composition according to claim 4, wherein the fine particles may be a mixture of fine particles having different properties, and are fine particles comprising colchicine and a polymer matrix, the polymer matrix comprising at least one poly(lactic acid-coglycolic acid) copolymer, in particular two copolymers having different molecular weights, at least one poly(caprolactone), or at least a mixture of at least one poly(lactic acid-coglycolic acid) copolymer and at least one poly(caprolactone).

6. The pharmaceutical composition according to claim 4 or 5, wherein the weight percentage ratio or drug load between colchicine and the total weight of the fine particles is in the range of 0.1 to 35% by weight, particularly 0.5 to 30% by weight, more specifically 1 to 25% by weight, and even more specifically 1 to 10% by weight.

7. The polymer matrix is ​​different from poly(lactic acid-coglycolic acid) copolymer, poly(lactide), poly(glycolide), poly(lactide-cocaprolactone), poly(ethylene glycol), poly(ethylene oxide), PLGA-b-PEO-b-PLGA, PLGA-b-PEO, polyhydroxyalkanoate, poly(hydroxybutyrate), poly(trimethylene carbonate), poly(dioxanone), poly(valerolactone), poly(alpha-hydroxy acid), poly(lactone), poly(amino acid), polyanhydride, poly(orthoester), poly(acetate) A pharmaceutical composition according to any one of claims 4 to 6, further comprising polysaccharides such as poly(ester-co-amide), polyurethane, polythioester, polyphosphoester, poly(ester-co-amide), poly(vinyl alcohol), PVA-g-PLGA, poly(ether ester) multiblock copolymer, polyvinylpyrrolidone, poly(methacrylate), PEO-PPO-PEO, gelatin, heparin, chondroitin sulfate; polysaccharides such as arginate, starch, chitosan, and dextran, and any combination thereof, particularly one or more additional polymers or copolymers selected from poly(lactide) and poly(caprolactone).

8. The polymer matrix is ​​(i) a poly(lactic acid-coglycolic acid) copolymer or a mixture of poly(lactic acid-coglycolic acid) copolymers having a molar ratio of lactic acid:glycolic acid of 50:50, particularly in the range of 40:60 to 75:25, more specifically in the range of 40:60 to 65:35, and even more specifically in the range of 40:60 to 60:40, for example, (ii) poly(caprolactone), and (iii) particularly in the range of 40:60 to 75:25, more specifically in the range of 40:60 to 65:35, and even more specifically in the range of 40:60 to 60:40 A pharmaceutical composition according to any one of claims 4 to 7, comprising at least one polymer selected from a poly(lactic acid-coglycolic acid) copolymer or a mixture of poly(lactic acid-coglycolic acid) copolymers having a molar ratio of lactic acid:glycolic acid in the range of 50:50, for example, a mixture of poly(lactic acid-coglycolic acid) copolymers and at least one poly(caprolactone), wherein the amount of the polymer selected from (i), (ii), and (iii) is greater than 70% by weight, more particularly greater than 80% by weight, and more specifically greater than 90% by weight, relative to the total weight of the polymer matrix.

9. The polymer matrix comprises, or further comprises, one first poly(lactic acid-coglycolic acid) copolymer and one second poly(lactic acid-coglycolic acid) copolymer, both poly(lactic acid-coglycolic acid) copolymers having a lactic acid:glycolic acid molar ratio in the range of 40:60 to 75:25, more specifically in the range of 40:60 to 65:35, and even more specifically in the range of 40:60 to 60:40, for example, 50:50, and the first poly(lactic acid-coglycolic acid) The pharmaceutical composition according to any one of claims 4 to 8, wherein the copolymer has a molecular weight of 20 to 100 kg / mol, more preferably 20 to 75 kg / mol, the second poly(lactic acid-coglycolic acid) copolymer has a molecular weight of 5 to 40 kg / mol, and the weight ratio P2 / (P1 + P2) is less than 30% by weight, particularly less than 20% by weight, with P1 being the weight of the first poly(lactic acid-coglycolic acid) copolymer and P2 being the weight of the second poly(lactic acid-coglycolic acid) copolymer.

10. A pharmaceutical composition according to any one of claims 1 to 9, wherein the anesthetic is selected from lidocaine, ropivacaine, bupivacaine, levobupivacaine, capsaicin, mepivacaine, prilocaine, pharmaceutically acceptable salts thereof, and mixtures thereof, particularly from lidocaine, bupivacaine, ropivacaine, and mepivacaine, more specifically from ropivacaine and bupivacaine, and even more specifically from ropivacaine.

11. A pharmaceutical composition according to any one of claims 1 to 10, wherein at least a portion of the anesthetic is contained in microparticles containing a polymer matrix, the polymer matrix containing or comprising at least one poly(lactic acid-coglycolic acid) copolymer having a lactic acid:glycolic acid molar ratio in the range of 40:60 to 75:25, more specifically in the range of 40:60 to 65:35, and even more specifically in the range of 40:60 to 60:40, for example, 50:

50.

12. A pharmaceutical composition in powder form comprising an anesthetic agent and a fast-release dosage form having colchicine in a dose specified in claim 2, or a controlled-release dosage form containing colchicine, in particular the controlled-release dosage form containing colchicine being in the form of fine particles, in particular fine particles containing a polymer matrix, more specifically fine particles having an average particle size of 10 μm or more as determined by laser diffraction measurement, and even more specifically the controlled-release dosage form containing colchicine being in the form of fine particles as specified in any one of claims 5 to 9, wherein the anesthetic agent is in particular the form specified in any one of claims 10 or 11, and the anesthetic agent is in the form of a fast-release dosage form, either partially or entirely.

13. A pharmaceutical composition according to any one of claims 1 to 11, in the form of a sterile and injectable dosage form selected from a solution, suspension, solid implant, semi-solid implant, powder, and in-situ depot.

14. The pharmaceutical composition according to claim 13, which is obtained by mixing a controlled-release dosage form containing colchicine, particularly colchicine-containing microparticles, more specifically those specified in any one of claims 3 to 8, with an aqueous injection vehicle and an anesthetic, particularly those specified in claim 10 or 11, in the form of a sterile and injectable suspension, and optionally containing an excipient selected from the group consisting of tonicity enhancers, wetting agents, viscosity enhancers, density enhancers and mixtures thereof.

15. The pharmaceutical composition according to claim 13 or 14, wherein colchicine is present in a sterile and injectable dosage form, particularly in a concentration of 2.5 to 2500 μg, particularly 2.5 to 1500 μg, particularly 2.5 to 1000 μg per 1 ml of suspension, more specifically in a sterile and injectable dosage form, particularly in a concentration of 2.5 to 500 μg, more specifically 2.5 to 250 μg, for example, 0.2 to 100 μg, particularly 2 to 50 μg.

16. The pharmaceutical composition according to any one of claims 13 to 15, wherein the anesthetic agent is present in a sterile and injectable dosage form, particularly in a concentration of 0.05 to 120 mg, more specifically 0.05 to 60 mg, more specifically 0.05 to 20 mg, for example 1 to 120 mg, particularly 1 to 10 mg per 1 ml of suspension.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the composition is in the form of a sterile and injectable suspension, the colchicine is in the form of fine particles containing a polymer matrix with an average particle size of 10 μm or more, as determined by laser diffraction, and the anesthetic is in an overall immediate-release dosage form and is directly solubilized in the suspension.

18. In a separate compartment: - (i) Aqueous injection vehicle and - (ii) an immediate-release dosage form containing colchicine, or a controlled-release dosage form containing colchicine, in particular the amounts defined below, as specified in claims 3 to 11, or as specified in claim 12, and optionally an anesthetic, A kit or product comprising (i) and (ii), wherein at least one of them comprises an anesthetic, and the anesthetic is in a partially or entirely immediate-release dosage form. A kit or manufactured product comprising, optionally, excipients selected from the group consisting of tonicity enhancers, wetting agents, viscosity enhancers, density enhancers, and mixtures thereof, for preparing a pharmaceutical composition suitable for intra-articular injection.

19. The kit or product according to claim 18, which is in the form of a vial or a pre-filled syringe or a medical device, or in the form of two separate vials.

20. A pharmaceutical composition obtained by mixing two compartments of a kit according to any one of claims 1, 3-11, and 13-17, for use in the treatment of crystal-associated acute inflammatory arthritis and non-crystal-associated acute inflammatory arthritis, particularly crystal-associated arthropathy or redness or acute type tendinitis and capsulitis, by intra-articular injection of the pharmaceutical composition into the joint, which provides particularly analgesia and inflammation relief, more specifically immediately and over the entire period of persistent redness, wherein the dissolution rate of colchicine is as follows: A controlled-release formulation containing a fixed amount of 20 mg of colchicine is suspended in 50 mL of phosphate-buffered saline (10 mM, pH 7.4) under stirring at 37°C. The supernatant of the sample collected periodically throughout the entire release period is then analyzed by 350 nm UV light. Measured according to the method, the concentration was 80% (w / w) for more than one day, and especially for more than 15 days. The colchicine is present in a sterile and injectable dosage form, particularly at a concentration in the range of 0.2 to 100 μg per 1 ml of suspension, especially in the range of 2 to 50 μg. The anesthetic agent is present in a sterile and injectable dosage form, particularly at a concentration of 1 to 120 mg, especially 1 to 10 mg, per 1 ml of suspension, and the dissolution rate of the anesthetic agent is as follows: A fixed amount of 20 mg of the anesthetic dosage form is suspended in 20 mL of phosphate-buffered saline (10 mM, pH 7.4) under agitation at 37°C. Then, 1 mL of the medium is periodically taken out throughout the entire release period, filtered through a 0.45 μm PTFE filter, and the filtered sample is analyzed by HPLC. Measured according to the method, the maximum is 80% (w / w) over 3 days. A pharmaceutical composition having a volume in the range of 0.1 ml to 5 ml.

21. A pharmaceutical composition for use according to claim 20, or a kit according to claim 18 or 19 for use in the treatment of crystal-associated acute inflammatory arthritis and non-crystal-associated acute inflammatory arthritis, particularly crystal-associated arthropathy or erythema or acute type of tendinitis and capsulitis, by intra-articular injection of the kit into the joint, wherein the crystal-associated acute inflammatory arthritis and non-crystal-associated acute inflammatory arthritis are selected from non-crystal-associated acute arthritis such as rheumatoid arthritis, ankylosing spondylitis, juvenile arthritis, psoriatic arthritis, lupus, and more specifically, crystal-associated arthropathy attacks or erythema or acute type of tendinitis and capsulitis, selected from gout, chondrocalcinosis, calcific tendinitis, and Milwaukee shoulder syndrome.

22. A pharmaceutical composition for the protection of joints, bones and / or cartilage, obtained by mixing the pharmaceutical composition according to any one of claims 1 to 11 and 13 to 17, or the two compartments of the kit according to claim 18 or 19.

23. A pharmaceutical composition for use according to any one of claims 20 or 22, wherein the dissolution rate of colchicine is 80% (w / w) in more than one day, for example, 1.5 days, which may be 10 days, more than one day, for example, 1.5 days, which may be 7 days, more than one day, for example, 1.5 days, which may be 5 days, for example, more than one day, for example, 1.5 days, which may be 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days, more specifically, more than one day, for example, 1.5 days, which may be 7 days, or a period of 2 to 15 days, 2 to 10 days and 2 to 7 days, and the dissolution rate of the anesthetic is 80% (w / w) in up to 3 days, for example, up to 2 days, in particular up to 1 day.

24. A pharmaceutical composition for use according to any one of claims 20 to 23, further characterized by being effective in maintaining a systemic concentration of colchicine 12 hours after intra-articular injection of less than 5 ng / ml, particularly less than 1 or 2 ng / ml, more specifically less than 0.5 or 1 ng / ml, and even more specifically less than 0.1 ng / ml, and in maintaining a synovial fluid concentration of colchicine greater than 0.5 ng / ml, for example greater than 1 ng / ml, particularly between 0.5 or 1 and 500 ng / ml, more specifically between 0.5 or 1 and 250 ng / ml, more specifically between 0.5 or 1 and 200 ng / ml, for example between 0.5 or 1 and 100 ng / ml, and even more specifically between 0.5 or 1 and 50 ng / ml.

25. A pharmaceutical composition for use according to any one of claims 20 to 24, which is effective in maintaining a synovial fluid concentration of an anesthetic, particularly ropivacaine, between 0.05 and 50 mg / ml, especially between 0.05 and 25 mg / ml, more specifically between 0.05 and 10 mg / ml, for example between 0.05 and 3 mg / ml, and is further characterized in that the synovial fluid concentration can be maintained for 1 hour, 4 hours, 8 hours, 1 day, 1.5 days, 2 days, or 3 days.

26. A pharmaceutical composition for use according to any one of claims 20 to 25, or a kit according to claim 18 or 19 for use in the treatment of crystal-associated acute inflammatory arthritis and non-crystal-associated acute inflammatory arthritis, particularly crystal-associated arthropathy or erythrosis or acute type tendinitis and capsulitis, by intra-articular injection of the kit into the joint, wherein the kit contains atazanavir, clarithromycin, dal, for use in crystal-associated acute inflammatory arthritis and non-crystal-associated acute inflammatory arthritis, particularly crystal-associated arthropathy or erythrosis or acute type tendinitis and capsulitis, or in patients with renal and / or hepatic impairment. A kit for use in protecting joints, bones, and / or cartilage in patients treated simultaneously, separately, sequentially, and nonexclusively with at least one active ingredient selected from navir, ritonavir, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, tipranavir, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, cyclosporine, lanolazine, macrolides, and statins, or in patients with chronic comorbidities such as hypertension, chronic kidney disease, diabetes, heart disease, infections, and / or immunosuppression.

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